Optical active substitution oxyphosphonate salt acetate and its use

A technology of phosphine oxide group and oxo propoxy group is applied in the field of high-efficiency optical resolution of substituted phosphinyl acetic acid, which can solve the problems of high solvent consumption and low yield of the optical resolution method, and achieves reduction of environmental pollution, Improve split yield, simple and efficient recovery

A technology of phosphine oxide group and oxo propoxy group is applied in the field of high-efficiency optical resolution of substituted phosphinyl acetic acid, which can solve the problems of high solvent consumption and low yield of the optical resolution method, and achieves reduction of environmental pollution, Improve split yield, simple and efficient recovery

CN1955185AInactive Publication Date: 2007-05-02SHANGHAI INST OF PHARMA IND CO LTD
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  • Optical active substitution oxyphosphonate salt acetate and its use
  • Optical active substitution oxyphosphonate salt acetate and its use
  • Optical active substitution oxyphosphonate salt acetate and its use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 10,11-Dihydrocinchonidine (4) (3.56g, 12mmol) and ethyl acetate (30ml) were mixed and stirred to form a suspension, and then added with [(R)-[(1S)-2-methyl 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 under stirring Dissolved and filtered while hot. Add seed crystals to the filtrate, cool and crystallize. Suction filtration and vacuum drying gave the salt (1) generated from (2) and 10,11-dihydrocinchonidine (4) 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 (2): [α] 20 D +45.2° (c=1, EtOAc), the ee value determined by chiral stationary phase HPLC is 97.3%.

[0038] Get above-mentioned salt (1) generated by (2) and 10,11-dihydrocinchonidine (4)...

Embodiment 2

[0042] 10,11-Dihydrocinchonidine (4) (7.11g, 24mmol) and ethyl acetate (68ml) were mixed and stirred to form a suspension, and then added by [(R)-[(1S)-2- 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. After suction filtration and vacuum drying, the salt (1) formed from (2) and 10,11-dihydrocinchonidine (4) was obtained as a white solid (5.88 g): melting point 122.1-125.4°C.

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

Embodiment 3

[0045] 10,11-Dihydrocinchonidine (4) (2.96g, 10mmol) and ethyl acetate (60ml) were mixed and stirred to form a suspension, and then added by [(R)-[(1S)-2- 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 (1) generated from (2) and 10,11-dihydrocinchonidine (4) 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 salt that is produced by [(R)-[(1S)-2-methyl-1- (1-keto-propoxy)propoxy](4-benzene butyl) oxygen phosphino]acetic acid and 10,11-di-H Cinchonidine, its structure is shown by formula(1). This invention also provides preparation of using this salt to optically split 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. Compared with present resolution preparation, the yield and optical purity of resolution is obviously raised, it needs not recryst many times to depurate, and dosis of resolution agent is reduced.

Description

technical field [0001] The present invention relates to the method for separating enantiomeric mixture in chemical field, be specifically related to by [(R)-[(1S)-2-methyl-1-(1-oxopropoxy) propoxy] A salt formed from (4-phenylbutyl)phosphinyl]acetic acid and 10,11-dihydrocinchonidine, and a method for carrying out high-efficiency optical resolution of the substituted phosphinylacetic acid through the salt. 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 fosinopril sodium (fosinopril sodium) is an important intermediate. [0003] [0004] ...

Claims

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Application Information

Patent Timeline
02 May 2007
Publication
CN1955185A
IPC
C07F9/32; C07D401/14
Inventors
张庆文; 刁圆圆