Preparation method of 3-ethyoxyl-4-carboxylphenylacetic acid

A technology of ethyl ethoxybenzoate and ethoxy, which is applied in the field of preparation of 3-ethoxy-4-carboxyphenylacetic acid, and can solve problems such as affecting the quality of the final product of repaglinide

Inactive Publication Date: 2015-02-18
北京华禧联合科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] If in reaction 1, ethyl 4-carboxymethyl-2-ethoxybenzoate reacts incompletely, then ethyl 4-carboxymethyl-2-ethoxybenzoate will also undergo hydrolysis reaction in reaction 2 , affecting the quality of repaglinide final product

Method used

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  • Preparation method of 3-ethyoxyl-4-carboxylphenylacetic acid

Examples

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Effect test

example 1

[0015] The preparation of example one 3-ethoxy group-4-carboxyphenylacetic acid

[0016] Take 5g of ethyl 4-carboxymethyl-3-ethoxybenzoate and add it to a 150ml three-neck flask with a condenser tube, add 50ml of ethanol to dissolve, heat up to 40°C, add 15.5ml of 1mol / L sodium hydroxide solution, Heat up to 60°C, keep stirring for 2h, cool down to 35°C, adjust pH to 5 with 1mol / L hydrochloric acid, keep stirring at 35°C for 30min, cool down to -5°C~0°C, stir for 1h, put in refrigerator for analysis Crystal overnight.

[0017] The above crystallization liquid was taken out, and colorless needle-like crystals were found to be precipitated. The filter cake was washed twice with 5 ml of water, and the obtained solid was vacuum-dried overnight at 50° C. to obtain 1.6 g of needle-like crystalline solid. Yield 36%, HPLC

[0018] Purity 96.83%.

example 2

[0019] The preparation of example two 3-ethoxy-4-carboxyphenylacetic acid

[0020] Take 5g of ethyl 4-carboxymethyl-3-ethoxybenzoate and add it to a 250ml three-neck flask with a condenser tube, add 100ml of ethanol to dissolve it, then heat up to 40°C, add 50ml of 1mol / L sodium hydroxide solution, and heat up to 60°C, control the temperature at 60°C ~ 65°C, keep stirring and react for 2 hours, apply the sample, after there is no raw material spot, cool down to 35°C, adjust the pH to 5 with 1mol / L hydrochloric acid, keep stirring at 35°C for 30min, Cool down to -5°C to 0°C, stir for 1 hour, and put it in the refrigerator for crystallization overnight.

[0021] The above crystallization liquid was taken out, and a large number of colorless needle crystals precipitated out. The filter cake was washed twice with 10 ml of water, and the obtained solid was vacuum-dried overnight at 50° C. to obtain 3.8 g of needle-like crystalline powder. The yield was 85.5%, and the purity by HPL...

example 3

[0022] The preparation of example three 3-ethoxy-4-carboxyphenylacetic acid

[0023] Take 5g of ethyl 4-carboxymethyl-3-ethoxybenzoate and add it to a 150ml three-neck flask with a condenser tube, add 50ml of ethanol to dissolve it, then raise the temperature to 40°C, add 25ml of 2mol / L sodium hydroxide solution, and heat up To 60°C, control the temperature at 60°C~65°C, keep stirring and react for 2 hours, apply the sample, after there is no raw material spot, cool down to 35°C, adjust the pH to 5 with 1mol / L hydrochloric acid, keep stirring at 35°C for 30min , cooled to -5°C to 0°C, stirred for 1 hour, and placed in a refrigerator for crystallization overnight.

[0024] The above crystallization liquid was taken out, and a large amount of colorless needle crystals were precipitated. The filter cake was washed twice with 10 ml of water, and the obtained solid was vacuum-dried overnight at 50° C. to obtain 4.1 g of needle-shaped crystalline powder. The yield was 92.3%, and th...

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Abstract

The invention relates to a preparation method of 3-ethyoxyl-4-carboxylphenylacetic acid. The 3-ethyoxyl-4-carboxylphenylacetic acid is listed to be a Repaglinide impurity A in the British Pharmacopoeia. In the method, 4-carboxymethyl-2-ethoxy ethyl benzoate is used as a raw material, and an ester bond is hydrolyzed off in an alkali metal hydroxide solution to obtain a target product. The method has simple reaction principle, moderate reaction condition, easy raw material obtaining and stable yield, and the obtained product can be used for qualitative or quantitative analysis.

Description

technical field [0001] The invention relates to a preparation method of 3-ethoxy-4-carboxyphenylacetic acid. technical background [0002] Repaglinide (repaglinide) trade name is Novolone, which is a non-sulfonylurea insulin secretion-stimulating drug. The feature of strong effect has been rapidly promoted in China. The drug was developed by Boehringer Ingelheim of Germany and developed by Novo Nordisk. It was launched in the United States in 1998 and entered China for the first time in 1999. [0003] In the existing synthetic method of repaglinide, the latter two steps basically adopt the following synthetic route: [0004] [0005] If in reaction 1, ethyl 4-carboxymethyl-2-ethoxybenzoate reacts incompletely, then ethyl 4-carboxymethyl-2-ethoxybenzoate will also undergo hydrolysis reaction in reaction 2 , affecting the quality of repaglinide final product. [0006] The reaction formula is as follows: [0007] [0008] 3-ethoxy-4-carboxyphenylacetic acid (I) is li...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C65/21C07C27/02
Inventor 刘元斌张志芳
Owner 北京华禧联合科技发展有限公司
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