Preparation method of S-(+)-o-chlorobenzoyl glycine

A technology of o-chlorophenylglycine and o-chlorobenzaldehyde is applied in the preparation of organic compounds, chemical instruments and methods, cyanide reaction preparation, etc., and can solve the problems of low actual yield, high raw material cost, long process route and the like, Achieve the effect of low cost of raw materials, less use of organic solvents and simple process

Inactive Publication Date: 2009-10-21
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 1. When performing resolution, it is necessary to use high-purity chiral acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, lactic acid, maleic acid, amino acids and derivatives of these acids, etc., and the cost of raw materials is high
[0006] 2. Synthesis of clopidogrel by splitting chiral intermediates, long process route and high energy consumption
[0007] 3. The theoretical yield of the resulting split product is only about 50%, and the actual yield is even lower

Method used

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  • Preparation method of S-(+)-o-chlorobenzoyl glycine
  • Preparation method of S-(+)-o-chlorobenzoyl glycine
  • Preparation method of S-(+)-o-chlorobenzoyl glycine

Examples

Experimental program
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Effect test

Embodiment 1

[0019] A preparation method of (±)-o-chlorophenylhydantoin, the synthetic route is as follows:

[0020]

[0021] The specific process of the preparation method is: 5.6g of o-chlorobenzaldehyde, 2.6g of potassium cyanide and 9.1g of ammonium carbonate are added to 50ml of 50% ethanol aqueous solution under stirring, and the temperature is raised to 55-65°C. , kept stirring and reacting for 24 hours, cooled to room temperature, adjusted pH 2 to 3 with hydrochloric acid, filtered, washed with water, and dried to obtain (±)-o-chlorophenylhydantoin crude product, which was recrystallized with water to obtain 6.8 g of white crystals. The yield is 80%, m.p175~177°C, and the purity (HPLC) is 99.80%.

Embodiment 2

[0023] A kind of preparation method of S-(+)-o-chlorophenylglycine formic acid, the reaction involved in it is shown in the following formula:

[0024]

[0025] The specific process of the preparation method is as follows: 6.8g of the crystallization of (±)-o-chlorophenylhydantoin obtained in Example 1 and 100ml of water are stirred and mixed evenly, and an aqueous sodium hydroxide solution is added to adjust the pH to 8.5, and Agrobacterium Agrabacterium radiobacter CPU4211 bacterium (provided by sigma-aldrich company) 1g, under nitrogen protection and 40 ℃, shake reaction for 42 hours, centrifuge, discard the precipitate, after the filtrate is decolorized with activated carbon, add 200ml dichloromethane, stir and At 0-5°C, adjust the pH to 4-5 with hydrochloric acid, separate the dichloromethane layer, and extract the water layer twice with 100ml of dichloromethane. The dichloromethane layers were combined, dried over anhydrous magnesium sulfate, and concentrated to dryne...

Embodiment 3

[0027] A kind of preparation method of S-(+)-o-chlorophenylglycine methyl ester, its specific process is as follows: the crystallization of (±)-o-chlorophenylhydantoin and 1000ml water of 70g embodiment 1 gained are stirred and mixed, Add aqueous sodium hydroxide solution to adjust the pH to 9, add 12 g of Agrabactarium radiobacter CPU4211 cells (provided by sigma-aldrich company), shake the reaction for 48 hours under nitrogen protection and a temperature of 40 ° C, centrifuge, discard the precipitate, After the filtrate was decolorized with activated carbon, 200ml of dichloromethane was added, and the pH was adjusted to 4-5 with hydrochloric acid under stirring at a temperature of 0-5°C. The dichloromethane layer was separated, and the aqueous layer was extracted twice with 1000ml of dichloromethane. The dichloromethane layers were combined, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain 54 g of white solid, namely S-(+)-o...

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Abstract

The invention relates to a preparation method of S-(+)-o-chlorobenzoyl glycine, which comprises the following steps: firstly, o-chlorobenzaldehyde, potassium cyanide and ammonium carbonate are used as raw materials for synthesizing (plus or minus) o-chlorobenzoyl-hydantoin; and then agrobacterium is used as enzyme and the S-(+)-o-chlorobenzoyl-hydantoin is selectively hydrolyzed into S-(+)-o-chlorobenzoyl glycine, and R-(-)-o-chlorobenzoyl-hydantoin is self-racemized and hydrolyzed into S-(+)-o-chlorobenzoyl glycine. Compared with the traditional splitting method, no chiral compound is used in the production technique, chiral products are obtained directly through enzyme catalysis and splitting is not needed, therefore, the production technique has high yield, low cost and simplified technique; in addition, as the technology of enzyme catalysis is used, less organic solvent is used and less waste is produced in the whole production technical process, thus being beneficial to the environmental protection.

Description

technical field [0001] The invention relates to a preparation method of S-(+)-o-chlorophenylglycine. Background technique [0002] Clopidogrel (Clopidogrel, chemical name is (2S)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothiophene[3,2-c]pyridin-5-yl ) methyl acetate) is a safe and effective platelet aggregation inhibitor, and its structural formula is as follows: [0003] [0004] In the prior art, there are many reports about the preparation method of clopidogrel, which are roughly divided into two categories: one is first to chemically synthesize (±) 2-(2-chlorophenyl)-2-(4,5,6,7 -tetrahydrothiophene[3,2-c]pyridin-5-yl)methyl acetate, and then the (±)2-(2-chlorophenyl)-2-(4, Methyl 5,6,7-tetrahydrothiopheno[3,2-c]pyridin-5-yl)acetate affords (2S)-2-(2-chlorophenyl)-2-(4,5,6, 7-tetrahydrothiophene [3,2-c] pyridin-5-yl) methyl acetate) that is, clopidogrel; another method is to obtain a chiral intermediate first, and then synthesize clopidogrel. In the second type of me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/04C07C229/36C07C227/24C07C227/32
Inventor 舒亮包志坚林昌军张爱青
Owner SUZHOU LIXIN PHARMA
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