Method for synthesizing repaglinide key intermediate

An intermediate and key technology, which is applied in the field of synthesizing key intermediates of repaglinide and preparing hypoglycemic drugs, can solve the problems of unsuitability for large-scale industrial production, complex process, long production cycle, etc., and achieve complete reaction and yield The effect of high rate and fast response

Inactive Publication Date: 2015-05-20
HUBEI YITAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] All of the above synthesis uses expensive reagents, and the process is complicated, the production cycle is long, the cost is high, and the yield is low, so it is not suitable for large-scale industrial production

Method used

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  • Method for synthesizing repaglinide key intermediate
  • Method for synthesizing repaglinide key intermediate
  • Method for synthesizing repaglinide key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] A method for synthesizing repaglinide key intermediate 4-ethoxycarbonyl-3-ethoxyphenylacetic acid, the process steps are as follows:

[0026] 1. Synthesis of compound (Ⅲ) 4-carboxymethyl-2-ethoxy-benzoic acid

[0027] Add 270g of drinking water to the reaction bottle, start stirring, put 50g of compound (Ⅳ), heat up to 50°C, start to drop 120g of 20% liquid caustic soda, after dropping, raise the temperature to 75~80°C, and keep warm for 3.5 hours. After the heat preservation is completed, lower the temperature to 50-60°C, slowly add about 48g of hydrochloric acid dropwise, and adjust the pH to 5-6. Add 5g of medicinal charcoal, decolorize for 30 minutes, filter with suction, and add about 47g of hydrochloric acid dropwise to the filtrate at 50~60°C to adjust pH=3.0~3.5. Cool down to 5-10°C, filter and dry to obtain 46.4 g of compound (Ⅲ), with a yield of 96.5% and a purity of 98.48%.

[0028] 2. Synthesis of compound (II) 3-ethoxy-4-ethoxycarbonyl-ethyl phenylacetate...

Embodiment 2

[0033] A method for synthesizing repaglinide key intermediate 4-ethoxycarbonyl-3-ethoxyphenylacetic acid, the process steps are as follows:

[0034] 1. Synthesis of compound (Ⅲ) 4-carboxymethyl-2-ethoxy-benzoic acid

[0035] Add 270g of drinking water to the reaction bottle, start stirring, put 50g of compound (Ⅳ), heat up to 50°C, start to drop 240g of 10% liquid caustic soda, after dropping, raise the temperature to 80~85°C, and keep warm for 5.0 hours. After the heat preservation is completed, lower the temperature to 50-60°C, slowly add about 48g of hydrochloric acid dropwise, and adjust the pH to 5-6. Add 5g of medicinal charcoal, decolorize for 30 minutes, filter with suction, add about 47g of hydrochloric acid dropwise to the filtrate at 50~60°C, and adjust the pH to 1.0~2.0. Cool down to 5-10°C, filter and dry to obtain 45.5 g of compound (Ⅲ), with a yield of 94.7% and a purity of 98.15%. The reaction time is long and the purity is low.

[0036] 2. Synthesis of compou...

Embodiment 3

[0041] A method for synthesizing repaglinide key intermediate 4-ethoxycarbonyl-3-ethoxyphenylacetic acid, the process steps are as follows:

[0042] 1. Synthesis of compound (Ⅲ) 4-carboxymethyl-2-ethoxy-benzoic acid

[0043] Add 270g of drinking water into the reaction bottle, start stirring, put 50g of compound (Ⅳ), heat up to 50°C, start to drop 120g of 20% liquid caustic soda, after dropping, raise the temperature to 80~85°C, and keep warm for 2.5~3.0 hours. After the heat preservation is completed, lower the temperature to 50-60°C, slowly add about 48g of hydrochloric acid dropwise, and adjust the pH to 5-6. Add 5g of medicinal charcoal, decolorize for 30 minutes, filter with suction, add about 47g of hydrochloric acid dropwise to the filtrate at 50~60°C, and adjust the pH to 2.0~2.5. Cool down to 5-10°C, filter and dry to obtain 47g of compound (Ⅲ), with a yield of 97.8% and a purity of 98.76%. The yield and quality both reached a high level.

[0044] 2. Synthesis ...

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Abstract

The invention relates to a method for synthesizing a repaglinide key intermediate, namely 4-ethoxycarbonyl-3-ethyoxy phenylacetic acid. The method comprises the following steps: by taking 3-ethyoxy-4-ethoxycarbonyl-benzyl cyanide as an initial raw material, performing hydrolysis, esterification, selective hydrolysis and the like, thereby obtaining the important intermediate 4-ethoxycarbonyl-3-ethyoxy phenylacetic acid of repaglinide. According to the key intermediate, the impurities of the product is less, the purity of the product is high and can reach over 99.7%, so that the quality of the subsequently synthesized repaglinide product is improved, the 100 percent first-pass yield of the subsequently synthesized repaglinide product can be basically reached, a refining step is avoided, and the synthetic yield is effectively improved. The process is easy and convenient to operate, the yield is high, the molar yield is 69.1 percent, the production cost is low, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and relates to the synthesis of 4-ethoxycarbonyl-3-ethoxyphenylacetic acid, in particular to a method for synthesizing a key intermediate of repaglinide for the preparation of hypoglycemic drugs. Background technique [0002] Non-sulfonylureas insulin secretagogues (Non-sulfonylureas, NSUR), also known as "meal glucose regulators", repaglinide (repaglinide) is one of the representatives. Regneret was developed by Boehringer Ingelheim of Germany and NovoNordisk of Denmark, and was first launched in the United States in 1998 under the trade name of Prandin, and in 2000 in China under the trade name of Nuohelong. [0003] Repaglinide plays a role by stimulating the secretion of insulin by pancreatic β cells. It is called a "dietary glucose regulator" and has the therapeutic characteristics of "taking medicine with meals, and not taking medicine without meals". As a non-sulfo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C27/02C07C69/92
CPCC07C51/09C07C67/08C07C67/313C07C65/21C07C69/92
Inventor 吴晓宇李时毅张运林
Owner HUBEI YITAI PHARMA
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