Process for the preparation of 4- { 8-amino-3- [ (2S) -1- (but-2-ynoyl) -pyrrolidin-2-yl ] imidazo [1,5-a ] -pyrazin-1-yl } N- (pyridin-2-yl) -benzamide

文档序号：788657 发布日期：2021-04-09 浏览：19次中文

阅读说明：本技术 制备4-{8-氨基-3-[(2S)-1-(丁-2-炔酰基)-吡咯烷-2-基]咪唑并[1,5-a]-吡嗪-1-基}N-(吡啶-2-基)-苯甲酰胺的方法 (Process for the preparation of 4- { 8-amino-3- [ (2S) -1- (but-2-ynoyl) -pyrrolidin-2-yl ] imidazo [1,5-a ] -pyrazin-1-yl } N- (pyridin-2-yl) -benzamide ) 是由 P·A·贝瑟尔 L·C·陈 K·G·库珀 R·J·科克斯 M·D·戈登 S·A·休斯 L 于 2019-08-28 设计创作，主要内容包括：本披露总体上涉及制备4-{8-氨基-3-[(2S)-1-(丁-2-炔酰基)吡咯烷-2-基]咪唑并[1,5-a]吡嗪-1-基}-N-(吡啶-2-基)-苯甲酰胺的改进的方法,特别是用于制造4-{8-氨基-3-[(2S)-1-(丁-2-炔酰基)吡咯烷-2-基]咪唑并[1,5-a]吡嗪-1-基}-N-(吡啶-2-基)苯甲酰胺的大规模方法和此类方法中采用的中间体。(The present disclosure relates generally to improved processes for the preparation of 4- { 8-amino-3- [ (2S) -1- (but-2-alkynoyl) pyrrolidin-2-yl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (pyridin-2-yl) -benzamide, and in particular to large scale processes for the manufacture of 4- { 8-amino-3- [ (2S) -1- (but-2-alkynoyl) pyrrolidin-2-yl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (pyridin-2-yl) benzamide and intermediates employed in such processes.)

1. A process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (VII)

Or a salt thereof, with 2-butyric acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base, in a reaction medium, to form a reaction mixture comprising the compound having formula (VIII), or a salt thereof, and one or more reaction byproducts; and is

Selectively separating the compound having formula (VIII), or salt thereof, from the reaction mixture relative to the one or more reaction byproducts.

2. The method of claim 1, wherein the contacting step comprises:

adding the compound having formula (VII), or salt thereof, and the base to the reaction medium;

adding the 2-butyric acid, or salt thereof, to the reaction medium comprising the compound having formula (VII), or salt thereof, and the base; and is

Adding the 1-propylphosphonic anhydride to a solution comprising the compound having formula (VII), or a salt thereof; 2-butyric acid, or a salt thereof; and said base in said reaction medium.

3. The method of claim 1 or 2, wherein the method comprises:

Reacting a compound having the structure of formula (VII)

Or a salt thereof, with 2-butyric acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base, in a reaction medium, to form a composition comprising the compound having formula (VIII), or a salt thereof; an unreacted compound having formula (VII), or a salt thereof; and reaction by-products; wherein the reaction by-product comprises a compound having the structure of formula (XIV):

or a salt thereof; and is

Separating the compound having the formula (VIII), or a salt thereof, from the reaction mixture selectively with respect to the compound having the formula (VII), or a salt thereof, and the compound having the formula (XIV), or a salt thereof.

4. The method of claim 1 or 2, wherein the method comprises:

reacting a compound having the structure of formula (VII)

Or a salt thereof;

extracting at least a portion of the compound having formula (VIII), or a salt thereof, from the reaction mixture into an aqueous phase, wherein the compound having formula (VIII), or a salt thereof, is selectively extracted into the aqueous phase relative to the compound having formula (XIV), or a salt thereof;

adjusting the pH of the aqueous phase; and is

Extracting at least a portion of the compound having formula (VIII), or salt thereof, from the aqueous phase into an organic phase, wherein the compound having formula (VIII), or salt thereof, is selectively extracted into the organic phase relative to the compound having formula (VII), or salt thereof.

5. The process of claim 4, wherein the process further comprises separating the compound having formula (VIII) from the organic phase into which the compound having formula (VIII) has been selectively extracted.

6. The process of claim 4 or 5, wherein the aqueous phase has a pH of less than about 2.5 during the aqueous phase extraction step.

7. The process of claim 4 or 5, wherein the aqueous phase has a pH of greater than about 4.0 during the organic phase extraction step.

8. A crystalline form of a compound having the structure of formula (VII):

Wherein the crystalline form is characterized by a reflected X-ray powder diffraction pattern selected from the group consisting of:

a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 9.9 + -0.2 deg. 2 theta, 11.1 + -0.2 deg. 2 theta, 12.8 + -0.2 deg. 2 theta, 14.1 + -0.2 deg. 2 theta, and 19.0 + -0.2 deg. 2 theta, and

a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 7.4 + -0.2 deg. 2 theta, 11.7 + -0.2 deg. 2 theta, 12.5 + -0.2 deg. 2 theta, 22.3 + -0.2 deg. 2 theta, and 21.6 + -0.2 deg. 2 theta.

9. The crystalline form of claim 8, wherein the crystalline form is characterized by a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 9.9 + -0.2 deg. 2 theta, 11.1 + -0.2 deg. 2 theta, 12.8 + -0.2 deg. 2 theta, 14.1 + -0.2 deg. 2 theta, and 19.0 + -0.2 deg. 2 theta.

10. A process for preparing a compound having the structure of formula (VII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (V)

Or a salt thereof, with a compound having the structure of formula (VI):

or a salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising the compound having formula (VII), or a salt thereof;

Reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising the compound having formula (VII), or a salt thereof; and is

Isolating the compound having formula (VII), or salt thereof, from the substantially anhydrous mixture.

11. The method of claim 10, wherein the separating step comprises filtering the substantially anhydrous mixture.

12. The process of claim 10 or 11, wherein the aqueous reaction medium further comprises an alkali metal halide.

13. The method of any one of claims 10 to 12, wherein the reducing step comprises:

separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound having formula (VII);

washing the organic phase with water;

treating the organic phase with a silica scavenger;

removing the silica scavenger from the organic phase;

washing the organic phase with an aqueous brine solution; and is

Distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase.

14. The method of any one of claims 10 to 13, wherein the substantially anhydrous mixture comprises less than about 5% by weight water.

15. A process for preparing a compound having the structure of formula (VI):

or a salt thereof, wherein the method comprises:

reacting a compound having formula (IV):

or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound having formula (IV) and form a reaction mixture comprising the compound having formula (VI), or a salt thereof, and a benzyl halide by-product;

removing at least a portion of the benzyl halide by-product from the reaction mixture; and is

Separating the compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

16. The method of claim 15, wherein the separating step comprises:

removing at least a portion of the benzyl halide by-product from the reaction mixture;

increasing the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium comprising the compound having formula (VI), or a salt thereof; and is

Isolating the compound having formula (VI), or a salt thereof, from the basic reaction mixture.

17. The method of claim 15, wherein the separating step comprises:

extracting at least a portion of the benzyl halide by-product from the reaction mixture into a waste organic phase;

Increasing the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium comprising the compound having formula (VI), or a salt thereof;

extracting the compound having formula (VI), or salt thereof, from the basic reaction medium into a product organic phase; and is

Separating the compound having formula (VI), or salt thereof, from the product organic phase.

18. The method of claim 15, wherein the separating step comprises:

selectively extracting at least a portion of the benzyl halide by-product from the reaction mixture into a waste organic phase relative to the compound having formula (VI);

increasing the pH of the resulting reaction mixture to a pH greater than about 7.0 to form an alkaline reaction mixture;

(ii) selectively pre-extracting at least a portion of the compound having formula (VI) from the basic reaction mixture into a product organic phase; and is

Distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase to form a distilled organic phase comprising the compound having (VI).

19. A process for preparing a compound having the structure of formula (V):

or a salt thereof, wherein the process comprises contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acid chloride intermediate, and then contacting the acid chloride intermediate in situ with 2-aminopyridine to form a reaction mixture comprising the compound having formula (V), or a salt thereof.

20. A crystalline sulfate salt of a compound having the structure of formula (IV):

21. the crystalline sulfate salt of claim 20, wherein the crystalline sulfate salt is characterized by a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 7.7 + -0.2 deg. 2 theta, 10.6 + -0.2 deg. 2 theta, 11.1 + -0.2 deg. 2 theta, 12.6 + -0.2 deg. 2 theta, and 13.5 + -0.2 deg. 2 theta.

22. A process for preparing a sulfate salt of a compound having the structure of formula (IV):

wherein the method comprises:

reacting a compound having the structure of formula (III)

Or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising the compound having formula (IV);

forming a sulfate salt of the compound having formula (IV); and is

Separating the sulfate salt.

23. A process for preparing a compound having the structure of formula (II):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form the compound having formula (II), or a salt thereof;

wherein the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity of the compound having formula (II), or salt thereof.

24. A process for preparing a compound having the structure of formula (III):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II);

or a salt thereof; and is

Brominating the compound having formula (II), or a salt thereof, with a brominating agent to provide the compound having the structure of formula (III):

or a salt thereof;

Technical Field

The present disclosure relates generally to improved processes for the preparation of 4- { 8-amino-3- [ (2S) -1- (but-2-alkynoyl) pyrrolidin-2-yl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (pyridin-2-yl) -benzamide, and in particular to large scale processes for the manufacture of 4- { 8-amino-3- [ (2S) -1- (but-2-alkynoyl) pyrrolidin-2-yl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (pyridin-2-yl) benzamide and/or intermediates employed in such processes.

Background

4- { 8-amino-3- [ (2S) -1- (but-2-ynoyl) pyrrolidin-2-yl]Imidazo [1,5-a ]]Pyrazin-1-yl } -N- (pyridin-2-yl) benzamide (also known by the international non-proprietary name for acaracinib) is a pharmaceutical productThe active pharmaceutical ingredient of (1). In 2017, awarded by the U.S. food and drug administrationApproved for marketing for the treatment of mantle cell lymphoma in adult patients who previously received at least one treatment. Evaluation ofFor the treatment of additional indications (including chronic lymphocytic leukemia and Waldenstrom's megakaryopathy)Globulinemia (A)macroglobulinemia) is in progress.

Example 6 of U.S. patent No. 9,290,504 discloses acarabtinib and reports the synthesis shown in scheme 1 below:

scheme 1

Study disclosure database No. 631028 (published numerically at 10.6.2016) reports the synthesis of acarabtinib shown in scheme 2 below:

scheme 2

However, the previously reported synthetic methods are not suitable for the manufacture of acaracinib on a large scale, in particular a commercial scale. The present disclosure provides improved methods that can be operated on a large scale and provide one or more advantages over previously reported synthetic methods, such as improved compound purity, improved compound isolation (e.g., filterability), reduced cycle time, less stringent process control requirements, higher yields, reduced costs, improved compliance with regulatory requirements for pharmaceutical starting materials, intermediates and products, and the like.

Brief description of the invention

As noted above, the present disclosure relates to improved large scale processes for the preparation of acaracinib and/or intermediates employed in the preparation of acaracinib.

In one aspect, the disclosure relates to methods for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (VII)

Or a salt thereof, with 2-butyric acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base, in a reaction medium, to form a reaction mixture comprising a compound having formula (VIII), or a salt thereof, and one or more reaction byproducts; and is

Selectively separating the compound having formula (VIII), or a salt thereof, from the reaction mixture relative to the one or more reaction byproducts.

In another aspect, the disclosure relates to a method for preparing a compound having the structure of formula (VII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (V)

Or a salt thereof, with a compound having the structure of formula (VI):

or a salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a reaction mixture comprising a compound having formula (VII), or a salt thereof;

Reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound having formula (VII), or a salt thereof; and is

Isolating a compound having formula (VII), or a salt thereof, from the substantially anhydrous mixture.

In another aspect, the disclosure relates to a method for preparing a compound having the structure of formula (VI):

or a salt thereof, wherein the method comprises:

reacting a compound having formula (IV):

Isolating a compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

In another aspect, the disclosure relates to a method for preparing a compound having the structure of formula (V):

In another aspect, the present disclosure relates to a process for preparing a sulfate salt of a compound having the structure of formula (IV):

wherein the method comprises:

reacting a compound having the structure of formula (III)

Or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having formula (IV);

forming a sulfate salt of a compound having formula (IV); and is

Separating the sulfate salt.

In another aspect, the disclosure relates to a method for preparing a compound having the structure of formula (III):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II);

or a salt thereof; and is

Brominating a compound having formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

or a salt thereof;

In another aspect, the disclosure relates to a method for preparing a compound having the structure of formula (II):

Or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II), or a salt thereof;

In another aspect, the disclosure relates to a crystalline form of a compound having the structure of formula (VII):

wherein the crystalline form is characterized by a reflected X-ray powder diffraction pattern selected from the group consisting of:

In another aspect, the disclosure relates to a crystalline form of a compound having the structure of formula (VII):

wherein the crystalline form is characterized by a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 9.9 + -0.2 deg. 2 theta, 11.1 + -0.2 deg. 2 theta, 12.8 + -0.2 deg. 2 theta, 14.1 + -0.2 deg. 2 theta, and 19.0 + -0.2 deg. 2 theta.

In another aspect, the disclosure relates to a crystalline sulfate salt of a compound having the structure of formula (IV):

drawings

Figure 1 illustrates an X-ray powder diffraction Pattern (PXRD) measured in reflection mode from a sample of crystalline sulfate salt of benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidinecarboxylate (having a stoichiometric ratio of about one sulfate molecule to one hydrogen sulfate molecule per three free base molecules).

Figure 2 illustrates the X-ray powder diffraction Pattern (PXRD) measured in reflection mode from a sample of form 2 crystalline form of 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide.

Figure 3 illustrates an X-ray powder diffraction Pattern (PXRD) measured in reflection mode from a sample of form 3 crystalline form of 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide.

Figure 4 illustrates the X-ray powder diffraction Pattern (PXRD) measured in reflection mode from a sample of form C crystalline form of 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide.

Detailed Description

This written description uses examples to disclose the invention and also to enable any person skilled in the art to practice the invention, including making and using any salts, materials, or compositions of the disclosure, and performing any methods or processes of the disclosure. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have elements that do not differ from the literal language of the claims, or if they include equivalent elements with insubstantial differences from the literal language of the claims.

I.Definition of

The section headings used in this section and throughout this disclosure are not intended to be limiting.

Where a range of values is recited, each intervening number within the range is explicitly recited with the same degree of accuracy. For example, for the range of 6 to 9, in addition to 6 and 9, the numbers 7 and 8 are also considered; and for the range of 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly considered. In the same manner, all recited ratios also include all sub-ratios falling within the broader ratio.

The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

The term "about" generally refers to a range of numbers that one of skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many cases, the term "about" may include numbers that are rounded to the nearest significant figure.

Unless the context requires otherwise, the terms "comprises," "comprising," and "comprising" are used in an explicit sense to mean that they are interpreted inclusively rather than exclusively, and that the applicant intends to interpret each of those terms in interpreting the patent (including the claims below).

The term "sulfate salt (2: 3)" refers to a sulfate salt having a stoichiometric ratio of sulfate salt to free base of about 2:3, including sulfate salts having one sulfate molecule and one hydrogen sulfate molecule for every three free base molecules.

The term "crystalline purity," when used in reference to a crystalline form of a compound, refers to the percentage of the crystalline form of the compound in a reference composition relative to another crystalline or amorphous form.

Abbreviations used throughout this disclosure have the meanings indicated in table 1 below.

TABLE 1

For clarity, table 2 below summarizes the compound identifiers, chemical names, and structures that are used interchangeably throughout this application with respect to each compound discussed.

TABLE 2

The present disclosure also discusses crystalline forms of certain compounds listed in table 2, including X-ray powder diffraction patterns characterizing such crystalline forms. It is known in the art that depending on the test conditions (e.g., equipment, sample preparation, or machinery used), an X-ray powder diffraction pattern can be obtained with one or more measurement errors. In particular, it is generally known that the intensity of an X-ray powder diffraction pattern can fluctuate, depending on the measurement conditions and sample preparation. For example, one of ordinary skill in the art of X-ray powder diffraction will recognize that the relative intensities of these peaks may vary depending on the orientation of the sample being examined and the type and setup of the instrument used. One of ordinary skill in the art will also recognize that the position of the reflection can be affected by the exact height at which the sample is located in the diffractometer and the zero point correction of the diffractometer. The surface planarity of the sample may also have a subtle effect. Thus, those of ordinary skill in the art will understand that the diffractogram data presented herein should not be construed as absolute, and that any crystalline form that provides a Powder diffractogram substantially consistent with those disclosed herein falls within the scope of the present disclosure (for further information, see Jenkins, R and Snyder, r.l. 'Introduction to X-Ray Powder diffraction ]' John Wiley & Sons [ John Wiley daddle ], 1996).

II.Synthesis of U.S. Pat. No. 9,290,504

As previously mentioned, the synthesis reported in example 6 of U.S. patent No. 9,290,504 is not suitable for large-scale manufacturing of acaracinib. The reported method, which provides no information about the chiral or achiral purity of the intermediate, among other limitations, uses chromatography to separate the intermediate at various points in the process and yields milligram amounts of the final product. The overall yield of acaracinib in this pilot scale synthesis starting from compound I is about 5%.

III.Clinical trial supply method

Scheme 3 below illustrates a method subsequently developed to manufacture a supply of acaracinib for clinical trials. Throughout this disclosure, the various steps of scheme 3 are discussed in further detail.

Scheme 3

Although this method is used to produce approximately 100 to 150 kg of acarabtinib for clinical trials, this method lacks robustness, is difficult to operate, and has long cycle times. Therefore, this method is considered to be unsuitable for large-scale production of acaracitinib.

More specifically, the approach of scheme 3 has many limitations, including the following:

(1) racemization of the chiral center is difficult to control during the step of producing compound (II) and leads to several batch failures.

(2) Many environmentally unfriendly solvents are used in several steps.

(3) One of the more problematic solvents used is dichloromethane. In addition to environmental concerns, the use of methylene chloride in the amine-involving step has another disadvantage in that the reaction of the amine with methylene chloride can produce aminal impurities and sometimes even lead to batch failures. During the step of producing compound (VI), for example, a methylene bridged dimer may be formed. Further, the acid-based liquid chromatography method used in conjunction with the step of producing compound (VI) cannot detect aminal impurities.

(4) The use of N, N-dimethylformamide in combination with thionyl chloride for the production of compound (V) can potentially lead to the formation of toxic dimethylcarbamoyl chlorides.

(5) The coupling reaction in the step of producing the compound (VII) is liable to be stopped. The addition of more palladium catalyst during the final step of producing acaracinib adds a burden to the purging step, which has required excessive recycle with silica-based scavengers.

(6) Isolation of compound (VII) by filtration is difficult and not suitable for large scale manufacture. On a 50kg scale, two pressure filters need to be used and the product is manually discharged as a wet paste many times, and this will only have a significant time loss.

(7) For acylation to produce acaracinib, multiple batch failures occur through multiple different failure modes.

(8) The use of distillation precipitation to isolate acaracinib does not provide control over the particle characteristics of the isolated product.

IV.Large scale process

In view of the limitations associated with clinical trial supply methods, improved methods have been developed that overcome those limitations and are suitable for large-scale manufacturing of acaracinib. Scheme 4 below illustrates one representative example of the large scale process for making acarabtinib. Throughout this disclosure, the various steps of scheme 4 are discussed in further detail.

Scheme 4

V.Benzyl (2S) -2- (8-chloro-imidazo [1, 5-a)]Process for preparing pyrazin-3-yl) pyrrolidine-1-carboxylic acid esters (compounds II) Preparation of

The present disclosure relates, in part, to processes for preparing benzyl (2S) -2- (8-chloro-imidazo [1,5-a ] pyrazin-3-yl) pyrrolidine-1-carboxylate (compound II), or a salt thereof, from benzyl (2S) -2- [ (3-chloropyrazin-2-yl) methylcarbamoyl ] pyrrolidine-1-carboxylate (compound I), or a salt thereof. Scheme 5 below illustrates the general process:

scheme 5

Cyclisation of compound (I) to form the imidazole ring present in compound (II) is advantageous because it confers stability to the chiral centre of the subsequent intermediate employed in the manufacture of acaracinib. However, the supply method in clinical trials is problematic because the non-cyclized compound (I) is easily racemized under the acidic condition of the cyclization reaction. This unwanted racemization reaction is difficult to control and leads to multiple batch failures. The use of a nitrogen purge to remove the liberated hydrochloric acid limits the chiral attack that occurs to some extent, but the extent of chiral attack remains highly variable.

The clinical trial supply method employed a reaction temperature of about 80 ℃ and a catalytic loading of about 0.2 molar equivalents of N, N-dimethylformamide. It has been determined that increasing N, N-dimethylformamide loading (e.g., to about 0.6 molar equivalents) and decreasing the reaction temperature (e.g., to about 40 ℃) limits the observed chiral degradation and typically results in the production of a chiral pure compound (II). The lower N, N-dimethylformamide catalytic loading employed in the clinical trial supply method resulted in reaction rates requiring higher temperatures for reaction completion, which then resulted in the observed chiral degradation. In contrast, the increased N, N-dimethylformamide catalytic loading of the improved process results in faster reaction rates and allows the reaction to be carried out at lower temperatures, which inhibits racemization. Chiral degradation is reduced and chiral integrity is maintained, thus increasing yield.

Thus, in one embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (II):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II), or a salt thereof;

Wherein the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 80% chiral purity of the compound having formula (II), or salt thereof.

As mentioned above, proper control of the reaction temperature during the cyclization reaction is important to maintain the appropriate chiral purity of the product. Generally, the temperature of the reaction medium is controlled during the cyclization reaction in a manner sufficient to maintain at least about 85% chiral purity of the compound having formula (II), or a salt thereof. In one aspect, the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 90% chiral purity of the compound having formula (II), or salt thereof. In another aspect, the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 95% chiral purity of the compound having formula (II), or salt thereof. In another aspect, the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 99% chiral purity of the compound having formula (II), or salt thereof.

Maintaining the reaction medium at a temperature of less than about 80 ℃ during the contacting step generally increases the chiral purity of the compound having formula (II) or salt thereof. In one aspect, the reaction medium is maintained at a temperature of less than about 70 ℃ during the contacting step. In another aspect, the reaction medium is maintained at a temperature of less than about 60 ℃ during the contacting step. In another aspect, the reaction medium is maintained at a temperature of less than about 50 ℃ during the contacting step. In another aspect, the reaction medium is maintained at a temperature of from about 30 ℃ to about 50 ℃ during the contacting step. In another aspect, the reaction medium is maintained at a temperature of about 40 ℃ during the contacting step.

The catalyst may comprise any suitable catalyst, in particular a catalyst selected from the group consisting of: n, N-dimethylformamide and N-methyltoluidine. In one aspect, the catalyst comprises N, N-dimethylformamide. In another aspect, the catalyst comprises N-methyl toluidine. As mentioned above, the amount of catalyst loaded into the reaction medium may also affect the chiral purity of the product. At least about 0.1 molar equivalents of catalyst relative to the compound having formula (I) or salt thereof is typically loaded into the reaction medium. In one aspect, at least about 0.4 molar equivalents of catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium. In another aspect, at least about 0.6 molar equivalents of catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium. In another aspect, at least about 0.1 to about 1.0 molar equivalents of catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium. In another aspect, at least about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium. In another aspect, the catalyst comprises N, N-dimethylformamide and from about 0.1 to about 1.0 molar equivalents of catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium. In another aspect, the catalyst comprises N, N-dimethylformamide and about 0.4 to about 1.0 molar equivalents of catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium. In another aspect, the catalyst comprises N, N-dimethylformamide and about 0.6 molar equivalents of the catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium.

The cyclisation agent may be any suitable cyclisation agent, in particular phosphorus oxychloride. The compound having formula (I) or a salt thereof is typically contacted with about 0.7 to about 10 molar equivalents of the cyclizing agent relative to the compound having formula (I) or a salt thereof. In one aspect, a compound having formula (I) or a salt thereof is contacted with about 1.5 to about 2.5 molar equivalents of a cyclizing agent relative to the compound having formula (I) or a salt thereof. In another aspect, a compound having formula (I) or a salt thereof is contacted with about 2.0 molar equivalents of a cyclizing agent relative to the compound having formula (I) or a salt thereof.

The reaction medium may be any suitable reaction medium, in particular a reaction medium comprising at least one solvent selected from the group consisting of: aromatic hydrocarbons, chlorinated hydrocarbons, ethers, and nitriles. In one aspect, the reaction medium comprises at least one compound selected from the group consisting of: acetonitrile, butyronitrile, dichloromethane, toluene, anisole, tetrahydrofuran, and 2-methyltetrahydrofuran. In another aspect, the reaction medium comprises acetonitrile. The volume of the reaction medium is generally from about 2 liters to about 20 liters of reaction medium per kilogram of compound having formula (I) or salt thereof loaded into the reaction medium. In one aspect, the volume of the reaction medium is from about 3 liters to about 10 liters of reaction medium per kilogram of compound having formula (I) or salt thereof loaded into the reaction medium.

The contacting step is typically carried out as a batch reaction, particularly a batch reaction wherein at least about 50 kg of the compound of formula (I) or salt thereof is loaded into the batch reaction. In one aspect, at least about 100 kilograms of a compound having formula (I) or salt thereof is loaded into the batch reaction. In another aspect, at least about 200 kilograms of a compound having formula (I) or a salt thereof is loaded into the batch reaction. In another aspect, at least about 300 kilograms of a compound having formula (I) or salt thereof is loaded into the batch reaction.

The process generally provides at least about a 50% stoichiometric process yield of the compound having formula (II) or a salt thereof. In one aspect, the stoichiometric process yield of the compound having formula (II) or salt thereof is at least about 65%. In another aspect, the stoichiometric process yield of the compound having formula (II) or salt thereof is at least about 80%. In another aspect, the compound having formula (II) or a salt thereof has a stoichiometric process yield of at least about 90%. In fact, the improved process has been able to achieve about 95% yield of good quality material on a scale exceeding 300kg (input).

In another representative embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (II):

Or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with phosphorus oxychloride in the presence of a catalyst in a reaction medium to form a compound having formula (II), or a salt thereof;

wherein during the contacting step, the reaction medium is maintained at a temperature of less than about 80 ℃;

wherein at least about 0.4 molar equivalents of catalyst, relative to the compound having formula (I) or salt thereof, is loaded into the reaction medium; and is

Wherein the compound having formula (II) or salt thereof has a chiral purity of at least about 80%.

In one aspect, during the contacting step, the reaction medium is maintained at a temperature of less than about 70 ℃; loading at least about 0.4 to about 1.0 molar equivalents of a catalyst relative to a compound having formula (I) or a salt thereof into a reaction medium; and the chiral purity of the compound having formula (II) or salt thereof is at least about 85%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature of less than about 60 ℃; loading at least about 0.4 to about 1.0 molar equivalents of a catalyst relative to a compound having formula (I) or a salt thereof into a reaction medium; and the chiral purity of the compound having formula (II) or salt thereof is at least about 90%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature of from about 30 ℃ to about 50 ℃; loading at least about 0.4 to about 1.0 molar equivalents of a catalyst relative to a compound having formula (I) or a salt thereof into a reaction medium; and the chiral purity of the compound having formula (II) or salt thereof is at least about 90%. In another aspect, during the contacting step, the reaction medium is maintained at a temperature of about 40 ℃; loading about 0.6 molar equivalents of catalyst to the reaction medium relative to the compound having formula (I) or a salt thereof; and the chiral purity of the compound having formula (II) or salt thereof is at least about 90%. In another aspect, the catalyst comprises N, N-dimethylformamide.

Scheme 6 below corresponds to the method described in example 3 and illustrates one representative example of an improved method for preparing compound (II).

Scheme 6

VI.Benzyl (2S) -2- (1-bromo-8-chloro-imidazo [1, 5-a)]Pyrazin-3-yl) -pyrrolidine-1-carboxylic acid esters (compounds) Preparation of substance III)

The present disclosure relates, in part, to processes for preparing benzyl (2S) -2- (1-bromo-8-chloro-imidazo [1,5-a ] pyrazin-3-yl) pyrrolidine-1-carboxylate (compound III), or a salt thereof, from benzyl (2S) -2- [ (3-chloropyrazin-2-yl) methylcarbamoyl ] pyrrolidine-1-carboxylate (compound I), or a salt thereof. As previously described, compound (II), or a salt thereof, is prepared from compound (I), or a salt thereof, and then brominated to produce compound (III), or a salt thereof. The following scheme 7 illustrates the general process:

scheme 7

Thus, in one embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (III):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II);

or a salt thereof; and is

Brominating a compound having formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

Or a salt thereof;

The brominating agent may be any suitable brominating agent, particularly N-bromosuccinimide. The compound having formula (III), or salt thereof, may be prepared from the compound having formula (II), or salt thereof, without first isolating the compound having formula (II), or salt thereof, from the reaction mixture (i.e., in situ bromination that may include a solvent exchange step), or, alternatively, the compound having formula (II), or salt thereof, may be isolated from the reaction medium and then brominated to provide the compound having formula (III), or salt thereof. In one aspect, the compound having formula (III), or salt thereof, is prepared from the compound having formula (II), or salt thereof, without first isolating the compound having formula (II), or salt thereof, from the reaction mixture (i.e., in situ bromination). In another aspect, a compound having formula (II), or a salt thereof, is isolated from a reaction medium (e.g., a solvent exchange process comprising isolating an oil containing a compound having formula (II), or a salt thereof) and then brominated to provide a compound having formula (III), or a salt thereof.

Wherein a compound having formula (II), or a salt thereof, is isolated from a reaction mixture and then contacted with a brominating agent in a bromination medium, which can be any suitable bromination medium, particularly a bromination medium comprising at least one solvent selected from the group consisting of: chlorinated hydrocarbons and polar aprotic solvents. In one aspect, the bromination medium comprises at least one solvent selected from the group consisting of: n, N-dimethylformamide, N-methylpyrrolidone, N-butylpyrrolidone, dimethyl sulfoxide, dimethylacetamide, and dichloromethane. In another aspect, the bromination medium comprises N, N-dimethylformamide. In another aspect, the bromination medium comprises N-methylpyrrolidone.

A compound having formula (II), or a salt thereof, is contacted with an effective amount of a brominating agent (e.g., about 0.8 to about 1.2 molar equivalents of brominating agent relative to the compound having formula (II), or a salt thereof). To avoid excessive reaction, it may be beneficial to "titrate" the brominating agent during the brominating agent addition, control the temperature of the reaction medium/bromination medium and/or control measurements in the process of repeating during the brominating agent addition. In one aspect, the reaction medium/bromination medium is maintained at a temperature of from about 5 ℃ to about 40 ℃ during the bromination step. In another aspect, the reaction medium/bromination medium is maintained at a temperature of about 20 ℃ during the bromination step. In another aspect, the brominating agent is titrated into the reaction/bromination medium.

The process may further comprise isolating the compound having formula (III) or a salt thereof from the final reaction mixture. In one aspect, an aqueous solution is added to the final reaction mixture to precipitate the compound having formula (III), or a salt thereof. In another aspect, an aqueous solution having a basic pH is added to the final reaction mixture to precipitate the compound having formula (III), or a salt thereof. In another aspect, an aqueous sodium bicarbonate solution is added to the final reaction mixture to precipitate the compound having formula (III), or a salt thereof. In another aspect, the sodium bicarbonate solution is about 1% to 10% by weight sodium bicarbonate. In another aspect, the sodium bicarbonate solution is about 2% by weight sodium bicarbonate.

In the case where compound (II), or a salt thereof, is isolated from the reaction mixture and then brominated, the bromination is typically conducted as a batch reaction, particularly a batch reaction in which at least about 50 kg of a compound having formula (II), or a salt thereof, is charged to the batch reaction. In one aspect, at least about 100 kilograms of a compound having formula (II) or salt thereof is loaded into the batch reaction. In another aspect, at least about 200 kilograms of a compound having formula (II) or a salt thereof is loaded into the batch reaction. In another aspect, at least about 300 kilograms of the compound having formula (II) or salt thereof is loaded into the batch reaction.

In the case of in situ bromination of compound (II), or a salt thereof, the in situ reaction is typically carried out as a batch reaction, in particular a batch reaction wherein at least about 50 kg of a compound having formula (I), or a salt thereof, is first loaded into the reaction. In one aspect, at least about 100 kilograms of a compound having formula (I), or a salt thereof, is first loaded into the reaction. In another aspect, at least about 200 kilograms of a compound having formula (I), or a salt thereof, is first loaded into the reaction. In another aspect, at least about 300 kilograms of a compound having formula (I), or a salt thereof, is first loaded into the reaction.

Reacting compound (II) or a salt thereof with a brominating agent (e.g., N-bromosuccinimide) to produce compound (III) or a salt thereof generally works well and produces high quality materials in high yield. The process generally provides at least about 50% stoichiometric process yield of the compound having formula (III) or a salt thereof. In one aspect, the stoichiometric process yield of the compound having formula (III) or salt thereof is at least about 65%. In another aspect, the stoichiometric process yield of the compound having formula (III) or salt thereof is at least about 80%. In another aspect, the stoichiometric process yield of the compound having formula (III) or salt thereof is at least about 90%. In fact, the improved process has been able to achieve about 95% yield of good quality material on a scale exceeding 300kg (input).

In another representative embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (III):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with phosphorus oxychloride in the presence of a catalyst in a reaction medium to form a compound having formula (II);

or a salt thereof; and is

Brominating a compound having formula (II), or a salt thereof, with N-bromosuccinimide to provide a compound having the structure of formula (III):

or a salt thereof;

wherein during the contacting step, the reaction medium is maintained at a temperature of less than about 80 ℃;

wherein at least about 0.4 molar equivalents of catalyst, relative to the compound having formula (I) or salt thereof, is loaded into the reaction medium; and is

Wherein the compound having formula (II) or salt thereof has a chiral purity of at least about 80%.

Scheme 8 below corresponds to the process described in example 3 and illustrates one representative example of an improved process for preparing compound (III), or a salt thereof.

Scheme 8

VII.Benzyl (2S) -2- (8-amino-1-bromoimidazo [1, 5-a)]Pyrazin-3-yl) -1-pyrrolidinecarboxylic acid esters Preparation of Compound IV) and the corresponding sulfate salt (2:3)

The present disclosure relates, in part, to processes for preparing benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidinecarboxylate (compound IV), or a salt thereof, from benzyl (2S) -2- (1-bromo-8-chloro-imidazo [1,5-a ] pyrazin-3-yl) pyrrolidine-1-carboxylate (compound III), or a salt thereof. Scheme 9 below illustrates the general process:

scheme 9

As reflected in scheme 9 above, compound (III) or a salt thereof is aminated with an aminating agent (e.g., ammonia, ammonium hydroxide, etc.) to produce compound (IV), which can be optionally converted to a salt, particularly a sulfate salt of compound (IV), as discussed further below. Because the amination reaction may result in the presence of residual ammonia, it may be beneficial to reduce the amount of residual ammonia prior to formation of the salt of compound (IV), particularly where a sulfate salt of compound (IV) is desired (e.g., by distillation of the crude compound (IV) product). For example, if the residual ammonia present in compound (IV) is not sufficiently removed when sulfate is produced, inorganic ammonium sulfate may be produced in addition to the sulfate of compound (IV), which may make it difficult to determine the exact stoichiometry of the sulfate produced. From a regulatory perspective, it may be desirable to know the exact stoichiometry of the sulfate produced (e.g., where sulfate is the starting material registered for regulatory purposes).

Thus, in one embodiment, the present disclosure relates to a process for preparing a sulfate salt of a compound having the structure of formula (IV):

wherein the method comprises:

reacting a compound having the structure of formula (III)

Or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having formula (IV);

forming a sulfate salt of a compound having formula (IV); and is

Separating the sulfate salt.

Typically, the sulfate salt of a compound having the structure of formula (IV) has a stoichiometric ratio of one sulfate molecule and one hydrogen sulfate molecule to three free base molecules. In one aspect, the sulfate salt is a crystalline salt. In another aspect, the crystalline sulfate salt is characterized by a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 7.7 + -0.2 deg. 2 theta, 10.6 + -0.2 deg. 2 theta, 11.1 + -0.2 deg. 2 theta, 12.6 + -0.2 deg. 2 theta, and 13.5 + -0.2 deg. 2 theta. In another aspect, the crystalline sulfate salt is characterized by a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 7.7 + -0.2 deg. 2 theta, 10.6 + -0.2 deg. 2 theta, 11.1 + -0.2 deg. 2 theta, 12.6 + -0.2 deg. 2 theta, 13.5 + -0.2 deg. 2 theta, 17.4 + -0.2 deg. 2 theta, 18.0 + -0.2 deg. 2 theta, 18.9 + -0.2 deg. 2 theta, 19.2 + -0.2 deg. 2 theta, and 21.9 + -0.2 deg. 2 theta.

The isolated crystalline sulfate salt typically has a crystalline purity of at least 50%. In one aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 60%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 70%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 80%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 90%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 95%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 96%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 97%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 98%. In another aspect, the isolated crystalline sulfate salt has a crystalline purity of at least 99%. In another aspect, the isolated crystalline sulfate salt is a substantially pure phase.

The aminating agent may be any suitable aminating agent, in particular ammonia or ammonium hydroxide. In one aspect, the aminating agent is gaseous ammonia. In another aspect, the aminating agent is ammonium hydroxide. The compound having formula (III), or salt thereof, is typically contacted with an effective amount of the aminating agent (e.g., about 5 to about 20 molar equivalents of the aminating agent relative to the compound having formula (III), or salt thereof).

The reaction medium may be any suitable reaction medium, in particular a reaction medium comprising at least one solvent selected from the group consisting of: alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, aromatic heterocycles, alcohols, ethers, and dipolar aprotic solvents. In one aspect, the reaction medium comprises at least one compound selected from the group consisting of: methanol, ethanol, propanol, butanol, pentanol, N-methylpyrrolidone, and N, N-dimethylformamide. In another aspect, the reaction medium comprises a fatty alcohol. In another aspect, the reaction medium comprises butanol. In another aspect, the reaction medium comprises 2-butanol. The volume of the reaction medium is generally from about 1.5 liters to about 40 liters of reaction medium per kilogram of compound having formula (III) or salt thereof loaded into the reaction medium. In one aspect, the volume of the reaction medium is from about 2.0 liters to about 30 liters of reaction medium per kilogram of compound having formula (III) or salt thereof loaded into the reaction medium.

During the contacting step, the reaction medium is generally maintained at a temperature above 70 ℃. In one aspect, the reaction medium is maintained at a temperature greater than 90 ℃ during the contacting step. In another aspect, the reaction medium is maintained at a temperature of from about 50 ℃ to about 100 ℃ during the contacting step. In another aspect, the reaction medium is maintained at a temperature of from about 60 ℃ to about 95 ℃ during the contacting step.

The contacting step is typically carried out as a batch reaction, particularly a batch reaction wherein at least about 50 kg of the compound having formula (III) or salt thereof is loaded into the batch reaction. In one aspect, at least about 100 kilograms of a compound having formula (III) or a salt thereof is loaded into the batch reaction. In another aspect, at least about 200 kilograms of a compound having formula (II) or a salt thereof is loaded into the batch reaction. In another aspect, at least about 300 kilograms of the compound having formula (III) or salt thereof is loaded into the batch reaction.

Where a sulfate salt of compound (IV) is desired, the forming step typically comprises contacting the compound having formula (IV) with sulfuric acid to form a sulfate salt mixture comprising the sulfate salt. In one aspect, the compound having formula (IV) is contacted with at least about 0.8 molar equivalents of sulfuric acid relative to the compound having formula (III). In another aspect, the compound having formula (IV) is contacted with about 1.25 to about 1.75 molar equivalents of sulfuric acid relative to the compound having formula (III).

The method optionally includes isolating the compound having formula (IV) as a free base from the reaction mixture prior to the forming step. Separating the free base prior to salt conversion may be beneficial to reduce the amount of residual ammonia present and avoid potential problems associated with the presence of residual ammonia. In one aspect, the process comprises isolating the compound having formula (IV) as a free base from the reaction medium; contacting the free base with sulfuric acid to form a sulfate salt; and isolating the sulfate salt. In another aspect, the method includes washing the reaction mixture to reduce the amount of ammonia present in the reaction mixture; isolating the compound having formula (IV) as a free base from the washed reaction medium; contacting the free base with sulfuric acid to form a sulfate salt; and isolating the sulfate salt. In another aspect, the method comprises washing the reaction mixture with a brine solution; distilling the washed reaction mixture to reduce the amount of ammonia present in the washed reaction mixture; separating the compound having formula (IV) as a free base from the distilled reaction medium; contacting the free base with sulfuric acid to form a sulfate salt; and isolating the sulfate salt. In another aspect, the sulfate is isolated by filtration.

The process generally provides at least about 50% of the stoichiometric process yield of the sulfate salt of formula (IV). In one aspect, the stoichiometric process yield of the sulfate salt of the compound having formula (IV) is at least about 65%. In another aspect, the stoichiometric process yield of the sulfate salt of formula (IV) is at least about 75%. In fact, the improved process has been able to achieve a good quality material in yields of about 85% on a scale exceeding 300kg (input).

In another representative embodiment, the present disclosure is directed to a process for preparing a sulfate salt of a compound having the structure of formula (IV):

wherein the method comprises:

reacting a compound having the structure of formula (III)

Or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having formula (IV);

isolating the compound having formula (IV) as a free base from the reaction mixture;

contacting the free base with sulfuric acid to form a sulfate salt of a compound having formula (IV); and is

Separating the sulfate salt;

wherein the sulfate salt has a stoichiometric ratio of one sulfate molecule and one hydrogen sulfate molecule to three free base molecules.

In one aspect, the sulfate salt is a crystalline salt. In another aspect, the crystalline sulfate salt is characterized by a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 7.7 + -0.2 deg. 2 theta, 10.6 + -0.2 deg. 2 theta, 11.1 + -0.2 deg. 2 theta, 12.6 + -0.2 deg. 2 theta, and 13.5 + -0.2 deg. 2 theta. In another aspect, the crystalline sulfate salt is characterized by a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 7.7 + -0.2 deg. 2 theta, 10.6 + -0.2 deg. 2 theta, 11.1 + -0.2 deg. 2 theta, 12.6 + -0.2 deg. 2 theta, 13.5 + -0.2 deg. 2 theta, 17.4 + -0.2 deg. 2 theta, 18.0 + -0.2 deg. 2 theta, 18.9 + -0.2 deg. 2 theta, 19.2 + -0.2 deg. 2 theta, and 21.9 + -0.2 deg. 2 theta. In another aspect, the crystalline sulfate salt is characterized by a reflected X-ray powder diffraction pattern comprising at least five peaks selected from the group of peaks.

Scheme 10 below corresponds to the method described in example 5 and illustrates one representative example of an improved method for preparing compound (II).

Scheme 10

VIII.4- (2-pyridylcarbamoyl) phenyl]Preparation of boronic acid (Compound V)

The present disclosure relates, in part, to a process for preparing 4- (2-pyridyl-carbamoyl) phenyl ] boronic acid (compound V), or a salt thereof, from 4-carboxyphenylboronic acid, or a salt thereof, and 2-aminopyridine. Scheme 11 below illustrates the general process:

scheme 11

The clinical trial supply method reacts 4-carboxyphenylboronic acid with 2-aminopyridine to produce compound (V). The coupling reaction is carried out in the presence of thionyl chloride and N, N-dimethylformamide. However, thionyl chloride and N, N-dimethylformamide can potentially react to produce toxic dimethylcarbamoyl chloride. To avoid this problem, the improved process replaces N, N-dimethylformamide with a compound (e.g., tetrabutylammonium chloride) that does not generate this toxic by-product and provides improved safety during this step.

Thus, in one embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (V):

or a salt thereof, wherein the process comprises contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acid chloride intermediate, and then contacting the acid chloride intermediate in situ with 2-aminopyridine to form a reaction mixture comprising a compound having formula (V), or a salt thereof. In one aspect, the method further comprises isolating the compound having formula (V), or a salt thereof, from the reaction mixture.

A molar excess of 2-aminopyridine relative to 4-carboxyphenylboronic acid, or a salt thereof, is typically loaded into the reaction medium. In one aspect, about 1.5 to about 5 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid, or a salt thereof, is loaded into the reaction medium. In another aspect, about 1.5 to about 3.5 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid, or a salt thereof, is loaded into the reaction medium. In another aspect, about 2 molar equivalents of 2-aminopyridine relative to 4-carboxyphenylboronic acid, or a salt thereof, is loaded into the reaction medium.

A molar excess of thionyl chloride relative to 4-carboxyphenylboronic acid, or a salt thereof, is typically loaded into the reaction medium. In one aspect, 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2 to about 5 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid, or a salt thereof. In another aspect, 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2 to about 3.5 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid, or a salt thereof. In another aspect, 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2.75 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid, or a salt thereof.

The catalyst may comprise any suitable catalyst, in particular a catalyst selected from the group consisting of: tetrabutylammonium chloride and N-methyl toluidine. In one aspect, the catalyst comprises tetrabutylammonium chloride. In another aspect, the catalyst comprises N-methyl toluidine. In another aspect, the catalyst does not comprise N, N-dimethylformamide. Typically, from about 0.01 to about 0.1 molar equivalents of catalyst, relative to 4-carboxyphenylboronic acid, or a salt thereof, is loaded into the reaction medium.

The reaction medium may be any suitable reaction medium, in particular a reaction medium comprising at least one solvent selected from the group consisting of: aromatic hydrocarbons, aromatic heterocycles, and nitriles. In one aspect, the reaction medium comprises a compound selected from the group consisting of: toluene, acetonitrile, and pyridine. In another aspect, the reaction medium comprises toluene. In another aspect, the reaction medium does not comprise N, N-dimethylformamide. In another aspect, neither the reaction medium nor the catalyst comprises N, N-dimethylformamide. The volume of the reaction medium is generally from about 3 liters to about 30 liters of reaction medium per kilogram of 4-carboxyphenylboronic acid or salt thereof loaded into the reaction medium. In one aspect, the volume of the reaction medium is from about 5 liters to about 15 liters of reaction medium per kilogram of 4-carboxyphenylboronic acid or salt thereof loaded into the reaction medium.

During the contacting step, the reaction medium is typically maintained at a temperature of from about 50 ℃ to about 90 ℃. In one aspect, the reaction medium is maintained at a temperature of from about 60 ℃ to about 80 ℃ during the contacting step.

The contacting step is typically carried out as a batch reaction, particularly a batch reaction wherein at least about 50 kg of 4-carboxyphenylboronic acid or salt thereof is loaded into the batch reaction. In one aspect, at least about 100 kilograms of 4-carboxyphenylboronic acid or salt thereof is loaded into the batch reaction.

The process generally provides at least about 50% stoichiometric process yield of the compound having formula (V) or a salt thereof. In one aspect, the stoichiometric process yield of the compound having formula (V) or salt thereof is at least about 60%. In another aspect, the stoichiometric process yield of the compound having formula (V) or salt thereof is at least about 65%. In another aspect, the compound having formula (V) or a salt thereof has a stoichiometric process yield of at least about 70%.

In another representative embodiment, the present disclosure relates to a process for preparing a compound having the structure of formula (V):

or a salt thereof, wherein the process comprises contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acid chloride intermediate, and then contacting the acid chloride intermediate in situ with 2-aminopyridine to form a reaction mixture comprising a compound having formula (V), or a salt thereof; wherein neither the reaction medium nor the catalyst comprises N, N-dimethylformamide.

In one aspect, the catalyst comprises a catalyst selected from the group consisting of: tetrabutylammonium chloride and N-methyl toluidine. In one aspect, the catalyst comprises tetrabutylammonium chloride. In another aspect, the catalyst comprises N-methyl toluidine. In another aspect, the reaction medium is maintained at a temperature of from about 50 ℃ to about 90 ℃ during the contacting step. In another aspect, the method further comprises isolating the compound having formula (V), or a salt thereof, from the reaction mixture.

Scheme 12 below corresponds to the method described in example 11 and illustrates one representative example of an improved method for preparing compound (V).

Scheme 12

IX.1-bromo-3- [ (2S) -2-pyrrolidinyl)]Imidazo [1,5-a ]]Preparation of pyrazin-8-amines (Compound VI)

The present disclosure relates, in part, to processes for preparing 1-bromo-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-8-amine (compound VI), or a salt thereof, from benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidinecarboxylate (compound IV), or a salt thereof. Scheme 13 below illustrates the general process:

scheme 13

Initial development efforts to avoid aggressive acidic conditions by deprotecting compound (IV) or a salt thereof and providing compound (VI) or a salt thereof by hydrogenation were unsuccessful due to the presence of unstable bromide on the imidazole ring. Further development efforts have met with challenges relating to the generation and/or removal of several impurities.

First, the deprotection reaction generates a benzyl halide (e.g., benzyl chloride), which can potentially be further reacted with compound (VI) or a salt thereof to yield an N-benzyl impurity having the structure of compound (IX):

second, the use of dichloromethane in the deprotection reaction can yield aminal impurities having the structure of compound (X):

Third, oxidized impurities having the structure of the following compound (XI) were observed in several batches of this process step:

the improved process addresses the N-benzyl impurity by removing the benzyl halide (e.g., by extraction with heptane) from the reaction mixture containing the crude compound (VI) product prior to isolating compound (VI) or a salt thereof from the reaction mixture. The improved process addresses aminal impurities by selecting a solvent that does not produce aminal impurities (e.g., 2-methyltetrahydrofuran instead of dichloromethane). The improved process addresses the oxidizing impurities by properly controlling the oxygen level in the reaction vessel during the process. Proper control of the inerting scheme (e.g., nitrogen purge) and vessel construction materials improves product quality by substantially preventing product discoloration and the formation of oxidizing impurities observed in prior activities and eliminating the need for prior carbon treatment.

Thus, in one embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VI):

or a salt thereof, wherein the method comprises:

reacting a compound having formula (IV):

or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound having formula (IV), or a salt thereof, and form a reaction mixture comprising the compound having formula (VI), or a salt thereof, and benzyl halide by-product;

Removing at least a portion of the benzyl halide by-product from the reaction mixture; and is

Isolating a compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

In one aspect, the sulfate salt of the compound having formula (IV) is contacted with an acidic medium.

The aminal impurities generally comprise compounds having the structure of formula (X):

or a salt thereof. In one aspect, an isolated compound having formula (VI), or a salt thereof, comprises less than 5% by weight aminal impurities. In another aspect, the isolated compound having formula (VI), or a salt thereof, comprises less than 3 wt.% aminal impurities. In another aspect, the isolated compound having formula (VI), or a salt thereof, comprises less than 1 wt% aminal impurities.

In one aspect, the acidic medium is an aqueous acidic medium. The aqueous acidic medium generally comprises an inorganic acid, particularly hydrochloric acid, and at least about 10 molar equivalents of the acid relative to the compound having formula (IV), or a salt thereof. In one aspect, the aqueous acidic medium comprises from about 10 to about 40 molar equivalents of acid relative to the compound having formula (IV), or a salt thereof. In another aspect, the aqueous acidic medium comprises from about 10 to about 25 molar equivalents of acid relative to the compound having formula (IV), or a salt thereof. The volume of the aqueous acidic medium is typically from about 2 liters to about 10 liters of aqueous acidic medium per kilogram of compound having formula (IV), or salt thereof, loaded into the acidic medium. In one aspect, the volume of the aqueous acidic medium is from about 3 liters to about 4 liters of aqueous acidic medium per kilogram of compound having formula (IV) or salt thereof loaded into the aqueous acidic medium. During the contacting step, the aqueous acidic medium is typically maintained at a temperature of from about 25 ℃ to about 70 ℃. In one aspect, the aqueous acidic medium is maintained at a temperature of from about 40 ℃ to about 50 ℃ during the contacting step.

In another embodiment, the method comprises removing at least a portion of the benzyl halide by-product from the reaction mixture; increasing the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium comprising a compound having formula (VI), or a salt thereof; and isolating the compound having formula (VI), or a salt thereof, from the basic reaction mixture.

In another embodiment, the method comprises removing at least a portion of the benzyl halide by-product from the reaction mixture by selectively extracting the benzyl halide by-product from the reaction mixture prior to isolating the compound having formula (VI), or a salt thereof. In one aspect, the benzyl halide by-product from the reaction mixture is selectively extracted into a waste organic phase relative to the compound having formula (VI), or a salt thereof. In another aspect, at least about 80 weight percent of the benzyl halide by-product present in the reaction mixture is extracted into the waste organic phase. In another aspect, less than about 20% by weight of the compound having formula (VI), or salt thereof, present in the reaction mixture is extracted into the waste organic phase. In another aspect, at least about 80 weight percent of the benzyl halide by-product present in the reaction mixture and less than about 20 weight percent of the compound having formula (VI), or a salt thereof, present in the reaction mixture is extracted into a waste organic phase. In another aspect, at least about 90 weight percent of the benzyl halide by-product present in the reaction mixture and less than about 10 weight percent of the compound having formula (VI), or a salt thereof, present in the reaction mixture is extracted into a waste organic phase. In another aspect, at least about 95 weight percent of the benzyl halide by-product present in the reaction mixture and less than about 5 weight percent of the compound having formula (VI), or a salt thereof, present in the reaction mixture is extracted into a waste organic phase.

The waste organic phase typically comprises at least one solvent selected from the group consisting of: alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers. In one aspect, the discarded organic phase comprises at least one compound selected from the group consisting of: pentane, hexane, heptane, octane, nonane, toluene, dichloromethane, methyl tert-butyl ether, and 2-methyltetrahydrofuran. In another aspect, the discarded organic phase comprises heptane.

In further embodiments, the method comprises increasing the pH of the reaction mixture after the extraction of the benzyl halide byproduct to form a basic reaction medium comprising a compound having formula (VI), or a salt thereof; and extracting the compound having formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase. In one aspect, the process comprises extracting at least a portion of the benzyl halide by-product from the reaction mixture into a waste organic phase; increasing the pH of the resulting reaction mixture (e.g., by adding sodium hydroxide) to a basic pH to form a basic reaction medium comprising a compound having formula (VI), or a salt thereof; extracting the compound having formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase; and separating the compound having formula (VI), or a salt thereof, from the product organic phase. The pH of the alkaline reaction mixture is typically increased to at least about 8.0. In one aspect, the pH of the alkaline reaction mixture is increased to at least about 10.0.

The product organic phase typically comprises at least one solvent selected from the group consisting of: alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers. In one aspect, the product organic phase comprises at least one compound selected from the group consisting of: 2-methyltetrahydrofuran and anisole. In another aspect, the product organic phase comprises 2-methyltetrahydrofuran. In another aspect, the product organic phase does not contain dichloromethane.

It may be beneficial to wash the product organic phase (e.g., with water) prior to isolating the compound having formula (VI), or a salt thereof. It may also be beneficial to distill the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase prior to isolating the compound having formula (VI), or a salt thereof. In one aspect, the method comprises washing the product organic phase with water and distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase. In another aspect, the product organic phase is distilled at atmospheric pressure. In another aspect, the product organic phase comprises 2-methyltetrahydrofuran and additional 2-methyltetrahydrofuran is loaded into the product organic phase during the distillation step.

The compound having formula (VI), or a salt thereof, may be isolated from the reaction mixture by any suitable means (particularly by crystallizing the compound having formula (VI), or a salt thereof, from the reaction mixture). In one aspect, the isolating step comprises seeding the reaction mixture with a crystalline form of the compound having formula (VI), or a salt thereof, to promote crystallization. In another aspect, the isolating step comprises seeding the reaction mixture with at least about 0.005 relative weight of a crystalline form of the compound having formula (VI), or a salt thereof, to promote crystallization. In another aspect, the isolating step comprises seeding the reaction mixture with at least about 0.01 relative weight of a crystalline form of the compound having formula (VI), or a salt thereof, to promote crystallization. In another aspect, the isolating step comprises seeding the reaction mixture with at least about 0.005 to about 0.02 relative weight of a crystalline form of the compound having formula (VI), or a salt thereof, to promote crystallization. It may also be beneficial to load an anti-solvent into the reaction mixture to promote crystallization. In one aspect, the anti-solvent is heptane.

The contacting step is typically carried out as a batch reaction, in particular the following batch reactions: wherein at least about 50 kg of a compound having formula (IV) or salt thereof is first loaded into the reaction. In one aspect, at least about 100 kilograms of a compound having formula (IV), or a salt thereof, is first loaded into the reaction. In another aspect, at least about 200 kilograms of a compound having formula (IV), or a salt thereof, is first loaded into the reaction. In another aspect, at least about 300 kilograms of a compound having formula (IV), or a salt thereof, is first loaded into the reaction.

The process generally provides at least about 50% stoichiometric process yield of the compound having formula (VI) or a salt thereof. In one aspect, the stoichiometric process yield of the compound having formula (VI) or a salt thereof is at least about 65%. In another aspect, the stoichiometric process yield of the compound having formula (VI) or a salt thereof is at least about 75%. In another aspect, the stoichiometric process yield of the compound having formula (VI) or a salt thereof is at least about 80%. In fact, the improved process has been able to achieve a good quality material in yields of about 85% on a scale exceeding 300kg (input).

In another representative embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VI):

Or a salt thereof, wherein the method comprises:

reacting a compound having formula (IV):

selectively extracting at least a portion of the benzyl halide by-product from the reaction mixture into a waste organic phase relative to a compound having formula (VI), or a salt thereof;

increasing the pH of the resulting reaction mixture to a pH greater than about 7.0 to form an alkaline reaction mixture;

selectively extracting at least a portion of the compound having formula (VI), or a salt thereof, from the basic reaction mixture into a product organic phase; and is

In one aspect, the waste organic phase comprises heptane. In another aspect, the product organic phase comprises 2-methyltetrahydrofuran. In another aspect, the discarded organic phase comprises heptane and the product organic phase comprises 2-methyltetrahydrofuran. In another aspect, the process further comprises crystallizing the compound having formula (VI), or a salt thereof, from the distilled organic phase.

Scheme 14 below corresponds to the method described in example 9 and illustrates one representative example of an improved method for preparing compound (VI).

Scheme 14

X.4- { 8-amino-3- [ (2S) -2-pyrrolidinyl]Imidazo [1,5-a ]]Pyrazin-1-yl } -N- (2-pyridyl) benzene Preparation of formamide (Compound VII)

The present disclosure relates, in part, to processes for preparing 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridinyl) benzamide (compound VII), or a salt thereof, from [4- (2-pyridylcarbamoyl) phenyl ] boronic acid (compound V), or a salt thereof, and 1-bromo-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-8-amine (compound VI), or a salt thereof. Scheme 15 below illustrates the general process:

scheme 15

The method employs a Suzuki (Suzuki) reaction to couple compound (V) and compound (VI) to produce compound (VII). Clinical trial the supply method was performed for suzuki coupling in aqueous 2-butanol medium. The crude compound (VII) was crystallized from aqueous 2-butanol medium in crystalline form (subsequently identified as form 2 crystalline form of compound (VII)), which was extremely difficult to filter from the medium, even on a 50kg scale. The form 2 crystalline form of compound (VII) was isolated as a thick, clay-like product, which required oven drying to remove the large amount of water that adhered to the wet paste upon discharge from the filter.

Efforts to improve filterability of crystalline compound (VII) led to the discovery of two additional crystalline forms of compound (VII), designated as crystalline form 3 and crystalline form C. Form 2 crystalline form has a very fine needle-like morphology and is considered to be a hemihydrate of the hemi-butanol solvate. Form 3 crystalline form has a needle-like morphology and is considered a butanol solvate. Form C crystalline form is an anhydrate with improved morphology, which results in larger crystals. It was found that crystallization of compound (VII) from a non-aqueous (typically less than 5 wt% water) medium can result in form 3 crystalline form and/or form C crystalline form. Both crystalline forms filter faster than form 2, but form C also filters faster than form 3. Therefore, further efforts have focused on reducing or substantially removing any water present (e.g., by distillation) prior to the initial isolation of compound (VII) in order to repeat the isolation of compound (VII) as the C-form crystalline form.

Although removal of water prior to isolation of compound (VII) generally provides form C crystalline form, occasionally batches still crystallize with different amounts of form 3 crystalline form present. Further studies have determined that form C is the thermodynamic form at temperatures above about 75 ℃. At this temperature, any crystalline form 3 present is generally converted to crystalline form C within a relatively short period of time. Form C crystalline form can be routinely produced as the thermodynamic form by incorporating a temperature cycle prior to isolation of compound (VII). Although the conversion from form C back to form 3 can occur upon cooling below 75 ℃ (particularly in the presence of residual water), the conversion is slow enough to allow cooling and filtration to occur without significant conversion back to form 3 crystalline form.

Additionally, it was found to be advantageous to move the silica scavenger treatment from the last step of producing acaracinib from compound (VII), as used in the clinical trial supply process, to the current step of producing compound (VII). This change in the silica scavenger treatment sequence provides a better balance of effective palladium removal versus product yield loss (scavenger).

Furthermore, it was found that during the suzuki reaction, long-term scale heating of the process (e.g., treatment at 80 ℃ and atmospheric distillation at 80 ℃ to 100 ℃) resulted in the formation of two impurities (compound (XII) and compound (XIII)) having the structures shown below:

however, by using lower temperatures (e.g., 60 ℃ or less treatment and atmospheric distillation), the formation of these impurities can be suppressed.

Thus, in one embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (V)

Or a salt thereof, with a compound having the structure of formula (VI):

Reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound having formula (VII), or a salt thereof; and is

Isolating a compound having formula (VII), or a salt thereof, from the substantially anhydrous mixture.

The compound having formula (VII), or a salt thereof, is isolated from the substantially anhydrous mixture as a substantially crystalline form of the compound having formula (VII), or a salt thereof. In one aspect, the substantially crystalline form of the compound having formula (VII) is characterized by a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 9.9 + -0.2 deg. 2 theta, 11.1 + -0.2 deg. 2 theta, 12.8 + -0.2 deg. 2 theta, 14.1 + -0.2 deg. 2 theta, and 19.0 + -0.2 deg. 2 theta. In another aspect, the substantially crystalline form of the compound having formula (VII) is characterized by a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 7.4 + -0.2 DEG 2 theta, 8.9 + -0.2 DEG 2 theta, 9.9 + -0.2 DEG 2 theta, 11.1 + -0.2 DEG 2 theta, 12.8 + -0.2 DEG 2 theta, 14.1 + -0.2 DEG 2 theta, 14.8 + -0.2 DEG 2 theta, 19.0 + -0.2 DEG 2 theta, and 21.6 + -0.2 DEG 2 theta. In another aspect, the substantially crystalline form of the compound having formula (VII) is characterized by a reflected X-ray powder diffraction pattern comprising at least five peaks selected from the group of peaks. In another aspect, the substantially crystalline form is a substantially anhydrous crystalline form of the compound having formula (VII).

The substantially crystalline form of the compound having formula (VII) is isolated from a substantially anhydrous mixture typically having a crystalline purity of at least 50% form C. In one aspect, the isolated substantially crystalline form has a form C crystalline purity of at least 60%. In another aspect, the isolated substantially crystalline form has a form C crystalline purity of at least 70%. In another aspect, the isolated substantially crystalline form has a form C crystalline purity of at least 80%. In another aspect, the isolated substantially crystalline form has a form C crystalline purity of at least 90%. In another aspect, the isolated substantially crystalline form has a form C crystalline purity of at least 95%. In another aspect, the isolated substantially crystalline form has a form C crystalline purity of at least 96%. In another aspect, the isolated substantially crystalline form has a form C crystalline purity of at least 97%. In another aspect, the isolated substantially crystalline form has a form C crystalline purity of at least 98%. In another aspect, the isolated substantially crystalline form has a form C crystalline purity of at least 99%. In another aspect, the isolated substantially crystalline form is a substantially pure phase C crystalline form.

In another embodiment, the aqueous reaction medium further comprises an alkali metal halide. In one aspect, the aqueous reaction medium comprises an alkali metal iodide. In another aspect, the aqueous reaction medium comprises potassium iodide. At least about 0.1 molar equivalents of alkali metal halide, relative to the compound having formula (VI), or salt thereof, is typically loaded into the aqueous reaction medium. In one aspect, about 0.1 to about 1.0 molar equivalents of alkali metal halide, relative to the compound having formula (VI), or salt thereof, is typically loaded into the aqueous reaction medium. In one aspect, about 0.1 to about 1.0 molar equivalents of potassium iodide, relative to the compound having formula (VI), or salt thereof, is loaded into the aqueous reaction medium. In another aspect, about 0.2 to about 0.4 molar equivalents of potassium iodide, relative to the compound having formula (VI), or salt thereof, is loaded into the aqueous reaction medium.

The compound having formula (VI), or a salt thereof, is typically contacted with about 0.5 to about 1.5 molar equivalents of the compound having formula (V), or a salt thereof, relative to the compound having formula (VI), or a salt thereof. In one aspect, a compound having formula (VI), or a salt thereof, is contacted with about 0.8 to about 1.2 molar equivalents of a compound having formula (V), or a salt thereof, relative to a compound having formula (VI), or a salt thereof. In another aspect, a compound having formula (VI), or a salt thereof, is contacted with about 0.9 to about 1.1 molar equivalents of a compound having formula (V), or a salt thereof, relative to a compound having formula (VI), or a salt thereof.

The base may be any suitable base, in particular a base comprising at least one compound selected from the group consisting of: triethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, tripropylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, methyldicyclohexylamine, and potassium phosphate. In one aspect, the base comprises triethylamine. In another aspect, the base comprises potassium carbonate. In another aspect, the base comprises triethylamine and potassium carbonate. About 0.5 to about 10 molar equivalents of base, relative to the compound having formula (VI), or a salt thereof, is typically loaded into the aqueous reaction medium. In one aspect, the base comprises triethylamine, and about 0.5 to about 10 molar equivalents of triethylamine relative to the compound having formula (VI), or a salt thereof, is loaded into the aqueous reaction medium. In another aspect, the base comprises triethylamine, and about 1.0 to about 2.0 molar equivalents of triethylamine relative to the compound having formula (VI), or a salt thereof, is loaded into the aqueous reaction medium. In another aspect, the base comprises potassium carbonate, and about 0.5 to about 10.0 molar equivalents of potassium carbonate, relative to the compound having formula (VI), or salt thereof, is loaded into the aqueous reaction medium. In another aspect, the base comprises potassium carbonate, and about 2.0 to about 3.0 molar equivalents of potassium carbonate, relative to the compound having formula (VI), or salt thereof, is loaded into the aqueous reaction medium. In another aspect, the base comprises potassium carbonate, and about 2.3 to about 2.7 molar equivalents of potassium carbonate, relative to the compound having formula (VI), or salt thereof, is loaded into the aqueous reaction medium.

The palladium catalyst may be any suitable palladium catalyst, in particular a catalyst comprising bis (tert-butyldicyclohexylphosphine) dichloropalladium (II). About 0.002 to about 0.05 molar equivalents of palladium catalyst relative to the compound having formula (VI), or a salt thereof, is typically loaded into the aqueous reaction medium. In one aspect, about 0.007 to about 0.013 molar equivalents of the palladium catalyst relative to the compound having formula (VI), or salt thereof, is loaded into the aqueous reaction medium.

The organic solvent may be any suitable organic solvent, in particular an organic solvent selected from the group consisting of: aromatic hydrocarbons, alcohols, ketones, ethers, esters, and nitriles. In one aspect, the organic solvent comprises at least one solvent selected from the group consisting of: methanol, ethanol, propanol, butanol, pentanol, dioxane, toluene, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, n-butyl acetate, and ethyl lactate. In another aspect, the organic solvent comprises 2-butanol.

The volume of the aqueous reaction medium is typically from about 10 liters to about 20 liters of aqueous reaction medium per kilogram of compound having formula (VI) or salt thereof loaded into the aqueous reaction medium. In one aspect, the volume ratio of water to organic solvent for the aqueous reaction medium is from about 1:3 to about 3: 1. During the contacting step, the aqueous reaction medium is typically maintained at a temperature of from about 50 ℃ to about 100 ℃. In one aspect, the aqueous reaction medium is maintained at a temperature of from about 70 ℃ to about 90 ℃ during the contacting step.

In one embodiment, the reducing step comprises separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound having formula (VII). In one aspect, the reducing step further comprises distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase and provide a substantially anhydrous mixture. In another aspect, the process further comprises washing the organic phase with water prior to distillation.

In further embodiments, the organic phase is treated with a silica scavenger prior to distillation. In one aspect, the organic phase is treated with a silica scavenger for a period of at least two hours prior to distillation. The silica scavenger typically comprises a propanethiol functionalized silica. In one aspect, the silica scavenger comprises QuadraSil^TMAnd (6) MP. The process may further comprise removing the silica scavenger from the organic phase prior to distillation. In one aspect, the silica scavenger is removed from the organic phase by filtration prior to distillation. In another aspect, the process further comprises washing the organic phase with an aqueous brine solution after removing the catalyst and before distillation.

In another embodiment, the reducing step comprises separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound having formula (VII), or a salt thereof; washing the organic phase with water; treating the organic phase with a silica scavenger; removing the silica scavenger from the organic phase; washing the organic phase with an aqueous brine solution; and distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase.

The distillation of the organic phase can be carried out under suitable conditions, in particular by distillation of the organic phase by vacuum distillation. In one aspect, the organic phase is distilled by continuous horizontal vacuum distillation. In another aspect, the organic phase is distilled at a temperature not exceeding about 60 ℃. In another aspect, the organic phase is distilled at a temperature of from about 50 ℃ to about 60 ℃. In another aspect, the organic phase comprises an alcohol. In another aspect, the organic phase is supplemented with alcohol during the distillation step. In another aspect, the organic phase comprises 2-butanol. In another aspect, the organic phase is supplemented with 2-butanol during the distillation step.

The substantially anhydrous mixture typically contains less than about 5% by weight water. In one aspect, the substantially anhydrous mixture comprises less than about 3% by weight water. In another aspect, the substantially anhydrous mixture comprises less than about 1 wt% water.

The isolation step typically comprises crystallizing the compound having formula (VII) as a form C crystalline form from a substantially anhydrous mixture. To ensure that the product crystallizes as form C crystalline form, the substantially anhydrous mixture is heated to a temperature of at least about 70 ℃ (e.g., at least about 75 ℃) and then cooled to crystallize the compound having formula (VII). The period of time for which the substantially anhydrous mixture is maintained at a temperature (or temperature range) of at least about 70 ℃ before cooling begins will depend on the temperature (or temperature range) selected. At higher temperatures, a shorter holding period is generally required to convert any non-C-form crystalline form present to C-form crystalline form. However, the temperature selected should not result in degradation of the compound having formula (VII) or exceed the boiling point of the substantially anhydrous mixture. Additionally, stirring the substantially anhydrous mixture during the holding period and/or inoculating the substantially anhydrous mixture with the form C crystalline form may be beneficial to further reduce the duration of any desired holding period. Thus, in various embodiments, after the crystallization begins and before cooling begins, the substantially anhydrous mixture is maintained at a selected temperature (or temperature range) for a period of time, wherein the selected temperature (or temperature range) and period of time are sufficient to produce substantially form C crystalline form of the compound having formula (VII) after cooling the substantially anhydrous mixture.

In one aspect, the substantially anhydrous mixture is heated to a temperature of at least about 80 ℃. In another aspect, the temperature is at least about 85 ℃. In another aspect, the temperature is at least about 90 ℃. In another aspect, the temperature is at least about 95 ℃. In another aspect, the temperature is from about 70 ℃ to about 105 ℃. In another aspect, the temperature is from about 75 ℃ to about 105 ℃. In another aspect, the temperature is from about 80 ℃ to about 105 ℃. In another aspect, the temperature is from about 85 ℃ to about 105 ℃. In another aspect, the temperature is from about 90 ℃ to about 105 ℃.

In one aspect, the temperature is selected to be sufficiently high that no further hold period is required before cooling begins. In another aspect, the hold period prior to cooling is at least about 15 minutes. In another aspect, the hold period prior to cooling is at least about 30 minutes. In another aspect, the hold period prior to cooling is at least about 1 hour. In another aspect, the hold period prior to cooling is at least about 1.5 hours. In another aspect, the hold period prior to cooling is at least about 2 hours.

In one aspect, the temperature is at least about 75 ℃ and the hold period before cooling is at least about two hours. In another aspect, the temperature is at least about 80 ℃ and the holding period is at least about 1.5 hours. In another aspect, the temperature is at least about 85 ℃ and the holding period is at least about 1 hour. In another aspect, the temperature is at least about 90 ℃ and the holding period is at least about 15 minutes. In another aspect, the temperature is at least about 90 ℃ and no holding period is required. In another aspect, the temperature is from about 75 ℃ to about 105 ℃ and the holding period is from about 15 minutes to about 3 hours. In another aspect, the temperature is from about 80 ℃ to about 105 ℃ and the holding period is from about 15 minutes to about 3 hours. In another aspect, the temperature is from about 85 ℃ to about 105 ℃ and the holding period is from about 15 minutes to about 3 hours. In another aspect, the temperature is from about 90 ℃ to about 105 ℃ and the holding period is from about 5 minutes to about 2 hours. In another aspect, the temperature is from about 90 ℃ to about 105 ℃ and no further hold period is required before cooling.

In each of the above aspects, the substantially anhydrous mixture can be seeded with form C crystalline form of the compound having formula (VII) to further promote crystallization of the desired crystalline form. For example, the substantially anhydrous mixture can be seeded with form C crystals form, maintained at a temperature of from about 85 ℃ to about 105 ℃ for a holding period of from about 5 minutes to about 3 hours, and then cooled to crystallize the compound having formula (VII).

The contacting step is typically carried out as a batch reaction, in particular the following batch reactions: wherein at least about 25 kg of a compound having formula (VI) or salt thereof is first loaded into the reaction. In one aspect, at least about 50 kilograms of a compound having formula (VI), or a salt thereof, is first loaded into the reaction. In another aspect, at least about 75 kilograms of a compound having formula (VI), or a salt thereof, is first loaded into the reaction. In another aspect, at least about 100 kilograms of a compound having formula (VI), or a salt thereof, is first loaded into the reaction.

The process generally provides at least about 50% stoichiometric process yield of the compound having formula (VII) or a salt thereof. In one aspect, the stoichiometric process yield of the compound having formula (VII) or salt thereof is at least about 65%. In another aspect, the stoichiometric process yield of the compound having formula (VII) or salt thereof is at least about 75%. In fact, the improved process has been able to achieve a good quality material in yields of about 80% on a scale exceeding 100kg (input). Furthermore, the improved process has a faster filtration time, which significantly reduces the cycle time of the process to less than one week.

In another representative embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (V)

Or a salt thereof, with a compound having the structure of formula (VI):

separating the reaction mixture into an aqueous waste phase and an organic phase comprising a compound having formula (VII), or a salt thereof;

treating the organic phase with a silica scavenger;

removing the silica scavenger from the organic phase;

distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase and form a substantially anhydrous mixture comprising the compound having (VII), or a salt thereof; and is

Crystallizing a compound having formula (VII) from the substantially anhydrous mixture;

wherein the compound having formula (VII) is crystallized in the form of C-form crystals.

In one aspect, the method further comprises washing the organic phase with water prior to the treating step. In another aspect, the method further comprises washing the organic phase with an aqueous brine solution after the removing step and before the distilling step. In another aspect, the organic phase is distilled by vacuum distillation during which dry butanol is added to the organic phase and functions to remove water present. In another aspect, prior to isolating the compound having formula (VII) from the substantially anhydrous mixture, the substantially anhydrous mixture is maintained at a temperature greater than 75 ℃ until any crystalline form present substantially converts to form C crystalline form.

Scheme 16 below corresponds to the method described in example 14 and illustrates one representative example of an improved process for preparing compound (VII).

Scheme 16

XII.Preparation of acaracitinib (compound VIII)

The present disclosure relates, in part, to processes for preparing acartinib, or a salt thereof, from 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridinyl) -benzamide (compound VII), and 2-butyric acid, or a salt thereof. Scheme 17 below illustrates the general process:

scheme 17

Reacting compound (VII) with 2-butyric acid in the presence of a coupling agent to produce acaracinib. This coupling step is difficult to handle in clinical trial supply methods. Addition of a small excess of 2-butyric acid to compound (VII) in dichloromethane produced a thick mixture containing the butynoate salt of compound (VII) that was difficult to stir. Subsequent addition of triethylamine to the thick mixture did not significantly improve the viscosity. However, the addition of triethylamine prior to the addition of 2-butyric acid avoids the formation of the butynoate salt of compound (VII) and produces a relatively thin stirrable slurry. However, subsequent addition of a coupling agent (e.g., 1-propylphosphoric anhydride) to the resulting slurry is difficult to control and has a narrow in-process control window in order to meet the quality standards for the acaracinib product. Insufficient addition of 1-propylphosphoric anhydride does not consume all of the starting material (i.e., compound (VII)), and excessive addition results in formation of an impurity having the structure of compound (XIV):

In the subsequent isolation of the acaracinib product, both unreacted compound (VII) and compound (XIV) impurities are difficult to remove and are responsible for multiple batch failures in the clinical trial supply process.

It has been found that the difficulties associated with removing both impurities can be overcome using a sequential extraction process. Acarabtinib is first selectively extracted from the reaction mixture with respect to the compound (XIV) impurity into an aqueous phase having a first acidic pH (e.g., pH 1.8 to 2.2), and the reaction mixture containing the compound (XIV) impurity is discarded. The pH of the aqueous phase comprising acaracinib is then adjusted to a second pH (e.g., pH 4.5 to 5.0) and acaracinib is selectively extracted from the aqueous phase into the organic phase relative to the compound (VII) impurity and the aqueous phase containing the compound (VII) impurity is discarded. Since the sequential extraction process results in the efficient removal of unwanted impurities from the final product, the 1-propylphosphoric anhydride addition does not require as stringent control as in the clinical trial supply process, and the 1-propylphosphoric anhydride addition is more stable.

Another problem encountered in the clinical trial supply method involves solvent exchange from dichloromethane to ethanol using multiple "put and take" distillation cycles. The acaracitinib product continues to oil or gel before final crystallization. The kinetics of the crystallization of acaracinib from ethanol was found to be exceptionally slow. The point at which the oil crystallizes cannot be controlled and the crystallized acarabtinib produces an undesirable amount of crystallization solvent. Therefore, the inclusion of dichloromethane in the acaracitinib lattice is a concern in the clinical trial supply method. A more controlled procedure has now been developed that employs continuous horizontal vacuum distillation (e.g., at 50 ℃, 18 to 20 relative volumes) that maintains acarabinib in solution throughout the distillation (even with complete replacement of the dichloromethane solvent by ethanol) and avoids the problem of oil formation. Once distillation is complete, seeding with crystalline acaracinib and maintaining the seeded solution at a suitable temperature (e.g., 50 ℃) results in controlled crystallization, where the acaracinib product can be isolated and have consistent particle properties. Crystallization further purifies the acaracitinib product, especially with respect to any excessively acylated by-products present.

Thus, in one embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (VII)

Selectively separating the compound having formula (VIII), or a salt thereof, from the reaction mixture relative to the one or more byproducts.

As previously mentioned, the order of addition of the method may have an impact. Typically, the contacting step comprises adding a compound having formula (VII), or a salt thereof, and the base to the reaction medium; adding the 2-butyric acid, or salt thereof, to the reaction medium comprising the compound having formula (VII), or salt thereof, and the base; and adding the 1-propylphosphonic anhydride to a composition comprising a compound having formula (VII), or a salt thereof; 2-butyric acid, or a salt thereof; and said base in said reaction medium.

In another embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VIII):

Or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (VII)

Or a salt thereof, with 2-butyric acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base, in a reaction medium, to form a composition comprising a compound having formula (VIII), or a salt thereof; an unreacted compound having formula (VII), or a salt thereof; and reaction by-products; wherein the reaction by-product comprises a compound having the structure of formula (XIV):

or a salt thereof; and is

Separating the compound having formula (VIII), or a salt thereof, from the reaction mixture selectively to the compound having formula (VII), or a salt thereof, and the compound having formula (XIV), or a salt thereof.

In one aspect, the selectively isolated compound having formula (VIII), or salt thereof, comprises less than about 1.0% by weight of the compound having formula (VII), or salt thereof. In another aspect, the selectively isolated compound having formula (VIII), or salt thereof, comprises less than about 0.8% by weight of the compound having formula (VII), or salt thereof. In another aspect, the selectively isolated compound having formula (VIII), or salt thereof, comprises less than about 0.6% by weight of the compound having formula (VII), or salt thereof. In another aspect, the selectively isolated compound having formula (VIII), or salt thereof, comprises less than about 0.4% by weight of the compound having formula (VII), or salt thereof. In another aspect, the selectively isolated compound having formula (VIII), or salt thereof, comprises about less than about 0.3% by weight of the compound having formula (VII), or salt thereof. In another aspect, the selectively isolated compound having formula (VIII), or salt thereof, comprises less than about 1.0 wt.% of the compound having formula (XIV), or salt thereof. In another aspect, the selectively isolated compound having formula (VIII), or salt thereof, comprises less than about 0.8% by weight of the compound having formula (XIV), or salt thereof. In another aspect, the selectively isolated compound having formula (VIII), or salt thereof, comprises less than about 0.6% by weight of the compound having formula (XIV), or salt thereof. In another aspect, the selectively isolated compound having formula (VIII), or salt thereof, comprises less than about 0.4% by weight of the compound having formula (XIV), or salt thereof. In another aspect, the selectively isolated compound having formula (VIII), or salt thereof, comprises less than about 0.3% by weight of the compound having formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or salt thereof, comprises less than about 1.0 wt% of the compound of formula (VII), or salt thereof, and less than about 1.0 wt% of the compound of formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or salt thereof, comprises less than about 0.8 wt% of the compound of formula (VII), or salt thereof, and less than about 0.8 wt% of the compound of formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or salt thereof, comprises less than about 0.6 wt% of the compound of formula (VII), or salt thereof, and less than about 0.6 wt% of the compound of formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or salt thereof, comprises less than about 0.4% by weight of the compound of formula (VII), or salt thereof, and less than about 0.4% by weight of the compound of formula (XIV), or salt thereof. In another aspect, the selectively isolated compound of formula (VIII), or salt thereof, comprises less than about 0.3 wt% of the compound of formula (VII), or salt thereof, and less than about 0.3 wt% of the compound of formula (XIV), or salt thereof.

In another embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (VII)

Or a salt thereof, with 2-butyric acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base, in a reaction medium, to form a composition comprising a compound having formula (VIII), or a salt thereof; an unreacted compound having formula (VII), or a salt thereof; and a reaction mixture of reaction by-products, wherein the reaction by-products comprise a compound having the structure of formula (XIV):

or a salt thereof;

adjusting the pH of the aqueous phase; and is

Extracting at least a portion of the compound having formula (VIII), or a salt thereof, from the aqueous phase into an organic phase, wherein the compound having formula (VIII), or a salt thereof, is selectively extracted into the organic phase relative to the compound having formula (VII), or a salt thereof.

The compound having formula (VII) is contacted with at least about 0.5 molar equivalents of 2-butyric acid, typically relative to the compound having formula (VII). In one aspect, the compound having formula (VII) is contacted with about 0.5 to about 5.0 molar equivalents of 2-butyric acid relative to the compound having formula (VII). In another aspect, the compound having formula (VII) is contacted with about 1.0 to about 1.3 molar equivalents of 2-butyric acid relative to the compound having formula (VII). In another aspect, the compound having formula (VII) is contacted with about 1.2 molar equivalents of 2-butyric acid relative to the compound having formula (VII).

Typically, at least about 0.3 molar equivalents of 1-propylphosphonic anhydride, relative to the compound of formula (VII), is loaded into the reaction medium. In one aspect, at least about 0.5 molar equivalents of 1-propylphosphonic anhydride, relative to the compound having formula (VII), is typically loaded into the reaction medium. In another aspect, at least about 1.0 molar equivalent of 1-propylphosphonic anhydride, relative to the compound having formula (VII), is typically loaded into the reaction medium. On the other hand, about 0.3 to about 3.0 molar equivalents of 1-propylphosphonic anhydride, relative to the compound of formula (VII), are generally loaded into the reaction medium. On the other hand, about 0.5 to about 2.0 molar equivalents of 1-propylphosphonic anhydride, relative to the compound of formula (VII), are generally loaded into the reaction medium. On the other hand, about 0.7 to about 1.5 molar equivalents of 1-propylphosphonic anhydride, relative to the compound of formula (VII), are generally loaded into the reaction medium. In another aspect, about 1.0 to about 1.2 molar equivalents of 1-propylphosphonic anhydride, relative to the compound having formula (VII), are loaded into the reaction medium.

The base may be any suitable base, in particular a base comprising at least one compound selected from the group consisting of: triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. In one aspect, the base comprises triethylamine. About 1.0 to about 10.0 molar equivalents of base, relative to the compound of formula (VII), are typically loaded into the reaction medium. In one aspect, about 2.0 to about 5.0 molar equivalents of base relative to the compound having formula (VII) is loaded into the reaction medium. In another aspect, about 2.4 to about 3.0 molar equivalents of base relative to the compound having formula (VII) is loaded into the reaction medium.

The reaction medium may be any suitable reaction medium, in particular a reaction medium comprising at least one solvent selected from the group consisting of: alkyl hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, ethers, esters, nitriles, and polar aprotic solvents. In one aspect, the reaction medium comprises at least one solvent selected from the group consisting of: dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-amyl alcohol, acetone, methyl isobutyl ketone, 2-butanol, methyl ethyl ketone, acetonitrile, and ethyl acetate. In another aspect, the reaction medium comprises dichloromethane. The volume of the reaction medium is generally from about 5 liters to about 20 liters of reaction medium per kilogram of compound having formula (VII) loaded into the reaction medium. During the contacting step, the reaction medium is typically maintained at a temperature of from about 10 ℃ to about 30 ℃.

Typically, after the aqueous phase extraction is complete, the aqueous phase comprises greater than about 75 area% of the compound having formula (VIII) and less than about 2.0 area% of the compound having formula (XIV), as measured by high performance liquid chromatography ("HPLC"). In one aspect, after the aqueous phase extraction is complete, the aqueous phase comprises greater than about 80 area% of the compound having formula (VIII), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises greater than about 85 area% of the compound having formula (VIII), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises greater than about 90 area% of the compound having formula (VIII), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises less than about 1.0 area% of the compound having formula (XIV), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises less than about 0.8 area% of the compound having formula (XIV), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises less than about 0.5 area% of the compound having formula (XIV), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises less than about 0.2 area% of the compound having formula (XIV), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises less than about 0.1 area% of the compound having formula (XIV), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises greater than about 80 area% of the compound having formula (VIII) and less than about 1.0 area% of the compound having formula (XIV), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises greater than about 85 area% of the compound having formula (VIII) and less than about 0.8 area% of the compound having formula (XIV), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises greater than about 85 area% of the compound having formula (VIII) and less than about 0.5 area% of the compound having formula (XIV), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises greater than about 85 area% of the compound having formula (VIII) and less than about 0.2 area% of the compound having formula (XIV), as measured by HPLC. In another aspect, after the aqueous phase extraction is complete, the aqueous phase comprises greater than about 90 area% of the compound having formula (VIII) and less than about 0.1 area% of the compound having formula (XIV), as measured by HPLC. The aqueous phase typically has a pH of less than about 2.5 during the aqueous phase extraction step. In one aspect, during the aqueous phase extraction step, the aqueous phase has a pH of from about 1.8 to about 2.2.

Typically, after the organic phase extraction is complete, the organic phase comprises greater than about 75 area% of the compound having formula (VIII) and less than about 2.0 area% of the compound having formula (VII), as measured by HPLC. In one aspect, after the organic phase extraction is complete, the organic phase comprises greater than about 80 area% of the compound having formula (VIII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises greater than about 85 area% of the compound having formula (VIII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises greater than about 90 area% of the compound having formula (VIII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises less than about 1.0 area% of the compound having formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises less than about 0.8 area% of the compound having formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises less than about 0.6 area% of the compound having formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises less than about 0.4 area% of the compound having formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises less than about 0.3 area% of the compound having formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises greater than about 80 area% of the compound having formula (VIII) and less than about 1.0 area% of the compound having formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises greater than about 85 area% of the compound having formula (VIII) and less than about 0.8 area% of the compound having formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises greater than about 85 area% of the compound having formula (VIII) and less than about 0.6 area% of the compound having formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises greater than about 85 area% of the compound having formula (VIII) and less than about 0.4 area% of the compound having formula (VII), as measured by HPLC. In another aspect, after the organic phase extraction is complete, the organic phase comprises greater than about 90 area% of the compound having formula (VIII) and less than about 0.3 area% of the compound having formula (VII), as measured by HPLC. During the organic phase extraction step, the aqueous phase typically has a pH greater than about 4.0. In one aspect, the aqueous phase has a pH of from about 4.5 to about 5.0 during the organic phase extraction step.

The organic phase may comprise any suitable solvent, in particular at least one solvent selected from the group consisting of: alkyl hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, ethers, esters, and nitriles. In one aspect, the organic phase comprises at least one compound selected from the group consisting of: methylene chloride, and 2-methyltetrahydrofuran, t-amyl alcohol, methyl isobutyl ketone, 2-butanol, methyl ethyl ketone, ethyl acetate, isopropyl acetate, N-butyl acetate, butyronitrile, toluene, xylene, heptane, hexane, isohexane, and chloroform. In another aspect, the organic phase comprises dichloromethane.

The compound of formula (VIII) may be isolated from the organic phase by any suitable means, particularly crystallization of the compound of formula (VIII) from the organic phase. In one aspect, the organic phase comprises an organic phase solvent, and the method further comprises exchanging the organic phase solvent with an alternative solvent to form a crystalline mixture comprising the compound having formula (VIII). In another aspect, the compound having formula (VIII) is crystallized from a crystallization mixture. In another aspect, the crystallization mixture is seeded with a crystalline form of the compound having formula (VIII). In another aspect, the crystallization mixture is seeded with at least about 0.01 relative weight of the crystalline form. In another aspect, the crystallization mixture is seeded with at least about 0.02 relative weight of crystalline form. In another aspect, the crystallization mixture is seeded with at least about 0.03 relative weight of the crystalline form. In another aspect, the crystalline form is an anhydrate crystalline form.

The organic phase solvent may comprise any suitable solvent, particularly a polar solvent. In one aspect, the organic phase solvent comprises at least one solvent selected from the group consisting of: chlorinated hydrocarbons and ethers. In another aspect, the organic phase solvent comprises at least one compound selected from the group consisting of: dichloromethane and 2-methyltetrahydrofuran. In another aspect, the organic phase solvent comprises dichloromethane.

The alternative solvent may comprise any suitable solvent. In one aspect, the replacement solvent comprises an alcohol. In another aspect, the alternative solvent comprises ethanol. On the other hand, the boiling point of the organic phase solvent is lower than that of the alternative solvent. In another aspect, the boiling point of the organic phase solvent is at least about 20 ℃ lower than the boiling point of the surrogate solvent. In another aspect, the organic phase solvent comprises a polar solvent and the surrogate solvent comprises an alcohol. In another aspect, the organic phase solvent comprises dichloromethane and the alternative solvent comprises ethanol.

In one embodiment, the organic phase solvent is replaced with an alternative solvent by continuous horizontal distillation. In one aspect, the continuous horizontal distillation during the continuous distillation is conducted under conditions sufficient to maintain the compound having formula (VIII) in solution. In another aspect, the continuous horizontal distillation is continuous horizontal vacuum distillation. In another aspect, the replacement solvent is loaded during the distillation in an amount sufficient to maintain at least about 15 relative volumes of total solvent per kilogram of compound having formula (VIII). In another aspect, the replacement solvent is loaded during the distillation in an amount sufficient to maintain at least about 18 relative volumes of total solvent per kilogram of compound having formula (VIII). In another aspect, the continuous horizontal vacuum distillation is conducted at a temperature not exceeding about 60 ℃.

It may often be beneficial to maintain the crystallization mixture at a temperature greater than about 40 ℃ for a period of time after crystallization begins (e.g., after seeding). In one aspect, the crystallization mixture is maintained at a temperature greater than about 40 ℃ for at least about one hour after crystallization has begun. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 ℃ for at least about two hours after crystallization has begun. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 ℃ for at least about three hours after crystallization has begun. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 ℃ for at least about four hours after crystallization has begun. In another aspect, the crystallization mixture is maintained at a temperature greater than about 40 ℃ for at least about five hours after crystallization has begun. In another aspect, the crystallization mixture is seeded with a crystalline form of the compound having formula (VIII). In another aspect, the crystallization mixture is cooled to a temperature of about 20 ℃ over a period of at least five hours prior to isolating the compound having formula (VIII). In another aspect, the crystallization mixture is seeded with a crystalline form of the compound having formula (VIII), maintained at a temperature greater than about 40 ℃ for at least about five hours, and then cooled to a temperature of about 20 ℃ over a period of at least five hours before isolating the compound having formula (VIII).

The contacting step is typically carried out as a batch reaction, in particular the following batch reactions: wherein at least about 25 kg of a compound having formula (VII) or salt thereof is first loaded into the reaction. In one aspect, at least about 50 kilograms of the compound having formula (VII), or salt thereof, is first loaded into the reaction. In another aspect, at least about 75 kilograms of a compound having formula (VII), or a salt thereof, is first loaded into the reaction. In another aspect, at least about 100 kilograms of a compound having formula (VII), or a salt thereof, is first loaded into the reaction.

The process generally provides at least about 50% of the stoichiometric process yield of the compound having formula (VIII) or a salt thereof. In one aspect, the compound having formula (VIII) or a salt thereof is in a stoichiometric process yield of at least about 60%. In another aspect, the compound having formula (VIII) or a salt thereof has a stoichiometric process yield of at least about 65%. In another aspect, the compound having formula (VIII) or a salt thereof has a stoichiometric process yield of at least about 70%. In fact, the improved process has been able to achieve a yield of about 75% of good quality material on a scale exceeding 100kg (input).

In another representative embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (VII)

Or a salt thereof, with 2-butyric acid, or a salt thereof, in the presence of 1-propylphosphonic anhydride and a base in a reaction medium to form a reaction mixture comprising a compound having formula (VIII), an unreacted compound having formula (VII), and reaction byproducts, wherein the reaction byproducts comprise a compound having the structure of formula (XIV):

or a salt thereof;

extracting at least a portion of the compound having formula (VIII), or a salt thereof, from the reaction mixture into an aqueous phase having a pH of from about 1.8 to about 2.2, wherein the compound having formula (VIII) is selectively extracted into the aqueous phase relative to the compound having formula (XIV);

adjusting the pH of the aqueous phase to about 4.5 to about 5.0; and is

Extracting at least a portion of the compound having formula (VIII) from the aqueous phase into an organic phase, wherein the compound having formula (VIII) is selectively extracted into the organic phase relative to the compound having formula (VII).

In one aspect, the contacting step comprises adding a compound having formula (VII), and the base, to the reaction medium; adding the 2-butyric acid to the reaction medium comprising a compound having formula (VII), and the base; and adding the 1-propylphosphonic anhydride to a reaction medium comprising a compound having formula (VII), 2-butyric acid, and a base. In another aspect, the reaction mixture is washed with water and the washed reaction mixture is separated into an aqueous phase and a waste phase, wherein the compound having formula (VIII) is selectively extracted into the aqueous phase. In another aspect, the organic phase comprises an organic phase solvent, and the method further comprises exchanging the organic phase solvent with an alternative solvent to form a crystalline mixture comprising the compound having formula (VIII). In another aspect, the method further comprises isolating the compound having formula (VIII) from the crystallization mixture. In another aspect, the crystallization mixture is seeded with a crystalline form of the compound having formula (VIII) and maintained at a temperature greater than about 40 ℃ for at least about five hours after crystallization begins.

Scheme 18 below corresponds to the method described in example 17 and illustrates one representative example of an improved process for the preparation of compound (VI).

Scheme 18

XIII.Further embodiments

Various embodiments of the various methods described above can be combined to provide further embodiments of the overall method of preparing acaracinib. The examples described below are representative examples that further describe the overall process. They are intended to illustrate, not to limit, the overall process.

In one embodiment, a compound having the structure of formula (VIII):

or a salt thereof, prepared by a process comprising:

reacting a compound having the structure of formula (VII)

Separating a compound having formula (VIII), or a salt thereof, selectively from the reaction mixture relative to the one or more byproducts;

wherein a compound having the structure of formula (VII), or a salt thereof, is prepared by a process comprising:

reacting a compound having the structure of formula (V)

Or a salt thereof, with a compound having the structure of formula (VI):

reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound having formula (VII), or a salt thereof; and is

Isolating a compound having formula (VII), or a salt thereof, from the substantially anhydrous mixture.

In another embodiment, a compound having the structure of formula (VIII):

or a salt thereof, prepared by a process comprising:

reacting a compound having the structure of formula (VII)

Or a salt thereof, with 2-butyric acid, or a salt thereof, in the presence of a coupling agent and a base, in a reaction medium, to form a composition comprising a compound having formula (VIII), or a salt thereof; an unreacted compound having formula (VII), or a salt thereof; and a reaction mixture of reaction by-products, wherein the reaction by-products comprise a compound having the structure of formula (XIV):

or a salt thereof;

Adjusting the pH of the aqueous phase; and is

wherein a compound having the structure of formula (VII), or a salt thereof, is prepared by a process comprising:

reacting a compound having the structure of formula (V)

Or a salt thereof, with a compound having the structure of formula (VI):

reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound having formula (VII), or a salt thereof; and is

Isolating a compound having formula (VII), or a salt thereof, from the substantially anhydrous mixture.

In another embodiment, the method further comprises preparing a compound having the structure of formula (VI), or a salt thereof, by a process comprising:

reacting a compound having formula (IV):

Removing at least a portion of the benzyl halide by-product from the reaction mixture; and is

Isolating a compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

In another embodiment, the method further comprises preparing a compound having the structure of formula (V), or a salt thereof, by a process comprising: contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acid chloride intermediate, which is then contacted in situ with 2-aminopyridine to form a reaction mixture comprising a compound having formula (V), or a salt thereof.

In another embodiment, the method further comprises preparing a compound having the structure of formula (IV), or a salt thereof, by a process comprising: reacting a compound having the structure of formula (III)

Or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having formula (IV);

forming a sulfate salt of a compound having formula (IV); and is

Separating the sulfate salt.

In another embodiment, the method further comprises preparing a compound having the structure of formula (III), or a salt thereof, by a process comprising: reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II);

or a salt thereof; and is

Brominating a compound having formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

or a salt thereof;

In another embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (V)

Or a salt thereof, with a compound having the structure of formula (VI):

or a salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a compound comprising a structure having the formula (VII):

or a salt thereof;

reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound having formula (VII), or a salt thereof;

isolating a compound having formula (VII), or a salt thereof, from the substantially anhydrous mixture; and is

Converting a compound having formula (VII), or a salt thereof, to a compound having formula (VIII), or a salt thereof.

In another embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (IV)

Or a salt thereof, with an acidic medium under conditions sufficient to deprotect a compound having formula (IV), or a salt thereof, and form a compound comprising a structure having formula (VI):

or a salt thereof, and a benzyl halide by-product;

removing at least a portion of the benzyl halide by-product from the reaction mixture;

isolating a compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities; and is

Converting a compound having formula (VI), or a salt thereof, to a compound having formula (VIII), or a salt thereof.

In another embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (III)

Or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having the structure of formula (IV):

Forming a sulfate salt of a compound having formula (IV);

separating the sulfate salt; and is

Converting the sulfate salt to a compound having formula (VIII), or a salt thereof.

In another embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II);

or a salt thereof;

brominating a compound having formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

or a salt thereof; and is

Converting a compound having formula (III), or a salt thereof, to a compound having formula (VIII), or a salt thereof;

In another embodiment, the disclosure relates to a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having the structure of formula (II):

Or a salt thereof; and is

Converting a compound having formula (II), or a salt thereof, to a compound having formula (VIII), or a salt thereof;

Overall, the improved large scale process has reduced batch failures and provides high quality acaracinib that can be routinely manufactured from compound (I) on a large scale with yields greater than 32%.

XIV.Examples of the invention

Example 1: benzyl (2S) -2- (1-bromo-8-chloro-imidazo [1, 5-a)]-pyrazin-3-yl) pyrrolidine-1-carboxylic acid ester Preparation of (Compound (III))

Benzyl (2S) -2- [ (3-chloropyrazin-2-yl) methylcarbamoyl ] pyrrolidine-1-carboxylate (compound (I); 179.4kg, 1.00mol. eq.) was mixed with acetonitrile (809.6kg, 4.5 relative weight) and N, N-dimethylformamide (6.8kg, 0.1mol. eq.) and phosphorus oxychloride (140.2kg, 1.9mol. eq.) was added slowly, maintaining the temperature below 25 ℃. The reaction mixture was heated at 72 ℃ to 82 ℃ under a nitrogen purge to remove the liberated hydrochloric acid until the reaction showed completion. The mixture was cooled to 35 ℃ to 45 ℃ and then concentrated to about 3.6 relative volumes while maintaining the temperature below 45 ℃. The mixture was concentrated to about 3.6 relative volumes by adding acetonitrile (350.2kg, 1.95 relative weight) and maintaining the temperature below 45 ℃ and repeating this operation once more. The mixture was cooled to 15 to 25 ℃ and then slowly transferred to a cooled solution of sodium bicarbonate (136.6kg, 8.0mol. eq.), water (1139L, 6.3 relative volume) and ice (375.8kg, 2.1 relative weight).

The product was then extracted twice from the mixture with dichloromethane (905kg, 5.0 relative weight). The combined organic extracts were then washed with a solution of sodium bicarbonate (114.4kg) in water (1139L), then with a solution of sodium chloride (75kg) in water (376L), filtered through celite (18kg) and then through silica (40kg), washing the silica cake twice with dichloromethane (909 kg). The temperature was maintained below 40 ℃ and the solvent was removed by vacuum distillation to about 1.0 relative volume. N-methylpyrrolidone (819kg, 4.6 relative weight) was added to dissolve the mixture, followed by incremental addition of N-bromosuccinimide (77.3kg, about 1.1mol. eq.) with stirring at 20 to 30 ℃ after each charge until the reaction was deemed complete. The mixture was then added to a solution of sodium bicarbonate (21.8kg) in water (1092L) and the product was then extracted with dichloromethane (1500kg, 8.4 relative weight) and then dichloromethane (907kg, 5.1 relative weight). The organic phases were combined and washed three times with water (682L) and then eight additional times with water (382L). The organic solution was concentrated to about 1.0 relative volume and concentrated from heptane (191kg, 1.1 relative volume) before adding heptane (191kg, 1.1 relative volume) to the crystallization. Filtered and dried to obtain benzyl (2S) -2- (1-bromo-8-chloro-imidazo [1,5-a ] pyrazin-3-yl) pyrrolidine-1-carboxylate (compound (III), 152.2kg, 75.6%) as a solid. The enantiomeric excess was 97.8%.

However, the above process conditions often result in batches with reduced chiral purity and yield, and sometimes even batch failures. The liberated hydrochloric acid produces acidic conditions which lead to racemization of the benzyl (2S) -2- [ (3-chloropyrazin-2-yl) methylcarbamoyl ] -pyrrolidine-1-carboxylate starting material. Although the use of a nitrogen purge to remove liberated hydrochloric acid reduces the extent of racemization, control of the extent of hand erosion is still highly variable.

Example 2: benzyl (2S) -2- (8-chloro-imidazo [1, 5-a)]Pyrazin-3-yl) pyrrolidine-1-carboxylic acid esters (compounds) (II)) preparation of

The effect of decreasing the reaction temperature and increasing the N, N-dimethylformamide loading on the chiral purity of benzyl (2S) -2- (8-chloro-imidazo [1,5-a ] pyrazin-3-yl) pyrrolidine-1-carboxylate was evaluated relative to the conditions of example 1. Increasing the amount of N, N-dimethylformamide catalyst to at least 0.6mol. equivalents increases the reaction rate and allows the reaction to proceed at lower temperatures, as described below. Changes in these process conditions increase the yield and provide improved control over the chiral purity of the product.

Benzyl (2S) -2- [ (3-chloropyrazin-2-yl) methylcarbamoyl ] pyrrolidine-1-carboxylate (compound (I), 1.00g) was combined with acetonitrile (5ml) in four vials with magnetic stir bars and N, N-dimethylformamide (0.08, 0.12, 0.16, and 0.20 g; 0.4, 0.6, 0.8, and 1.0mol. equivalents) was added. Phosphorus oxychloride (0.82g, 2.0mol. eq) was added to each vial and the contents were stirred for 15 minutes, then placed in a heating block preheated to 42 ℃ and stirred. The temperature in the flask reached 41 ℃. 0.50ml samples were withdrawn from each vial at 1, 3, 5 and 21 hours. The sample was quenched into 10ml of saturated sodium bicarbonate solution, extracted into 5ml of methyl tert-butyl ether, and the organic layer was separated and dried over magnesium sulfate. The extract was analyzed by HPLC for purity and chirality. The results are shown in table 3 below.

TABLE 3

Example 3: benzyl (2S) -2- (1-bromo-8-chloro-imidazo [1, 5-a)]Pyrazin-3-yl) pyrrolidine-1-carboxylic acid esters Preparation of Compound (III))

The synthesis described in example 1 was modified in view of the results of example 2 and the modified procedure performed on a large scale. The modified process provides improved yields and largely avoids the racemization problems previously encountered during cyclization.

Benzyl (2S) -2- [ (3-chloropyrazin-2-yl) methylcarbamoyl ] pyrrolidine-1-carboxylate (compound (I), 337.5kg, 1.00mol. eq.) was mixed with acetonitrile (1688L, 5.0 rel vol.) and N, N-dimethylformamide (39.5kg, 0.6mol. eq.) and phosphorus oxychloride (276.1kg, 2.0mol. eq.) was added slowly, maintaining the temperature below 30 ℃. The reaction mixture was heated at 40 ℃ for 3 hours. The mixture was cooled and then slowly transferred to a cooled solution of sodium bicarbonate (605.1kg, 8.0mol. eq.) and water (3375L, 10.0 relative volume). The product was then extracted three times from the mixture with methyl tertiary-butyl ether (1013L, 3.0 relative volume). The combined organic extracts were then washed with a solution of sodium bicarbonate (151.3kg, 2.0mol. eq.) in water (2025L, 6.0 relative volume), then with a 25% w/w aqueous saline solution (675kg, 2.0 relative weight), and then recycled through a bag filter containing magnesium sulfate. The solvent was removed by vacuum distillation (jacket temperature 30 ℃) to give a dark red oil. N, N-dimethylformamide (1350L, 4.0 relative volume) was added to dissolve the oil, followed by incremental addition of N-bromosuccinimide (160.3kg, 1.0mol. eq.) with stirring at 20 ℃ after each loading. After deemed complete, the reaction was maintained at a temperature below 10 ℃, the mixture was cooled to 5 ℃ and a 2% w/w aqueous sodium bicarbonate (2531L, 7.5 relative volume) solution was slowly added to precipitate the product. The mixture was filtered and washed with a pre-mixed solution of water (675L, 2.0 relative volume) and N, N-dimethylformamide (338L, 1.0 relative volume) and then twice with water (675L, 2.0 relative volume). The resulting solid was returned to the reactor and reslurried in water to liquefy (1688L, 5.0 relative volume). The product was isolated and washed twice with water (675L, 2.0 relative volume) and dried under vacuum at 45 ℃ to obtain solid benzyl (2S) -2- (1-bromo-8-chloro-imidazo [1,5-a ] pyrazin-3-yl) pyrrolidine-1-carboxylate (compound (III), 353.6kg, 90.1%). Enantiomeric excess > 99.8%.

The compound exists as a mixture of conformers in solution and resonances are cited only for the major conformers. 1H NMR (500MHz, DMSO-d6) δ 1.86-1.94(m,1H),2.02-2.09(m,1H),2.10-2.18(m,1H),2.27-2.34(m,1H),3.49-3.54(m,1H),3.55-3.61(m,1H),4.59(d, J ═ 12.3Hz,1H),4.99(d, J ═ 12.3Hz,1H),5.41(dd, J ═ 7.7,4.6Hz,1H),6.67-6.71(m,2H),7.08-7.13(m,2H),7.16-7.22(m,2H),8.28(d, J ═ 5.0Hz, 1H). 13C NMR (126MHz, DMSO-d6) delta 23.5,32.3,46.9,51.5,65.9,109.6,115.4,119.3,126.7,127.1,127.7,128.0,136.0,142.8,143.0,153.3.

Example 4: benzyl (2S) -2- (8-amino-1-bromoimidazo [1, 5-a)]Process for preparation of pyrazin-3-yl) -1-pyrrolidinecarboxylic acid esters Preparation of sulfate salt (sulfate salt of Compound (IV))

Benzyl (2S) -2- (1-bromo-8-chloro-imidazo [1,5-a ] pyrazin-3-yl) pyrrolidine-1-carboxylate (compound (III), 90.0kg, 1.00mol. equivalents) was mixed with isopropanol (351kg, 3.0 relative weight) and N-methylpyrrolidinone (180kg, 2.0 relative weight) in a sealed autoclave. Ammonia (451kg, 5.0 relative weight) was pumped into the mixture, which was then heated to 90 to 95 ℃ until the reaction was complete. The reaction mixture was cooled to 50 to 60 ℃ and added to water (900kg, 10.0 relative volume). Cooled to 20 ℃ to 30 ℃ and extracted with dichloromethane (957kg, 10.6 relative weight) and then extracted with dichloromethane (360kg, 4.0 relative weight). The organic phases were combined and washed with water and then concentrated to about 2.5 relative volumes. Maintaining the temperature below 25 ℃, ethanol (574kg, 6.4 relative weight) was added to the mixture and then concentrated sulfuric acid (30.4kg, 1.5mol. eq.) was slowly added. The resulting slurry was cooled to 0 to 5 ℃ and then filtered and dried under vacuum at 40 ℃ to obtain an off-white crystalline solid which was the sulfate salt of benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidinecarboxylate (compound (IV), 89.2kg, 83.5%, based on the monosulfate hypothesis).

Example 5: benzyl (2S) -2- (8-amino-1-bromoimidazo [1, 5-a)]Pyrazin-3-yl) -1-pyrrolidinecarboxylic acid esters Preparation of sulfate salt (2:3) of (Compound (IV))

The synthesis described in example 4 assumes a 1:1 ratio of free base to salt of the final product, but the assay and mass balance are not consistent. Thus, the synthesis is further modified as described below to obtain a final product with a defined stoichiometry that may meet the regulatory requirements for characterizing intermediates used in the preparation of the registered drug substance. The presence of inorganic ammonium sulfate in the product of example 4 makes it difficult to accurately determine the stoichiometry of the sulfate. The following modified process removes residual ammonia prior to sulfate formation and substantially eliminates this problem.

Benzyl (2S) -2- (1-bromo-8-chloro-imidazo [1,5-a ] pyrazin-3-yl) pyrrolidine-1-carboxylate (compound (III), 336.5kg, 1.00mol. eq.) was mixed with 2-butanol (1683L, 5.0 relative volume) and 30% w/w ammonium hydroxide (841kg, 2.5 relative weight) in a sealed autoclave and heated to 90 ℃ to 95 ℃ for 32 hours. The reaction mixture was cooled to 20 ℃ and the lower aqueous phase was removed. The organic phase was washed twice with 50:50 aqueous salt solution (337L, 1.0 relative volume) and then distilled under vacuum at about 40 ℃ to about one third of its volume. 2-butanol (1346L, 4.0 relative volume) and water (841L, 2.5 relative volume) were added to dissolve the oil and the lower aqueous phase was removed and discarded. The organic phase was filtered to remove interfacial material and then 93% sulfuric acid (122.2kg, 1.5mol. eq.) was slowly added maintaining the temperature below 25 ℃. The resulting slurry was cooled to 0 ℃ to 5 ℃ and then filtered, washed with 10% v/v aqueous 2-butanol (673L, 2.0 relative volume) and then dried under vacuum at 40 ℃ to obtain an off-white crystalline solid which was benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidine-carboxylate (compound (IV), 324.4kg, 87.2%, calculated as the sulfate salt of sulfate (2: 3).

The compound exists as a mixture of conformers in solution and resonances are cited only for the major conformers. 1H NMR (500MHz, DMSO-d6 with 10% TFA) δ 1.84-1.94(m,1H),1.98-2.05(m,1H),2.07-2.17(m,2H),2.25-2.34(m,1H),3.47-3.60(m,2H),4.57(d, J ═ 12.1Hz,1H),5.02(d, J ═ 12.1Hz,1H),5.30(dd, J ═ 7.6,5.3Hz,1H),6.79-6.84(m,3H),7.12-7.22(m,3H),7.73(d, J ═ 6.0Hz,1H),9.48 (brs, 2H). 13C NMR (126MHz, DMSO-d6 with 10% TFA) delta 23.8,32.7,47.2,51.6,66.4,108.8,112.9,116.1,117.1,127.9,128.2,128.3,136.4,147.3,148.7,153.5. X-ray powder diffraction of the solid gives a diffraction pattern in accordance with figure 1.

Example 6: benzyl (2S) -2- (8-amino-1-bromoimidazo [1, 5-a)]Process for preparation of pyrazin-3-yl) -1-pyrrolidinecarboxylic acid esters Analysis of sulfate salt (sulfate salt of Compound (IV))

A.Confirmation of salt stoichiometry

Purified benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidinecarboxylate (compound (IV) free base, 500mg) was combined with ethanol (8ml) in four vials with magnetic stir bars and concentrated sulfuric acid (0.25, 0.50, 0.75 and 1.0mol. equivalents) was added. Held for one hour and then cooled to 0 ℃ for one hour, then filtered and dried under vacuum. The results are presented in table 4 below and demonstrate that the stoichiometry is not consistent with the previously assumed 1:1 salt ratio, but is consistent with the 2:3 ratio.

TABLE 4

B.Single crystal X-ray diffraction analysis

Benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] S grown by slow evaporation from dimethyl sulfoxide]A single crystal of a sulfate salt of pyrazin-3-yl) -1-pyrrolidinecarboxylic acid ester (compound (IV)). Suitable crystals for single X-ray diffraction were identified and analyzed by single crystal diffraction. Details of crystal data: 3 (C)₁₈H₁₉BrN₅O₂).SO₄.HSO₄.H₂O.,M_r1463.02, trigonal system, R3(No.146), α＝90°,β＝90°,γ＝120°,t100 (2) K, Z3, Z' 0.33333, μ (CuK α) 3.748, 30561 reflections were measured, and a unique 3873 reflections (R) was used in all calculations_int0.0306). Final wR₂Is 0.0791 (all data) and R₁Is 0.0292 (I)>2 (I)). The Flack parameter is-0.023 (5).

The stoichiometry was confirmed to be three molecules of benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidinecarboxylate and one molecule of sulfate and one molecule of bisulfate. Although analysis of the crystal structure also identified one molecule of water per three molecules of benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidinecarboxylate, further diffraction studies and thermal analysis indicate that this can be variable without a substantial effect on the overall structure or salt stoichiometry.

C.X-ray powder diffraction analysis

By reacting benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ]]Pyrazin-3-yl) -1-pyrrolidinecarboxylic acid ester (Compound (IV)) sulfate powder was fixed to a silicon wafer holder and samples were analyzed using a Bruker D4 Endevivor diffractometerTo collect X-ray powder diffraction data. The samples were measured in reflection geometry in a theta-2 theta scan pattern configuration over a 2 deg. to 40 deg. 2 theta scan range with 0.12 second exposure per 0.02 deg. increment. X-rays were generated by a copper long thin focusing tube operating at 40kV and 40 mA. The resulting X-ray diffraction pattern is shown in fig. 1, with selected peaks and relative intensities reported in table 5 below.

TABLE 5

Peak(s)	Relative strength	Peak(s)	Relative strength
				7.7	23	23.5	99
10.6	49	23.9	41
				11.1	8	24.6	93
12.6	100	25.2	36
				13.0	2	26.0	38
13.5	59	27.0	37
				16.8	3	27.6	35
17.4	51	28.3	49
				18.0	42	28.6	34
18.9	30	29.3	20
				19.2	43	30.2	13
21.1	18	31.3	19
				21.9	81	32.1	28
23.0	28

The characteristic peaks of the crystalline form include peaks at 7.7, 10.6, 11.1, 12.6, 13.5, 17.4, 18.0, 18.9, 19.2 and 21.9 ± 0.2 ° 2 θ, particularly peaks at 7.7, 10.6, 11.1, 12.6 and 13.5 ± 0.2 ° 2 θ.

Example 7: 1-bromo-3- [ (2S) -2-pyrrolidinyl)]Imidazo [1,5-a ]]Preparation of pyrazin-8-amine (Compound (VI)) Prepare for

Benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidinecarboxylate (compound (IV), 261kg, 1.0mol. eq) of sulfate (2:3) and concentrated aqueous hydrochloric acid (996L, 3.8 relative weight) were mixed and heated to 40 ℃ to 50 ℃ for at least two hours under an inert atmosphere. The batch was cooled and washed four times with methyl tertiary-butyl ether (192kg, 4x 0.73 relative weight). An aqueous sodium hydroxide solution was slowly added with cooling to achieve a pH greater than 12. The product was extracted with dichloromethane (3632kg, 13.9 relative weight), clarified with celite, and then decolorized with palladium on charcoal (13kg, 0.05 relative weight). The organic extract was concentrated to about 0.86 relative volume at atmospheric pressure. Methyl tertiary-butyl ether (519L, 1.99 relative weight) was added, the mixture was cooled to 20 ℃, and the resulting slurry was filtered and washed with a mixture of methyl tertiary-butyl ethers, then dried under vacuum at 40 ℃ to obtain solid 1-bromo-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-8-amine (compound (VI), 119kg, 78% yield).

Example 8: 1-bromo-3- [ (2S) -2-pyrrolidinyl)]Imidazo [1,5-a ]]Preparation of pyrazin-8-amine (Compound (VI)) Prepare for

The sulfate salt (2:3) of benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidinecarboxylate (compound (IV), 370kg) and concentrated aqueous hydrochloric acid were mixed and heated to 50 ℃ for at least six hours. The batch was cooled and washed with methyl tert-butyl ether and then with heptane. An aqueous sodium hydroxide solution was slowly added with cooling to achieve a pH greater than 12. The product was extracted with dichloromethane and methanol was added. The solution was clarified with celite and then decolorized with palladium on charcoal. The organic extract was concentrated and exchanged to methyl tertiary butyl ether at atmospheric pressure. The resulting mixture was cooled, the resulting slurry was filtered and washed with a mixture of methyl tertiary-butyl ether, and then dried under vacuum to obtain solid 1-bromo-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-8-amine (compound (VI), 188.8 kg). The product needs further purification to remove aminal impurities by slurrying in ethyl acetate, filtering and washing the filter cake with ethyl acetate.

Example 9: 1-bromo-3- [ (2S) -2-pyrrolidinyl)]Imidazo [1,5-a ]]Preparation of pyrazin-8-amine (Compound (VI)) Prepare for

The syntheses illustrated in examples 7 and 8 sometimes result in increased impurities (e.g., aminal impurities when using dichloromethane as the extraction solvent) and poor operability. Therefore, the process described below was developed to improve the purity of the final product.

Benzyl (2S) -2- (8-amino-1-bromoimidazo [1,5-a ] pyrazin-3-yl) -1-pyrrolidinecarboxylate (compound (IV), 343kg, 1.0mol. eq) sulfate (2:3) and 37% w/w aqueous hydrochloric acid (1142L, 3.33 relative volumes) were mixed and heated to 40 ℃ for 14 hours under an inert atmosphere. The batch was cooled and washed twice with heptane (1715L, 5.0 relative volume). A 30% w/w aqueous sodium hydroxide solution (104.4kg, 1.10mol.eq.) was slowly added with cooling to achieve a pH of greater than 10. The product was extracted twice with 2-methyltetrahydrofuran (2401L, 7.0 relative volume) and the combined extracts were washed with water (343L, 1.0 relative volume) and then concentrated to a volume of 3.5 relative volume at atmospheric pressure. 2-methyltetrahydrofuran (1029L, 3.0 relative volume) was added and the mixture was concentrated at atmospheric pressure to a volume of 1200L, 3.5 relative volume. The mixture was cooled to 70 ℃ and crystalline 1-bromo-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-8-amine (compound (VI), 0.34kg, 0.001 relative weight) was added to seed the mixture. The mixture was cooled to 20 ℃ and heptane (686L, 2.0 relative volume) was added. The resulting slurry was filtered and washed with a mixture of 2-methyltetrahydrofuran (309L, 0.90 relative volume) and heptane (206L, 0.60 relative volume) and then dried under vacuum at 40 ℃ to obtain 1-bromo-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-8-amine (compound (VI), 168kg, 84% yield) as a tan crystalline solid.

1H NMR(500MHz,DMSO-d6)δ1.65-1.75(m,1H),1.77-1.86(m,1H),1.98-2.06(m,1H),2.09-2.17(m,1H),2.75-3.06(m,3H),4.44(dd,J＝7.6,6.7Hz,1H),6.61(br s,2H),6.96(d,J＝5.0Hz,1H),7.70(d,J＝5.0Hz,1H)。13C NMR(126MHz,DMSO-d6)δ25.7,29.4,46.5,54.0,105.1,107.5,115.3,128.1,142.8,150.8。

Example 10: [4- (2-Pyridylcarbamoyl) phenyl]Preparation of boric acid (Compound (V))

4-Carboxyphenylboronic acid (116.0kg, 1.0mol. eq.) was mixed with toluene (696kg, 6.0 rel vol.) and N, N-dimethylformamide (2.0kg, 0.04mol. eq.) at 50 ℃. Thionyl chloride (249.5kg, 3.0mol. eq.) was slowly loaded into the slurry. The reaction was heated to 60 ℃ and stirred for 8 hours, then cooled. The mixture was then concentrated under vacuum to remove 348L (3.0 relative volume) of solvent, and then toluene (348L, 3.0 relative volume) was added. This was repeated three more times to remove excess thionyl chloride. The mixture was then concentrated under vacuum to remove 348L (3.0 relative volume) of solvent, and then pyridine (348L, 3.0 relative volume) was added. This was repeated once to remove toluene. Pyridine (580L, 5.0 relative volume) was added to the slurry and the mixture was cooled to-5 ℃. While maintaining the temperature below 20 ℃, a solution of 2-aminopyridine (131.6kg, 2.0mol. eq.) in pyridine (232.0L, 2.0 relative volume) was added as quickly as possible. The reaction was slowly heated to 65 ℃ to 70 ℃ and stirred for 8 hours. The mixture was then concentrated under vacuum to remove 812L (7.0 relative volume) of solvent. The reaction mixture was adjusted to a temperature of 65 ℃ to 70 ℃, water (116L, 1.0 relative volume) was added, and the mixture was stirred at a temperature of 65 ℃ to 70 ℃ for 12 hours. Toluene (232L, 2.0 relative volume) and then water (928L, 8.0 relative volume) were loaded at a temperature of 65 ℃ to 70 ℃. The mixture was then cooled to 20 ℃ and filtered. The filter cake was washed four times with water (464L, 4.0 relative volume) and dried at 50 ℃ to obtain [4- (2-pyridylcarbamoyl) phenyl ] -boronic acid (compound (V), 141.8kg, 83.8% of theory) as a white crystalline solid.

Example 11: [4- (2-Pyridylcarbamoyl) phenyl]Preparation of boric acid (Compound (V))

The synthesis described in example 10 was further modified, in particular to identify suitable alternative solvents for N, N-dimethylformamide, which would reduce the potential formation of unwanted side products, in particular dimethylcarbamoyl chloride.

4-Carboxyphenylboronic acid (7.0g, 1.0mol. eq.) was combined with toluene (66.5ml,9.5 rel vol.) and tetrabutylammonium chloride (0.59g, 0.05mol. eq.) at 50 ℃. The slurry was slowly loaded with thionyl chloride (13.8g, 2.75mol. eq) followed by a wash of toluene (3.5ml, 0.5 relative volume). The reaction was heated to 70 ℃ and stirred for at least six hours, then cooled. The mixture was then concentrated under vacuum to about 4.0 relative volume and pyridine (56ml, 8.0 relative volume) was then added. The mixture was then concentrated under vacuum to about 4.0 relative volume and then added to a solution of 2-aminopyridine (7.94g, 2.0mol. eq.) in pyridine (35ml, 5.0 relative volume) followed by a pyridine (7ml, 1.0 relative volume) wash. The reaction was slowly heated to 70 ℃ and stirred for at least 18 hours. The mixture was then concentrated under vacuum to about 3.0 relative volume. Water (7ml, 1.0 relative volume) was added and the mixture was stirred at 70 ℃ for at least one hour. Water (56ml, 8.0 relative volume) was loaded at 70 ℃. The mixture was then cooled to 20 ℃ and filtered. The filter cake was washed four times with water (28ml, 4.0 relative volume) and dried at 50 ℃ to obtain [4- (2-pyridylcarbamoyl) phenyl ] -boronic acid (compound (V), 8.79kg, 85% of theory) as a white crystalline solid.

The compound exists as a mixture of conformers in solution and resonances are cited only for the major conformers. 1H NMR (500MHz, DMSO-d6) δ 7.16(ddd, J ═ 7.2,4.9,0.9Hz,1H),7.83(ddd, J ═ 8.3,7.2,1.9Hz,1H),7.87-7.90(m,2H),7.95-7.99(m,2H),8.17-8.20(m,1H),8.24(br s,2H),8.38(ddd, J ═ 4.9,1.9,0.8Hz,1H),10.74(s, 1H). 13C NMR (126MHz, DMSO-d6) delta 114.7,119.8,126.8,134.0,135.3,138.1,138.3,147.9,152.2,166.1.

Example 12: 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl]Imidazo [1,5-a ]]Pyrazin-1-yl } -N- (2-pyridines) Preparation of Yl) benzamide (Compound (VII))

1-bromo-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-8-amine (compound (VI), 49.7kg, 1.00mol. equivalents) and [4- (2-pyridylcarbamoyl) phenyl ] boronic acid (compound (V), 44.7kg, 1.05mol. equivalents) were mixed with bis (tert-butyldicyclohexylphosphine) dichloropalladium (II)) (0.61kg, 0.005mol. equivalents), potassium iodide (9.0kg, 0.30 rel vol) and triethylamine (54kg, 3.0mol. equivalents) in water (422L, 8.45 rel vol) and 2-butanol (184L, 4.55 rel vol). The reaction mixture was then heated to 82 ℃ under nitrogen for at least 24 hours. The reaction mixture was slowly cooled to about 23 ℃ and then thermally cycled by warming to about 42 ℃, cooling to about 23 ℃ and warming to about 42 ℃.

Water (727L, 15 relative volumes) was then slowly added and the mixture was cooled to about 20 ℃, then filtered and washed with water. The filtration and washing cycle is very slow. During the treatment, two filters and multiple discharges are required, which typically takes 3 to 4 days to complete. X-ray powder diffraction of the material isolated in this filtration step gave a diffraction pattern consistent with that of figure 2 (i.e., type 2). The water wet product was further dried by refluxing in heptane (964L) for 29 hours under Dean Stark conditions, and then filtered and dried under vacuum at 45 ℃ to obtain 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] -imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridinyl) benzamide (compound (VII), 61.6kg, 81.5%) as a yellow crystalline solid.

Example 13: 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl]Imidazo [1,5-a ]]Pyrazin-1-yl } -N- (2-pyridines) Preparation of Yl) benzamide (Compound (VII))

The synthesis described in example 12 was further modified, in particular to improve the filtration of the crude product and to reduce the cycle time of the synthesis.

1-bromo-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-8-amine (compound (VI), 26.5kg, 1.00mol. eq.) and [4- (2-pyridylcarbamoyl) phenyl ] boronic acid (compound (V), 25kg, 1.10mol. eq.) were mixed with bis (tert-butyldicyclohexylphosphine) dichloropalladium (II)) (0.64kg, 0.01mol. eq.), potassium iodide (4.7kg, 0.30 rel. vol.) and triethylamine (28.9kg, 1.50mol. eq.) in water (224L, 8.45 rel. vol.) and 2-butanol (120L, 4.55 rel. vol.). The reaction mixture was then heated to 82 ℃ for 15 hours. The reaction mixture was diluted with 2-butanol (149L, 5.6 relative volume), water (11L, 0.4 relative volume) and 3M aqueous potassium carbonate solution (53L, 2.0 relative volume) at 75 ℃ to 82 ℃ and the aqueous layer was removed and discarded. The organic layer was treated with QuadraSil MP (5.3kg, 0.20 relative weight) for 18 hours at 80 ℃. At 80 ℃, the scavenger was removed by filtration and washed with 2-butanol (27L, 1.0 relative volume). The organic mixture was washed with a solution of water (56L, 2.1 relative volume) and 3M aqueous potassium carbonate (9L, 0.33 relative volume) at a temperature of 75 ℃ to 82 ℃ and then with water (55L, 2.0 relative volume) at a temperature of 75 ℃ to 82 ℃. 2-butanol was added to adjust the volume of the solution to 16 relative volumes and the mixture was distilled at atmospheric pressure while maintaining a constant volume of about 16 relative volumes in the vessel by further addition of 2-butanol until the mixture reached a temperature above 97 ℃. The mixture was seeded with 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide (compound (VII), 0.13kg, 0.005 relative weight) crystallization and further distilled at atmospheric pressure to reduce the volume to about 10 relative volumes. The mixture was slowly cooled to 20 ℃, then filtered and washed with 2-butanol (106L, 4.0 rel vol), then 2-butanol (53L, 2.0 rel vol) followed by heptane (53L, 2.0 rel vol) and dried under vacuum at 45 ℃ to a yellow crystalline solid 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide (compound (VII), 26.8kg, 75%). The filtration and washing cycle was achieved in less than 24 hours using a single discharge on one filter.

Solid 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide (compound (VII), 40.6kg, 1.0mol. eq) was purified by slurrying in 1M aqueous potassium carbonate solution (162.4L, 4.0 relative volume) to remove the impurity 4- [ 8-amino-3- [ (2S) -pyrrolidin-2-yl ] imidazo [1,5-a ] pyrazin-1-yl ] benzoic acid (compound (XII)), followed by filtration and washing with water (81.2L, 2.0 relative volume) and then heptane (81.2L, 2.0 relative volume) to obtain yellow crystalline 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1 [ -1 ] in yellow 5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide (Compound (VII), 39.7kg, 98%). In addition to 4- [ 8-amino-3- [ (2S) -pyrrolidin-2-yl ] imidazo [1,5-a ] pyrazin-1-yl ] benzoic acid (compound (XII)) as an impurity, another impurity, 4- [ 8-amino-3- [ (2S) -1- [4- [ 8-amino-3- [ (2S) -pyrrolidin-2-yl ] imidazo [1,5-a ] pyrazin-1-yl ] benzoyl ] pyrrolidin-2-yl ] imidazo [1,5-a ] pyrazin-1-yl ] -N- (2-pyridyl) benzamide (compound (XIII)) was also observed and not removed by this repetition.

Example 14: 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl]Imidazo [1,5-a ]]Pyrazin-1-yl } -N- (2-pyridines) Preparation of Yl) benzamide (Compound (VII))

Although the process described in example 13 resulted in improved filtration and cycle times, two undesirable impurities were formed due to prolonged heating under the process conditions. Thus, the process has been further modified, inter alia, to reduce the formation of these impurities and to improve the purity of the final product.

1-bromo-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-8-amine (compound (VI), 115.0kg, 1.00mol. eq.) and [4- (2-pyridylcarbamoyl) phenyl ] boronic acid (compound (V), 96.7kg, 0.98mol. eq.) were mixed with bis (tert-butyldicyclohexylphosphine) dichloropalladium (II)) (2.8kg, 0.01mol. eq.), potassium iodide (20.3kg, 0.30mol. eq.) and potassium carbonate (135.2kg, 2.40mol. eq.) in water (920L, 8.0 relative volume) and 2-butanol (978L, 8.5 relative volume). The reaction mixture was then heated to 80 ℃ for 16 hours. The layers were separated and the aqueous layer was discarded. The organic layer was diluted with 2-butanol (460L, 4.0 relative volume), washed with water (575L, 5.0 relative volume) at 60 ℃, then water (460L, 4.0 relative volume), and then treated with QuadraSil MP (23kg, 0.20 relative weight) at 60 ℃ for 9 hours. At 60 ℃, the scavenger was removed by filtration and washed with 2-butanol (173L, 1.5 relative volume). The resulting mixture was washed with a solution of sodium chloride (46kg, 0.40 relative weight) in water (230L, 2.0 relative volume) at 60 ℃. The mixture was seeded with crystalline 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) -benzamide (compound (VII), 1.15kg, 0.01 relative weight) and then distilled under vacuum (0.2 bar) while maintaining a constant volume of 1840L (16 relative volume) in the vessel by the further addition of 2-butanol (1610L, 14.0 relative volume) and maintaining the temperature below 60 ℃. The mixture was then distilled (at 0.2 bar) to a volume of 1380L (12.0 relative volume), maintaining the temperature below 60 ℃. Heat to 80 ℃ for two hours, then cool to 20 ℃ and filter. The product was washed with 2-butanol (460L, 4.0 rel vol), then 2-butanol (230L, 2.0 rel vol), followed by heptane (230L, 2.0 rel vol) and dried under vacuum at 45 ℃ to a yellow crystalline solid 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] -imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) -benzamide (compound VII, 131.7kg, 80.4%). The filtration and washing cycle is achieved in less than 24 hours using a single drain and one filter.

1H NMR (500MHz, DMSO-d6) δ 1.71-1.80(m,1H),1.83-1.92(m,1H),2.06-2.14(m,1H),2.22-2.30(m,1H),2.89(t, J ═ 6.8Hz,2H),4.55(t, J ═ 7.2Hz,1H),6.11(br, 2H),7.07(d, J ═ 5.0Hz,1H),7.17(ddd, J ═ 7.4,4.9,0.9Hz,1H),7.72-7.75(m,2H),7.77(d, J ═ 5.0Hz,1H),7.85(ddd, J ═ 8.4,7.4,2.0, 1H), 8.8.13-8.13 (m, 8.7, 8.4, 8.7.2H), 8.7.8, 8.8, 8.7, 8, 8.7.8, 8, 8.7H, 1H, 8, 8.9H, 1H, 8, 1H. 13C NMR (126MHz, DMSO-d6) delta 25.8,29.5,46.6,54.2,107.4,114.6,114.7,119.8,127.5,128.3,129.0,132.3,132.6,138.1,138.1,142.8,148.0,151.5,152.2,165.7. X-ray powder diffraction of the obtained crystalline solid gave a diffraction pattern consistent with that of fig. 4 (i.e., form C).

Example 15: 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl]Imidazo [1,5-a ]]Pyrazin-1-yl } -N- (2-pyridines) Yl) X-ray powder diffraction analysis of benzamide (Compound (VII))

A.Assay protocol

By X-ray powder diffraction on 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl]Imidazo [1,5-a ]]Crystal samples of form 2, form 3 and form C of pyrazin-1-yl } -N- (2-pyridyl) benzamide (compound (VII)) were analyzed. The samples were mounted on a silicon wafer holder and measured with a PANalytical CubiX PRO diffractometerAnd (6) analyzing. The samples were measured in reflection geometry in a theta-theta configuration over a 2 deg. to 40 deg. 2 theta scan range with a nominal 25 second exposure per 0.02 deg. increment. X-rays were generated by a copper long thin focusing tube operating at 45kV and 40 mA. The results for crystalline forms 2, 3 and C are reported below in sections A, B and C, respectively.

B.Analysis of form 2 crystalline form

A sample of crystalline 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide form 2 (compound (VII)) was analyzed by X-ray powder diffraction. The resulting X-ray diffraction pattern is shown in fig. 2, where selected peaks and relative intensities are reported in table 6 below.

TABLE 6

Peak(s)	Relative strength	Peak(s)	Relative strength
				5.0	32	15.6	21
5.7	32	16.2	18
				7.2	100	17.2	6
9.0	19	18.1	21
				9.9	80	18.3	13
10.3	16	18.6	9
				10.6	13	19.1	15
11.2	83	19.5	21
				12.7	15	19.8	28
13.4	8	20.2	30
				14.1	13	20.7	20
14.9	75

The form 2 crystalline form exhibits characteristic peaks at 5.0, 5.7, 7.2, 9.0, 9.9, 11.2, 12.7, 14.1, and 14.9 ± 0.2 ° 2 Θ, particularly peaks at 5.0, 5.7, 7.2, 9.9, and/or 11.2 ± 0.2 ° 2 Θ. As previously described, the product isolated from the first filtration of example 12 corresponds to form 2 crystalline form.

C.Analysis of form 3 crystalline form

A sample of crystalline 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridinyl) benzamide form 3 (compound (VII)) was analyzed by X-ray powder diffraction and was produced by slurrying form 2 in pure butanol at ambient conditions for 7 days. The resulting X-ray diffraction pattern is shown in fig. 3, where selected peaks and relative intensities are reported in table 7 below.

TABLE 7

Peak(s)	Relative strength	Peak(s)	Relative strength
				4.8	21	15.8	10
5.8	8	16.9	11
				7.4	51	17.6	5
7.7	27	18.9	25
				9.6	15	19.7	16
9.9	7	21.6	38
				11.1	11	22.0	19
11.7	43	22.3	43
				12.5	100	22.8	15
12.8	26	23.8	11
				14.1	22	25.7	7
14.7	8	28.8	6
				15.3	30

The form 3 crystalline form exhibits characteristic peaks at 4.8, 7.4, 7.7, 9.6, 11.7, 12.5, 12.8, 15.3, 22.3, and/or 21.6 ± 0.2 ° 2 Θ, particularly peaks at 7.4, 11.7, 12.5, 22.3, and/or 21.6 ± 0.2 ° 2 Θ.

D.Analysis of crystalline form C

A sample of crystalline 4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) benzamide form C (compound (VII)) was analyzed by X-ray powder diffraction. The resulting X-ray diffraction pattern is shown in fig. 4, where selected peaks and relative intensities are reported in table 8 below.

TABLE 8

Form C crystalline forms exhibit characteristic peaks at 7.4, 8.9, 9.9, 11.1, 12.8, 14.1, 14.8, 19.0, and/or 21.6 ± 0.2 ° 2 Θ, particularly peaks at 9.9, 11.1, 12.8, 14.1, and 19.0 ± 0.2 ° 2 Θ. As previously described, the product isolated from the filtration of example 14 corresponds to form C crystalline form.

Example 16: 4- { 8-amino-3- [ (2S) -1- (but-2-ynoyl) pyrrolidin-2-yl]Imidazo [1,5-a ]]Pyridine (II) Preparation of oxazin-1-yl } -N- (pyridin-2-yl) benzamide (Compound (VIII))

4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) -benzamide (compound (VII), 70kg, 1.0mol. eq.) and 2-butyric acid (17.5kg, 1.2mol. eq.) were mixed in dichloromethane (1537kg,22 rel vol.) to give a thick slurry. Triethylamine (44.5kg, 2.5mol. eq) was added followed by 1-propylphosphoric anhydride (T3P) (about 111.4kg, 1.0mol. eq) (additional aliquots of T3P were added in portions until the reaction was deemed complete). The organic solution of the resulting product was washed twice with water (525kg, 7.5 relative volumes) and then concentrated to about 2 to 3 relative volumes. Water (700kg, 10.0 relative volume) was added and the mixture was then acidified with 6M aqueous hydrochloric acid to reach about pH 2, then the organic phase was separated and discarded. The aqueous layer (containing product) was washed three times with 2-methyltetrahydrofuran (478kg, 8.0 rel vol) and then two more washes with 2-methyltetrahydrofuran (180kg, 3.0 rel vol). Dichloromethane (742kg, 8.0 relative volumes) was added to the aqueous phase and the mixture was adjusted to pH 7.0 to 8.5 with triethylamine (variable) to extract the product into the organic phase. The organic phase was separated and washed twice with water (350kg, 5.0 relative volumes), then filtered through carbon, and then treated repeatedly with Quadrasil-MP (17.5kg, 0.25 relative weight), washing the spent scavenger cake with methanol each time until the palladium specification was met. The filtrate was concentrated to 5 relative volumes. Ethanol (276kg, 5 relative volumes) was added and concentrated to 5 relative volumes and this operation was repeated two further times. The mixture was then heated to 50 ℃, cooled to 20 ℃, and filtered. The product was washed twice with ethanol (55kg, 1.0 relative volume) and then the wet cake was returned to the vessel and dissolved in methanol (831kg, 15 relative volume) at 60 ℃. The filtrate was concentrated to 5 relative volumes. Ethanol (276kg, 5 relative volumes) was added and concentrated to 5 relative volumes and repeated once. The mixture was then heated to 50 ℃, cooled to 20 ℃, and filtered. The product was washed twice with ethanol (55kg, 1.0 relative volume) and then dried under vacuum at 50 ℃ to obtain acarabtinib (compound VIII, 52.2kg, 64%) as a white crystalline solid.

Example 17: 4- { 8-amino-3- [ (2S) -1- (but-2-ynoyl) pyrrolidin-2-yl]Imidazo [1,5-a ]]Pyridine (II) Preparation of oxazin-1-yl } -N- (pyridin-2-yl) benzamide (Compound (VIII))

The synthesis described in example 17 was further modified, in particular to allow greater flexibility in operating conditions, while still yielding a product with appropriate purity. Among other advantages, the modified synthesis results in improved removal of certain impurities.

4- { 8-amino-3- [ (2S) -2-pyrrolidinyl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (2-pyridyl) -benzamide (compound (VII), 131.7kg, 1.0mol. eq.) was slurried in dichloromethane (955L, 7.25 rel vol.) and triethylamine (90.1kg, 2.7mol. eq.). 2-butyric acid (33.3kg, 1.2mol. eq) in dichloromethane (263.4L, 2.0 relative volume) was added followed by 1-propylphosphoric anhydride (T3P) (50% w/w dichloromethane solution, 209.8kg, 1.0mol. eq). The resulting organic solution of the product was washed twice with water (658.5L, 5.0 relative volume) and then water (1317L, 10.0 relative volume) was added. The mixture was then acidified with 6M aqueous hydrochloric acid to about pH 2.2 and then 2M aqueous hydrochloric acid was added to reach pH 1.8 to 2.2, then the organic phase was separated and discarded. Dichloromethane (1317L, 10.0 relative volume) was added to the aqueous phase and the mixture was adjusted to pH 4.5 to 5.0 with triethylamine. The organic phase was separated and the aqueous phase re-extracted with dichloromethane (527L, 4.0 relative volume). The combined dichloromethane extracts were screened and the organic phase was concentrated to about 5.0 relative volume. Ethanol (1712L, 13.0 rel vol) was added and the mixture was distilled (about 360mbar), maintaining a constant volume (18.0 rel vol) by adding ethanol (1580L, 12.0 rel vol). A portion of crystalline 4- { 8-amino-3- [ (2S) -1- (but-2-ynoyl) pyrrolidin-2-yl ] imidazo [1,5-a ] pyrazin-1-yl } -N- (pyridin-2-yl) benzamide (compound (VIII), 1.32kg, 0.01 relative weight) was added as seed crystals and the solution was held at 50 ℃ for 10 hours to crystallize the product. The mixture was then cooled over 7 hours and filtered. The product was washed twice with ethanol (527L, 4.0 relative volume) and then dried under vacuum at 50 ℃ to obtain acarabtinib (compound VIII, 113.6kg, 74%) as a white crystalline solid.

The compound exists as a mixture of conformers in solution and resonances are cited only for the major conformers. 1H NMR (500MHz, DMSO-d6) δ 1.95-2.02(m,4H),2.09-2.15(m,1H),2.23-2.38(m,2H),3.81(t, J ═ 6.7Hz,2H),5.47(dd, J ═ 7.6,4.3Hz,1H),6.13(br, 2H),7.11(d, J ═ 5.1Hz,1H),7.17(ddd, J ═ 7.4,4.8,0.8Hz,1H),7.70-7.73(m,2H),7.78(d, J ═ 5.1Hz,1H),7.82-7.87(m,1H),8.13-8.16(m,2H),8.20-8.23(m,1H), 8.8 (m, 8, 8.83, 8.8, 8 (H), 8(m, 8, 8.1H, 1H, 8, 8.83 (ddd, 1H), 1H, 8, 8.83 (d, 10H). 13C NMR (126MHz, DMSO-d6) delta 3.3,23.9,31.2,48.2,51.3,74.3,88.3,107.0,113.8,114.7,119.8,127.9,128.3,129.0,132.7,133.2,137.9,138.1,141.0,148.0,151.4,151.8,152.2,165.7.

Example 18: benzyl (2S) -2- [ (3-chloropyrazin-2-yl) methyl-carbamoyl]Pyrrolidine-1-carboxylate (formula) Preparation of Compound (I))

A.Compound (I)(7) Preparation of

To a solution of (2S) -1-benzyloxycarbonylpyrrolidine-2-carboxylic acid (1.039kg, 1.0mol.eq.) and toluene (6.3L, 6.0 rel vol.) was added thionyl chloride (0.75kg, 1.5mol.eq.) and the mixture was stirred at 30 ℃ for 7 hours. The reaction mixture was concentrated (to about 4.5 relative volumes) at 35 ℃ to 45 ℃ under vacuum. Toluene (2.1L, 2.0 relative volume) was added under vacuum at 35 ℃ to 45 ℃ and the reaction mixture was concentrated (to about 4.5 relative volume). Assay of a solution of the test product (compound (7)) (5.6kg @ 18.3% w/w ═ 1.03kg, 91.8% yield).

B.Benzyl (2S) -2- [ (3-chloropyrazin-2-yl) methylcarbamoyl]-pyrrolidine-1-carboxylic acid ester (compound) (I) Preparation of

Step 1:diphenylazomethine (compound (1), 1.44kg, 1.0mol. eq.) and glycine methyl ester hydrochloride (compound (2), 1.099kg, 1.1mol. eq.) were mixed in acetonitrile (7.2L, 5.0 relative volume) at 35 ℃ to 40 ℃ for 3 hours. Cooled to 20 ℃ to 25 ℃ and filtered, and the cake was washed twice with acetonitrile (2.88L, 2.0 relative volume). Assay of a solution of the product (compound (3)) (10.05kg @ 18.9% w/w ═ 1.9kg, 94.4% yield) was measured.

Step 2:2, 3-bipyrazine (compound (4), 0.911kg, 1.0mol. eq) and cesium carbonate (2.39kg, 1.2mol. eq) were added to the filtrate solution (10.05kg @ 18.9% w/w ═ 1.9kg, 1.2mol. eq) and the mixture was heated to 80 ℃ to 85 ℃ for 13 hours. Cooled to 20 ℃ to 25 ℃ for filtration and the cake was washed twice with acetonitrile (1.8L, 2.0 relative volume). Assay of a solution of the product (compound (5)) (14.7kg @ 13.3% w/w ═ 1.96kg, 89.0% yield) was measured.

And step 3:water (3.6kg, 2.0 relative volume) was added to a solution of compound (5) (13.5kg @ 13.3% w/w ═ 1.8kg) in acetonitrile and the mixture was distilled under vacuum to 2.5 relative volume. Water (3.6kg, 2.0 relative volumes) was further added and the mixture was distilled under vacuum to 3.5 relative volumes. Concentrated hydrochloric acid (1.8L, 1.0 relative volume of the amount of compound (5)) was added and heated to 80 ℃ to 85 ℃ for 7 hours. Cooled to 20 ℃ and washed with toluene (5.4L, 3.0 rel) Product) and acetonitrile (3.6L, 2.0 rel vol) and further washed with toluene (5.4L, 3.0 rel vol). The assay of the aqueous phase containing compound (6) (10.25kg @ 5.9% w/w ═ 0.605kg, 85.8% yield) was measured.

And 4, step 4:to a solution of compound (6) (6.1kg @ 5.9% w/w 0.36kg, 1.0mol. eq.) was added a 25% aqueous NaOH solution (to about pH 8-9). Toluene (1.8L, 5.0 relative volume) and a solution of compound (7) (in toluene) (4.4kg @ 18.3% w/w ═ 0.805kg, 1.2mol. eq.) were added at 10 ℃ to 15 ℃ (while the reaction mixture was loaded with 25% aqueous sodium hydroxide to maintain the pH at 8 to 9). Stirring was continued for three hours and extracted with a mixture of toluene (1.8L, 5.0 relative volume) and acetonitrile (1.44L, 4.0 relative volume) and the aqueous phase was then separated and extracted with a mixture of toluene (1.8L, 5.0 relative volume) and acetonitrile (0.72L, 2.0 relative volume). The organic phases were combined and washed with brine (1.8L, 5.0 relative volume) and then water (1.8L, 5.0 relative volume).

The organic phase was concentrated (to about 5.0 relative volume) and the mixture was heated to 60 ℃ under vacuum at 40 ℃ to 45 ℃. Stirring was continued for 15 minutes to obtain a solution, and then the mixture was cooled to 50 ℃. Methyl tertiary butyl ether (1.6L, 4.4 relative volumes) was added dropwise to the mixture until a suspension was observed. The mixture was cooled to 5 ℃ to 10 ℃ for 3 hours and stirred for 12 hours. The wet cake was filtered and dried (at 45 ℃) to isolate the product (compound (I), (920.0g, 96.3%) (72% yield from 2, 3-bipyrazine.) this compound existed as a mixture of conformers in solution and the resonances were quoted only for the major conformers. ¹H NMR(500MHz,DMSO-d₆)δ1.75-1.85(m,2H),1.87-1.93(m,1H),2.12-2.21(m,1H),3.34-3.40(m,1H),3.42-3.48(m,1H),4.29(dd,J＝8.6,3.5Hz,1H),4.43(dd,J＝16.2,5.4Hz,1H),4.49(dd,J＝16.2,5.4Hz,1H),4.98(d,J＝13.0Hz,1H),5.04(d,J＝13.0Hz,1H),7.24-7.31(m,5H),8.39(d,J＝2.4Hz,1H),8.49(t,J＝5.4Hz,1H),8.53(d,J＝2.4Hz,1H)。¹³C NMR(126MHz,DMSO-d₆)δ23.0,31.2,41.4,47.1,59.5,65.7,126.9,127.5,128.1,137.0,142.6,142.7,147.1,151.5,153.8,172.3。

XV.Alternative embodiments

Example 1. a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (VII)

Selectively separating the compound having formula (VIII), or a salt thereof, from the reaction mixture relative to the one or more reaction byproducts.

Embodiment 2. the method of embodiment 1, wherein the contacting step comprises:

adding a compound having formula (VII), or a salt thereof, and the base to the reaction medium;

adding the 2-butyric acid, or salt thereof, to the reaction medium comprising the compound having formula (VII), or salt thereof, and the base; and is

Adding the 1-propylphosphonic anhydride to a solution comprising a compound having formula (VII), or a salt thereof; 2-butyric acid, or a salt thereof; and said base in said reaction medium.

Embodiment 3. the method of embodiment 1 or 2, wherein the method comprises:

Reacting a compound having the structure of formula (VII)

or a salt thereof; and is

Embodiment 4. the method of embodiment 1 or 2, wherein the method comprises:

reacting a compound having the structure of formula (VII)

or a salt thereof;

Adjusting the pH of the aqueous phase; and is

Embodiment 5. the method of embodiment 3 or 4, wherein the selectively isolated compound having formula (VIII), or salt thereof, comprises less than about 1.0% by weight of the compound having formula (VII), or salt thereof.

Embodiment 6. the method of embodiment 3 or 4, wherein the selectively isolated compound of formula (VIII), or salt thereof, comprises less than about 1.0 wt.% of the compound of formula (XIV), or salt thereof.

Embodiment 7. the method of embodiment 3 or 4, wherein the selectively isolated compound of formula (VIII), or salt thereof, comprises less than about 1.0% by weight of the compound of formula (VII), or salt thereof, and less than about 1.0% by weight of the compound of formula (XIV), or salt thereof.

Embodiment 8. the method of any of embodiments 4 to 7, wherein the reaction mixture is washed with water and the washed reaction mixture is separated into an aqueous phase and a waste phase, wherein the compound having formula (VIII) is selectively extracted into the aqueous phase.

Embodiment 9. the method of any one of embodiments 4 to 8, wherein the method further comprises separating the compound having formula (VIII) from the organic phase into which the compound having formula (VIII) has been selectively extracted.

Embodiment 10. the method of any one of embodiments 4 to 9, wherein after completion of the aqueous phase extraction, the aqueous phase comprises greater than about 75 area% of the compound having formula (VIII) as measured by high performance liquid chromatography.

Embodiment 11. the method of any one of embodiments 4 to 9, wherein after completion of the aqueous phase extraction, the aqueous phase comprises less than about 2.0 area% of the compound having formula (XIV), as measured by high performance liquid chromatography.

Embodiment 12. the method of any one of embodiments 4 to 9, wherein after aqueous phase extraction is complete, the aqueous phase comprises greater than about 75 area% of the compound having formula (VIII) and less than about 2.0 area% of the compound having formula (XIV), as measured by high performance liquid chromatography.

Embodiment 13. the method of any one of embodiments 4 to 12, wherein after completion of the organic phase extraction, the organic phase comprises at least about 75 area% of the compound having formula (VIII) as measured by high performance liquid chromatography.

Embodiment 14. the method of any one of embodiments 4 to 12, wherein after completion of the organic phase extraction, the organic phase comprises less than about 2.0 area% of the compound having formula (VII) as measured by high performance liquid chromatography.

Embodiment 15 the method of any one of embodiments 4 to 12, wherein after completion of the organic phase extraction, the organic phase comprises at least about 75 area% of the compound having formula (VIII) and less than about 2.0 area% of the compound having formula (VII), as measured by high performance liquid chromatography.

Embodiment 16 the method of any one of embodiments 4 to 15, wherein the aqueous phase has a pH of less than about 2.5 during the aqueous phase extraction step.

Embodiment 17 the method of any one of embodiments 4 to 15, wherein the aqueous phase has a pH of from about 1.8 to about 2.2 during the aqueous phase extraction step.

Embodiment 18 the method of any one of embodiments 4 to 15, wherein the aqueous phase has a pH greater than about 4.0 during the organic phase extraction step.

Embodiment 19. the method of any of embodiments 4 to 15, wherein the aqueous phase has a pH of from about 4.5 to about 5.0 during the organic phase extraction step.

Embodiment 20 the method of any one of embodiments 4 to 19, wherein the reaction medium comprises at least one solvent selected from the group consisting of: alkyl hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, ethers, esters, nitriles, and polar aprotic solvents.

Embodiment 21. the method of any one of embodiments 4 to 19, wherein the reaction medium comprises at least one solvent selected from the group consisting of: dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-amyl alcohol, acetone, methyl isobutyl ketone, 2-butanol, methyl ethyl ketone, acetonitrile, and ethyl acetate.

Embodiment 22. the method of any one of embodiments 4 to 19, wherein the reaction medium comprises dichloromethane.

Embodiment 23. the method of any one of embodiments 4 to 22, wherein the base comprises at least one compound selected from the group consisting of: triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

Embodiment 24 the method of any one of embodiments 4 to 22, wherein the base comprises triethylamine.

Embodiment 25. the method of any one of embodiments 4 to 24, wherein the organic phase comprises at least one solvent selected from the group consisting of: alkyl hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ketones, ethers, esters, and nitriles.

Embodiment 26. the method of any of embodiments 4 to 24, wherein the organic phase comprises at least one compound selected from the group consisting of: methylene chloride, methyltetrahydrofuran, and 2-methyltetrahydrofuran, t-amyl alcohol, methyl isobutyl ketone, 2-butanol, methyl ethyl ketone, ethyl acetate, isopropyl acetate, N-butyl acetate, butyronitrile, toluene, xylene, heptane, hexane, isohexane, and chloroform.

Embodiment 27 the method of any one of embodiments 4 to 24, wherein the organic phase comprises dichloromethane.

Embodiment 28 the method of any one of embodiments 4 to 27, wherein the compound having formula (VII) is contacted with about 0.5 to about 5.0 molar equivalents of 2-butyric acid relative to the compound having formula (VII).

Embodiment 29. the method of any one of embodiments 4 to 27, wherein the compound having formula (VII) is contacted with about 1.0 to about 1.3 molar equivalents of 2-butyric acid relative to the compound having formula (VII).

Embodiment 30. the method of any one of embodiments 4 to 27, wherein the compound having formula (VII) is contacted with about 1.2 molar equivalents of 2-butyric acid relative to the compound having formula (VII).

Embodiment 31. the method of any one of embodiments 4 to 30, wherein about 0.3 to about 3.0 molar equivalents of 1-propylphosphonic anhydride, relative to the compound having formula (VII), is loaded into the reaction medium.

Embodiment 32. the method of any one of embodiments 4 to 30, wherein about 0.5 to about 2.0 molar equivalents of 1-propylphosphonic anhydride, relative to the compound having formula (VII), is loaded into the reaction medium.

Embodiment 33. the method of any one of embodiments 4 to 30, wherein about 0.7 to about 1.5 molar equivalents of 1-propylphosphonic anhydride, relative to the compound having formula (VII), is loaded into the reaction medium.

Embodiment 34. the method of any one of embodiments 4 to 30, wherein about 1.0 to about 1.2 molar equivalents of 1-propylphosphonic anhydride, relative to the compound having formula (VII), are loaded into the reaction medium.

Embodiment 35. the method of any one of embodiments 4 to 34, wherein about 1.0 to about 10.0 molar equivalents of base, relative to the compound having formula (VII), is loaded into the reaction medium.

Embodiment 36. the method of any one of embodiments 4 to 34, wherein about 2.0 to about 5.0 molar equivalents of base, relative to the compound having formula (VII), is loaded into the reaction medium.

Embodiment 37. the method of any one of embodiments 4 to 34, wherein about 2.4 to about 3.0 molar equivalents of base, relative to the compound having formula (VII), is loaded into the reaction medium.

Embodiment 38. the method of embodiments 4 to 37, wherein during the contacting step, the reaction medium is maintained at a temperature of from about 10 ℃ to about 30 ℃.

Embodiment 39. the method of any one of embodiments 4 to 38, wherein the volume of the reaction medium is about 5 liters to about 20 liters of reaction medium per kilogram of compound having formula (VII) loaded into the reaction medium.

Embodiment 40. the method of any one of embodiments 4 to 39, wherein the contacting step is performed as a batch reaction.

Example 41. the method of example 40, wherein at least about 25 kg of the compound having formula (VII) is loaded into the batch reaction.

Example 42. the method of example 40, wherein at least about 50 kg of the compound having formula (VII) is loaded into the batch reaction.

Embodiment 43. the method of embodiment 40, wherein at least about 75 kg of the compound having formula (VII) is loaded into the batch reaction.

Example 44. the method of example 40, wherein at least about 100 kg of the compound having formula (VII) is loaded into the batch reaction.

Embodiment 45. the method of any one of embodiments 4 to 44, wherein the compound having formula (VIII) is isolated from the organic phase by crystallization.

Embodiment 46. the method of any of embodiments 4 to 44, wherein the organic phase comprises an organic phase solvent, and the method further comprises exchanging the organic phase solvent with an alternative solvent to form a crystalline mixture comprising the compound having formula (VIII).

Embodiment 47. the method of embodiment 46, wherein the method further comprises crystallizing the compound having formula (VIII) from the crystallization mixture.

Embodiment 48. the method of embodiment 47, wherein the crystallization mixture is seeded with a crystalline form of the compound having formula (VIII).

Embodiment 49 the method of embodiment 48, wherein the crystallization mixture is seeded with at least about 0.01 relative weight of the crystalline form.

Embodiment 50 the method of embodiment 49, wherein the crystallization mixture is seeded with at least about 0.03 relative weight of the crystalline form.

Embodiment 51 the method of any one of embodiments 48 to 50, wherein the crystalline form is an anhydrate crystalline form.

Embodiment 52 the method of any of embodiments 46 to 51, wherein the organic phase solvent comprises a polar solvent.

Embodiment 53 the method of any one of embodiments 46 to 51, wherein the organic phase solvent comprises at least one solvent selected from the group consisting of: chlorinated hydrocarbons and ethers.

Embodiment 54 the method of any of embodiments 46 to 51, wherein the organic phase solvent comprises at least one compound selected from the group consisting of: dichloromethane and 2-methyltetrahydrofuran.

Embodiment 55 the method of any one of embodiments 46 to 51, wherein the organic phase solvent comprises dichloromethane.

Embodiment 56 the method of any one of embodiments 46 to 55, wherein the alternative solvent comprises an alcohol.

The embodiment 57. the method of any one of embodiments 46 to 55, wherein the alternative solvent comprises ethanol.

Embodiment 58. the method of any of embodiments 46 to 51, wherein the organic phase solvent comprises a polar solvent and the replacement solvent comprises an alcohol.

Embodiment 59. the method of any of embodiments 46 to 51, wherein the organic phase solvent comprises dichloromethane and the alternative solvent comprises ethanol.

Embodiment 60 the method of any of embodiments 46 to 51, wherein the organic phase solvent has a boiling point lower than the boiling point of the alternative solvent.

Embodiment 61 the method of embodiment 60, wherein the boiling point of the organic phase solvent is at least about 20 ℃ lower than the boiling point of the replacement solvent.

Embodiment 62. the method of any of embodiments 46 to 61, wherein the organic phase solvent is replaced with the replacement solvent by continuous horizontal distillation.

Embodiment 63. the method of embodiment 62, wherein the continuous horizontal distillation during the continuous distillation is conducted under conditions sufficient to maintain the compound having formula (VIII) in solution.

Embodiment 64. the method of embodiment 62 or 63, wherein the continuous horizontal distillation is continuous horizontal vacuum distillation.

Embodiment 65. the method of any one of embodiments 62 to 64, wherein the alternative solvent is loaded during distillation in an amount sufficient to maintain at least about 15 relative volumes of total solvent per kilogram of compound of formula (VIII).

Embodiment 66. the method of any one of embodiments 62 to 64, wherein the alternative solvent is loaded during distillation in an amount sufficient to maintain at least about 18 relative volumes of total solvent per kilogram of compound of formula (VIII).

The embodiment 67. the method of any one of embodiments 62 to 66, wherein the continuous horizontal vacuum distillation is conducted at a temperature of no more than about 60 ℃.

Embodiment 68. the method of any one of embodiments 46 to 67, wherein the crystallization mixture is seeded with a crystalline form of the compound having formula (VIII) and maintained at a temperature greater than about 40 ℃ for at least about five hours after seeding.

Embodiment 69 the method of any one of embodiments 46 to 68, wherein the crystallization mixture is cooled to a temperature of about 20 ℃ over a period of at least five hours prior to isolating the compound having formula (VIII).

Embodiment 70. the method of any one of embodiments 1 to 69, wherein the stoichiometric process yield of the compound having formula (VIII) is at least about 50%.

Embodiment 71. the process of any one of embodiments 1 to 69, wherein the stoichiometric process yield of the compound having formula (VIII) is at least about 60%.

Example 72 a crystalline form of a compound having the structure of formula (VII):

Example 73. a process for preparing a compound having the structure of formula (VII):

Or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (V)

Or a salt thereof, with a compound having the structure of formula (VI):

reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound having formula (VII), or a salt thereof; and is

Isolating a compound having formula (VII), or a salt thereof, from the substantially anhydrous mixture.

Embodiment 74. the method of embodiment 73, wherein the separating step comprises filtering the substantially anhydrous mixture.

Embodiment 75. the method of embodiment 73 or 74, wherein the aqueous reaction medium further comprises an alkali metal halide.

Embodiment 76. the method of embodiment 73 or 74, wherein the aqueous reaction medium further comprises an alkali iodide.

Embodiment 77 the method of embodiment 73 or 74, wherein the aqueous reaction medium further comprises potassium iodide.

Embodiment 78 the method of any one of embodiments 73 to 77, wherein the organic solvent comprises at least one solvent selected from the group consisting of: aromatic hydrocarbons, alcohols, ketones, ethers, esters, and nitriles.

Embodiment 79 the method of any of embodiments 73 to 77, wherein the organic solvent comprises at least one solvent selected from the group consisting of: methanol, ethanol, propanol, butanol, pentanol, dioxane, toluene, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, n-butyl acetate, and ethyl lactate.

Embodiment 80 the method of any one of embodiments 73 to 77, wherein the organic solvent comprises 2-butanol.

The method of any one of embodiments 73 to 80, wherein the base comprises at least one compound selected from the group consisting of: triethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, tripropylamine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, methyldicyclohexylamine, and potassium phosphate.

The embodiment 82. the method of any one of embodiments 73 to 80, wherein the base comprises triethylamine.

Embodiment 83 the method of any one of embodiments 73 to 80, wherein the base comprises potassium carbonate.

Embodiment 84. the method of any one of embodiments 73 to 80, wherein the base comprises triethylamine and potassium carbonate.

Embodiment 85. the method of any of embodiments 73 to 84, wherein the palladium catalyst comprises bis (tert-butyldicyclohexylphosphine) dichloropalladium (II).

Embodiment 86. the method of any one of embodiments 73 to 85, wherein the compound having formula (VI) is contacted with about 0.5 to about 1.5 molar equivalents of the compound having formula (V) relative to the compound having formula (VI).

Embodiment 87 the method of any one of embodiments 73 to 85, wherein the compound having formula (VI) is contacted with about 0.8 to about 1.2 molar equivalents of the compound having formula (V) relative to the compound having formula (VI).

Embodiment 88 the method of any one of embodiments 73 to 85, wherein the compound having formula (VI) is contacted with about 0.9 to about 1.1 molar equivalents of the compound having formula (V) relative to the compound having formula (VI).

Embodiment 89 the process of any one of embodiments 77 to 88, wherein about 0.1 to about 1.0 molar equivalents of potassium iodide, relative to the compound having formula (VI), is loaded into the aqueous reaction medium.

Embodiment 90 the process of any one of embodiments 77 to 88, wherein about 0.2 to about 0.4 molar equivalents of potassium iodide, relative to the compound having formula (VI), is loaded into the aqueous reaction medium.

Embodiment 91 the method of any one of embodiments 73 to 90, wherein about 0.5 to about 10 molar equivalents of base relative to the compound having formula (VI) is loaded into the aqueous reaction medium.

Embodiment 92 the method of any one of embodiments 73 to 90, wherein the base comprises triethylamine relative to the compound having formula (VI) and about 0.5 to about 10 molar equivalents of triethylamine is loaded into the aqueous reaction medium.

Embodiment 93. the method of any one of embodiments 73 to 90, wherein the base comprises triethylamine relative to the compound having formula (VI) and about 1.0 to about 2.0 molar equivalents of triethylamine is loaded into the aqueous reaction medium.

Embodiment 94. the method of any one of embodiments 73 to 90, wherein the base comprises potassium carbonate relative to the compound having formula (VI) and about 0.5 to about 10.0 molar equivalents of potassium carbonate are loaded into the aqueous reaction medium.

Embodiment 95. the method of any one of embodiments 73 to 90, wherein the base comprises potassium carbonate relative to the compound of formula (VI) and about 2.0 to about 3.0 molar equivalents of potassium carbonate are loaded into the aqueous reaction medium.

Embodiment 96. the method of any one of embodiments 73 to 90, wherein the base comprises potassium carbonate relative to the compound of formula (VI) and about 2.3 to about 2.7 molar equivalents of potassium carbonate are loaded into the aqueous reaction medium.

Embodiment 97 the method of any one of embodiments 73 to 96, wherein about 0.002 to about 0.05 molar equivalents of palladium catalyst relative to the compound having formula (VI) is loaded into the aqueous reaction medium.

Embodiment 98 the method of any one of embodiments 73 to 96, wherein about 0.007 to about 0.013 molar equivalents of palladium catalyst relative to the compound having formula (VI) is loaded into the aqueous reaction medium.

Embodiment 99 the method of any one of embodiments 73 to 98, wherein during the contacting step, the aqueous reaction medium is maintained at a temperature of from about 50 ℃ to about 100 ℃.

Embodiment 100 the method of any one of embodiments 73 to 98, wherein during the contacting step, the aqueous reaction medium is maintained at a temperature of from about 70 ℃ to about 90 ℃.

Embodiment 101 the method of any one of embodiments 73 to 100, wherein the volume of the aqueous reaction medium is about 10 liters to about 20 liters of aqueous reaction medium per kilogram of compound having formula (VI) loaded into aqueous reaction medium.

Embodiment 102 the method of any one of embodiments 73 to 101, wherein the volume ratio of water to organic solvent for the aqueous reaction medium is about 1:3 to about 3: 1.

Embodiment 103 the method of any one of embodiments 73 to 101, wherein the contacting step is performed as a batch reaction.

Embodiment 104. the method of embodiment 103, wherein at least about 25 kg of the compound having formula (VI) is loaded into the batch reaction.

Embodiment 105. the method of embodiment 103, wherein at least about 50 kg of the compound having formula (VI) is loaded into the batch reaction.

Embodiment 106. the method of embodiment 103, wherein at least about 75 kg of the compound having formula (VI) is loaded into the batch reaction.

Embodiment 107. the method of embodiment 103, wherein at least about 100 kg of the compound having formula (VI) is loaded into the batch reaction.

Embodiment 108 the method of any one of embodiments 73 to 107, wherein the reducing step comprises separating the reaction mixture into an aqueous waste phase and an organic phase comprising the compound having formula (VII).

Embodiment 109 the method of embodiment 108, wherein the reducing step further comprises distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase and provide a substantially anhydrous mixture.

Embodiment 110 the method of embodiment 109, wherein the method further comprises washing the organic phase with water prior to distilling.

Embodiment 111 the method of any one of embodiments 109 or 110, wherein the organic phase is treated with a silica scavenger prior to distillation.

Embodiment 112 the method of any one of embodiments 109 to 111, wherein the organic phase is treated with a silica scavenger for a period of at least two hours prior to distillation.

Embodiment 113 the method of embodiment 111 or 112, wherein the silica scavenger comprises a propanethiol functionalized silica.

Embodiment 114. the method of embodiment 111 or 112, wherein the silica scavenger comprises QuadraSil^TM MP。

Embodiment 115 the method of any one of embodiments 111 to 114, wherein the method further comprises removing the silica scavenger from the organic phase prior to distilling.

Embodiment 116 the method of any one of embodiments 111 to 114, wherein the method further comprises removing the silica scavenger from the organic phase by filtration prior to distillation.

Embodiment 117. the method as in embodiment 115 or 116, wherein the method further comprises washing the organic phase with an aqueous brine solution after removing the catalyst and before distillation.

Embodiment 118 the method of any one of embodiments 109 to 117, wherein the reducing step comprises:

separating the reaction mixture into an aqueous waste phase and an organic phase comprising a compound having formula (VII);

washing the organic phase with water;

treating the organic phase with a silica scavenger;

removing the silica scavenger from the organic phase;

washing the organic phase with an aqueous brine solution; and is

Distilling the organic phase under conditions sufficient to reduce the amount of water present in the organic phase.

Embodiment 119 the method of any one of embodiments 109 to 118, wherein the organic phase is distilled by vacuum distillation.

Embodiment 120 the method of any one of embodiments 109 to 118, wherein the organic phase is distilled by continuous horizontal vacuum distillation.

Embodiment 121 the method of any one of embodiments 109 to 120, wherein the organic phase is distilled at a temperature of not more than about 60 ℃.

Embodiment 122 the method of any one of embodiments 109 to 120, wherein the organic phase is distilled at a temperature of from about 50 ℃ to about 60 ℃.

The method of any one of embodiments 109 to 122, wherein the organic phase comprises an alcohol.

Embodiment 124. the method of embodiment 123, wherein the organic phase is supplemented with alcohol during the distilling step.

Embodiment 125 the method of any one of embodiments 109 to 122, wherein the organic phase comprises 2-butanol.

Embodiment 126 the process of embodiment 125, wherein the organic phase is supplemented with 2-butanol during the distillation step.

The embodiment 127. the method of any one of embodiments 73 to 126, wherein the substantially anhydrous mixture comprises less than about 5% by weight water.

Embodiment 128 the method of any one of embodiments 73 to 126, wherein the substantially anhydrous mixture comprises less than about 3% by weight water.

Embodiment 129 the method of any one of embodiments 73 to 128, wherein the isolating step comprises crystallizing the compound having formula (VII) from the substantially anhydrous mixture.

Embodiment 130. the method of embodiment 129, wherein the substantially anhydrous mixture is seeded with a crystalline form of the compound having formula (VII).

Embodiment 131 the method of embodiment 129 or 130, wherein the substantially anhydrous mixture is maintained at a temperature of at least about 70 ℃ for a period of at least two hours after crystallization begins.

Embodiment 132. the method of embodiment 129 or 130, wherein the substantially anhydrous mixture is maintained at a temperature of at least about 70 ℃ for a period of at least two hours after crystallization begins and then cooled to crystallize the compound having formula (VII).

Embodiment 133 the method of any one of embodiments 73 to 132, wherein the stoichiometric process yield of the compound having formula (VII) is at least about 50%.

Embodiment 134 the method of any one of embodiments 73 to 132, wherein the stoichiometric process yield of the compound having formula (VII) is at least about 65%.

The embodiment 135. the method of any one of embodiments 73 to 132, wherein the stoichiometric process yield of the compound having the formula (VII) is at least about 75%.

Example 136. a process for preparing a compound having the structure of formula (VI):

or a salt thereof, wherein the method comprises:

reacting a compound having formula (IV):

removing at least a portion of the benzyl halide by-product from the reaction mixture; and is

Isolating a compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

Embodiment 137 the method of embodiment 136, wherein the separating step comprises:

removing at least a portion of the benzyl halide by-product from the reaction mixture;

increasing the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium comprising a compound having formula (VI), or a salt thereof; and is

Isolating the compound having formula (VI), or a salt thereof, from the basic reaction mixture.

Embodiment 138 the method of embodiment 136, wherein the separating step comprises:

extracting at least a portion of the benzyl halide by-product from the reaction mixture into a waste organic phase;

increasing the pH of the resulting reaction mixture to a basic pH to form a basic reaction medium comprising a compound having formula (VI), or a salt thereof;

extracting the compound having formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase; and is

Separating the compound having formula (VI), or a salt thereof, from the product organic phase.

Embodiment 139 the method of any one of embodiments 136 to 138, wherein the acidic medium is an aqueous acidic medium.

Embodiment 140 the method of any one of embodiments 136 to 139, wherein the sulfate salt of the compound having formula (IV) is contacted with the acidic medium.

Embodiment 141 the method of any one of embodiments 136 to 140, wherein the acidic medium comprises a mineral acid.

Embodiment 142 the method of any one of embodiments 136 to 140, wherein the acidic medium comprises hydrochloric acid.

Embodiment 143 the method of any one of embodiments 136 to 142, wherein the acidic medium comprises at least about 10 molar equivalents of acid relative to the compound having formula (IV), or a salt thereof.

Embodiment 144 the method of any one of embodiments 136 to 142, wherein the acidic medium comprises from about 10 to about 40 molar equivalents of acid relative to the compound having formula (IV), or a salt thereof.

Embodiment 145 the method of any one of embodiments 136 to 142, wherein the acidic medium comprises from about 10 to about 25 molar equivalents of acid relative to the compound having formula (IV), or salt thereof.

Embodiment 146 the method of any one of embodiments 136 to 145, wherein the volume of the acidic medium is about 2 liters to about 10 liters of acidic medium per kilogram of compound having formula (IV), or salt thereof, loaded into the acidic medium.

Embodiment 147. the method of any of embodiments 136 to 145, wherein the volume of the acidic medium is about 3 liters to about 4 liters of acidic medium per kilogram of compound having formula (IV), or salt thereof, loaded into the acidic medium.

Embodiment 148 the method of any of embodiments 136 to 147, wherein during the contacting step, the acidic medium is maintained at a temperature of from about 25 ℃ to about 70 ℃.

Embodiment 149 the method of any one of embodiments 136 to 147, wherein during the contacting step, the acidic medium is maintained at a temperature of from about 40 ℃ to about 50 ℃.

Embodiment 150 the method of any one of embodiments 136 to 149, wherein the contacting step is performed as a batch reaction.

Embodiment 151. the method of embodiment 150, wherein at least about 50 kg of the compound having formula (IV) is loaded into the batch reaction.

Embodiment 152 the method of embodiment 150, wherein at least about 100 kg of the compound having formula (IV) is loaded into the batch reaction.

Embodiment 153 the method of embodiment 150, wherein at least about 200 kg of the compound having formula (IV) is loaded into the batch reaction.

Embodiment 154 the method of embodiment 150, wherein at least about 300 kg of the compound having formula (IV) is loaded into the batch reaction.

Embodiment 155 the method of any one of embodiments 136 to 154, wherein the method comprises selectively extracting at least a portion of the benzyl halide byproduct from the reaction mixture into a waste organic phase prior to the separating step relative to the compound having formula (VI).

Embodiment 156 the process of embodiment 155, wherein at least about 80% by weight of the compounds of benzyl halide by-product present in the reaction mixture are extracted into the waste organic phase.

Embodiment 157 the method of embodiment 155, wherein less than about 20% by weight of the compound having formula (VI) present in the reaction mixture is extracted into the waste organic phase.

Embodiment 158 the process of embodiment 155, wherein at least about 80 weight percent of the compounds of benzyl halide by-products present in the reaction mixture and less than about 20 weight percent of the compounds having formula (VI) present in the reaction mixture are extracted into the waste organic phase.

Embodiment 159. the method of embodiment 155, wherein at least about 90 weight percent of the compounds of benzyl halide by-product present in the reaction mixture and less than about 10 weight percent of the compounds having formula (VI) present in the reaction mixture are extracted into the waste organic phase.

Embodiment 160. the method of embodiment 155, wherein at least about 95 weight percent of the compounds of benzyl halide by-product present in the reaction mixture and less than about 5 weight percent of the compounds having formula (VI) present in the reaction mixture are extracted into the waste organic phase.

Embodiment 161 the method of any one of embodiments 155 to 160, wherein the discarded organic phase comprises at least one solvent selected from the group consisting of: alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers.

Embodiment 162 the method of any of embodiments 155 to 160, wherein the discarded organic phase comprises at least one compound selected from the group consisting of: pentane, hexane, heptane, octane, nonane, toluene, dichloromethane, methyl tert-butyl ether, and 2-methyltetrahydrofuran.

The method of any one of embodiments 155 to 160, wherein the discarded organic phase comprises heptane.

Embodiment 164 the method of any one of embodiments 155 to 163, wherein the method further comprises:

increasing the pH of the reaction mixture after the benzyl halide byproduct extraction to form a basic reaction medium comprising a compound having formula (VI), or a salt thereof; and is

Extracting the compound having formula (VI), or a salt thereof, from the basic reaction medium into a product organic phase.

Embodiment 165 the method of embodiment 164, wherein the pH of the basic reaction mixture is at least about 8.0.

Embodiment 166. the method of embodiment 164, wherein the pH of the basic reaction mixture is at least about 10.0.

Embodiment 167 the method of any one of embodiments 164 to 166, wherein the product organic phase comprises at least one solvent selected from the group consisting of: alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, and ethers.

Embodiment 168 the method of any one of embodiments 164 to 166, wherein the product organic phase comprises at least one compound selected from the group consisting of: dichloromethane, 2-methyltetrahydrofuran and anisole.

The embodiment 169. the method of any one of embodiments 164 to 166, wherein the product organic phase comprises 2-methyltetrahydrofuran.

The embodiment 170. the method of any one of embodiments 164 to 169, wherein the method further comprises washing the product organic phase with water.

The embodiment 171. the method of any one of embodiments 164 to 170, wherein the method further comprises distilling the product organic phase under conditions sufficient to reduce the amount of water present in the product organic phase.

Embodiment 172. the method of embodiment 171, wherein the product organic phase comprises 2-methyltetrahydrofuran and additional 2-methyltetrahydrofuran is loaded into the product organic phase during the distilling step.

Embodiment 173. the method of embodiments 171 or 172, wherein the product organic phase is distilled at atmospheric pressure.

Embodiment 174 the method of any one of embodiments 136 to 173, wherein the isolating step comprises crystallizing the compound having formula (VI).

Embodiment 175 the method of embodiment 174, wherein the isolating step further comprises seeding with a crystalline form of the compound having formula (VI) to promote crystallization.

Embodiment 176 the method of embodiment 174, wherein the isolating step comprises seeding with at least about 0.0005 relative weight of the crystalline form of the compound having formula (VI) to promote crystallization.

Embodiment 177 the method of embodiment 174, wherein the isolating step comprises seeding with at least about 0.001 relative weight of the crystalline form of the compound having formula (VI) to promote crystallization.

Embodiment 178 the method of any one of embodiments 175 to 177, wherein the method further comprises loading an anti-solvent to promote crystallization.

Example 179. the process of example 178, wherein the anti-solvent is heptane.

Embodiment 180 the method of embodiment 136, wherein the separating step comprises:

selectively extracting at least a portion of the benzyl halide by-product from the reaction mixture into a waste organic phase relative to a compound having formula (VI);

increasing the pH of the resulting reaction mixture to a pH greater than about 7.0 to form an alkaline reaction mixture;

(ii) selectively pre-extracting at least a portion of the compound having formula (VI) from the basic reaction mixture into a product organic phase; and is

Embodiment 181. the process of embodiment 180, wherein the process further comprises crystallizing the compound having formula (VI) from the distilled organic phase.

Embodiment 182 the method of any one of embodiments 136 to 181, wherein the aminal impurity comprises a compound having a structure of formula (X):

or a salt thereof.

Embodiment 183 the method of any one of embodiments 136 to 182, wherein the isolated compound of formula (VI), or salt thereof, comprises less than 5% aminal impurity by weight.

Embodiment 184 the process of any one of embodiments 136 to 182, wherein the isolated compound having formula (VI), or salt thereof, comprises less than 3 wt% aminal impurity.

Embodiment 185 the method of any one of embodiments 136 to 182, wherein the isolated compound having formula (VI), or salt thereof, comprises less than 1 weight percent aminal impurity.

The embodiment 186 the method of any one of embodiments 136 to 185, wherein the stoichiometric process yield of the compound having the formula (VI) is at least about 50%.

Embodiment 187 the process of any one of embodiments 136 to 185, wherein the stoichiometric process yield of the compound having formula (VI) is at least about 65%.

Embodiment 188. the method of any one of embodiments 136 to 185, wherein the stoichiometric process yield of the compound having formula (VI) is at least about 80%.

Example 189. a process for preparing a compound having the structure of formula (V):

Embodiment 190 the process of embodiment 189, wherein the process further comprises isolating the compound having formula (V), or a salt thereof, from the reaction mixture.

Embodiment 191 the method of embodiment 189 or 190, wherein the catalyst comprises tetrabutylammonium chloride.

Embodiment 192. the method of embodiment 189 or 190, wherein the catalyst comprises N-methyl toluidine.

Embodiment 193 the method of embodiment 189 or 190, wherein the catalyst does not comprise N, N-dimethylformamide.

The process of any one of embodiments 189 to 193, wherein the reaction medium does not comprise N, N-dimethylformamide.

Embodiment 195 the method of any one of embodiments 189 to 194, wherein the organic solvent comprises at least one solvent selected from the group consisting of: aromatic hydrocarbons, aromatic heterocycles, and nitriles.

Embodiment 196 the method of any one of embodiments 189 to 194, wherein the organic solvent comprises a compound selected from the group consisting of: toluene, acetonitrile, and pyridine.

The method of any one of embodiments 189 to 194, wherein the organic solvent comprises toluene.

Embodiment 198. the method of any one of embodiments 189 to 197, wherein the volume of the reaction medium is from about 3 liters to about 30 liters per kilogram of 4-carboxyphenylboronic acid, or salt thereof, loaded into the reaction medium.

Embodiment 199 the method of any one of embodiments 189 to 197, wherein the volume of the reaction medium is about 5 liters to about 15 liters of reaction medium per kilogram of 4-carboxyphenylboronic acid, or salt thereof, loaded into the reaction medium.

Embodiment 200 the method of any one of embodiments 189 to 199, wherein during the contacting step, the reaction medium is maintained at a temperature of from about 50 ℃ to about 90 ℃.

Embodiment 201 the method of any one of embodiments 189 to 199, wherein during the contacting step, the reaction medium is maintained at a temperature of from about 60 ℃ to about 80 ℃.

Embodiment 202 the method of any one of embodiments 189 to 201, wherein the contacting step is performed as a batch reaction.

Embodiment 203 the method of any one of embodiments 189 to 202, wherein 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2 to about 5 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid, or a salt thereof.

Embodiment 204 the method of any one of embodiments 189 to 202, wherein 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2 to about 3.5 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid, or a salt thereof.

Embodiment 205 the method of any one of embodiments 189 to 202, wherein 4-carboxyphenylboronic acid, or a salt thereof, is contacted with about 2.75 molar equivalents of thionyl chloride relative to 4-carboxyphenylboronic acid, or a salt thereof.

Embodiment 206. the method of any one of embodiments 189 to 205, wherein about 1.5 to about 5 molar equivalents of 2-aminopyridine is loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

Embodiment 207 the method of any one of embodiments 189 to 205, wherein about 1.5 to about 3.5 molar equivalents of 2-aminopyridine is loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

Embodiment 208. the method of any one of embodiments 189 to 205, wherein about 2 molar equivalents of 2-aminopyridine are loaded into the reaction medium relative to 4-carboxyphenylboronic acid, or a salt thereof.

Embodiment 209 the method of any one of embodiments 189 to 208, wherein the stoichiometric process yield of the compound having formula (V) is at least about 50%.

The embodiment 210. the method of any one of embodiments 189 to 208, wherein the stoichiometric process yield of the compound having the formula (V) is at least about 70%.

Example 211. a crystalline sulfate salt of a compound having the structure of formula (IV):

embodiment 212. the crystalline sulfate salt of embodiment 211, wherein the crystalline sulfate salt has a stoichiometric ratio of one sulfate molecule and one hydrogen sulfate molecule to three free base molecules.

Embodiment 213 the crystalline sulfate salt of embodiment 211 or 212, wherein the crystalline sulfate salt is characterized by a reflected X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of: 7.7 + -0.2 deg. 2 theta, 10.6 + -0.2 deg. 2 theta, 11.1 + -0.2 deg. 2 theta, 12.6 + -0.2 deg. 2 theta, and 13.5 + -0.2 deg. 2 theta.

Example 214. a process for preparing a sulfate salt of a compound having the structure of formula (IV):

wherein the method comprises:

reacting a compound having the structure of formula (III)

Or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having formula (IV);

forming a sulfate salt of a compound having formula (IV); and is

Separating the sulfate salt.

Embodiment 215 the method of embodiment 214, wherein the sulfate salt has a stoichiometric ratio of one sulfate molecule and one hydrogen sulfate molecule to three free base molecules.

Embodiment 216. the method of embodiment 214 or 215, wherein the method comprises isolating the compound having formula (IV) as a free base from the reaction mixture prior to the forming step.

Embodiment 217 the method of embodiment 214 or 215, wherein the method comprises:

isolating the compound having formula (IV) as a free base from the reaction medium;

contacting the free base with sulfuric acid to form the sulfate salt; and is

Separating the sulfate salt.

Embodiment 218. the method of embodiment 214 or 215, wherein the method comprises:

washing the reaction mixture to reduce the amount of ammonia present in the reaction mixture;

isolating the compound having formula (IV) as a free base from the washed reaction medium;

contacting the free base with sulfuric acid to form the sulfate salt; and is

Separating the sulfate salt.

Embodiment 219 the method of embodiment 214 or 215, wherein the method comprises:

washing the reaction mixture with a brine solution;

distilling the washed reaction mixture to reduce the amount of ammonia present in the washed reaction mixture;

separating the compound having formula (IV) as a free base from the distilled reaction medium;

Contacting the free base with sulfuric acid to form the sulfate salt; and is

Separating the sulfate salt.

The embodiment 220. the method of any one of embodiments 214 to 219, wherein the method further comprises isolating the sulfate salt by filtration.

Embodiment 221 the method of any one of embodiments 214 to 220, wherein the aminating agent is ammonia.

Embodiment 222 the method of any one of embodiments 214 to 220, wherein the aminating agent is ammonium hydroxide.

Embodiment 223 the method of any one of embodiments 214 to 221, wherein the reaction medium comprises at least one solvent selected from the group consisting of: alkyl hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, aromatic heterocycles, alcohols, ethers, and dipolar aprotic solvents.

Embodiment 224 the method of any one of embodiments 214 to 221, wherein the reaction medium comprises at least one compound selected from the group consisting of: methanol, ethanol, propanol, butanol, pentanol, N-methylpyrrolidone, and N, N-dimethylformamide.

Embodiment 225 the method of any one of embodiments 214 to 221, wherein the reaction medium comprises a fatty alcohol.

Embodiment 226. the method of any one of embodiments 214 to 221, wherein the reaction medium comprises butanol.

Embodiment 227 the method of any one of embodiments 214 to 221, wherein the reaction medium comprises 2-butanol.

Embodiment 228 the method of any one of embodiments 214 to 227, wherein during the contacting step, the reaction medium is maintained at a temperature greater than 70 ℃.

Embodiment 229 the method of any one of embodiments 214 to 227, wherein during the contacting step, the reaction medium is maintained at a temperature greater than 90 ℃.

The method of any one of embodiments 214 to 227, wherein during the contacting step, the reaction medium is maintained at a temperature of from about 50 ℃ to about 100 ℃.

The method of any one of embodiments 214 to 227, wherein during the contacting step, the reaction medium is maintained at a temperature of from about 60 ℃ to about 95 ℃.

Embodiment 232 the method of any one of embodiments 214 to 231, wherein the volume of the reaction medium is about 1.5 liters to about 40 liters of reaction medium per kilogram of compound having formula (III), or salt thereof, loaded into the reaction medium.

Embodiment 233. the method of any one of embodiments 214 to 231, wherein the volume of the reaction medium is about 2.0 liters to about 30 liters of reaction medium per kilogram of compound having formula (III), or salt thereof, loaded into the reaction medium.

Embodiment 234 the method of any one of embodiments 214 to 233, wherein the contacting step is performed as a batch reaction.

Embodiment 235 the method of embodiment 234, wherein at least about 50 kg of the compound having formula (III) is loaded into the batch reaction.

Embodiment 236. the method of embodiment 234, wherein at least about 100 kg of the compound of formula (III) is loaded into the batch reaction.

Embodiment 237. the method of embodiment 234, wherein at least about 200 kg of the compound of formula (III) is loaded into the batch reaction.

Embodiment 238 the method of embodiment 234, wherein at least about 300 kg of the compound having formula (III) is loaded into the batch reaction.

Embodiment 239 the method of any of embodiments 214 to 238, wherein the forming step comprises contacting the compound having formula (IV) with sulfuric acid to form a sulfate mixture comprising the sulfate salt.

Embodiment 240 the process of embodiment 239, wherein the compound having formula (IV) is contacted with at least about 0.5 molar equivalent of sulfuric acid relative to the compound having formula (III).

Embodiment 241 the process of embodiment 239, wherein the compound of formula (IV) is contacted with about 1.25 to about 1.75 molar equivalents of sulfuric acid relative to the compound of formula (III).

Embodiment 242 the method of any one of embodiments 214 to 241, wherein the stoichiometric process yield of sulfate salt having formula (IV) is at least about 50%.

Embodiment 243. the process of any one of embodiments 214 to 241, wherein the stoichiometric process yield of sulfate salt having formula (IV) is at least about 65%.

The embodiment 244. the method of any one of embodiments 214 to 241, wherein the stoichiometric process yield of the sulfate salt having the formula (IV) is at least about 80%.

Example 245 a process for preparing a compound having the structure of formula (II):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II), or a salt thereof;

Embodiment 246. the method of embodiment 245, wherein the cyclizing agent comprises phosphorus oxychloride.

Embodiment 247 the method of embodiment 245 or 246, wherein the catalyst comprises a catalyst selected from the group consisting of: n, N-dimethylformamide and N-methyltoluidine.

Embodiment 248 the method of embodiment 245 or 246, wherein the catalyst comprises N, N-dimethylformamide.

Embodiment 249 the method of any one of embodiments 245 to 248, wherein the reaction medium comprises at least one solvent selected from the group consisting of: aromatic hydrocarbons, chlorinated hydrocarbons, ethers and nitriles.

Embodiment 250 the method of any one of embodiments 245 to 248, wherein the reaction medium comprises at least one compound selected from the group consisting of: acetonitrile, butyronitrile, dichloromethane, toluene, anisole, tetrahydrofuran, and 2-methyltetrahydrofuran.

The embodiment 251 the method of any one of embodiments 245 to 248, wherein the reaction medium comprises acetonitrile.

Embodiment 252 the method of any one of embodiments 245 to 251, wherein the compound having formula (I) or salt thereof is contacted with about 0.7 to about 10 molar equivalents of the cyclizing agent relative to the compound having formula (I) or salt thereof.

Embodiment 253 the method of any one of embodiments 245 to 251, wherein the compound having formula (I) or salt thereof is contacted with about 1.5 to about 2.5 molar equivalents of the cyclizing agent relative to the compound having formula (I) or salt thereof.

Embodiment 254 the method of any one of embodiments 245 to 251, wherein the compound having formula (I) or salt thereof is contacted with about 2.0 molar equivalents of the cyclizing agent relative to the compound having formula (I) or salt thereof.

Embodiment 255 the method of any one of embodiments 245 to 254, wherein at least about 0.1 molar equivalents of the catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium.

Embodiment 256. the method of any one of embodiments 245 to 254, wherein about 0.1 to about 1.0 molar equivalents of the catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium.

Embodiment 257 the method of any one of embodiments 245 to 254, wherein at least about 0.4 molar equivalents of the catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium.

Embodiment 258. the method of any one of embodiments 245 to 254, wherein about 0.4 to about 1.0 molar equivalents of the catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium.

Embodiment 259. the method of any one of embodiments 245 to 254, wherein the catalyst comprises N, N-dimethylformamide and at least about 0.1 molar equivalent of the catalyst is loaded into the reaction medium relative to the compound having formula (I) or salt thereof.

Embodiment 260 the method of any one of embodiments 245 to 254, wherein the catalyst comprises N, N-dimethylformamide and from about 0.1 to about 1.0 molar equivalents of the catalyst relative to the compound having formula (I), or salt thereof, is loaded into the reaction medium.

Embodiment 261. the method of any one of embodiments 245 to 254, wherein the catalyst comprises N, N-dimethylformamide and at least about 0.4 molar equivalents of the catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium.

Embodiment 262 the method of any one of embodiments 245 to 254, wherein the catalyst comprises N, N-dimethylformamide, and about 0.4 to about 1.0 molar equivalents of the catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium.

Embodiment 263 the method of any one of embodiments 245 to 254, wherein the catalyst comprises N, N-dimethylformamide, and at least about 0.6 molar equivalents of the catalyst relative to the compound having formula (I) or salt thereof is loaded into the reaction medium.

Embodiment 264 the method of any one of embodiments 245 to 254, wherein the catalyst comprises N, N-dimethylformamide and about 0.6 molar equivalents of the catalyst is loaded into the reaction medium relative to the compound having formula (I) or salt thereof.

Embodiment 265. the method of any one of embodiments 245 to 264, wherein the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 90% chiral purity of the compound having formula (II), or salt thereof.

Embodiment 266 the method of any one of embodiments 245 to 264, wherein the temperature of the reaction medium is controlled during the contacting step in a manner sufficient to maintain at least about 95% chiral purity of the compound having formula (II), or salt thereof.

Embodiment 267 the method of any one of embodiments 245 to 266, wherein during the contacting step, the reaction medium is maintained at a temperature of less than about 80 ℃.

Embodiment 268 the method of any one of embodiments 245 to 266, wherein during the contacting step, the reaction medium is maintained at a temperature of less than about 50 ℃.

The embodiment 269. the method of any one of embodiments 245 to 266, wherein during the contacting step, the reaction medium is maintained at a temperature of from about 30 ℃ to about 50 ℃.

Embodiment 270 the method of any one of embodiments 245 to 269, wherein during the contacting step, the reaction medium is maintained at a temperature of about 40 ℃.

Embodiment 271. the method of any one of embodiments 245 to 270, wherein the volume of the reaction medium is about 2 liters to about 20 liters of reaction medium per kilogram of compound having formula (I) or salt thereof loaded into the reaction medium.

Embodiment 272. the method of any one of embodiments 245 to 270, wherein the volume of the reaction medium is from about 3 liters to about 10 liters of reaction medium per kilogram of compound having formula (I) or salt thereof loaded into the reaction medium.

Embodiment 273 the method of any one of embodiments 245 to 272, wherein the contacting step is performed as a batch reaction.

Embodiment 274 the method of embodiment 273, wherein at least about 50 kg of the compound of formula (I) is loaded into the batch reaction.

Embodiment 275 the method of embodiment 273, wherein at least about 100 kg of the compound of formula (I) is loaded into the batch reaction.

Embodiment 276. the method of embodiment 273, wherein at least about 200 kg of the compound of formula (I) is loaded into the batch reaction.

Embodiment 277. the method of embodiment 273, wherein at least about 300 kg of the compound of formula (I) is loaded into the batch reaction.

The embodiment 278. the method of any one of embodiments 245 to 277, wherein the stoichiometric process yield of the compound having formula (II) is at least about 50%.

The embodiment 279 the method of any one of embodiments 245 to 277, wherein the stoichiometric process yield of the compound having the formula (II) is at least about 65%.

The embodiment 280. the method of any one of embodiments 245 to 277, wherein the stoichiometric process yield of the compound having the formula (II) is at least about 80%.

Example 281. a method for preparing a compound having the structure of formula (III):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II);

or a salt thereof; and is

Brominating a compound having formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

or a salt thereof;

Embodiment 282 the process of embodiment 281, wherein the brominating agent comprises N-bromosuccinimide.

Embodiment 283 the method of embodiment 281 or 282, wherein the compound having the formula (II) or salt thereof is contacted with about 0.8 to about 1.2 molar equivalents of brominating agent relative to the compound having the formula (II) or salt thereof.

Embodiment 284 the process of any one of embodiments 281 to 283, wherein the compound having formula (II) or salt thereof is isolated from the reaction medium prior to the bromination step.

Embodiment 285 the method of embodiment 284, wherein the compound having formula (II) or salt thereof is contacted with the brominating agent in a bromination medium that comprises at least one solvent selected from the group consisting of: chlorinated hydrocarbons and polar aprotic solvents.

Embodiment 286 the method of embodiment 284, wherein the compound having formula (II) or salt thereof is contacted with the brominating agent in a bromination medium, the bromination medium comprising at least one solvent selected from the group consisting of: n, N-dimethylformamide, N-methylpyrrolidone, N-butylpyrrolidone, dimethyl sulfoxide, dimethylacetamide and dichloromethane.

Embodiment 287 the method of embodiment 284, wherein the compound having formula (II) or salt thereof is contacted with the brominating agent in a bromination medium, the bromination medium comprising N, N-dimethylformamide.

Embodiment 288 the method of embodiment 284, wherein the compound having formula (II) or salt thereof is contacted with the brominating agent in a bromination medium, the bromination medium comprising N-methylpyrrolidone.

Embodiment 289 the method of any one of embodiments 284 to 288, wherein during the bromination step, the bromination medium is maintained at a temperature of from about 5 ℃ to about 40 ℃.

Embodiment 290 the method of any one of embodiments 284 to 288, wherein during the bromination step, the bromination medium is maintained at a temperature of about 20 ℃.

Embodiment 291 the method of any one of embodiments 284 to 290, wherein the bromination step is conducted as a batch reaction.

Embodiment 292. the method of embodiment 291, wherein at least about 50 kg of the compound of formula (II) is loaded into the batch reaction.

Embodiment 293. the method of embodiment 291, wherein at least about 100 kg of the compound of formula (II) is loaded into the batch reaction.

Embodiment 294. the method of embodiment 291, wherein at least about 200 kg of the compound of formula (II) is loaded into the batch reaction.

Example 295. the method of example 291, wherein at least about 300 kg of the compound of formula (II) is loaded into the batch reaction.

Embodiment 296. the method of any one of embodiments 284 to 295, wherein the method comprises isolating the compound having formula (III) or a salt thereof from the bromination medium.

Embodiment 297. the method of embodiment 296, wherein an aqueous solution is added to the bromination medium to isolate the compound having formula (III) or a salt thereof.

Embodiment 298 the method of embodiment 296, wherein an aqueous solution having a basic pH is added to the bromination medium to isolate the compound having formula (III) or a salt thereof.

Embodiment 299 the method of embodiment 296, wherein an aqueous sodium bicarbonate solution is added to the bromination mixture to isolate the compound having formula (III) or a salt thereof.

Embodiment 300 the method of embodiment 299, wherein the sodium bicarbonate solution is about 1% to 10% sodium bicarbonate by weight.

Embodiment 301 the method of embodiment 299, wherein the sodium bicarbonate solution is about 2% sodium bicarbonate by weight.

Embodiment 302 the process of any one of embodiments 281 to 283, wherein the compound having formula (III), or salt thereof, is prepared from the compound having formula (II), or salt thereof, without isolating the compound having formula (II), or salt thereof, from the reaction mixture.

The embodiment 303. the method of any one of embodiments 281 to 302, wherein the stoichiometric process yield of the compound having the formula (III) is at least about 50%.

Embodiment 304 the method of any one of embodiments 281 to 302, wherein the stoichiometric process yield of the compound having formula (III) is at least about 65%.

The embodiment 305. the method of any one of embodiments 281 to 302, wherein the stoichiometric process yield of the compound having the formula (III) is at least about 80%.

Embodiment 306. the process of embodiment 1, wherein the compound having formula (VII), or a salt thereof, is prepared by a process comprising:

reacting a compound having the structure of formula (V)

Or a salt thereof, with a compound having the structure of formula (VI):

or a salt thereof, in the presence of a base and a palladium catalyst in a reaction medium comprising water and an organic solvent to form a reaction mixture comprising a compound having formula (VII), or a salt thereof;

reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound having formula (VII), or a salt thereof; and is

Isolating a compound having formula (VII), or a salt thereof, from the substantially anhydrous mixture.

Embodiment 307 the method of embodiment 306, wherein the compound having formula (VI), or a salt thereof, is prepared by a process comprising:

reacting a compound having formula (IV):

Isolating a compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities.

Embodiment 308. the method of embodiment 306, wherein the compound having formula (V), or a salt thereof, is prepared by a process comprising: contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acid chloride intermediate, and then contacting the acid chloride intermediate in situ with a 2-aminopyridine to form a reaction mixture comprising a compound having formula (V), or a salt thereof.

Embodiment 309. the method of embodiment 306, wherein:

a compound having formula (VI), or a salt thereof, is prepared by a process comprising:

Reacting a compound having formula (IV):

or a salt thereof, with an acidic medium under conditions sufficient to deprotect the compound having formula (IV), or a salt thereof, and form a reaction mixture comprising the compound having the structure of formula (VI), or a salt thereof, and benzyl halide by-product; and is

Isolating a compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities; and is

A compound having formula (V), or a salt thereof, is prepared by a process comprising: contacting 4-carboxyphenylboronic acid, or a salt thereof, with thionyl chloride and a catalyst in a reaction medium comprising an organic solvent to form an acid chloride, and then contacting the acid chloride in situ with 2-aminopyridine to form a reaction mixture comprising a compound having formula (V), or a salt thereof.

Embodiment 310 the method of any one of embodiments 306 to 309, wherein the compound having formula (IV), or a salt thereof, is a sulfate; and the sulfate salt is prepared by a process comprising:

reacting a compound having the structure of formula (III)

Or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having formula (IV);

Forming a sulfate salt of a compound having formula (IV); and is

Separating the sulfate salt.

Embodiment 311 the process of embodiment 310, wherein the compound having formula (III), or a salt thereof, is prepared by a process comprising:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II);

or a salt thereof; and is

Brominating a compound having formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III), or a salt thereof;

Example 312. a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (V)

Or a salt thereof, with a compound having the structure of formula (VI):

or a salt thereof, in the presence of a base and a palladium catalyst in an aqueous reaction medium comprising an organic solvent to form a compound comprising a structure having the formula (VII):

or a salt thereof;

Reducing the amount of water present in the reaction mixture to form a substantially anhydrous mixture comprising a compound having formula (VII), or a salt thereof;

isolating a compound having formula (VII), or a salt thereof, from the substantially anhydrous mixture; and is

Converting a compound having formula (VII), or a salt thereof, to a compound having formula (VIII).

Example 313. a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (IV)

Or a salt thereof, with an acidic medium under conditions sufficient to deprotect a compound having formula (IV) and form a compound comprising a structure having formula (VI):

or a salt thereof, and a benzyl halide by-product;

isolating a compound having formula (VI), or a salt thereof, from the reaction mixture under conditions sufficient to substantially avoid the formation of aminal impurities; and is

Converting a compound having formula (VI), or a salt thereof, to a compound having formula (VIII), or a salt thereof.

Example 314. a process for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (III)

Or a salt thereof, with an aminating agent in a reaction medium to form a reaction mixture comprising a compound having the structure of formula (IV):

forming a sulfate salt of a compound having formula (IV);

separating the sulfate salt; and is

Converting the sulfate salt to a compound having formula (VIII), or a salt thereof.

Example 315 a method for preparing a compound having the structure of formula (VIII):

or a salt thereof, wherein the method comprises:

reacting a compound having the structure of formula (I)

Or a salt thereof, with a cyclizing agent in the presence of a catalyst in a reaction medium to form a compound having formula (II);

or a salt thereof;

brominating a compound having formula (II), or a salt thereof, with a brominating agent to provide a compound having the structure of formula (III):

or a salt thereof; and is

Converting a compound having formula (III), or a salt thereof, to a compound having formula (VIII), or a salt thereof;

***********

All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of these references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or portion of any reference) is relevant prior art (or prior art). Applicants reserve the right to challenge the accuracy and pertinency of the cited references.

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Process for the preparation of 4- { 8-amino-3- [ (2S) -1- (but-2-ynoyl) -pyrrolidin-2-yl ] imidazo [1,5-a ] -pyrazin-1-yl } N- (pyridin-2-yl) -benzamide

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