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A kind of preparation method of 2,4,5-trifluorophenylacetic acid

A technology of trifluorophenylacetic acid and trifluoronitrobenzene, which is applied in the field of anti-diabetic drugs, can solve the problems of high cost, complex process, and large pollution, and achieve the effect of less synthesis steps, easy-to-obtain raw materials, and low cost

Active Publication Date: 2016-01-13
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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  • A kind of preparation method of 2,4,5-trifluorophenylacetic acid
  • A kind of preparation method of 2,4,5-trifluorophenylacetic acid
  • A kind of preparation method of 2,4,5-trifluorophenylacetic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042]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.

[0043] 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

[0048] Add potassium hydroxide (85% content, 12.8g, 0.195mol), 2,4,5-trifluoronitrobenzene (35.4g, 0.2mol), diethyl malonate (30.4g, 0.2mol) in the four-necked flask .,19mol) and N,N-dimethylacetamide (200mL), stirred at 40°C for 6h, added saturated brine, extracted with dichloromethane (3x100mL), washed the organic phase with saturated brine, dried over anhydrous sodium sulfate , and concentrated to obtain a light brown oil, which was directly used in the next reaction without purification.

[0049] 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 wi...

Embodiment 3

[0054] 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.

[0055] 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 of 2,4,5-trifluorophenylacetic acid, which is characterized by the following four reaction steps: A.? Condensation of 2,4,5-trifluoronitrobenzene (I) with diethyl malonate to prepare 2,5-difluoro-4-nitrophenylmalonate (II), B. The hydrolysis, acidification and decarboxylation reaction of dibasic ester, the reduction reaction of C. nitro group, the diazotization fluorination reaction of D. amino group, described four reaction steps can follow A, B, C, D successively, or A, C, B, D, or A, C, D, B in order. The present invention utilizes the high substitution activity of nitro-para-fluorine in 2,4,5-trifluoronitrobenzene (I), so that 2,4,5-trifluoronitrobenzene (I) and diethyl malonate The condensation of the ester is easy to carry out, and the raw material 2,4,5-trifluoronitrobenzene (I) used is cheap and easy to obtain, and it is also easy to prepare from 2,4-dichlorofluorobenzene through the two-step reaction of nitration and fluorination. Compared with the prior art, the present invention has the characteristics of cheap and easy-to-obtain raw materials, mild reaction conditions, high total yield, low production cost, etc., and is more 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 CN1749232 / CN101659611 reports that 1,2,4-trifluorobenzene reacts with paraformaldehyde and a chlorinating agent to obtain 2,4,5-triflu...

Claims

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Application Information

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Patent Type & Authority Patents(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