阅读说明：本技术 供给一氧化氮的***素类似物的制备方法 (Nitric oxide donating prostaglandin analogs ) 是由 N·阿尔米兰特 于 2019-02-12 设计创作，主要内容包括：本发明涉及制备式(I)的己酸,6-(硝基氧基)-,(1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(乙基氨基)-7-氧代-2-庚烯-1-基]-3,5-二羟基环戊基]-1-(2-苯基乙基)-2-丙烯-1-基酯的方法。根据本发明,通过使硼酸酯保护形式的比马前列素与6-(硝基氧基)己酰氯偶联和除去硼酸酯保护基,可以以高纯度有效地制备化合物(I)。6-(硝基氧基)己酰氯中间体通过2-己内酯的开环反应、随后用HNO<Sub>3</Sub>和H<Sub>2</Sub>SO<Sub>4</Sub>的混合物在二氯甲烷中使6-羟基己酸钾盐硝化来制备。<Image he="665" wi="700" file="DDA0002637969630000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to a process for the preparation of hexanoic acid of formula (I), 6- (nitrooxy) -, (1S,2E) -3- [ (1R,2R,3S,5R) -2- [ (2Z) -7- (ethylamino) -7-oxo-2-hepten-1-yl]-3, 5-dihydroxycyclopentyl]-1- (2-phenylethyl) -2-propen-1-yl ester. According to the present invention, compound (I) can be efficiently produced with high purity by coupling bimatoprost in a borate-protected form with 6- (nitrooxy) hexanoyl chloride and removing the borate protecting group. 6- (Nitroxy) hexanoyl chloride intermediate by ring opening of 2-caprolactone followed by HNO 3 And H 2 SO 4 Is prepared by nitrating potassium 6-hydroxycaproate in dichloromethane.)

1. A process for the preparation of hexanoic acid, 6- (nitrooxy) -, (1S,2E) -3- [ (1R,2R,3S,5R) -2- [ (2Z) -7- (ethylamino) -7-oxo-2-hepten-1-yl ] -3, 5-dihydroxycyclopentyl ] -1- (2-phenylethyl) -2-propen-1-yl ester of formula (I),

the method comprises the following steps:

a) reacting a compound of formula (II):

with 6- (nitrooxy) hexanoyl chloride of formula (IV) in the presence of 4-dimethylaminopyridine in free form,

obtaining a compound of formula (III):

b) removing the boronic ester protecting group of the compound of formula (III) to obtain the compound of formula (I).

2. The process according to claim 1, wherein step a) is carried out in an aprotic organic solvent.

3. The process according to claim 2, wherein the aprotic organic solvent is selected from methyl tert-butyl ether, N-dimethylformamide or dichloromethane.

4. A process according to claim 3, wherein the aprotic organic solvent is methyl tert-butyl ether.

5. The process according to any one of claims 1-4, wherein in step a) the molar ratio of the compound of formula (II) to the 6- (nitrooxy) hexanoyl chloride of formula (IV) is from 1:1.4 to 1:1.6 and the molar ratio of the compound of formula (II) to 4-dimethylaminopyridine is from 1:2.0 to 1: 2.4.

6. The process according to any one of claims 1-5, wherein step a) is carried out at a temperature of from 0 ℃ to room temperature.

7. The process according to any one of the preceding claims, wherein the 6- (nitrooxy) hexanoyl chloride of formula (IV) is obtained by a process comprising the steps of:

i) reacting a 2-caprolactone of formula (V):

with an inorganic base selected from KOH, NaOH and LiOH to obtain a 6-hydroxycaproic acid salt of formula (VI):

wherein M is K, Na or Li;

ii) with HNO₃And H₂SO₄Nitrating the compound of formula (VI) to obtain 6- (nitrooxy) hexanoic acid of formula (VII),

iii) converting the 6- (nitrooxy) hexanoic acid of formula (VII) to 6- (nitrooxy) hexanoic acid chloride of formula (IV) with a chlorinating agent.

8. The process according to claim 7, wherein the 6- (nitrooxy) hexanoyl chloride of formula (IV) obtained in step iii) is used directly in step a) without further purification.

9. The process according to claim 7 or 8, wherein the inorganic base used in step i) is potassium hydroxide.

10. A process according to any one of claims 7 to 9, wherein step i) is carried out in a solvent selected from methanol, ethanol or isopropanol.

11. The process according to claim 10, wherein the organic solvent is methanol.

12. The process according to any one of claims 7-11, wherein step ii) is carried out in dichloromethane.

13. The process according to any one of claims 7-12, wherein step iii) is performed by using oxalyl chloride as chlorinating agent.

14. A process according to any one of claims 7 to 13, wherein step iii) is carried out in dichloromethane.

15. A process according to any one of the preceding claims, wherein the compound of formula (II) is obtained by reacting bimatoprost with butyl boronic acid.

Technical Field

The present invention relates to an improved process for the large scale preparation of hexanoic acid, 6- (nitrooxy) -, (1S,2E) -3- [ (1R,2R,3S,5R) -2- [ (2Z) -7- (ethylamino) -7-oxo-2-hepten-1-yl ] -3, 5-dihydroxycyclopentyl ] -1- (2-phenylethyl) -2-propen-1-yl ester of formula (I).

Background

Hexanoic acid, 6- (nitrooxy) -, (1S,2E) -3- [ (1R,2R,3S,5R) -2- [ (2Z) -7- (ethylamino) -7-oxo-2-hepten-1-yl ] -3, 5-dihydroxycyclopentyl ] -1- (2-phenylethyl) -2-propen-1-yl ester of formula (I)

Are prostaglandin analogs that have been shown to be effective IOP lowering agents (ImpaginatielloF, TorisCB, BatugoM, PrasannaG, BorgiV, BastiaE, Onginie, KraussAHP; InvestOphtalmolVis Sci.2015; 56: 6558-64).

WO 2009/136281 discloses a process for the preparation of compounds of formula (I).

WO 2009/136281 discloses in particular the synthesis of compound (I) and discloses in general the preparation of 15-alkyl nitrates of bimatoprost.

WO 2009/136281 discloses the synthesis of compounds of formula (I) (example B-1) as follows: the compound of formula (I) is obtained by reacting a boronic ester protected form of bimatoprost (compound of formula (II)) with 6-bromohexanoyl chloride to give the 15- (6-bromohexanoyl) ester of bimatoprost (compound of formula (VIII)) in boronic ester protected form, which is converted to a nitric acid derivative by silver nitrate in acetonitrile and deprotected/purified under reverse phase chromatography.

The main drawbacks of the above synthesis are the use of more than equimolar amounts of 6-bromohexanoyl chloride in the esterification reaction, which presents a structural alert of potential mutagenicity, and the use of silver nitrate in the last step, which produces large amounts of silver salts in the waste water. Another major drawback of this process is the formation of impurities and by-products such as 15- (6-bromohexanoyl) ester of bimatoprost (compound (IX)) and 15- (6-chlorohexanoyl) ester of bimatoprost (compound (X)) which are difficult to remove even after multiple purifications, because they have a similar polarity, similar lipophilicity and/or solubility in chromatography as compound (I).

According to the procedure disclosed in WO 2009/136281, the 15- (6-bromohexanoyl) ester of bimatoprost (compound (IX)) is an impurity after removal of the borate protection, resulting from incomplete reaction of compound (VIII) with silver nitrate. The 15- (6-chlorohexanoyl) ester of bimatoprost (compound (X)) is a by-product formed by the halogen exchange reaction between the bromine atom of the 15- (6-bromohexanoyl) ester of bimatoprost (compound (VIII)) in the boronate ester protected form and the free chloride anion of the 4-dimethylaminopyridine hydrochloride formed during the esterification step. The 15- (6-chlorohexanoyl) ester of bimatoprost (VIIIa) in boronate protected form (fig. 3-scheme 3) does not react with silver nitrate and compound (X) is formed after removal of the protecting group.

WO 2009/136281 also discloses an alternative method for preparing 15-acylalkylnitric acid bimatoprost derivatives (examples N-1 and O-1). The synthesis involves reacting a boronic ester protected form of bimatoprost (compound of formula (II)) with a nitrate-alkyl carboxylic acid chloride in the presence of 4-Dimethylaminopyridine (DMAP) supported on a resin (PS-DMAP), followed by removal of the boronic ester protecting group and purification by silica gel chromatography.

The above process avoids the use of 6-bromohexanoyl chloride and the removal of silver salts from the final product. However, another major disadvantage of this process is the use of 4-dimethylaminopyridine supported on a resin, which makes the process unsuitable for commercial scale-up and expensive. Moreover, the nitrate-alkylcarboxylic acid chloride is added in two consecutive steps and in a large excess with respect to the compound of formula (II), indeed, the alkylcarboxylic acid chloride is added in an amount of about 2 to 4 equivalents.

WO 2009/136281 also discloses another process for the preparation of 15-acylalkylnitric acid bimatoprost derivatives (example Q1). In this process, the compound is obtained by esterifying a boronic ester protected form of bimatoprost (II) with an excess of nitric acid-alkyl- (p-nitrophenyl) -carboxylic acid ester in the presence of 4-dimethylaminopyridine.

The main disadvantage of this process is the use of chromatography to remove unreacted nitric acid-alkyl- (p-nitrophenyl) -carboxylic acid ester and the by-product p-nitrophenol formed in equimolar amounts to the compound of formula (I).

WO 2016/155906 discloses 15-nitrooxy derivatives of fluprostenol, which reports the synthesis of 15-nitrooxy-hexyl esters of isoproyl fluprostenol. The compound is prepared by reacting isoproyl fluprostenol in the borate protected form with (4-nitrophenyl) -6-nitrohexoate in the presence of an excess of 4-dimethylaminopyridine.

As reported above, the main drawback of this process is the removal of the unreacted nitrate-alkyl- (p-nitrophenyl) -carboxylate and especially the removal of the p-nitrophenol by-product by chromatography.

Over the past several years, regulatory agencies have emphasized purity requirements and impurity identification in Active Pharmaceutical Ingredients (API). At present, any impurity is considered to be an organic substance other than a drug substance, which may affect the efficacy and safety of a pharmaceutical product. Therefore, identification and quantification of various impurities, especially those with mutagenic structural warnings, has become a mandatory regulatory requirement. In addition, because the products are intended for medical use, the range of industrially acceptable reagents, solvents, catalysts, etc., which can be used for the synthesis of the active ingredients is limited to those having medical industrial acceptability.

The compound of formula (I) is an oil, the purification of which in large quantities is difficult because it cannot be crystallized, and therefore the presence of impurities is a critical issue for large-scale production. Since the main sources of impurities are synthetic intermediates and by-products, the purity of the intermediates and the control of the reaction conditions are important requirements for obtaining a final product with a pharmaceutically acceptable purity.

The prior art processes for the preparation of compounds of formula (I) have some drawbacks; for example, the use of bromohexanoyl chloride and reaction conditions resulted in the formation of the 15- (6-chlorohexanoyl) ester of bimatoprost (compound (X)) as a by-product with a potential mutagenic structural warning; the use of silver nitrate for the preparation of the intermediate nitrate-alkylcarboxylic acid chloride or the nitration of the 15- (6-bromohexanoyl) ester of bimatoprost in borate protected form (compound (VIII)) leads to the management of a large amount of silver nitrate waste water and, in addition, the metal content in the active pharmaceutical ingredient must meet certain accepted criteria.

Therefore, there is a need to provide compounds of formula (I) with high purity and good yield.

It has been found that the compounds of formula (I) can be prepared in high purity by using a 6- (nitrooxy) hexanoyl chloride intermediate efficiently prepared via a caprolactone ring-opening reaction followed by nitration.

The present invention provides a large scale production process which provides compounds of formula (I) having high chemical purity and in particular a content of the 15- (6-chlorohexanoyl) ester impurity of bimatoprost below safe levels.

Description of the invention

The object of the present invention is a process for the preparation of hexanoic acid, 6- (nitrooxy) -, (1S,2E) -3- [ (1R,2R,3S,5R) -2- [ (2Z) -7- (ethylamino) -7-oxo-2-hepten-1-yl ] -3, 5-dihydroxycyclopentyl ] -1- (2-phenylethyl) -2-propen-1-yl ester of formula (I):

the method comprises the following steps:

a) reacting a compound of formula (II):

with 6- (nitrooxy) hexanoyl chloride of formula (IV) in the presence of 4-dimethylaminopyridine in free form,

obtaining a compound of formula (III):

b) removing the boronic ester protecting group of the compound of formula (III) to obtain the compound of formula (I).

Free form of 4-Dimethylaminopyridine (DMAP) refers to DMAP not bound to a resin.

Step a) is preferably carried out in an aprotic organic solvent, preferably selected from methyl tert-butyl ether, N-dimethylformamide or dichloromethane. Most preferably, the organic solvent is methyl tert-butyl ether.

The molar ratio of the compound of the formula (II) to the 6- (nitrooxy) hexanoyl chloride of the formula (IV) is preferably from 1:1.4 to 1: 1.6.

The molar ratio of the compound of the formula (II) to 4-dimethylaminopyridine is preferably from 1:2.0 to 1: 2.4.

The reaction of step a) is carried out at a temperature of from 0 ℃ to room temperature.

Preferably, the removal of the boronic ester protecting group (step b) is carried out by reaction with methanol at a temperature of 17 ℃ to 24 ℃.

The 6- (nitrooxy) hexanoyl chloride of formula (IV) is preferably obtained by a process comprising the following steps:

i) reacting a 2-caprolactone of formula (V):

with an inorganic base selected from KOH, NaOH and LiOH to obtain a 6-hydroxycaproic acid salt of formula (VI):

wherein M is K, Na or Li;

ii) with HNO₃And H₂SO₄Nitrating the compound of formula (VI) to obtain 6- (nitrooxy) hexanoic acid of formula (VII),

iii) converting the 6- (nitrooxy) hexanoic acid of formula (VII) to 6- (nitrooxy) hexanoic acid chloride of formula (IV) with a chlorinating agent.

The 6- (nitrooxy) hexanoyl chloride of formula (IV) obtained in step iii) can be reacted directly with the compound of formula (II) in step a) without further purification.

The inorganic base used in step i) is preferably potassium hydroxide.

Step i) is preferably carried out in a solvent selected from methanol, ethanol or isopropanol, most preferably methanol.

Steps ii) and iii) are carried out in dichloromethane.

The chlorinating agent used in step iii) is oxalyl chloride.

The compound of formula (II) is obtained by reacting bimatoprost with butyl boronic acid. Preferably, the reaction is carried out in methyl tert-butyl ether solvent.

Schemes 1 and 2 (fig. 1 and 2) describe in more detail a preferred process for preparing compound (I), which comprises:

step 1) reacting 2-caprolactone of formula (V) with potassium hydroxide in methanol to obtain potassium 6-hydroxycaproate (a compound of formula (VI) wherein M is potassium);

step 2) reacting 6-hydroxycaproic acid potassium salt with HNO₃And H₂SO₄In dichloromethane to obtain 6- (nitrooxy) hexanoic acid (compound of formula (VII));

step 3) reacting 6- (nitrooxy) hexanoic acid with oxalyl chloride to obtain 6- (nitrooxy) hexanoyl chloride (compound of formula (IV), which was used without further purification;

step 4) reacting bimatoprost with butyl boronic acid (1.1-1.8 equivalents) in methyl tert-butyl ether (MTBE) at a temperature of about 40 ℃ followed by removal of water by azeotropic distillation to obtain bimatoprost boronate (compound of formula (II);

step 5) reacting bimatoprost borate (compound of formula (II) with 6- (nitrooxy) hexanoyl chloride (IV) (1.4-1.6 equivalents) in methyl tert-butyl ether in the presence of 4-dimethylaminopyridine (2.0-2.4 equivalents) at a temperature of 0 ℃ to about room temperature to obtain a compound of formula (III);

step 6) reacting the compound shown in the formula (III) with methanol at room temperature to remove a protecting group, so as to obtain a crude product of the compound shown in the formula (I);

and 7) purifying the crude compound of the formula (I) to obtain the compound (I) with the chemical purity higher than 99%.

The process of the present invention is characterized by preparing an intermediate of 6- (nitrooxy) hexanoyl chloride (compound (IV)) in high chemical purity and high yield by ring-opening reaction of 2-caprolactone.

The experimental operation of the steps of the method of the invention is described in detail below. All steps were performed under nitrogen atmosphere.

6- (nitrooxy) hexanoyl chloride (IV) is prepared starting from 2-caprolactone in high purity and high yield (FIG. 1-scheme 1); the synthesis comprises the following steps:

step 1) dropwise adding a solution of potassium hydroxide (1 equivalent) in methanol to a solution of 2-caprolactone (1 equivalent) in methanol; after the addition is complete, the mixture is allowed to cool at about 5 ℃ to 20 ℃ and stirred at 15 ℃ to 20 ℃ for about 5 hours; removing the solvent (at a temperature of 40 ℃ C. or lower), slurrying the crude product in methyl tert-butyl ether, filtering off potassium 6-hydroxycaproate (VI), washing with methyl tert-butyl ether, and drying. Potassium 6-hydroxycaproate (VI) (product of the reaction of (VI)) is obtained in 95% yield and 98.5% purity¹H-NMR and HCl analysis);

step 2) Potassium 6-hydroxycaproate (VI) (1 eq) was added in portions to HNO cooled at 0 ℃ to 5 ℃ in about 30 minutes under nitrogen₃(4.6 equiv.) and H₂SO₄(3.1 equivalents) in a mixture in dichloromethane while maintaining the temperature below 10 ℃; stirring the resulting mixture at 0 ℃ to 10 ℃ for about 2-3 hours by¹H-NMR analysis is carried out to monitor the reaction end point; cooling the mixture at a temperature of 0 ℃ to 5 ℃,a saturated aqueous solution of sodium chloride was added dropwise over about 20 minutes. Maintaining the reaction mixture at a temperature below 10 ℃; drying the organic layer over anhydrous sodium sulfate, removing the solvent to give 6- (nitrooxy) hexanoic acid (VII) in 86-88% yield and 97% HPLC purity;

step 3) adding N, N-dimethylformamide and oxalyl chloride dropwise to a solution of 6- (nitrooxy) hexanoic acid (VII) in dichloromethane, maintaining the solution temperature at 0 ℃ to 5 ℃ for 1 hour, and then stirring the mixture at 15 ℃ to 30 ℃ for 24 hours; the solvent was removed by evaporation to give 6- (nitrooxy) hexanoyl chloride (IV) in 88-97% yield, which was used without further purification.

The esterification process between bimatoprost and 6- (nitrooxy) hexanoyl chloride comprises the synthetic steps disclosed below:

step 4) adding bimatoprost to methyl tert-butyl ether and cooling the resulting solution to about 15 ℃ to 18 ℃; n-butylboronic acid (1.11-1.18 equivalents) is then added in one portion and the mixture is stirred at 40 ℃ for about 1-1.5 hours. By passing¹HNMR analysis monitors the reaction endpoint; the reaction mixture is cooled to about 20 ℃ to 25 ℃, filtered and the water formed is removed by azeotropic distillation with methyl tert-butyl ether at a temperature equal to or lower than 40 ℃ until the water content is lower than or equal to 0.25% to give the crude bimatoprost boronate (II) which is used directly in the next step;

step 5) add crude bimatoprost borate to methyl tert-butyl ether, cool the resulting solution to about 0 ℃ to 5 ℃, add 4-dimethylaminopyridine (about 2.1-2.3 equivalents), add 6- (nitrooxy) hexanoyl chloride (compound (IV)) (1.5 equivalents) dissolved in methyl tert-butyl ether dropwise while maintaining the mixture temperature at about 0 ℃ to 5 ℃. After addition, the mixture was stirred at about 0 ℃ to 5 ℃ for up to 4 hours and then stirred up to 15 ℃ to 20 ℃ overnight; the end of the reaction was monitored by HPLC analysis; isolation of (1S,2E) -3- { (6R,7R) -3-butyl-7 [ (2Z) -7- (ethylamino) -7-oxohept-2-en-1-yl ] -2, 4-dioxa-3-borabicyclo [3.2.1] oct-6-yl } -1- (2-phenylethyl) -prop-2-en-1-yl-6- (nitrooxy) hexanoate (compound (III)) by standard work-up procedures (example 1 describes an example of work-up);

step 6) dissolving the compound (III) in methanol, and stirring the resulting solution at 17 ℃ to 25 ℃ for about 18 hours; by passing¹H NMR monitored the conversion of compound (III) to compound (I). Once the reaction had stopped, the mixture was evaporated and redissolved in fresh methanol until complete conversion; the reaction mixture is then concentrated in vacuo at a temperature below 40 ℃ and the crude compound (I) is isolated by standard work-up procedures;

step 7) the crude product of the product (I) obtained is purified by column chromatography using a silica gel column and a mixed solvent of dichloromethane and methanol to obtain the compound (I) in a combined yield higher than 60% starting from bimatoprost and in a purity higher than 99%.

The process of the present invention provides compounds of formula (I) in high yield and purity while reducing the amount of by-products, in particular (S, E) -1- ((1R,2R,3S,5R) -2- ((Z) -7- (ethylamino) -7-oxohept-2-enyl) -3, 5-dihydroxycyclopentyl) -5-phenylpent-1-en-3-yl 6-chlorohexanoate (compound (X)) with a potential mutagenic structure warning.

The above advantages make the process of the present invention a cost effective process that can be easily converted to an industrial scale.

Examples

All synthesis steps described below were carried out under nitrogen atmosphere.