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Preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production

A technology of p-hydroxyphenylglycine methyl ester and hydrochloride, which is applied in the field of preparation of D-p-hydroxyphenylglycine methyl ester hydrochloride, can solve the problems of high raw material and production costs, long production cycle, and low production efficiency. Achieve the effects of avoiding the use of splitting agents, improving production efficiency, reducing costs and three wastes

Pending Publication Date: 2021-11-09
HUBEI HONGYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, there are some technical problems in the prior art scheme that have not yet been resolved. The first is that the prior art route is long, and it takes five steps of technology (not counting resolving agent recovery) to obtain D-p-hydroxyphenylglycine hydrochloride from phenol as the starting material. Apply mechanically), the process route is long, the production cycle is long, the production efficiency is low, and the product yield is low
Second, the existing technology produces a large amount of wastewater in the step of synthesizing racemic DL-p-hydroxyphenylglycine. Although the patent CN109354261A reports a wastewater treatment method, this treatment method has high energy consumption and low efficiency, and the generation of solid waste cannot be avoided
The 3rd, existing resolution technology adopts arylsulfonic acid or camphorsulfonic acid as resolving agent, and resolving agent is expensive, causes the raw material of product and production cost height

Method used

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  • Preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production
  • Preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production
  • Preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production

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Experimental program
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Effect test

Embodiment 1

[0037] The synthesis of embodiment 1 intermediate 1

[0038]

[0039] In a 1L three-necked flask, add 500 milliliters of toluene, then 60 milliliters of toluene solution of methyl glyoxylate (50% concentration, 0.3 mol) and 36.4 grams of S-phenylethylamine (0.3 mol), and stir at 20 to 30 ° C for 2 Then add 5.2 grams (0.03mol) of p-toluenesulfonic acid (0.03mol) and 33.8 grams of phenol (0.36mol), and stir for 12 hours at 20~30°C. After the reaction finishes, add 150 milliliters of hydrogen chloride methanol solution (10%), and heat to 70-80°C, then lower the temperature to 20-30°C, filter with suction to obtain intermediate 1, and dry it in vacuum at 50°C for 8 hours to obtain 70.3 g of solid, with a yield of 73%.

Embodiment 2

[0040]The synthesis of embodiment 2 intermediate 1

[0041]

[0042] In a 1L three-neck flask, add 500 ml of dichloromethane, then 60 ml of toluene solution of methyl glyoxylate (50% concentration, 0.3 mol) and 36.4 g of S-phenylethylamine (0.3 mol), at 20 to 30 °C Stir for 2 hours, then add 2.9 grams of methanesulfonic acid (0.03mol) and 33.8 grams of phenol (0.36mol), and stir for 12 hours at 20 to 30°C. After the reaction is over, add 150 milliliters of hydrogen chloride ethanol solution (10%), and heat to reflux, then lower the temperature to 20-30°C, filter with suction to obtain intermediate 1, and dry it in vacuum at 50°C for 8 hours to obtain 59.7 g of solid, with a yield of 62%.

Embodiment 3

[0043] The synthesis of embodiment 3 intermediate 1

[0044]

[0045] In a 1L three-necked flask, add 500 ml of xylene, then 60 ml of toluene solution of methyl glyoxylate (50% concentration, 0.3 mol) and 36.4 g of S-phenylethylamine (0.3 mol), and stir at 20 to 30 ° C 2 hours, then add 3.4 grams (0.03mol) of trifluoroacetic acid and 33.8 grams of phenol (0.36mol), stir at 20~30 ℃ for 12 hours, after the reaction finishes, add 150 milliliters of hydrogen chloride methanol solution (10%), heat to 70-80°C, then lower the temperature to 20-30°C, filter with suction to obtain intermediate 1, and vacuum-dry at 50°C for 8 hours to obtain 73.2 g of solid, with a yield of 76%.

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Abstract

The invention discloses a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production, and relates to a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production. In the first step of reaction, methyl glyoxylate and phenol are used as raw materials, cheap S-(-)-arylethylamine is used as a chiral induction reagent, and (R)-2-(4-hydroxyphenyl)-2-(((S)-1-arylethyl) amino) methyl acetate hydrochloride (intermediate 1) is obtained through reaction. In the second reaction step, the intermediate 1 is subjected to hydrogenolysis of a protecting group under the Pd / C catalytic condition. The method provided by the invention has the main characteristics that 1, the process is simple, only two-step chemical reaction is adopted, and the production efficiency is high; and 2, a cheap chiral induction reagent S-(-)-arylethylamine is used for replacing an expensive resolution reagent chiral camphorsulfonic acid or chiral phenylethanesulfonic acid, so that the raw material cost and the production cost are greatly reduced;.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production. Background technique [0002] D-p-Hydroxyphenylglycine methyl ester hydrochloride (CAS: 57591-61-4) is a key intermediate in the enzymatic process of the broad-spectrum antibiotic amoxicillin (amoxicillin). Compared with the chemical synthesis process, the enzymatic process has great advantages in terms of environmental protection, energy consumption, and production efficiency. Therefore, the enzymatic production of amoxicillin has driven the market for the intermediate D-hydroxyphenylglycine methyl ester hydrochloride. need. The structure of D-p-hydroxyphenylglycine methyl ester hydrochloride (CAS: 57591-61-4) is as follows: [0003] [0004] For the resolution process of p-hydroxyphenylglycine, a large number of patents have reported related resolution...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/36
CPCC07C227/18C07C227/10C07B2200/07C07C229/36Y02P20/55
Inventor 李晓晖张志海杨明高陈威
Owner HUBEI HONGYUAN PHARMA
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