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Preparation method 2,4,5-trifluorophenylacetic acid

A technology of trifluorophenylacetic acid and trifluoronitrobenzene, applied in the field of antidiabetic drugs, can solve the problems of high cost, large pollution, complicated process and the like, and achieve the effects of few synthesis steps, low cost and easy availability of raw materials

Active Publication Date: 2013-04-03
江苏中丽新材料有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0027] In order to overcome the disadvantages of complex process, high cost and large pollution in the prior art, the present invention provides a new method for the preparation of 2,4,5-trifluorophenylacetic acid

Method used

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  • Preparation method 2,4,5-trifluorophenylacetic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0044]Add sodium hydroxide (7.8g, 0.195mol), 2,4,5-trifluoronitrobenzene (35.4g, 0.2mol), diethyl malonate (30.4g, 0.19mol) into the four-necked flask and N,N-dimethylformamide (200mL), stirred and reacted at 40°C for 6h, added saturated brine, extracted with dichloromethane (3x100mL), washed the organic phase with saturated brine, dried over anhydrous magnesium sulfate, concentrated to obtain shallow The brown oil was directly used in the next reaction without purification.

[0045] The product 2,5-difluoro-4-nitrophenylmalonate diethyl ester obtained above, water (180mL), acetic acid (220mL) and concentrated sulfuric acid (65mL) were mixed, stirred and heated to reflux for 24h, after cooling Extract with dichloromethane (3x100mL), wash the organic phase with saturated brine, then adjust the pH to 10 with potassium carbonate solution, acidify the separated aqueous phase to pH 2 with 3mol / L hydrochloric acid, then extract with dichloromethane, and use the organic phase with W...

Embodiment 2

[0050] Add potassium hydroxide (85% content, 12.8g, 0.195mol), 2,4,5-trifluoronitrobenzene (35.4 g, 0.2 mol), diethyl malonate (30.4 g, 0 .,19 mol) and N,N-dimethylacetamide (200mL), stirred at 40°C for 6 h, added saturated brine, extracted with dichloromethane (3x100mL), washed the organic phase with saturated brine, anhydrous sulfuric acid It was dried over sodium and concentrated to obtain a light brown oil, which was directly used in the next reaction without further purification.

[0051] After the product 2,5-difluoro-4-nitrophenylmalonate diethyl ester, water (180mL), acetic acid (220mL) and concentrated sulfuric acid (65mL) were mixed, stirred and heated to reflux for 24h, after cooling Extract with dichloromethane (3x100mL), wash the organic phase with saturated brine, then adjust the pH to 10 with sodium carbonate solution, acidify the separated aqueous phase to pH 2 with 3mol / L hydrochloric acid, then extract with dichloromethane, and use the organic phase with Was...

Embodiment 3

[0056] Add sodium methylate (10.5g, 0.195mol), 2,4,5-trifluoronitrobenzene (35.4g, 0.2mol), diethyl malonate (30.4g, 0.19mol) and N- Methylpyrrolidone (200mL), stirred at 40°C for 6h, added saturated brine, extracted with dichloromethane (3x100mL), washed the organic phase with saturated brine, dried over anhydrous magnesium sulfate, concentrated to give a light brown oil without purification used directly in the next reaction.

[0057] The product 2,5-difluoro-4-nitrophenylmalonate diethyl ester obtained above, water (180mL), acetic acid (220mL) and concentrated sulfuric acid (65mL) were mixed, stirred and heated to reflux for 24h, after cooling Extract with dichloroethane (3x100mL), wash the organic phase with saturated brine, then adjust to pH10 with sodium carbonate solution, acidify the separated aqueous phase with 2mol / L hydrochloric acid to pH2, then extract with dichloroethane, organic The phase was washed with saturated brine, dried over anhydrous magnesium sulfate, ...

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Abstract

The invention discloses a preparation method 2,4,5-trifluorophenylacetic acid. The method is characterized by consisting of four reaction steps of: A, reaction of 2,4,5-trifluoronitrobenzene (I) and diethyl malonate which are condensed to prepare 2,5-difloro-4-nitrobenzophenone diethyl malonate; B, hydrolysis, acidification and decarboxylic reaction of dibasic ester; C, reduction reaction of nitryl; and D, diazotization fluoridation of amino. The four reaction steps can be sequentially carried out according to A, B, C and D, or A, C, B and D, or A, C, D and B. According to the preparation method provided by the invention, condensation of 2,4,5-trifluoronitrobenzene (I) and diethyl malonate is easy to realize by means of high substituting activity of nitryl p-fluorine, and the raw material 2,4,5-trifluoronitrobenzene (I) is low in cost and easy to obtain and can be easily prepared by nitration and fluorination of 2,4-dichlor fluorbenzene. Compared with the prior art, the preparation method provided by the invention has the characteristics of low-cost and easily obtained raw materials, mild reaction condition, high total yield, low production cost and the like, and is comparatively suitable for industrialized production.

Description

technical field [0001] The invention relates to a synthesis method of an intermediate 2,4,5-trifluorophenylacetic acid of an antidiabetic drug sitagliptin. Background technique [0002] 2,4,5-Trifluorophenylacetic acid is an important intermediate in the synthesis of antidiabetic drug sitagliptin. [0003] Sitagliptin is a new type of diabetes treatment drug first developed and marketed by Merck Company of the United States in 2006, and is mainly used for the treatment of type II diabetes. Due to its unique mechanism of action and good curative effect, sitagliptin has become the best-selling anti-diabetic drug with a market sales of more than 2 billion US dollars. [0004] 2,4,5-Trifluorophenylacetic acid is the key intermediate of sitagliptin, and the main synthetic route reported in the literature is as follows: [0005] 1. Chinese patent CN 1749232 / CN 101659611 reports that 1,2,4-trifluorobenzene reacts with paraformaldehyde and chlorinating agent to obtain 2,4,5-triflu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C57/58C07C51/363C07C51/38
Inventor 郑土才吾国强吕延文
Owner 江苏中丽新材料有限公司
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