Enzymatic synthesis of ivabradine midbody and application in the synthesis of ivabradine and addition salts thereof

A synthetic method and enzymatic technology, which can be used in organic chemistry methods, chemical instruments and methods, preparation of organic compounds, etc., and can solve problems such as low yields

Inactive Publication Date: 2013-08-14
SERVIER LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] This very low yield is caused by the low yield (4-5%)

Method used

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  • Enzymatic synthesis of ivabradine midbody and application in the synthesis of ivabradine and addition salts thereof
  • Enzymatic synthesis of ivabradine midbody and application in the synthesis of ivabradine and addition salts thereof
  • Enzymatic synthesis of ivabradine midbody and application in the synthesis of ivabradine and addition salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0124] Example 1 :3,4-Dimethoxybicyclo[4.2.0]oct-1,3,5-triene-7-carboxylic acid

[0125] 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (11 g, 58.1 mmol) was suspended in 1N sodium hydroxide solution (70 mL) and The reaction mixture was refluxed (110°C) for 2 hours.

[0126] After returning to ambient temperature, the mixture was acidified with concentrated hydrochloric acid. Precipitation was observed.

[0127] The product was dissolved in 200 mL of dichloromethane, and the aqueous phase was extracted. with MgSO 4 Drying and evaporation gave the title product in 95.9% yield (11.6 g).

Embodiment 2

[0128] Example 2 :(7S)-3,4-Dimethoxybicyclo[4.2.0]oct-1,3,5-triene-7-carboxylic acid

[0129] 0.5 g (c=200 g / L) of the racemic acid obtained in Example 1 was dissolved in 2.5 mL of an 8 / 2 mixture of acetonitrile / methanol.

[0130] Then 0.1g (c=40g / L) lipase of Candida antarctica (Candida antarctica) (Novozymes Denmark) was added to the mixture (E / S ratio 1 / 5). The reaction mixture was kept at 30° C. with rotary stirring at 220 rpm for 48 hours.

[0131] The reaction was monitored by chiral phase HPLC under conditions enabling the determination of the enantiomeric excess of both the ester and the acid:

[0132] IC250*4.6 column

[0133] 30% anhydrous ethanol + 0.1% TFA + 70% heptane + 0.1% TFA

[0134] 1ml / min, 25°C, 288nm

[0135]

[0136] The chiral phase HPLC chromatograms of the racemic compound and the product after 48 hours are shown in figure 1 and 2 shown.

[0137] After 48 hours, optically pure ester and acid were seen to be provided at an optimal acid...

Embodiment 3

[0141] Example 3 : Methyl 3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-triene-7-carboxylate

[0142] Suspend methyl (7R)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate (445 mg) (ee>96%) in isopropyl Alcohol (2.5 mL), and diazabicycloundecene (58 μl-1.5 eq) was added.

[0143] The reaction mixture was heated at 65°C for 2 hours. Complete racemization was observed at the end of 2 hours of the ester reaction.

[0144] Analysis conditions:

[0145] IC250*4.6 column

[0146] 30% anhydrous ethanol + 0.1% TFA + 70% heptane + 0.1% TFA

[0147] 1ml / min, 25°C288nm

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Abstract

Preparing an optically pure (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid compound (I), comprises enantioselective enzymatically esterifying a racemic acid or 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (a), using a lipase or esterase, in a mixture of an alcohol and an organic cosolvent, at a temperature of 25-40[deg] C, where (a) is not pure, has a concentration of 5-500 g/l, and has an enzyme/substrate (E/S) ratio of 10/1:1/100. Preparing an optically pure (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid compound (I), comprises enantioselective enzymatically esterifying a racemic acid or 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (a), using a lipase or esterase, in a mixture of an alcohol of formula (ROH) and an organic cosolvent, at a temperature of 25-40[deg] C, where (a) is not pure, has a concentration of 5-500 g/l, and has an enzyme/substrate (E/S) ratio of 10/1:1/100. R : linear or branched 1-6C-alkyl, preferably methyl. Independent claims are included for: (1) process-II for preparing an optically pure compound of formula (S)3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid compound of formula (II) by enantioselective enzymatic hydrolysis of the racemic ester or ester compound of formula (b) using the lipase or esterase, in water and in a buffer solution of pH 5-8 or in a mixture of organic solvent and water or buffer at a temperature of 25-40[deg] C, where (b) is not pure, and has E/S ratio of 10/1:1/100; and (2) process-III for preparing ((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-trien-7-ylmethyl)-methyl-amine compound (III) comprising either hydrolyzing 3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (IV) to form (a), enzymatically esterifying (a) to form (I), converting (I) into an optically pure (S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid methylamide amide (c) and reducing (c), or hydrolyzing (IV) to form (a), alkylating (a) to form (b), enzymatically hydrolyzing (b) to obtain (II), converting (II) into (c), and reducing (c). [Image].

Description

technical field [0001] The present invention relates to the method for enzymatically synthesizing the compound of formula (I): [0002] [0003] where R 1 stands for hydrogen atom or C 1 -C 6 Alkyl group, preferably methyl, [0004] It also relates to its role in the synthesis of ivabradine or 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octane-1,3,5- Trien-7-yl]methyl}(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine Use of -2-ketones, their addition salts with pharmaceutically acceptable acids, and their hydrates [0005] Background technique [0006] Ivabradine and its addition salts with pharmaceutically acceptable acids, more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, which These compounds can be used to treat or prevent various clinical manifestations of myocardial ischemia, such as angina pectoris, myocardial infarction and related rhythm disturbances, an...

Claims

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Application Information

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IPC IPC(8): C12P41/00C12P7/40C12P7/62C12P13/00
CPCC12P17/10C07D223/16C07C69/753C07C213/08C12Y301/01C07C51/08C07C217/58C07C67/08C12P7/62C07C62/34C07C2102/06C12P13/001C12P7/40C12P41/005A61P9/00C07B2200/07C07C213/02C07C231/02C07C2602/06C07C69/757C07C217/74C07C235/40C07C61/04C12N9/14C12P23/00C12P41/00Y02P20/52
Inventor S·佩德拉戈萨莫罗F·勒富隆
Owner SERVIER LAB
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