Preparation methods of 2, 4, 5-trifluoro-benzyl chloride and 2, 4, 5-trifluoro-phenylacetic acid

A technology of trifluorophenylacetic acid and trifluorobenzyl chloride, applied in the field of medicine and chemical industry, can solve the problems of high waste liquid waste treatment cost and large amount of three wastes, and achieve the effects of less amount of three wastes, low treatment cost and high yield

Inactive Publication Date: 2012-09-26
NANTONG SHIMEIKANG PHARMA CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the use of zinc chloride, sodium chloride or potassium chloride will produce a large amount of inorganic salts, the amount of three wastes is large, and the treatment cost of waste liquid and residue is high

Method used

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  • Preparation methods of 2, 4, 5-trifluoro-benzyl chloride and 2, 4, 5-trifluoro-phenylacetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Preparation of 2,4,5-trifluorobenzyl chloride

[0025] Under normal temperature and pressure, hydrogen chloride gas is passed into 500ml of 80% sulfuric acid solution for 2-3 hours to obtain a saturated hydrogen chloride solution.

[0026] Add 66 grams (0.5 mol) of 1,2,4-trifluorobenzene and 18.8 grams of paraformaldehyde (equivalent to 0.62 mol monomer formaldehyde) into a 250ml four-necked reaction flask, and add the prepared saturated hydrogen chloride dropwise at 30°C Sulfuric acid solution 90ml, after the dropwise addition, stirred and reacted for 1-2 hours, poured into ice water, separated the organic layer, washed with water until neutral, dried and distilled under reduced pressure to obtain 82 grams of 2,4,5-trifluorobenzyl chloride, Content 99.4%, yield 91.1%.

[0027] 1 H NMR (300MHz, CDCl 3 ) δppm: 4.51 (2H, s, CH 2 Cl) 6.32 (4H, s, 2 CH 2 ).

[0028] MS (FAB, m / z): 195.5 (M + +1).

Embodiment 2

[0029] Example 2 Preparation of 2,4,5-trifluorobenzyl chloride

[0030] Under normal temperature and pressure, hydrogen chloride gas is passed into 500ml of 90% sulfuric acid solution for 2-3 hours to obtain a saturated hydrogen chloride solution.

[0031] Add 66 grams (0.5 mol) of 1,2,4-trifluorobenzene and 18.8 grams of paraformaldehyde (equivalent to 0.62 mol of monomeric formaldehyde) into a 500ml four-necked reaction flask, and add the prepared saturated hydrogen chloride dropwise at 20°C Sulfuric acid solution 190ml, stirred and reacted for 1-2 hours after the dropwise addition, poured into ice water, separated the organic layer, washed with water until neutral, dried and distilled under reduced pressure to obtain 85 grams of 2,4,5-trifluorobenzyl chloride, Content 99.2%, yield 94.4%.

Embodiment 3

[0032] Example 3 Preparation of 2,4,5-trifluorobenzyl chloride

[0033] Under normal temperature and pressure, hydrogen chloride gas is passed into 500ml of 95% sulfuric acid solution for 2-3 hours to obtain a saturated hydrogen chloride solution.

[0034] Add 66 grams (0.5 mol) of 1,2,4-trifluorobenzene and 18.8 grams of paraformaldehyde (equivalent to 0.62 mol of monomeric formaldehyde) into a 500ml four-necked reaction flask, and add the prepared saturated hydrogen chloride dropwise at 0°C 260ml of sulfuric acid solution, after the dropwise addition, stirred and reacted for 1-2 hours, poured into ice water, separated the organic layer, washed with water until neutral, dried and distilled under reduced pressure to obtain 83 grams of 2,4,5-trifluorobenzyl chloride, Content 99.5%, yield 92.2%.

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Abstract

The invention provides a preparation method of 2, 4, 5-trifluoro-benzyl chloride. The preparation method of the 2, 4, 5-trifluoro-benzyl chloride comprises the following steps of: adding sulfuric acid solution with hydrogen chloride gas and sulphuric acid concentration being 80-95 percent into 1, 2, 4-trifluoro-benzene and paraformaldehyde so as to be used as a chlorinating agent, and carrying out chloromethylation reaction to obtain the 2, 4, 5-trifluoro-benzyl chloride. The invention also provides a preparation method of 2, 4, 5-trifluoro-phenylacetic acid. The preparation method of the 2, 4, 5-trifluoro-phenylacetic acid comprises the following steps of: adding the sulfuric acid solution with the hydrogen chloride gas and the sulphuric acid concentration being 80-95 percent into the 1, 2, 4-trifluoro-benzene and the paraformaldehyde so as to be used as the chlorinating agent, carrying out chloromethylation reaction to obtain the 2, 4, 5-trifluoro-benzyl chloride, carrying out cyaniding reaction in organic solvent of cyaniding reagent to obtain the 2, 4, 5-trifluoro-benzyl chloride, heating and hydrolyzing the 2, 4, 5-trifluoro-benzyl chloride in acidic or alkaline aqueous solution, after the reaction is finished, and processing to obtain the 2, 4, 5-trifluoro-phenylacetic acid. According to the preparation methods, the discharging of waste liquor in a production process can be reduced, the production cost is reduced, the environmental and economic benefits are achieved, the product purity is good, and the yield is high.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of 2,4,5-trifluorophenylacetic acid and its intermediate 2,4,5-trifluorobenzyl chloride. Background technique [0002] 2,4,5-Trifluorophenylacetic acid is a key intermediate in the synthesis of sitagliptin, a drug for treating type Ⅱ diabetes. The Chinese patent document with application number 200510030162.0 and authorized announcement number CN100347142C discloses a preparation method of 2,4,5-trifluorophenylacetic acid. The specific steps are (1) adding 1,2,4-trifluorobenzene and poly Add chlorinating agent to polyoxymethylene for chloromethylation to obtain 2,4,5-trifluorobenzyl chloride; (2) Add 2,4,5-trifluorobenzyl chloride to the organic solvent of cyanide reagent for cyanation Reaction to obtain 2,4,5-trifluorobenzyl cyanide; (3) 2,4,5-trifluorobenzyl cyanide is heated and hydrolyzed in acidic or alkaline aqueous solution, t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C25/13C07C17/32C07C57/58C07C51/08
Inventor 刘一超王秀云孙为仁王俊华
Owner NANTONG SHIMEIKANG PHARMA CHEM
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