阅读说明：本技术 医药中间体的新晶型及其制备方法和应用 (Novel crystal form of medical intermediate, preparation method and application thereof ) 是由 李桢 陈伟 于 2020-03-31 设计创作，主要内容包括：本发明提供了一种医药中间体的新晶型及其制备方法和应用,涉及医药技术领域。医药中间体(式I化合物)的新晶型,其X射线粉末衍射在衍射角2θ＝8.7°±0.2°、13.5°±0.2°、14.0°±0.2°、15.9°±0.2°、17.8°±0.2°、19.3°±0.2°处有特征峰。本发明提供的医药中间体(式I化合物)的新晶型,与式I化合物的常规固体形态相比,质量更稳定,可在较高温度(50℃-60℃)进行干燥,干燥时间短,缩短了生产周期,提高了产品质量,解决了式I化合物固体在干燥时不耐高温,放置时间增加时易发生分解,造成生产周期长、质量下降的技术问题。(The invention provides a novel crystal form of a medical intermediate, a preparation method and application thereof, and relates to the technical field of medicines. The X-ray powder diffraction of the new crystal form of the medical intermediate (the compound shown in the formula I) has characteristic peaks at diffraction angles 2 theta of 8.7 degrees +/-0.2 degrees, 13.5 degrees +/-0.2 degrees, 14.0 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 17.8 degrees +/-0.2 degrees and 19.3 degrees +/-0.2 degrees. Compared with the conventional solid form of the compound of the formula I, the novel crystal form of the medical intermediate (the compound of the formula I) provided by the invention has more stable quality, can be dried at a higher temperature (50-60 ℃), shortens the drying time, improves the product quality, and solves the technical problems that the solid of the compound of the formula I is not high-temperature resistant during drying, is easy to decompose when the standing time is increased, and causes long production period and quality reduction.)

1. A novel crystal form of a pharmaceutical intermediate is characterized in that a compound shown in a formula I exists in a crystal form, and has characteristic peaks at diffraction angles 2 theta of 8.7 degrees +/-0.2 degrees, 13.5 degrees +/-0.2 degrees, 14.0 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 17.8 degrees +/-0.2 degrees and 19.3 degrees +/-0.2 degrees by X-ray powder diffraction, wherein the structural formula of the compound shown in the formula I is as follows:

2. a process for preparing a novel crystalline form of the pharmaceutical intermediate of claim 1, comprising the steps of: dissolving the compound of the formula I in a crystallization solvent, concentrating, and crystallizing to obtain a new crystal form of the compound of the formula I; the crystallization solvent is selected from one or a combination of methanol, acetone or ether solvents.

3. A process for preparing a novel crystalline form of the pharmaceutical intermediate of claim 1, comprising the steps of: dissolving the compound of the formula I in a crystallization solvent and water, concentrating and crystallizing to obtain a new crystal form of the compound of the formula I; the crystallization solvent is selected from one or a combination of methanol, acetone or ether solvents.

4. The process for the preparation of the novel crystalline form of the pharmaceutical intermediate according to claim 3, characterized in that the weight to volume ratio of the compound of formula I to water is 1: (0.1-0.2).

5. The method for preparing a novel crystal form of a pharmaceutical intermediate according to any one of claims 2 to 4, wherein the crystallization solvent is selected from the group consisting of methanol and ether solvents, and the volume ratio of methanol to ether solvents is 1: (5-20).

6. The method for preparing the novel crystal form of the pharmaceutical intermediate according to claim 5, wherein the weight/volume ratio of the compound of formula I to the crystallization solvent is 1: (10-20).

7. The method for preparing the novel crystal form of the pharmaceutical intermediate according to claim 5, wherein a cosolvent is further added; the cosolvent is selected from dichloromethane and/or chloroform.

8. The method for preparing the novel crystal form of the pharmaceutical intermediate as claimed in claim 7, wherein the weight volume ratio of the compound of formula I to the cosolvent is 1: (0.5-2); the weight volume ratio of the compound of the formula I to the crystallization solvent is 1: (3-6).

9. The process for the preparation of a new crystalline form of a pharmaceutical intermediate according to any one of claims 2 to 4,6 to 8, characterized in that the crystallization temperature is from-10 ℃ to 20 ℃.

10. Use of the novel crystalline form of the pharmaceutical intermediate according to claim 1, the novel crystalline form of the pharmaceutical intermediate prepared by the preparation process according to any one of claims 2 to 9 for the preparation of canrenone, spironolactone or eplerenone and intermediates thereof.

Technical Field

The invention relates to the technical field of medicines, in particular to a novel crystal form of a medicine intermediate, and a preparation method and application thereof.

Background

Canrenone (canrenone), chemically 17 β -hydroxy-3-oxo-17 α -pregna-4, 6-diene-21-carboxylic acid- γ -lactone, is an important intermediate in the synthesis of the aldosterone receptor antagonists spironolactone (spironolactone) and eplerenone (eplerenone). Spironolactone has been used clinically for the treatment of hypertension and congestive heart failure since 1957; eplerenone is the first approved and selective aldosterone receptor antagonist with therapeutic efficacy similar to spironolactone but with virtually no endocrine side effects of spironolactone and better tolerability. Therefore, the research on the synthesis process of canrenone has higher application value. Wherein, the intermediate epoxide (3-alkoxy-17 beta-oxirane-androstane-3, 5-diene) is a key intermediate of canrenone, and the structural formula is as follows:

r is C1-C6 alkyl.

In the prior art, the synthesis of canrenone generally takes 4-androstenedione (4-AD) as an initiator, and is prepared by etherifying, an intermediate epoxy compound and the like, wherein the reaction formula is as follows:

the prior art is concerned with the preparation of intermediate epoxides by preparing intermediate epoxides from etherates in the above reaction schemes.

In US 3919198: the etherate (3-methoxy-3, 5-androstadiene-17-one) is subjected to epoxidation reaction in the presence of tetrahydrofuran, sodium methoxide, trimethyl sulfur bromide and dimethyl sulfoxide, the obtained product is diluted in water after the reaction is finished, an intermediate epoxy compound (R ═ methyl) crude product is obtained by separation, and the crude product is refined by ethanol recrystallization.

In addition, an etherate (3-ethoxy-3, 5-androstadiene-17-one) is subjected to epoxidation reaction in the presence of tetrahydrofuran, sodium hydride, triethylsulfur iodide and dimethyl sulfoxide, the obtained product is diluted in water after the reaction is finished, an intermediate epoxy compound (R ═ ethyl) crude product is obtained by separation, and the crude product is refined by acetone recrystallization.

In chinese patent CN 110028543A: the etherate (3-ethoxy-3, 5-androstadiene-17-one) is subjected to epoxidation reaction in the presence of tetrahydrofuran, sodium ethoxide, trimethyl sulfur bromide and dimethyl sulfoxide, and after the reaction is finished, concentration, extraction, filtration, separation and reconcentration are carried out to obtain the intermediate epoxy compound (R ═ ethyl).

In chinese patent CN 107629101A: dissolving etherate (3-ethoxy-3, 5-androstadiene-17-one) in an organic solvent, adding trimethyl sulfur iodide, reacting under the catalysis of sodium hydride strong base, destroying excessive alkali after the reaction is finished, then decompressing, concentrating and recovering the organic solvent, crystallizing by water precipitation, treating to obtain an intermediate epoxy (R ═ ethyl) crude product, and decoloring and recrystallizing the crude product by using alcohol and activated carbon.

In the literature, the synthesis process improvement of eplerenone intermediate canrenone (china journal of pharmaceutical chemistry, 2005, volume 15, phase 4): adding sodium hydroxide and water into dimethyl sulfoxide, heating to 75 ℃, sequentially adding tetrabutylammonium bromide, etherate (3-ethoxy-3, 5-androstadiene-17-one) and trimethyl sulfur iodide, after the reaction is finished, carrying out elutriation crystallization, and carrying out treatment to obtain an intermediate epoxy (R ═ ethyl) crude product, and then recrystallizing with methanol.

In the synthesis of spironolactone (journal of the Chinese pharmaceutical industry, 2005, vol. 36, stage 1): trimethyl sulfonium iodide, acetonitrile water and potassium hydroxide react at 60 ℃, an acetonitrile solution of etherate (3-ethoxy-3, 5-androstadiene-17-one) is dripped to continue the reaction, after the reaction is finished, cooling, filtering, washing with acetonitrile, recycling washing liquor, diluting the residue with water, and refining and crystallizing to obtain an intermediate epoxy compound (R ═ ethyl).

The above documents report the preparation method of the intermediate epoxy compound, and the intermediate epoxy compound (R ═ methyl or ethyl) obtained in the documents is all solid, but no crystal form report about the intermediate epoxy compound is found.

The research of the invention finds that the intermediate epoxy compound (R ═ ethyl) can be recrystallized by any solvent under the existing conditions, and the obtained solid can only be dried below 40 ℃ without high temperature resistance during drying. The stability of the intermediate epoxy (R ═ methyl) solid was then further investigated. The intermediate epoxy compound (R ═ methyl) was precipitated directly from water to give a solid, which was measured by X-ray powder diffraction to have an amorphous structure, as shown in fig. 1. The amorphous structure is extremely unstable, can not resist high temperature during drying, can only be dried at room temperature, and is easy to decompose when the standing time is prolonged. Using the method reported in US3919198, the intermediate epoxy (R ═ methyl) was recrystallized from ethanol and it was found that a mixture of intermediate epoxy (R ═ methyl) and intermediate epoxy (R ═ ethyl) was finally obtained, and it was not possible to obtain a more pure and more stable intermediate epoxy (R ═ methyl).

Through intensive research of the invention, a new crystal form of an intermediate epoxy compound (R ═ methyl), namely a new crystal form of a compound shown in a formula I, is finally found, and the technical problems that the intermediate epoxy compound is poor in stability and not suitable for long-time standing or high-temperature drying are solved.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The main object of the present invention is to provide a new crystalline form of a pharmaceutical intermediate, a process for its preparation and its use, in order to at least partially solve at least one of the above mentioned technical problems.

As a first aspect of the present invention, the present invention provides a novel crystalline form of a pharmaceutical intermediate, that is, a compound of formula I exists in a crystalline form, and its X-ray powder diffraction has characteristic peaks at diffraction angles 2 θ of 8.7 ° ± 0.2 °, 13.5 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.8 ° ± 0.2 °, and 19.3 ° ± 0.2 °, wherein the compound of formula I has a structural formula as follows:

compared with the conventional solid form of the compound of the formula I, the novel crystal form of the medical intermediate (the compound of the formula I) provided by the invention has more stable quality, can be dried at a higher temperature (50-60 ℃), shortens the drying time, improves the product quality, and solves the technical problems that the solid of the compound of the formula I is not high-temperature resistant during drying, is easy to decompose when the standing time is increased, and causes long production period and quality reduction.

Further, the compound of formula I is present in a crystalline form having an X-ray powder diffraction having characteristic peaks at diffraction angles 2 θ of 7.8 ° ± 0.2 °, 8.7 ° ± 0.2 °, 13.5 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.9 ° ± 0.2 °, 17.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 23.7 ° ± 0.2 °, 24.3 ° ± 0.2 °, 28.9 ° ± 0.2 °.

As a second aspect of the present invention, the present invention provides a method for preparing a novel crystalline form of a pharmaceutical intermediate, comprising the steps of: dissolving the compound of the formula I in a crystallization solvent, concentrating, and crystallizing to obtain a new crystal form of the compound of the formula I; the crystallization solvent is selected from one or a combination of methanol, acetone or ether solvents.

It is noted that the novel crystalline form of the compound of formula I used to prepare the intermediate of the present invention may be in any physical form, including but not limited to crystalline solids or non-crystalline solids, oils. And compounds of formula I include, but are not limited to, an anhydrate of a compound of formula I, a hydrate of a compound of formula I, or a solvate of a compound of formula I. The compound of formula I in the new crystal form for preparing the intermediate of the present invention is allowed to contain less than 20% of moisture, and the generation of the new crystal form of the compound of formula I is not affected by the moisture of less than 20%.

The preparation method of the new crystal form of the medical intermediate (the compound of the formula I) provided by the invention takes one or a combination of several of methanol, acetone or ether solvents as a crystallization solvent, and the new crystal form of the compound of the formula I is obtained by dissolving, concentrating and crystallizing the compound of the formula I, the used reagent is cheap and easy to obtain, the operation is simple and convenient, and compared with the conventional solid form of the compound of the formula I, the new crystal form of the compound of the formula I has more stable quality, can be dried at a higher temperature (50 ℃ -60 ℃), has short drying time, shortens the production cycle, improves the product quality, and solves the technical problems that the solid of the compound of the formula I is not high-temperature resistant during drying, is easy to decompose when the standing time is increased, and causes long production cycle and quality reduction.

As a third aspect of the present invention, the present invention provides a method for preparing a novel crystalline form of a pharmaceutical intermediate, comprising the steps of: dissolving the compound of the formula I in a crystallization solvent and water, concentrating and crystallizing to obtain a new crystal form of the compound of the formula I; the crystallization solvent is selected from one or a combination of methanol, acetone or ether solvents.

It is noted that the novel crystalline form of the compound of formula I used to prepare the intermediate of the present invention may be in any physical form, including but not limited to crystalline solids or non-crystalline solids, oils. And compounds of formula I include, but are not limited to, an anhydrate of a compound of formula I, a hydrate of a compound of formula I, or a solvate of a compound of formula I. The novel crystalline form of the compound of formula I that is used to prepare the intermediate of the present invention contains no or a small amount of water (less than 2%), which allows the addition of a suitable amount of water during the crystallization process without affecting the formation of the novel crystalline form of the compound of formula I.

Further, the weight-to-volume ratio of the compound of formula I to water is 1: (0.1-0.2) (g/mL).

In the present invention, a typical but non-limiting weight to volume ratio of the compound of formula I to water may be, for example, 1: 0.1, 1: 0.15 or 1: 0.2.

further, the ether solvent is selected from methyl tert-butyl ether and/or isopropyl ether.

The invention fully considers the safety and feasibility under the test condition or the production condition, the ether solvent is selected from methyl tert-butyl ether and/or isopropyl ether, and other ether solvents capable of obtaining the novel crystal form of the compound shown in the formula I are also within the protection scope of the invention.

Further, the crystallization solvent is selected from a combination of methanol and an ether solvent, and the volume ratio of the methanol to the ether solvent is 1: (5-20).

In the present invention, a typical but non-limiting volume ratio of methanol to ether solvent may be, for example, 1: 5. 1: 6. 1: 7. 1: 8. 1: 9. 1: 10. 1: 11. 1: 12. 1: 13. 1: 14. 1: 15. 1: 16. 1: 17. 1: 18. 1: 19 or 1: 20.

the novel crystal form of the compound of the formula I has certain selectivity on crystallization solvents. When the crystallization solvent is selected from one or a combination of methanol, acetone or ether solvents, the compound of the formula I obtained by crystallization has a new crystal structure, the crystal quality is more stable, the drying can be carried out at a higher temperature (50 ℃ -60 ℃), and the drying time is short. When the crystallization solvent is selected from the group consisting of methanol and ether solvents, a significant improvement in yield and purity is achieved over the use of methanol alone, acetone alone or methyl tert-butyl ether alone. Further, the required volume ratio of methanol to the ether solvent is also important, and when the volume ratio of methanol to the ether solvent is within the range defined in the application, the product quality is more stable and the yield and purity are both considerable under the same other preparation conditions.

Further, the crystallization solvent is selected from a combination of methanol and an ether solvent, and the volume ratio of the methanol to the ether solvent is 1: (10-18).

Further, the weight-to-volume ratio of the compound of formula I to the crystallization solvent is 1: (10-20) (g/mL).

In the present invention, a typical but non-limiting weight to volume ratio of the compound of formula I to the crystallization solvent may be, for example, 1: 10. 1: 11. 1: 12. 1: 13. 1: 14. 1: 15. 1: 16. 1: 17. 1: 18. 1: 19 or 1: 20.

furthermore, a cosolvent is also added; the cosolvent is selected from dichloromethane and/or chloroform.

The invention fully considers the solubility of the compound of the formula I in the crystallization solvent and the crystallization condition, adds the cosolvent in the crystallization process, does not influence the generation of a new crystal form of the compound of the formula I, can reduce the dosage of the crystallization solvent, ensures the product quality and reduces the production cost.

Further, the weight volume ratio of the compound of formula I to the cosolvent is 1: (0.5-2) (g/mL).

In the present invention, a typical but non-limiting weight to volume ratio of the compound of formula I to co-solvent may be, for example, 1: 0.5, 1: 0.6, 1: 0.7, 1: 0.8, 1: 0.9, 1: 1. 1: 1.1, 1: 1.2, 1: 1.3, 1: 1.4, 1: 1.5, 1: 1.6, 1: 1.7, 1: 1.8, 1: 1.9 or 1: 2.

the invention further optimizes the addition amount of the cosolvent, and when the weight volume ratio of the compound shown in the formula I to the cosolvent is 1: (0.5-2) (g/mL), the compound of formula I can be sufficiently dissolved by matching with a crystallization solvent, and the dosage of the crystallization solvent is greatly reduced.

Further, the weight-to-volume ratio of the compound of formula I to the crystallization solvent is 1: (3-6) (g/mL).

In the present invention, a typical but non-limiting weight to volume ratio of the compound of formula I to the crystallization solvent may be, for example, 1: 3. 1: 3.1, 1: 3.2, 1: 3.3, 1: 3.4, 1: 3.5, 1: 3.6, 1: 3.7, 1: 3.8, 1: 3.9, 1: 4. 1: 4.1, 1: 4.2, 1: 4.3, 1: 4.4, 1: 4.5, 1: 4.6, 1: 4.7, 1: 4.8, 1: 4.9, 1: 5. 1: 5.1, 1: 5.2, 1: 5.3, 1: 5.4, 1: 5.5, 1: 5.6, 1: 5.7, 1: 5.8, 1: 5.9 or 1: 6.

the invention adds the cosolvent to ensure that the weight-volume ratio of the compound shown in the formula I to the crystallization solvent reaches 1: (3-6) (g/mL), the amount of crystallization solvent used was greatly reduced compared to when no co-solvent was added.

Further, the crystallization temperature is-10 ℃ to 20 ℃.

Typical but not limiting temperatures for crystallization in the present invention may be, for example, -10 ℃, -9 ℃, -8 ℃, -7 ℃, -6 ℃, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃, 3 ℃, 4 ℃,5 ℃,6 ℃, 7 ℃, 8 ℃, 9 ℃, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃ or 20 ℃.

Further, the crystallization temperature is-5 ℃ to 5 ℃.

As a fourth aspect of the invention, the invention provides a new crystal form of the medical intermediate and application of the new crystal form of the medical intermediate prepared by the preparation method in preparation of canrenone, spironolactone or eplerenone and intermediates thereof.

When the new crystal form of the medical intermediate (the compound of the formula I) provided by the invention or the new crystal form of the medical intermediate (the compound of the formula I) prepared by the preparation method provided by the invention is used for preparing canrenone, spironolactone or eplerenone and the intermediate thereof, the defects caused by unstable solid of the compound of the formula I are effectively overcome, the quality control of the canrenone, spironolactone or eplerenone and the intermediate thereof is facilitated, the product quality can be better ensured, and the method is suitable for industrial production.

It should be noted that the diffraction intensity of the characteristic peak of the X-ray powder diffraction may vary slightly depending on the crystal preparation technique, the sample mounting method and the measuring instrument, and should be within the scope of the present invention. In addition, the diffraction 2 θ value may be affected by the difference of instruments and other factors, so that the above-mentioned diffraction angle 2 θ value having characteristic peaks may vary within ± 0.2 ° from the existing value.

Compared with the prior art, the invention has the following beneficial effects:

compared with the conventional solid form of the compound of the formula I, the novel crystal form of the intermediate (the compound of the formula I) provided by the invention has more stable quality, can be dried at a higher temperature (50-60 ℃), has short drying time, shortens the production period, improves the product quality, and solves the technical problems that the solid of the compound of the formula I is not high-temperature resistant during drying, is easy to decompose when the standing time is increased, and causes long production period and quality reduction.

The preparation method of the new crystal form of the medical intermediate (the compound of the formula I) provided by the invention takes one or a combination of several of methanol, acetone or ether solvents as a crystallization solvent, and the new crystal form of the compound of the formula I is obtained by dissolving, concentrating and crystallizing the compound of the formula I, the used reagent is cheap and easy to obtain, the operation is simple and convenient, and compared with the conventional solid form of the compound of the formula I, the new crystal form of the compound of the formula I has more stable quality, can be dried at a higher temperature (50 ℃ -60 ℃), has short drying time, shortens the production cycle, improves the product quality, and solves the technical problems that the solid of the compound of the formula I is not high-temperature resistant during drying, is easy to decompose when the standing time is increased, and causes long production cycle and quality reduction.

When the new crystal form of the medical intermediate (the compound of the formula I) provided by the invention or the new crystal form of the medical intermediate (the compound of the formula I) prepared by the preparation method provided by the invention is used for preparing canrenone, spironolactone or eplerenone and the intermediate thereof, the defects caused by unstable solid of the compound of the formula I are effectively overcome, the quality control of the canrenone, spironolactone or eplerenone and the intermediate thereof is facilitated, the product quality can be better ensured, and the method is suitable for industrial production.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.

FIG. 1 is an X-ray powder diffraction pattern of the product obtained in example 1-2;

FIG. 2 is an X-ray powder diffraction pattern of the products obtained in examples 2-5.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples were carried out under the conventional conditions, unless otherwise specified. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

EXAMPLE 1 preparation of Compounds of formula I

Examples 1 to 1

450.7g of etherate (3-methoxy-3, 5-androstadiene-17-one), 390.2g of trimethyl sulfonium bromide and 2500mL of tetrahydrofuran are added into a reaction bottle, 375mL of 10% sodium hydroxide solution is slowly added at 20-25 ℃ for epoxy reaction, TLC is used for monitoring that no 3-methoxy-3, 5-androstadiene-17-one exists, the mixture is diluted in water after the reaction is completed, and centrifugal filtration is carried out to obtain 525.1g of the compound shown in the formula I (the water content is about 11%), and the HPLC purity is 97.3% (calculated on a dry product basis).

Examples 1 to 2

200.2g of the compound of the formula I obtained in example 1-1 were dried under vacuum at room temperature for 10 hours to give 177.6g of the compound of the formula I (water content: about 2%) with an HPLC purity of 95.2% (on a dry basis).

The product obtained in example 1-2 was determined to be amorphous by X-ray powder diffraction measurement, as shown in FIG. 1.

EXAMPLE 2 preparation of novel crystalline forms of the Compound of formula I

Example 2-1

10.6g of the compound of the formula I obtained in example 1-1 and 106mL of methanol were added to a reaction flask, stirred until the mixture was completely dissolved, concentrated under reduced pressure until about 20mL remained, cooled to-5 ℃ for crystallization, filtered, and dried at 60 ℃ for 5 hours to obtain 8.4g of a white solid with a yield of 89.3% (calculated as an etherate) and an HPLC purity of 98.2%.

Examples 2 to 2

10.4g of the compound of the formula I obtained in example 1-1 and 156mL of acetone were added to a reaction flask, stirred until the mixture was completely dissolved, concentrated under reduced pressure until about 20mL remained, cooled to 5 ℃ for crystallization, filtered, and dried at 60 ℃ for 5 hours to obtain 8.3g of a white solid with the yield of 87.6% (calculated as an etherate) and the HPLC purity of 98.2%.

Examples 2 to 3

10.6g of the compound of the formula I obtained in example 1-1 and 212mL of methyl tert-butyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 10 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.2g of a white solid with a yield of 86.7% (calculated as etherate) and an HPLC purity of 98.3%.

Examples 2 to 4

10.5g of the compound of formula I obtained in example 1-1, 35mL of methanol and 175mL of isopropyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to-10 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 9.0g of a white solid with a yield of 95.4% (calculated as etherate) and an HPLC purity of 98.5%.

Examples 2 to 5

10.6g of the compound of the formula I obtained in example 1-1, 10mL of methanol and 150mL of methyl tert-butyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 9.1g of a white solid with a yield of 96.4% (calculated as etherate) and an HPLC purity of 98.8%.

When the white solids obtained in examples 2 to 5 were subjected to X-ray powder diffraction measurement, characteristic peak positions of 2 θ were 7.8 °, 8.7 °, 13.5 °, 14.0 °, 15.9 °, 17.8 °, 19.3 °, 23.7 °, 24.3 °, and 28.9 °.

Examples 2 to 6

10.5g of the compound of the formula I obtained in example 1-1, 5mL of methanol and 100mL of isopropyl ether were added to a reaction flask, stirred until the mixture was completely dissolved, concentrated under reduced pressure until about 20mL remained, cooled to 20 ℃ for crystallization, filtered, and dried at 60 ℃ for 5 hours to obtain 8.7g of a white solid with a yield of 92.2% (calculated as an etherate) and an HPLC purity of 98.5%.

Examples 2 to 7

10.4g of the compound of formula I obtained in example 1-1 and 160mL of methanol were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.3g of a white solid with a yield of 87.6% (calculated as etherate) and an HPLC purity of 98.2%.

Examples 2 to 8

10.5g of the compound of the formula I obtained in example 1-1 and 160mL of acetone were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.4g of a white solid with a yield of 89.3% (calculated as etherate) and an HPLC purity of 98.2%.

Examples 2 to 9

10.5g of the compound of formula I obtained in example 1-1 and 160mL of methyl tert-butyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to a residual volume of about 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.4g of a white solid with a yield of 89.3% (based on etherate) and an HPLC purity of 98.3%.

Examples 2 to 10

10.6g of the compound of the formula I obtained in example 1-1, 10mL of acetone and 150mL of methyl tert-butyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.4g of a white solid with a yield of 89.3% (calculated as etherate) and an HPLC purity of 98.4%.

Examples 2 to 11

10.4g of the compound of the formula I obtained in example 1-1, 10mL of methanol and 150mL of acetone are added into a reaction flask, stirred until the mixture is completely dissolved, concentrated under reduced pressure until about 20mL of the mixture remains, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5 hours to obtain 8.3g of a white solid, wherein the yield is 87.6% (calculated as etherate) and the HPLC purity is 98.4%.

Examples 2 to 12

10.5g of the compound of the formula I obtained in example 1-1, 27mL of methanol and 133mL of methyl tert-butyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure until about 20mL remained, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.9g of a white solid with a yield of 94.5% (calculated as etherate) and an HPLC purity of 98.8%.

Examples 2 to 13

10.6g of the compound of the formula I obtained in example 1, 7.5mL of methanol and 152.5mL of methyl tert-butyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.8g of a white solid with a yield of 93.3% (calculated as an etherate) and an HPLC purity of 98.7%.

Examples 2 to 14

10.5g of the compound of formula I obtained in example 1-1, 14.5mL of methanol and 145.5mL of methyl tert-butyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 9.1g (in terms of etherate) of a white solid with a yield of 96.4% and an HPLC purity of 98.9%.

Examples 2 to 15

10.5g of the compound of formula I obtained in example 1-1, 8.5mL of methanol and 151.5mL of methyl tert-butyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 9.0g of a white solid with a yield of 95.4% (calculated as etherate) and an HPLC purity of 98.8%.

Examples 2 to 16

10.5g of the compound of the formula I obtained in example 1-1, 80mL of methanol and 80mL of methyl tert-butyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.5g of a white solid with a yield of 90.1% (calculated as etherate) and an HPLC purity of 98.6%.

Examples 2 to 17

10.4g of the compound of the formula I obtained in example 1-1, 4mL of methanol and 156mL of methyl tert-butyl ether were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.6g of a white solid with a yield of 91.2% (calculated as etherate) and an HPLC purity of 98.7%.

Examples 2 to 18

10.5g of the compound of formula I obtained in example 1-1, 5mL of methanol, 25mL of methyl tert-butyl ether and 20mL of dichloromethane were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to-10 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.9g of a white solid with a yield of 94.3% (based on etherate) and an HPLC purity of 98.8%.

Examples 2 to 19

10.4g of the compound of formula I obtained in example 1-1, 2mL of methanol, 38mL of methyl tert-butyl ether and 10mL of dichloromethane were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 9.1g of a white solid with a yield of 96.4% (based on etherate) and an HPLC purity of 98.8%.

Examples 2 to 20

10.5g of the compound of the formula I obtained in example 1-1, 3mL of methanol, 60mL of methyl tert-butyl ether and 5mL of dichloromethane were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 20 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.8g of a white solid with a yield of 93.3% (based on etherate) and an HPLC purity of 98.7%.

Examples 2 to 21

10.4g of the crude compound of the formula I obtained in example 1-1, 4mL of methanol, 32mL of isopropyl ether and 16mL of chloroform were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 10 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.9g of a white solid with a yield of 94.3% (based on etherate) and an HPLC purity of 98.6%.

Examples 2 to 22

10.4g of the compound of formula I obtained in example 1-1, 4mL of methanol, 48mL of isopropyl ether and 20mL of chloroform were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to leave about 20mL, cooled to 15 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.8g of a white solid with a yield of 93.3% (based on etherate) and an HPLC purity of 98.5%.

Examples 2 to 23

10.5g of the compound of the formula I obtained in example 1-1, 20mL of methanol, 20mL of methyl tert-butyl ether and 10mL of dichloromethane were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.5g of a white solid with a yield of 90.1% (calculated as etherate) and an HPLC purity of 98.4%.

Examples 2 to 24

10.5g of the compound of formula I obtained in example 1-1, 1mL of methanol, 39mL of methyl tert-butyl ether and 10mL of dichloromethane were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to leave about 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.6g of a white solid with a yield of 91.2% (based on etherate) and an HPLC purity of 98.5%.

Examples 2 to 25

8.5g of the compound of the formula I obtained in example 1-2, 40mL of methanol and 62mL of acetone are added into a reaction flask, stirred until the mixture is completely dissolved, concentrated under reduced pressure until about 20mL of the remaining mixture is obtained, cooled to-10 ℃ for crystallization, filtered, and dried at 60 ℃ for 5 hours to obtain 8.1g of a white solid, wherein the yield is 95.3% and the HPLC purity is 98.5%.

Examples 2 to 26

8.5g of the compound of the formula I obtained in example 1-2, 53mL of acetone and 100mL of isopropyl ether were added to a reaction flask, stirred until the mixture was completely dissolved, concentrated under reduced pressure until about 20mL remained, cooled to 20 ℃ for crystallization, filtered, and dried at 60 ℃ for 5 hours to obtain 7.9g of a white solid, the yield was 92.9%, and the HPLC purity was 98.5%.

Examples 2 to 27

8.5g of the compound of the formula I obtained in example 1-2, 28mL of methanol, 142mL of isopropyl ether and 1mL of water were added to a reaction flask, stirred until complete dissolution was achieved, concentrated under reduced pressure to the remaining 20mL, cooled to-5 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.3g of a white solid with a yield of 97.6% and an HPLC purity of 98.7%.

Examples 2 to 28

8.5g of the compound of formula I obtained in example 1-2, 8mL of methanol, 121mL of methyl tert-butyl ether and 1.3mL of water were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining about 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.3g of a white solid with a yield of 97.6% and an HPLC purity of 98.9%.

Examples 2 to 29

8.5g of the compound of the formula I obtained in example 1-2, 7.5mL of methanol, 76.5mL of methyl tert-butyl ether and 1.7mL of water were added to a reaction flask, stirred until complete dissolution, concentrated under reduced pressure to the remaining 20mL, cooled to 5 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 8.2g of a white solid with a yield of 96.5% and an HPLC purity of 98.8%.

Examples 2 to 30

8.5g of the compound of the formula I obtained in example 1-2, 25.5mL of methyl tert-butyl ether, 17mL of dichloromethane and 1mL of water were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining about 20mL, cooled to-5 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 7.8g of a white solid with a yield of 91.8% and an HPLC purity of 98.5%.

Examples 2 to 31

8.5g of the compound of the formula I obtained in example 1-2, 34mL of acetone, 8.5mL of dichloromethane and 1.3mL of water were added to a reaction flask, stirred until complete dissolution, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 7.7g of a white solid with a yield of 90.6% and an HPLC purity of 98.6%.

Examples 2 to 32

8.5g of the compound of the formula I obtained in example 1-2, 51mL of methanol, 4.3mL of dichloromethane and 1mL of water were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to leave about 20mL, cooled to 5 ℃ for crystallization, filtered, and dried at 60 ℃ for 5h to obtain 7.6g of a white solid with a yield of 89.4% and an HPLC purity of 98.6%.

The diffraction angle 2 theta values of characteristic peaks of the white solids obtained in examples 2-1 to 2-4 and examples 2-6 to 2-32 measured by X-ray powder diffraction are changed within +/-0.2 degrees from the diffraction angle 2 theta values of the white solids obtained in examples 2-5, and the white solids are proved to have the same crystal forms as the white solids obtained in examples 2-5 and are all new crystal forms of the compound shown in the formula I.

From examples 2-1 to 2-32, it can be seen that when the crystallization solvent is one or a combination of several selected from methanol, acetone or ether solvents, the compound of formula I obtained by crystallization has a new crystal structure. When the crystallization solvent is selected from the combination of methanol and ether solvents, the yield and the purity are obviously improved compared with the single use of methanol, acetone or methyl tert-butyl ether. Further, the required volume ratio of methanol to the ether solvent is also important, and when the volume ratio of methanol to the ether solvent is within the range defined in the application, the product quality is more stable and the yield and purity are both considerable under the same other preparation conditions. The added cosolvent can not influence the generation of a new crystal form of the compound shown in the formula I, and can reduce the dosage of a crystallization solvent, ensure the product quality and reduce the production cost. In general, the preparation method provided by the invention can obviously improve the quality and stability of the compound shown in the formula I, and proves that the method for preparing the novel crystal form of the compound shown in the formula I is an effective method for improving the product quality.

Comparative example 1

10.5g of the compound of the formula I obtained in example 1-1 and 160mL of ethanol were added to a reaction flask, stirred until completely dissolved, concentrated under reduced pressure to the remaining 20mL, cooled to 0 ℃ for crystallization, filtered, and dried at room temperature for 24h to obtain 8.8g of a white solid with a yield of 93.3% (based on etherate).

HPLC analysis showed that the HPLC purity of the recrystallized compound of formula I (intermediate epoxy (R ═ methyl)) was 92.3% and the HPLC purity of the intermediate epoxy (R ═ ethyl) was 5.2%. When ethanol is used as the crystallization solvent, the methoxy group at C3 in the compound of formula I (intermediate epoxide (R ═ methyl)) is exchanged for the ethoxy group in the ethanol solvent, resulting in a mixture of intermediate epoxide (R ═ methyl) and intermediate epoxide (R ═ ethyl), resulting in a decrease in HPLC purity.

Test examples stability test

(1) The white solids obtained in examples 1-1 to 1-2, examples 2-1 to 2-6 and examples 2-25 to 2-29 of the present invention were dried at room temperature for one week, respectively, and subjected to a stability test. (2) The white solids obtained in examples 1-1 to 1-2, examples 2-1 to 2-6 and examples 2-25 to 2-29 of the present invention were dried in an oven at 60 ℃ for 5 hours, respectively, to perform stability tests, and the test results of each group are shown in table 1.

TABLE 1 stability test

From the above table, the new crystal form of the compound of formula I provided by the present invention has more stable quality, can be dried at a higher temperature of 60 ℃, and can be stored at normal temperature for a long time. The product obtained in comparative example 1 is dried at room temperature for one week or 60 ℃ for 5 hours, and the HPLC purity is obviously reduced, which indicates that the amorphous structure of the compound of formula I is extremely unstable and is easy to decompose during long-time storage at higher temperature, thus causing the quality reduction of the product.

The white solids obtained in examples 2-7 to 2-24 and examples 2-30 to 2-32 were dried at room temperature for one week or 60 ℃ for 5 hours, respectively, and subjected to stability tests, which showed similar effects to those of examples 2-1 to 2-6 and examples 2-25 to 2-29, and thus, they were not repeated herein.

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.