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CN-116829537-B - Process for preparing prostaglandin analogues supplied with nitric oxide

CN116829537BCN 116829537 BCN116829537 BCN 116829537BCN-116829537-B

Abstract

The present invention relates to a process for the preparation of (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 6- (nitrooxy) -hexanoate of formula (I). According to the present invention, by coupling a borate protected form of bimatoprost with 6- (nitroxide) hexanoyl chloride and removing the borate protecting group, compound (I) can be efficiently prepared in high purity. The invention also relates to a process for preparing 6- (nitroxyl) hexanoic acid having an HPLC purity of equal to or greater than 99% and containing 6- { [6- (nitroxyl) hexanoyl ] oxy } hexanoic acid (compound (IXa)) in an amount of equal to or less than 0.2%.

Inventors

  • N. Almilant
  • RONSIN GAEL
  • K. Dixie
  • G. GOLAN
  • J. Kuzan
  • A. Bruno

Assignees

  • 尼科斯股份有限公司

Dates

Publication Date
20260508
Application Date
20210203

Claims (11)

  1. 1. A process for the preparation of (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 6- (nitrooxy) -hexanoate of formula (I), The method comprises the following steps: step A) the 6- (nitroxide) hexanoyl chloride (VIIIb) is prepared as follows: 1a) Making epsilon-caprolactone With an inorganic base selected from KOH, naOH and LiOH in a solvent selected from methanol, ethanol or isopropanol at a temperature of 20 ℃ to the reflux temperature of the solvent to obtain a 6-hydroxyhexanoate salt of formula (X) Wherein M is K, na or Li; 2a) Purifying the 6-hydroxyhexanoate salt of formula (X) obtained in step 1 a), comprising: i. Adding methyl tert-butyl ether to the reaction mixture of step 1 a) in a methyl tert-butyl ether/reaction mixture volume ratio of 2:1; filtering the solid; Slurrying the solid with a mixture of methyl tertiary butyl ether, methanol and water in a ratio of 3:1 to 5:1, the amount of water being 0.3-1 mole per mole of epsilon-caprolactone; isolating a 6-hydroxyhexanoate salt solid of formula (X); 3a) Reacting 6-hydroxyhexanoate with a mixture of fuming HNO 3 and concentrated H 2 SO 4 in methylene chloride at a temperature in the range of 0 ℃ to 10 ℃; 4a) Adding water to the nitration mixture of step 3 a) while maintaining the temperature between 0 ℃ and 5 ℃; 5a) The organic phase is separated, dried over sodium sulphate and the solvent is distilled off to obtain crude 6- (nitroxide) hexanoic acid (VIIIa) 6A) Reacting crude 6- (nitroxide) hexanoic acid (VIIIa) with a chlorinating agent in dichloromethane to obtain crude 6- (nitroxide) hexanoyl chloride (VIIIb); Step B) preparation of (1 s,2 e) -3- [ (1 r,2r,3s,5 r) -2- [ (2Z) -7- (ethylamino) -7-oxo-2-hepten-1-yl ] -3, 5-dihydroxycyclopentyl ] -1- (2-phenylethyl) -2-propen-1-yl 6- (nitrooxy) -hexanoate (I), comprising the steps of: 1b) Reacting bimatoprost with butyl boric acid in methyl tert-butyl ether at a temperature of 40 ℃ to obtain compound (II): 2b) Reacting compound (II) with crude 6- (nitroxide) hexanoyl chloride (VIIIb) of step 6 a) in the presence of 4-dimethylaminopyridine in free form in an aprotic organic solvent to obtain compound (XI) 3B) Removing the borate protecting group to obtain a crude compound of formula (I); 4b) The crude compound (I) was purified by column chromatography.
  2. 2. The process according to claim 1, wherein in step 1 a) the inorganic base is KOH, the solvent is methanol, and the reaction is carried out at the reflux temperature of methanol.
  3. 3. The process according to claim 2, wherein in step 3 a) the potassium salt of 6-hydroxycaproic acid is added to a mixture of fuming HNO 3 and concentrated H 2 SO 4 in dichloromethane at a temperature of 0 ℃ to 10 ℃, and the reaction mixture is vigorously stirred at a temperature of 0 ℃ to 5 ℃ for 60±15 minutes.
  4. 4. The process according to claim 1, wherein in step 6 a) the chlorinating agent is oxalyl chloride.
  5. 5. The process according to claim 2, wherein in step 6 a) the chlorinating agent is oxalyl chloride.
  6. 6. A process according to claim 3, wherein in step 6 a) the chlorinating agent is oxalyl chloride.
  7. 7. The process according to any one of claims 1 to 6, wherein in step 2 b) the aprotic solvent is methyl tert-butyl ether at a temperature in the range of 0 ℃ to 20±3 ℃.
  8. 8. The process according to any one of claims 1 to 6, wherein in step 2 b) the molar ratio of compound (II) to 4-dimethylaminopyridine is from 1:2.0 to 1:2.4.
  9. 9. The process according to any one of claims 1 to 6, wherein in step 3 b) the solvent used in the reaction is methanol and the reaction is carried out at room temperature.
  10. 10. The process according to any one of claims 1 to 6, wherein in step 4 b) the crude compound (I) is purified using high performance silica gel chromatography and dichloromethane/methanol as mobile phase.
  11. 11. A method of synthesizing 6- (nitroxide) hexanoic acid comprising: 1a) Making epsilon-caprolactone With KOH in methanol at the reflux temperature of the solvent; 2a) Adding methyl tert-butyl ether to the reaction mixture of step 1 a) in a methyl tert-butyl ether/reaction mixture volume ratio of 2:1; 2a) Filtering the potassium 6-hydroxycaproate solid; 2a) Slurrying the solid with a mixture of methyl tert-butyl ether, methanol and water in a ratio of 3:1 to 5:1, the amount of water being 0.3-1 mole per mole of epsilon-caprolactone; 2a) Isolating a potassium 6-hydroxycaproic acid salt solid; 3a) Adding the potassium salt of 6-hydroxycaproic acid of step 2 a) to a mixture of fuming HNO 3 and concentrated H 2 SO 4 in methylene chloride at a temperature in the range of 0 ℃ to 10 ℃, vigorously stirring the reaction mixture at a temperature of 0 ℃ to 5 ℃; 4a) Adding water to the nitration mixture of step 3 a) while maintaining the temperature between 0 ℃ and 5 ℃; 5a) The organic phase is separated, dried over sodium sulphate and the solvent is distilled off to obtain 6- (nitroxyl) hexanoic acid characterized by a chemical purity equal to or greater than 99% and a content of 6- { [6- (nitroxyl) hexanoyl ] oxy } hexanoic acid equal to or lower than 0.2%.

Description

Process for preparing prostaglandin analogues supplied with nitric oxide Technical Field The present invention relates to a process suitable for the large-scale preparation of (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 6- (nitrooxy) -hexanoate of formula (I), which allows obtaining said product with high chemical purity. The invention also describes the preparation of high purity 6- (nitroxide) hexanoic acid (VIIIa) as a key intermediate for synthesis. Background (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 6- (nitrooxy) -hexanoate of formula (I) Is a prostaglandin analogue which has been shown to be effective as an IOP-lowering agent (Impagnatiello F,Toris CB,Batugo M,Prasanna G,Borghi V,Bastia E,Ongini E,Krauss AHP;Invest Ophthalmol Vis Sci.2015;56:6558-64). The effect of two ophthalmic solutions containing compound (I) as active pharmaceutical ingredient (0.065% and 0.1%) on lowering intraocular pressure (IOP) was evaluated in open angle glaucoma or ocular hypertension patients in a first phase 3 clinical trial beginning at 6 of 2020. Over the past few years, various regulatory authorities have emphasized purity requirements and impurity identification in Active Pharmaceutical Ingredients (APIs). Presently, any impurity is considered to be an organic substance that can affect the efficacy and safety of a pharmaceutical product in addition to the drug substance. Thus, identification and quantification of individual impurities, particularly those that carry a mutagenic structural alert, has become a mandatory regulatory requirement. In addition, since the active pharmaceutical ingredient is intended for pharmaceutical use, reagents, solvents, catalysts, etc. useful in the synthesis of the active ingredient are limited to those acceptable in the pharmaceutical industry. The (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 6- (nitrooxy) -hexanoate (I) is an oil whose large scale purification is difficult because of the inability of the compound (I) to crystallize, and the presence of impurities is a key issue for large scale production. The main impurities are, as known from the prior art processes for preparing compound (I), 15- (6-chlorohexanoyl) ester of bimatoprost (bimatoprost) of formula (V) when the nitration step is carried out at the end of the synthesis as disclosed in WO 2009/136281; Or by-products of the nitration step of preparing the intermediate 6- (nitroxide) hexanoic acid (VIIIa), resulting in the formation of bimatoprost 6- { [6- (nitroxide) hexanoyl ] oxy } hexanoate (VII) Thus, control of reagent purity and reaction conditions is an important requirement to obtain compound (I) with pharmaceutically acceptable purity. WO 2009/136281 discloses a process for preparing a compound of formula (I). WO 2009/136281 discloses the synthesis and generalization of compound (I) and the preparation of bimatoprost 15-alkyl nitrate. WO 2009/136281 discloses the synthesis of compounds of formula (I) (example B-1) by reacting a borate protected form of bimatoprost (II) with 6-bromohexanoyl chloride to give a borate protected form of bimatoprost 15- (6-bromohexanoyl) ester of formula (III), which is converted to a nitric acid derivative by silver nitrate in acetonitrile, deprotected and purified under reverse phase chromatography to give compounds of formula (I). The main disadvantages of the above synthesis are the use of more than equimolar amounts of 6-bromohexanoyl chloride in the esterification reaction, which presents a potentially mutagenic structural warning, and the use of silver nitrate in the final step, which generates large amounts of silver salts in the wastewater. Another major disadvantage of this process is the formation of impurities and byproducts such as the bimatoprost 15- (6-bromohexanoyl) ester of formula (IV) and the bimatoprost 15- (6-chlorohexanoyl) ester of formula (V) which are difficult to remove even after multiple purifications, because they have similar polarity, similar lipophilicity and/or solubility in chromatography as compound (I). Moreover, compound (V) was predicted positive for bacterial in vitro mutagenicity according to statistical-based methods and expert rule-based methods as required by regulatory authorities. Compound (IV) also has a structurally-alerted halogenated chain that is recognized as potentially genotoxic. The removal of these impurities requires repeated purification, which further reduces the yield and increases the cost of preparing compound (I) on a commercial scale. According to the procedure disclosed in WO 2009/136281, bimatoprost 15- (6-bromohexanoyl) ester (IX) is an impurity derived from incomplete reaction of compound (III) with silver nitrate aft