Novel method of producing repaglinide key intermediate

A technology of Grignard reagents and compounds, applied in the field of new preparation of 4-ethoxycarbonyl-3-ethoxyphenylacetic acid, can solve the problems of many side reactions, difficult purification of products, cumbersome operation, etc., and increase the safety of the reaction , shorten the reaction steps, reduce the effect of by-products

Inactive Publication Date: 2008-04-02
BEIJING D VENTUREPHARM TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is dangerous due to the use of the highly toxic substance sodium cyanide.
At the same time, it is necessary to control the amount of alkali used during hydrolysis, as there are many side reactions, and the resulting products are difficult to purify
Moreover, there are many steps in the reaction, the operation is cumbersome, and the environmental pollution is relatively large.

Method used

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  • Novel method of producing repaglinide key intermediate
  • Novel method of producing repaglinide key intermediate
  • Novel method of producing repaglinide key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] N 2 Under protection, add 15g of magnesium chips into the dry reaction flask, add 30ml of tetrahydrofuran to cover the magnesium chips, and slowly raise the temperature to initiate the Grignard reaction. Another 270ml of tetrahydrofuran was mixed with 28.6g of ethyl 4-bromomethyl-2-ethoxybenzoate (compound of formula (III)), and transferred into a constant pressure dropping funnel. Add dropwise under weak reflux, and continue the reflux reaction for 1 hour after the drop is completed. After cooling down to 0°C, the solution was poured into 8.8 g of dry ice. Add 100ml of water dropwise and stir for 1 hour. Acidify with 10% hydrochloric acid to adjust the pH value of the system to 2.0. Extract with toluene (60ml×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove toluene. The residue was dropped into 150ml of n-hexane and stirred overnight at room temperature. Filter and dry to obtain 10 g of white solid with a yield of 40%.

Embodiment 2

[0021] N 2 Under protection, add 15g of magnesium chips into the dry reaction flask, take 30ml of isopropyl ether to cover the magnesium chips, and add a small grain of iodine to trigger the Grignard reaction. Another 270ml of isopropyl ether was mixed with 28.6g of ethyl 4-bromomethyl-2-ethoxybenzoate (compound of formula (III)), transferred into a constant pressure dropping funnel, and added dropwise under weak reflux. After dropping, react at room temperature for 1 hour. Cool down to -5°C, pour the solution into 8.8 g of dry ice, add 100 ml of water dropwise, and stir for 1 hour. Acidify with 10% hydrochloric acid to adjust the pH value of the system to 2.0. Extract with toluene (60ml×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove toluene. The residue was dropped into 150ml of n-hexane and stirred overnight at room temperature. After filtering and drying, 9.8 g of white solid was obtained with a yield of 39%.

Embodiment 3

[0023] N 2 Under protection, add 15g of magnesium chips into a dry reaction flask, take 30ml of a mixture of isopropyl ether and tetrahydrofuran (the volume ratio of the two is 1:1) to cover the magnesium chips, and slowly raise the temperature to initiate a Grignard reaction. Take another 270ml isopropyl ether and tetrahydrofuran mixed solution (the volume ratio of the two is 1:1) and mix with 28.6g ethyl 4-bromomethyl-2-ethoxybenzoate (compound of formula (III)), transfer to constant pressure In the dropping funnel, add dropwise under weak reflux. After dropping, the reaction was carried out under reflux for 1 hour. Cool down to 5°C. 4.4 g of dry ice was added to the solution, 100 ml of water was added dropwise, and stirred for 1 hour. Acidify with 10% hydrochloric acid, adjust the pH of the system to 2.0, extract with toluene (60ml×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove toluene. The residue was dropped into 150ml of n-hex...

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Abstract

The present invention relates to a method of preparing 4-ethoxycarbonyl-3-ethoxy phenylacetic acid. In a ether solvent, the 4-bromomethyl-2-ethoxy-benzoic acid ethyl ester and metal magnesium react at a certain temperature to produce Gers agent preparation of the compound. Without treatment, the reagent is directly dropped into dry ice. At last, a key intermediate 4-ethoxycarbonyl-3-ethoxy phenylacetic acid for preparation of repaglinide can be separated through hydrolysis.

Description

technical field [0001] The invention relates to a new preparation method of 4-ethoxycarbonyl-3-ethoxyphenylacetic acid (compound of formula I), which is a key intermediate of the hypoglycemic drug repaglinide. Background technique [0002] Repaglinide is an insulin release enhancer first approved by the US FDA in 1998 and launched in China in 2000. Based on the analysis of the current market share of the major varieties of antidiabetic drugs, repaglinide is the variety with the highest growth rate in the past two years. Its chemical name is S(+)-2-ethoxy-4-{2-[(3-methyl-1-(2-(1-piperidinyl)phenyl)butyl)amino]-2- Oxyethyl}benzoic acid. The structural formula is as follows: [0003] [0004] The compound represented by the above formula (I) is an important intermediate for the synthesis of repaglinide. Document J.Med.Chem., 1988,41,5129 and US5312924 report the conventional synthetic route of synthetic formula (II) compound with formula (I) compound as follows: [0005...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/767C07C67/313
Inventor 张海平
Owner BEIJING D VENTUREPHARM TECH DEV
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