Process for producing optically active carboxylic acid

A production method and technology of water ethyl acetate, applied in the production field of optically active carboxylic acid, can solve the problems such as expensive D-pantolactone

Inactive Publication Date: 2012-01-11
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, D-pantolactone is expensive

Method used

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  • Process for producing optically active carboxylic acid
  • Process for producing optically active carboxylic acid
  • Process for producing optically active carboxylic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0132] (Example 1) (R)-α-phenethylamine salt of (S)-3-cyclohexene-1-carboxylic acid

[0133] 3-Cyclohexene-1-carboxylic acid (1.0 kg) was dissolved in 4.8% aqueous acetone (7.5 L). To this solution was gradually added a solution of (R)-α-phenethylamine (624.3 g) dissolved in 4.8% aqueous acetone (500 ml) at 50°C, and the mixture was stirred at this temperature for 4 hours. The suspension was cooled to 35°C and stirred at this temperature for 16 hours, then further stirred at 10°C for 3 hours. The suspension was filtered under reduced pressure to obtain 837.1 g of the title compound as white crystals. Its optical purity is 63%de. Subsequently, 4.8% aqueous acetone (5.6 L) was added to the obtained salt (700 g), and the mixture was stirred under heating to reflux for 5 hours, at 30° C. for 13 hours, and then under cooling with ice for 3 hours. The suspension was filtered under reduced pressure to obtain 519.4 g of the title compound as white crystals. Its optical purity is 8...

Embodiment 2

[0138] (Example 2) (R)-α-phenethylamine salt of (S)-3-cyclohexene-1-carboxylic acid

[0139] 3-Cyclohexene-1-carboxylic acid (30 g) was dissolved in 3% aqueous ethyl acetate (150 ml). To this solution was gradually added a solution of (R)-α-phenethylamine (23.0 g) dissolved in 3% aqueous ethyl acetate (30 ml) at 55°C, and the mixture was stirred at this temperature for 6 hours. The suspension was stirred at 25°C for 5 hours and further at -10°C for 2.5 hours. The suspension was filtered under reduced pressure to obtain 32.9 g of the title compound as white crystals. Its optical purity is 49%de. To the obtained salt (32.7 g) was then added 3% aqueous ethyl acetate (196 ml), and the mixture was stirred at 55°C for 3 hours, then at 25°C for 5 hours, and further at -10°C for 2.5 hours. The suspension was filtered under reduced pressure to obtain 24.7 g of the title compound as white crystals. Its optical purity is 78%. To the obtained salt (24.6 g) was further added 3% aqueou...

Embodiment 3

[0146] (Example 3) (S)-3-cyclohexene-1-carboxylic acid

[0147] To (R)-α-phenethylamine salt of (S)-3-cyclohexene-1-carboxylic acid (1.0 g, 97% de) was added methyl tert-butyl ether (20 ml) and 1N hydrochloric acid solution until the The pH of the solution becomes 1. The mixture was stirred at room temperature for 1 hour. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain 504 mg of the title compound as a colorless oil.

[0148] 1H-NMR (CDCl3) δ: 1.64-1.75 (1H, m), 1.99-2.20 (3H, m), 2.24-2.30 (2H, m), 2.56-2.63 (1H, m), 5.63-5.70 (2H, m)

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Abstract

It has been demanded to provide a process for industrially producing an intermediate for a compound that exhibits an inhibitory effect on activated blood coagulation factor X and is useful as a preventive and / or therapeutic agent for thrombotic diseases. The present invention provides a process for producing the (R-+--phenylethylamine salt of (S)-3-cyclohexene-1-carboxylic acid, comprising reacting 3-cyclohexene-1-carboxylic acid and (R)-+--phenylethylamine using a mixed solvent of water and acetone or a mixed solvent of water and ethyl acetate as a solvent.

Description

technical field [0001] The present invention relates to a production method of an intermediate of a compound that exhibits an inhibitory effect on activated blood coagulation factor X (also called activated factor X or FXa) and can be used as a preventive and / or therapeutic drug for thrombotic diseases . Background technique [0002] Known, for example, N represented by the following formula (X) 1 -(5-chloropyridin-2-yl)-N 2 -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c] Pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (ethanediamide): [0003] [0004] Or its salt, or its hydrate, for example the p-toluenesulfonic acid monohydrate of the compound X represented by following formula (Y): [0005] [0006] is a compound that exhibits an inhibitory effect on activated blood coagulation factor X (also referred to as activated factor X or FXa) and is useful as a prophylactic and / or therapeutic drug for thrombotic diseases ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/41C07B57/00C07C51/02C07C51/09C07C51/43C07C51/493C07C61/22
CPCC07C51/43C07C51/02C07C2101/16C07C51/412C07C51/353C07B2200/07C07B57/00C07C2601/16C07C61/22C07C51/41
Inventor 佐藤耕司久保田和夫
Owner DAIICHI SANKYO CO LTD
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