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Process for producing trifluoro benzene acetic acid and sitagliptin

A technology of trifluorophenylacetic acid and sitagliptin, which is applied in the field of preparation of trifluorophenylacetic acid and sitagliptin, can solve the problems of unsuitability for industrial production, excessive three wastes, and expensive raw materials, and achieve low cost and less three wastes , the effect of mild conditions

Active Publication Date: 2009-05-13
ZHEJIANG HISOAR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] U.S. Patent No. 6,870,067 discloses a method in which 2,4,5-trifluorobromobenzene is used to make a Grignard reagent and react with vinyl bromide, and then oxidized with an oxidizing agent to obtain 2,4,5-trifluorophenylacetic acid, but the method uses Raw materials are more expensive, there are more three wastes, and it is not suitable for industrial production

Method used

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  • Process for producing trifluoro benzene acetic acid and sitagliptin
  • Process for producing trifluoro benzene acetic acid and sitagliptin
  • Process for producing trifluoro benzene acetic acid and sitagliptin

Examples

Experimental program
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Embodiment 1

[0045]In a 250ml three-necked flask, 6.6g (0.275mol) of magnesium chips, 100g of ether, and 1ml of bromoethane (1%) were put into a 250ml three-necked flask under nitrogen protection. Raise the temperature to 40°C, start to add 7g (0.038mol) of 2,4,5-trifluorobenzyl chloride dropwise, and keep the reaction for 30 minutes after initiation, then continue to add 38g (0.212mol) of 2,4,5-trifluorobenzyl chloride dropwise After the dropwise addition, keep warm for 30 minutes, then cool to 5°C, start to feed carbon dioxide gas, control the flow of carbon dioxide to keep the internal temperature at 10-15°C, until the reaction system no longer releases heat and the temperature does not rise, stop the flow of carbon dioxide , and react at 10 °C for another 0.5 h. After the reaction, the reaction solution was added to 15% hydrochloric acid aqueous solution, hydrolyzed for half an hour, the aqueous layer was extracted twice with 100 g of methyl tert-butyl ether, the organic layers were co...

Embodiment 2

[0049] In a 250ml three-necked flask, 6g (0.25mol) of magnesium chips, 70g of ether and 70g of toluene were dropped under nitrogen protection, and 2g of the previous batch of Grignard reagent was used as an initiator (1.5%). Raise the temperature to 55°C, start to add 7g (0.038mol) of trifluorobenzyl chloride dropwise, and keep it warm for 30 minutes after initiation, then continue to add 38g (0.212mol) of 2,4,5-trifluorobenzyl chloride dropwise, and keep warm after the addition is complete 30 minutes, then cooled to 5°C, started to feed carbon dioxide gas, controlled the flow of carbon dioxide to maintain the internal temperature of 15-20°C, until the reaction system no longer exothermic, when the temperature no longer rises, stop the flow of carbon dioxide, and at 5°C React for another 1 hour. After the reaction, the reaction solution was added to 15% hydrochloric acid aqueous solution, hydrolyzed for half an hour, the aqueous layer was extracted twice with 100g toluene, the...

Embodiment 3

[0051] In a 500ml three-necked flask, 14.4g (0.6mol) of magnesium chips, 100g of ether and 150g of toluene were dropped under nitrogen protection, and 3g of the previous batch of Grignard reagent was used as an initiator (1.2%). Raise the temperature to 60°C, start to add 14g (0.076mol) of chlorobenzyl trifluorobenzyl dropwise, and keep the reaction for 30 minutes after initiation, then continue to add 76g (0.424mol) of 2,4,5-chlorobenzyl trifluorobenzyl dropwise, and keep warm after the addition is complete 60 minutes, then cooled to 5°C, began to feed carbon dioxide gas, controlled the flow of carbon dioxide to maintain the internal temperature of 5-10°C, until the reaction system no longer exothermic, when the temperature no longer rises, stop the flow of carbon dioxide, and at 5°C React for another 1 hour. After the reaction, the reaction solution was added to 15% hydrochloric acid aqueous solution, hydrolyzed for half an hour, the aqueous layer was extracted twice with 20...

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Abstract

The invention discloses a method for preparing trifluoro-phenylacetic acid. The method comprises the following steps: (1) in the presence of an evocating agent, trifluoro-benzyl halides and magnesium in an organic solvent react to obtain a Grignard reagent; (2) carbon dioxide gas is introduced into the Grignard reagent for reaction; and (3) a product obtained in the step (2) is hydrolyzed to obtain the trifluoro-phenylacetic acid. The invention also discloses a method for preparing sitagliptin. The method has the characteristics of high yield, good purity, low cost, simple process, mild condition, few three wastes and good safety, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of an important intermediate of sitagliptin, 2,4,5-trifluorophenylacetic acid or analogs thereof, and a preparation method of sitagliptin. Background technique [0002] 2,4,5-Trifluorophenylacetic acid is a key intermediate of the new drug Sitagliptin developed by Merck, USA, and Sitagliptin is used to treat type 2 diabetes. In 2006, the U.S. Food and Drug Administration (FDA) approved Sitagliptin for the treatment of type 2 diabetes in the United States, and the EU also approved Sitagliptin for the treatment of type 2 diabetes in March 2007. [0003] There have been descriptions about the synthesis process of 2,4,5-trifluorophenylacetic acid in the prior art. U.S. Patent No. 6,395,921 discloses a method for decarboxylation of 2,4,5-trifluorobromobenzene and malonate diester after reaction with alkali, and hydrolysis to obtain 2,4,5-trifluorophenylacetic acid, but this method is not suitable for industrial...

Claims

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Application Information

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IPC IPC(8): C07C57/58C07C51/15C07D403/04
Inventor 张群辉黄明旺陶开跃
Owner ZHEJIANG HISOAR PHARMA
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