Synthetic method of p-hydroxyphenylglycine methyl ester

A technology for p-hydroxyphenylglycine methyl ester and p-hydroxyphenylglycine, which is applied in the field of synthesis of p-hydroxyphenylglycine methyl ester, can solve the problems of reducing the product recovery rate, high esterification temperature, affecting the esterification reaction, etc., and achieves accelerated evaporation. rate, avoid oxidation, and reduce methanol consumption

Pending Publication Date: 2021-05-25
河南绿园药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method esterification reaction temperature is higher, easily causes the oxidation of methanol, affects the carrying out of esterification reaction; Adopt strong base such as sodium hydroxide, potassium hydroxide to adjust pH value, easily cause the hydrolysis of D-hydroxyphenylglycine crystal, reduce product recovery rate

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] A synthetic method for p-hydroxyphenylglycine methyl ester, comprising the following steps:

[0015] (1) Add D-p-hydroxyphenylglycine to methanol, stir evenly, and then add thionyl chloride dropwise at 30°C to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester, D-p-hydroxyphenylglycine The mol ratio of phenylglycine, methanol and thionyl chloride is 1:6:1.02;

[0016] (2) The methanol solution of D-p-hydroxyphenylglycine methyl ester is decompressed to produce methanol, the decompression condition is vacuum degree≤0.090MPa, then add water and stir, and the amount of water added is 6 times of the weight of D-p-hydroxyphenylglycine methyl ester , decolorizing activated carbon under acidic conditions to obtain an aqueous solution of D-p-hydroxyphenylglycine methyl ester;

[0017] (3) In the aqueous solution of D-p-hydroxyphenylglycine methyl ester, dropwise add 15wt% ammoniacal liquor, adjust pH to be 9-10, the time of ammoniacal liquor dripping is 3h, D-...

Embodiment 2

[0019] A synthetic method for p-hydroxyphenylglycine methyl ester, comprising the following steps:

[0020] (1) Add D-p-hydroxyphenylglycine to methanol, stir evenly, and then add thionyl chloride dropwise at 40°C to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester, D-p-hydroxyphenylglycine The mol ratio of phenylglycine, methanol and thionyl chloride is 1:6:1.02;

[0021] (2) The methanol solution of D-p-hydroxyphenylglycine methyl ester is decompressed to get methanol, the decompression condition is vacuum degree≤0.090MPa, then add water and stir, and the amount of water added is 5 times of the weight of D-p-hydroxyphenylglycine methyl ester , decolorizing activated carbon under acidic conditions to obtain an aqueous solution of D-p-hydroxyphenylglycine methyl ester;

[0022] (3) In the aqueous solution of D-p-hydroxyphenylglycine methyl ester, dropwise add 15wt% ammoniacal liquor, adjust pH to be 9-10, the ammoniacal liquor dripping time is 5h, D-p-hydro...

Embodiment 3

[0024] A synthetic method for p-hydroxyphenylglycine methyl ester, comprising the following steps:

[0025] (1) Add D-p-hydroxyphenylglycine to methanol, stir evenly, and then add thionyl chloride dropwise at 50°C to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester, D-p-hydroxyphenylglycine The mol ratio of phenylglycine, methanol and thionyl chloride is 1:6:1.02;

[0026] (2) The methanol solution of D-p-hydroxyphenylglycine methyl ester is decompressed to produce methanol, the decompression condition is vacuum degree≤0.090MPa, then add water and stir, and the amount of water added is 3 times of the weight of D-p-hydroxyphenylglycine methyl ester , decolorizing activated carbon under acidic conditions to obtain an aqueous solution of D-p-hydroxyphenylglycine methyl ester;

[0027] (3) In the aqueous solution of D-p-hydroxyphenylglycine methyl ester, dropwise add 15wt% ammoniacal liquor, adjust pH to be 9-10, the time of ammoniacal liquor dripping is 6h, D-...

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PUM

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Abstract

The invention provides a synthetic method of p-hydroxyphenylglycine methyl ester. The synthetic method comprises the following steps: (1) adding D-p-hydroxyphenylglycine into methanol, conducting uniform stirring, and then dropwise adding thionyl chloride at 30-50 DEG C to obtain a methanol solution of D-p-hydroxyphenylglycine methyl ester; (2) decompressing the methanol solution of D-p-hydroxyphenylglycine methyl ester to obtain methanol under the condition that a vacuum degree is less than or equal to 0.090 MPa, then adding water, performing stirring, and carrying out decolorizing with activated carbon under an acidic condition to obtain an aqueous solution of the D-p-hydroxyphenylglycine methyl ester; and (3) dropwise adding 15-20wt% of ammonia water into the aqueous solution of D-p-hydroxyphenylglycine methyl ester to adjust a pH value to 9-10, wherein the dropwise adding time of the ammonia water is 3-6 hours, subjecting D-p-hydroxyphenylglycine methyl ester to crystallization and precipitation, and finally, carrying out centrifugal separation to obtain a D-p-hydroxyphenylglycine methyl ester product. The D-p-hydroxyphenylglycine methyl ester prepared by the method disclosed by the invention is high in recovery rate and high in purity.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a method for synthesizing p-hydroxyphenylglycine methyl ester. Background technique [0002] P-Hydroxyphenylglycine methyl ester is an important intermediate of antibiotics, which is used to synthesize the side chains of β-lactam semi-synthetic antibiotics. The existing preparation method of p-hydroxyphenylglycine methyl ester has problems such as long reaction time and difficult crystallization and purification of the product. Chinese patent CN111153821A discloses a preparation method of D-p-hydroxyphenylglycine methyl ester, under the condition of concentrated sulfuric acid, in the presence of concentrated sulfuric acid, under the condition of 65-80 ℃, D-p-hydroxyphenylglycine and methanol produce methyl ester reaction to obtain D-p-hydroxyphenylglycine sulfate, then distill methanol and water under reduced pressure, add D-p-hydroxyphenylglycine seed crystals ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/36C07C227/18C07C227/40C07C227/42
CPCC07C227/18C07C227/40C07C227/42C07B2200/07C07C229/36
Inventor 李利强李飞张志强
Owner 河南绿园药业有限公司
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