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Chemical-enzymatic method for preparing D-serine

A technology of serine and phenylacetylserine, which is applied in the field of chemical-enzymatic preparation of D-serine, can solve the problems of poor selectivity and the optical purity of D-serine cannot meet the quality requirements, so as to reduce the process cost, easy to obtain the source, and high The effect of optical activity

Inactive Publication Date: 2012-01-18
CHONGQING UNIV OF POSTS & TELECOMM
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AI Technical Summary

Problems solved by technology

Obviously, due to the poor selectivity of the physical resolution method, the optical purity of the prepared D-serine cannot meet the quality requirements

Method used

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  • Chemical-enzymatic method for preparing D-serine
  • Chemical-enzymatic method for preparing D-serine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: Preparation of DL-N-phenylacetylserine

[0021] 42g (0.4mol) of DL-serine and 40g (1.0mol) of NaOH were dissolved in 400ml of water, then cooled to 0°C in an ice bath, and 64ml (0.48mol) of phenylacetyl chloride was added dropwise. The rate of addition is controlled, and the temperature of the reaction solution does not exceed 5°C. After the dropwise addition, the stirring reaction was continued for 12h. The reaction solution was adjusted to a pH of about 1-2, filtered with suction, the solid was washed twice with water, and dried to obtain 86 g of DL-N-phenylacetylserine with a yield of 96.4%.

Embodiment 2

[0022] Example 2: DL-N-phenylacetylserinase-catalyzed hydrolysis

[0023] Add 66.9g (0.3mol) of DL-N-phenylacetylserine to 600ml of water, adjust the pH to 8.0 with ammonia water until completely dissolved, add 13g of immobilized penicillin acylase, and stir for 28 hours at room temperature. After the reaction was completed, the immobilized penicillin acylase was removed by suction filtration. CuSO was added to the filtrate 4 ·5H 2 O 18.8g, suction filtration, remove L-serine copper complex. The filtrate was adjusted to pH 1-2 with concentrated hydrochloric acid, filtered with suction, the solid was washed with cold water, and dried to obtain 32 g of D-N-phenylacetylserine with a yield of 47.8%.

Embodiment 3

[0024] Example 3: D-serine preparation

[0025] Add 32g of D-N-phenylacetylserine into 200ml of 6mol / L hydrochloric acid, acidify at 100°C for 8h, and add 10g of activated carbon for decolorization. Concentrate the decolorized solution to 40 ml, extract three times with ethyl acetate (40ml×3), adjust the pH of the aqueous layer to 5.8 with ammonia water, let stand overnight at 0-5°C, filter and wash the filter cake with a small amount of deionized water, and dry it 13.6 g of D-serine was obtained, the yield was 90%, and the ee measured by HPLC was 99.6%.

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Abstract

The present invention provides a chemical-enzymatic method for preparing D-serine. According to the method, DL-serine is adopted as a raw material and is derived into DL-N-phenylacetyl serine by using an acylating agent; immobilized penicillin acylase is adopted as a biocatalyst, correspondingly and selectively catalyze the DL-N-phenylacetyl serine in an aqueous medium to obtain L-serine, phenylacetic acid and D-N-phenylacetyl serine; a metal complexation method and an isoelectric point crystallization method are adopted to carry out separation to obtain optically pure D-phenylacetyl serine; the D-N-phenylacetyl serine is subjected to acid hydrolysis, concentration and crystallization to obtain the D-serine, wherein the yield of the D-serine is 45%, ee of the D-serine is 99.6%. The method provided by the present invention has characteristics of high yield, high chemical purity, high optical purity, environment-friendly property, and is suitable for the large-scale production of the D-serine.

Description

technical field [0001] The invention relates to a chemical-enzymatic method for preparing D-serine, which belongs to the technical field of preparing chiral drug intermediates by biocatalytic hydrolysis. Background technique [0002] D-serine is an endogenous brain information co-transmission substance, which can be used to prevent or treat brain damage caused by cerebral ischemia or hypoxia. D-serine is also an important intermediate of some chiral drugs such as cycloserine and lacosamide. Cycloserine, also known as oxymycin, is a broad-spectrum antibiotic discovered from streptomyces metabolites. It has certain curative effects on tuberculosis, non-tuberculous respiratory infections, otitis media, and diarrhea. It is mainly used clinically against Mycobacterium tuberculosis, especially Mycobacterium tuberculosis resistant to Streptomyces. Cycloserine is not only used clinically as a second-line anti-tuberculosis drug, but also an important intermediate in the synthesis o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/06C07C229/22C07C227/20
Inventor 夏仕文方国兰
Owner CHONGQING UNIV OF POSTS & TELECOMM
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