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Method for preparing repaglinide intermediate

A technology of intermediates and Grignard reagents, applied in the field of preparation of repaglinide intermediates, can solve the problems of many side reactions, difficult product purification, complicated operations, etc., and achieves increased reaction safety, shortened reaction steps, and reduced side effects. product effect

Inactive Publication Date: 2013-07-10
天津市嘉凡生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Method for preparing repaglinide intermediate
  • Method for preparing repaglinide intermediate
  • Method for preparing repaglinide intermediate

Examples

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Effect test

Embodiment 1

[0019] Under the protection of N2, 15g of magnesium chips was added into the dry reaction flask, 30ml of THF was added to cover the magnesium chips, and the temperature was raised slowly to initiate the Grignard reaction. Another 270ml of THF was mixed with 28.6g of ethyl 4-bromomethyl-2-ethoxybenzoate, 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 ethanol. 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. Toluene ((60m1×2) was extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove toluene. The residue was dropped into 150m1 n-hexane and stirred at room temperature overnight. Filtered and dried to obtain 16.75g of white solid with a yield of 67%.

Embodiment 2

[0021] Under the protection of N2, 15g of magnesium chips was added into the dry reaction flask, 30ml of isopropyl ether was added to cover the magnesium chips, and the temperature was raised slowly to initiate the Grignard reaction. Another 270ml of THF was mixed with 28.6g of ethyl 4-bromomethyl-2-ethoxybenzoate, 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 ethanol. 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. Toluene ((60m1×2) was extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove toluene. The residue was dropped into 150m1 n-hexane and stirred at room temperature overnight. Filtered and dried to obtain 16.25g of white solid with a yield of 65%.

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Abstract

The invention relates to a method for preparing a repaglinide intermediate shown in a formula (I). The method comprises steps of: adding a Grignard reagent into ethanol, and hydrolyzing to obtain the repaglinide intermediate shown in the formula (I).

Description

technical field [0001] The present invention relates to a preparation method of repaglinide intermediate represented by formula (I), which comprises adding Grignard reagent into ethanol and hydrolyzing to prepare repaglinide intermediate represented by formula (I). Background technique [0002] The chemical name of repaglinide is S(+)-2-ethoxy-4-[N-{1-(2-piperidinylphenyl)-3-methyl-1-butyl}aminocarbonylmethyl Base] benzoic acid, the structural formula is [0003] [0004] This is known from US Patent (Patent No.: US5312924). Studies have shown that repaglinide is an enantiomer, and R(-)-2-ethoxy-4-[N-{1-(2-piperidinylphenyl)-3-methyl-1 Compared with -butyl}aminocarbonylmethyl]benzoic acid, it has a long-term biological activity in the human body and can be eliminated more quickly. It is a new type of oral hypoglycemic drug that can promote insulin secretion and absorption With the characteristics of fast and short action time, it can simulate physiological insulin secr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/92C07C67/313
Inventor 王进
Owner 天津市嘉凡生物科技有限公司
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