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A method for synthesizing d-p-hydroxyphenylglycine methyl ester

A technology for p-hydroxyphenylglycine methyl ester and p-hydroxyphenylglycine, which is applied in the field of synthesizing D-p-hydroxyphenylglycine methyl ester and can solve the problems of low yield and the like

Active Publication Date: 2016-05-11
山西双雁生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to overcome the defect that the yield is low when adopting the existing method to produce D-hydroxyphenylglycine methyl ester, and to provide a new method for producing D-parahydroxyphenylglycine methyl ester with high yield

Method used

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  • A method for synthesizing d-p-hydroxyphenylglycine methyl ester

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Embodiment approach

[0018] The D-p-hydroxyphenylglycine resolving agent salt can be obtained commercially, or can be prepared according to various methods known to those skilled in the art. According to a preferred embodiment of the present invention, the D-p-hydroxyphenylglycine resolving agent salt is obtained by mixing DL-p-hydroxyphenylglycine and sodium phenylethanesulfonate in hydrochloric acid and salicylaldehyde at 100-110°C. Reaction in the presence of 8-12 hours to obtain. In the preparation process, relative to 100 parts by weight of sodium phenylethanesulfonate, the amount of DL-p-hydroxyphenylglycine can be 75-90 parts by weight, and the amount of hydrochloric acid can be 50-60 parts by weight, The amount of the salicylic acid can be 2-3 parts by weight; preferably, relative to 100 parts by weight of sodium phenylethanesulfonate, the amount of DL-p-hydroxyphenylglycine is 80-85 parts by weight, the The amount of hydrochloric acid is 53-56 parts by weight, and the amount of salicylal...

specific Embodiment approach

[0026] In the present invention, the method for removing salicylaldehyde in step (3) is not particularly limited, and various existing methods can be used to carry out. According to a specific embodiment of the present invention, salicylaldehyde is removed by the following method: add water to the reaction product obtained after the reaction, and then evaporate water to entrain and remove salicylaldehyde. The specific operation is a technology in the art It is well-known to the personnel and will not be described in detail here.

[0027] The present invention will be described in detail below by way of examples.

[0028] In the following examples and comparative examples:

[0029] In step (1), the yield of D-p-hydroxyphenylglycine methyl phenylethanesulfonate=the actual output of D-p-hydroxyphenylglycine methyl phenylethanesulfonate ÷ D-p-hydroxyphenylglycine methyl benzene Theoretical yield of ethyl ethanesulfonate × 100%.

[0030] The yield of D-p-hydroxyphenylglycine methy...

Embodiment 1

[0032] This embodiment is used to illustrate the method for synthesizing D-p-hydroxyphenylglycine methyl ester provided by the present invention.

[0033] (1) Esterification:

[0034] Add 11700mL of methanol into a 30L glass reactor, start stirring, take 6000g of D-p-hydroxyphenylglycine phenylethanesulfonate (also known as DD salt, the same below) into the glass reactor, and control the temperature below 25 2230 g of thionyl chloride was added dropwise at °C. After the dropwise addition of the thionyl chloride, the temperature was raised to a reflux state, and the reflux was maintained for 3 hours. After the esterification reaction was completed, an esterification liquid was obtained. Detected by HPLC, the yield of D-p-hydroxyphenylglycine methyl phenylethanesulfonate in the esterified solution was 98.5%.

[0035] (2) Neutralization:

[0036] Add water 2000mL and D-hydroxyphenylglycine methyl ester 50g (as seed crystal) in 3L glass reaction bottle, control temperature at 1...

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Abstract

The present invention relates to the field of compound synthesis and discloses a method for synthesizing D-para-hydroxyphenylglycine methyl ester. The method comprises the steps of: (1) in the presence of thionyl chloride, carrying out an esterification reaction of D-para-hydroxyphenylglycine resolving agent salt and methanol to obtain a D-para-hydroxyphenylglycine methyl ester resolving agent salt; (2) dropwise adding the D-para-hydroxyphenylglycine methyl ester resolving agent salt and an alkaline metal hydroxide to an aqueous D-para-hydroxyphenylglycine methyl ester solution at 10-15°C, controlling the pH value of the system at 6.5-7 during the dropwise addition, after completing the dropwise addition of the D-para-hydroxyphenylglycine methyl ester resolving agent salt, continuing the dropwise addition of the alkaline metal hydroxide until the pH value of the system is 7.5-8, then growing crystals under the conditions of a temperature of 10-15°C and the pH value of 7.5-8, and subsequently filtering the resultant crystallization liquid to obtain D-para-hydroxyphenylglycine methyl ester crystals and a mother liquor. With the adoption of the method provided by the present invention, D-para-hydroxyphenylglycine methyl ester can be produced with a higher yield.

Description

technical field [0001] The invention relates to a method for synthesizing D-p-hydroxyphenylglycine methyl ester. Background technique [0002] As a pharmaceutical intermediate, D-p-hydroxyphenylglycine methyl ester is used in the enzymatic synthesis of broad-spectrum antibiotic amoxicillin (amoxicillin). Because enzymatic production of amoxicillin has great advantages in terms of environmental protection, energy consumption, and production efficiency compared with other methods, the extensive use of enzymatic production of amoxicillin in the world has further driven the development of intermediate D-p-hydroxy Development of phenylglycine methyl ester. [0003] The synthetic method of D-p-hydroxyphenylglycine methyl ester is usually to resolve DL-p-hydroxyphenylglycine with chiral resolving agent (usually phenylethanesulfonic acid) at present, obtains L-p-hydroxyphenylglycine resolving agent salt and The mixture of D-p-hydroxyphenylglycine resolving agent salt, and the mixt...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/36C07C227/18C07C227/42
CPCC07C227/18C07C227/42C07C229/36
Inventor 王启斌
Owner 山西双雁生物科技有限公司
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