Optical resolution method substituting oxyphosphonate acetate

An optical resolution, phosphine-based technology, applied in the optical resolution of racemates, splitting and substituting phosphinyl acetic acid to obtain its single enantiomer, can solve the problem of high solvent consumption and poor optical resolution method It can reduce the environmental pollution, increase the separation yield, and achieve the effect of simple and efficient recycling

Inactive Publication Date: 2009-06-10
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In order to overcome the existing [(R)-[(1S)-2-methyl-1-(1-oxopropoxy) propoxy] (4-phenylbutyl) phosphinyl] acetic acid and [ The optical properties of the racemate composed of (S)-[(1R)-2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid The yield of the resolution method is not high, and there are many defects such as solvent consumption, the present invention is proposed

Method used

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  • Optical resolution method substituting oxyphosphonate acetate
  • Optical resolution method substituting oxyphosphonate acetate
  • Optical resolution method substituting oxyphosphonate acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Mix and stir 10,11-dihydrocinchonidine (1) (3.56g, 12mmol) and ethyl acetate (30ml) to form a suspension, then add Base-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid (2) and [(S)-[(1R)-2-methyl-1- (1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]racemate (7.68g, 20mmol) composed of acetic acid (3), heated to reflux with stirring until all solids Dissolved and filtered while hot. Add seed crystals to the filtrate, cool and crystallize. Suction filtration and vacuum drying gave the salt (4) generated from (2) and 10,11-dihydrocinchonidine (1) as a white solid (4.3g): melting point 125-126°C, [α] 20 D -31.7° (c=1, MeOH). A part of it was acidified and freed with dilute hydrochloric acid, and then extracted with dichloromethane to obtain oil (1): [α] 20 D +45.2° (c=1, EtOAc), the ee value determined by chiral stationary phase HPLC is 97.3%.

[0037] Get the above-mentioned salt (4) generated by (2) and 10,11-dihydrocinchonidine (1) and recrystallize on...

Embodiment 2

[0042] Mix and stir 10,11-dihydrocinchonidine (1) (7.11g, 24mmol) and ethyl acetate (68ml) to form a suspension, then add Base-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid (2) and [(S)-[(1R)-2-methyl-1- (1-Oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid (3) racemate (11.53g, 30mmol), stirred and heated until all solids were dissolved. Cool and crystallize. Suction filtration and vacuum drying gave the salt (4) formed from (2) and 10,11-dihydrocinchonidine (1) as a white solid (5.88g): melting point 122.1-125.4°C.

[0043] Get the above-mentioned salt (4) generated by (2) and 10,11-dihydrocinchonidine (1), and recrystallize once in ethyl acetate to obtain purified salt (4) produced by (2) and 10,11-dihydrocinchonidine (1). The salt (4) formed by hydrocinchonidine (1) is a white solid with a melting point of 123.4—126.5°C.

Embodiment 3

[0045] Mix and stir 10,11-dihydrocinchonidine (1) (2.96g, 10mmol) and ethyl acetate (60ml) to form a suspension, then add Base-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid (2) and [(S)-[(1R)-2-methyl-1- (1-Oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid (3) racemate (7.68g, 20mmol), stirred and heated until all solids were dissolved. Cool and crystallize. Suction filtration and vacuum drying gave the salt (4) generated by (2) and 10,11-dihydrocinchonidine (1) as a white solid (3.13g): melting point 124.9—126°C, [α] 20 D -29.6° (c=1, MeOH).

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Abstract

This invention provides a optical resolution preparation that substitutes oxygen phosphino-acetic acid, concretely relating to optical resolution preparation of racemoid which consists of [(R)-[(1S)-2-methyl-1-(1-keto-propoxy) propoxy] ( 4-benzene butyl)oxygen phosphino]acetic acid and [(S)-[(1R)-2-methyl-1- (1-keto-propoxy)propoxy](4- benzene butyl)oxygen phosphino]acetic acid. The preparation of this invention uses 10,11-di-H Cinchonidine shown in following formula(1) as resolution agent, compared with present resolution preparation, the yield and optical purity of resolution is obviously raised, it need not recryst many times to depurate, and dosis of resolution agent is reduced.

Description

technical field [0001] The invention relates to a method for resolving enantiomer mixtures in the chemical field, in particular to a method for resolving substituted phosphinyl acetic acid to obtain its single enantiomer. More specifically, the present invention relates to the formation of [(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid and [(S)-[(1R)-2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid racemate optical resolution method. Background technique [0002] [(R)-[(1S)-2-Methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid and [(S)-[( 1R)-2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid is shown in the following formulas (2) and (3), Their optical properties are opposite, and they form racemates together under equal conditions. Wherein [(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid is an angiotensin-converting enzyme (ACE) inhibitor fosi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D451/02C07F9/32
Inventor 张庆文刁圆圆许艳艳时惠麟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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