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Synthetic method of D-p-hydroxyphenylglycine methyl ester

A technology of p-hydroxyphenylglycine methyl ester and p-hydroxyphenylglycine, which is applied in the field of synthesis of D-p-hydroxyphenylglycine methyl ester, can solve the problem that D-p-hydroxyphenylglycine methyl ester cannot meet the raw material index of β-lactam antibiotics Requirements and other issues to achieve the effect of avoiding hydrolysis risk, excellent quality indicators, and shortening the process

Inactive Publication Date: 2015-07-01
HENAN NEWLAND PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The D-p-hydroxyphenylglycine methyl ester obtained by this method cannot meet the raw material index requirements of β-lactam antibiotics, and a new synthetic method needs to be developed

Method used

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  • Synthetic method of D-p-hydroxyphenylglycine methyl ester
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  • Synthetic method of D-p-hydroxyphenylglycine methyl ester

Examples

Experimental program
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Effect test

Embodiment 1

[0040] The synthesis of embodiment 1 D-p-hydroxyphenylglycine methyl ester hydrochloride

[0041] Add 800 g of D-p-hydroxyphenylglycine and 800-8000 g of methanol into a 3000 mL three-necked flask, and stir. Weigh 569.4-683.2 g of thionyl chloride and add it dropwise slowly. During the dropping process, control the temperature to ≤65°C. After the dropwise addition of thionyl chloride is completed, control the reaction temperature to -10-65°C and keep the temperature for 10 hours. After the heat preservation reaction was completed, the temperature was lowered to 10°C, stirred for 1 h, filtered with suction, and the filter cake was rinsed with ethyl acetate to obtain 867.7 g of solid, with a yield of 83.3%.

[0042] After testing, the obtained solid was D-p-hydroxyphenylglycine methyl ester hydrochloride.

[0043]

Embodiment 2

[0044] The synthesis of embodiment 2 D-p-hydroxyphenylglycine methyl ester

[0045] Add 100 g of D-p-hydroxyphenylglycine methyl ester hydrochloride prepared in Example 1 to a 2L beaker, add methanol to the beaker, stir and dissolve, then add ammonia water dropwise to the above solution for neutralization, and the neutralization process controls the reaction The temperature is ≤80°C, and when the pH value of the reaction solution is higher than 7, the neutralization is completed, and the dropwise addition is stopped. After suction filtration, 83.25 g of solids were obtained, with a yield of 97.5%.

[0046] After testing, the obtained solid is D-p-hydroxyphenylglycine methyl ester, and the ee value of D-p-hydroxyphenylglycine methyl ester can reach more than 99%.

[0047]

Embodiment 3

[0048] The synthesis of embodiment 3 D-p-hydroxyphenylglycine methyl ester

[0049]Add 800g of D-p-hydroxyphenylglycine and 800-2400mL of methanol into a 3000mL three-necked flask, stir, and cool down in an ice-water bath. Weigh 569.4-683.2 g of thionyl chloride and add it dropwise slowly. During the dropping process, control the temperature to ≤65°C. After the dropwise addition of thionyl chloride is completed, control the reaction temperature to -10-65°C and keep the temperature for 10 hours. After the heat preservation reaction is completed, transfer the material to a 50L reactor, add 8-15L of distilled water, stir and dissolve, then add ammonia water dropwise to the above solution for neutralization, and control the reaction temperature ≤ 80°C during the neutralization process until the pH value of the reaction solution When it is higher than 7, the neutralization is completed and the dropwise addition is stopped. After centrifugation, 814.3 g of solids were obtained, w...

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Abstract

The invention relates to the medicine field, and especially relates to a synthetic method of D-p-hydroxyphenylglycine methyl ester. The invention provides a synthetic method by directly using d-p-hydroxyphenylglycine as an initial raw material without splitting and separation, a target compound D-p-hydroxyphenylglycine methyl ester can be obtained through one-pot synthesis, a technology process is shortened, and hydrolysis risk of ester in a long production process can be avoided. According to the invention, yield can reach more than 96%, the ee value of D-p-hydroxyphenylglycine methyl ester can reach more than 99%, and the quality index is excellent.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a method for synthesizing D-p-hydroxyphenylglycine methyl ester. Background technique [0002] p-Hydroxyphenylglycine derivatives, especially its ester derivatives, can be used to synthesize β-lactam antibiotics by biological methods, for example, under the catalysis of enzymes, D-p-hydroxyphenylglycine ester can be condensed with β-lactam nucleus to generate corresponding β-lactam antibiotics. D-Hydroxyphenylglycine is an optically active phenylglycine derivative, which is widely used in the synthesis of β-lactam antibiotics. It can be condensed with 6-APA (6-aminopenicillinic acid) to generate penicillin, and 7- ADCA (7-aminodesacetoxycephalosporanic acid) is condensed to give cefadroxil. [0003] D-p-hydroxyphenylglycine methyl ester hydrochloride is one of the raw materials for the biosynthesis of amoxicillin, and it is the hydrochloride salt of the product obtained by the esterific...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/36C07C227/16
Inventor 谢建中刘超
Owner HENAN NEWLAND PHARMA
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