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Preparation method of 2, 4,5-trifluoro phenylacetic acid

A technology of trifluorophenylacetic acid and trifluorophenyl, which is applied in the field of preparation of 2,4,5-trifluorophenylacetic acid, can solve the problems of harsh reaction conditions, high industrial production cost, and high price of oxidant, and achieves cheap, The effect of low material cost

Inactive Publication Date: 2015-03-18
SINOCHEM LANTIAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] U.S. Patent US2004068141 reported that 2,4,5-trifluorobromobenzene and diethyl malonate were used as raw materials to obtain 2,4,5-trifluorophenylacetic acid through coupling reaction and hydrolysis deacidification reaction. Harsh conditions and high industrial production costs
[0004] U.S. Patent US20040077901 reported that 2,4,5-trifluorobromobenzene underwent a Grignard reaction and a substitution reaction with allyl bromide to obtain 1-(2-allyl)-2,4,5-trifluorobenzene, and finally After oxidation of ruthenium trichloride and sodium periodate, 2,4,5-trifluorophenylacetic acid is obtained. The oxidant of this route is expensive and not suitable for industrial production
[0005] Chinese patent CN1749232 reported that 1,2,4-trifluorobenzene was used as raw material to obtain 2,4,5-trifluorophenylacetic acid through chloromethylation, cyanation, and hydrolysis. This route used highly toxic cyanide, There are certain safety hazards in production

Method used

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  • Preparation method of 2, 4,5-trifluoro phenylacetic acid
  • Preparation method of 2, 4,5-trifluoro phenylacetic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Example 1 Preparation of ethyl 2-cyano-2-(2,4,5-trifluorophenyl)acetate

[0026] Under nitrogen protection, add ethyl cyanoacetate (0.13mol) to N-methylpyrrolidone (30.0mL) containing sodium hydride (0.13mol, content 60%), when the gas is released, add 1,2,4 , 5-tetrafluorobenzene (0.0439mol), the reaction system was sealed, heated to 120 ° C, and reacted for 24 hours. 75 mL of water was added, extracted with ethyl acetate, and the organic phase was desolvated under reduced pressure to obtain 7.47 g of a yellow transparent liquid with a yield of 70%.

[0027] After testing, the yellow transparent liquid is ethyl 2-cyano-2-(2,4,5-trifluorophenyl)acetate, and the NMR data are as follows: 1 HNMR (400Hz, CDCl 3 ):δ7.42-7.37(m,1H),7.09-7.02(m,1H),4.96(s,1H),4.31(q,2H),1.33(t,3H).

Embodiment 2

[0028] Example 2 Preparation of ethyl 2-cyano-2-(2,4,5-trifluorophenyl)acetate

[0029] Potassium tert-butoxide (0.13mol) was used to replace sodium hydride, and the rest was the same as in Example 1. After the reaction was completed, 5.76 grams of ethyl 2-cyano-2-(2,4,5-trifluorophenyl)acetate was obtained. The yield was 54%.

Embodiment 3

[0030] Example 3 Preparation of ethyl 2-cyano-2-(2,4,5-trifluorophenyl)acetate

[0031] N,N-Dimethylacetamide (30mL) was used instead of N-methylpyrrolidone, the rest was the same as in Example 1, and the reaction was completed to obtain 2-cyano-2-(2,4,5-trifluorophenyl)acetic acid Ethyl ester 7.00 g, yield 66%.

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Abstract

The invention provides a preparation method of 2,4,5-trifluoro phenylacetic acid. 1,2,4,5-tetrafluorobenzene and cyano alkyl acetate as raw materials first generate 2-cyano-2-(2,4,5-trifluorophenyl) alkyl acetate, and 2,4,5-trifluoro phenylacetic acid is further prepared. The method provided by the invention is simple and safe for operation, and applicable to industrialized production. The prepared 2,4,5-trifluoro phenylacetic acid can be applied to the synthesis of an important intermediate for a novel medicament sitagliptin for treating diabetes.

Description

technical field [0001] The invention relates to a preparation method of 2,4,5-trifluorophenylacetic acid. Background technique [0002] 2,4,5-Trifluorophenylacetic acid is an important intermediate in the synthesis of sitagliptin, a new drug for treating diabetes. Its preparation method has the following reports in the prior art: [0003] U.S. Patent US2004068141 reported that 2,4,5-trifluorobromobenzene and diethyl malonate were used as raw materials to obtain 2,4,5-trifluorophenylacetic acid through coupling reaction and hydrolysis deacidification reaction. The conditions are harsh and the cost of industrialized production is high. [0004] U.S. Patent US20040077901 reported that 2,4,5-trifluorobromobenzene undergoes Grignard reaction and substitution reaction with allyl bromide to obtain 1-(2-allyl)-2,4,5-trifluorobenzene, and finally After oxidizing with ruthenium trichloride and sodium periodate, 2,4,5-trifluorophenylacetic acid is obtained. The oxidizing agent of th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C57/58C07C27/02C07C255/41C07C253/30
Inventor 冯启夏旭建郑昀红孔小林
Owner SINOCHEM LANTIAN
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