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Preparation method of 3-difluoromethyl-1-methyl-pyridine-4-carbonyl chloride

A technology of difluoromethyl and carbonyl chloride, which is applied in the field of pharmaceutical chemical synthesis, can solve problems such as large environmental pollution, difficult reaction control, and harsh conditions, and achieve the effects of reducing operational pollution, high synthesis yield, and fewer synthesis steps

Inactive Publication Date: 2019-02-22
ZHEJIANG BENLI TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this reaction, hydrogen fluoride is used as the fluorinated reagent, and the reaction is performed at high temperature, the reaction is difficult to control, the fluorinated yield is low, and the environmental pollution is large.
[0007] WO 01 / 42223 describes the synthetic route of N-(o-phenyl)-1-methyl-3-difluoromethylpyridine-4-carboxanilide. Compared with this route, the steps are complicated and the conditions are harsh. 3- The synthesis yield of difluoromethyl-1-methyl-pyridine-4-carbonyl chloride is low and does not meet the requirements of today's green development

Method used

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  • Preparation method of 3-difluoromethyl-1-methyl-pyridine-4-carbonyl chloride
  • Preparation method of 3-difluoromethyl-1-methyl-pyridine-4-carbonyl chloride
  • Preparation method of 3-difluoromethyl-1-methyl-pyridine-4-carbonyl chloride

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Experimental program
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Effect test

specific Embodiment 1

[0026] At 22°C, 45g of acetic acid solution containing 80% 1,1-difluoro-4-ethoxy-3-buten-2-one (0.24mol) was added dropwise to 20% methylhydrazine aqueous solution , the aqueous solution of methylhydrazine is 99% pure, 11.6g, 0.24mol. The resulting reaction solution was stirred at 22° C. for 19 hours in 560 ml of acetic acid. Acetic acid was then removed under reduced pressure. The oily residue was dissolved in 300 ml methyl tert-butyl ether (MTBE) and washed with 250 ml water. The aqueous phase was extracted once with 150 ml MTBE. The collected organic solutions were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure (40° C. / 400 to 30 mbar). The 23.5 g residue was subjected to fractional distillation to isolate the product. 21.5 g of the main fraction (conversion temperature 52°C, 22 mbar) contained 3-difluoromethyl-1-methyl-pyridine and 5-difluoromethyl-1-methyl-pyridine in a ratio of 3:1. 3-Difluoromethyl-1-pyridine The overall yield...

specific Embodiment 2

[0027] At 22°C, in 45g of acetic acid solution containing 80% of 1,1-difluoro-4-ethoxy-3-buten-2-one (0.24mol), add dropwise to 460ml of methylhydrazineacetic acid solution (99% pure, 12.2 g, 0.26 mol). Under these conditions, the reaction was incubated for 19 hours. The mixture was freed of acetic acid under reduced pressure. The residual oily mixture was dissolved in methyl tert-butyl ether (MTBE, 300ml) and washed with water (250ml). The aqueous phase was extracted once with MTBE (150ml). The collected organic solutions were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue (23.5 g) was subjected to fractional distillation to isolate the product. The main fraction was distilled under reduced pressure to obtain 21.5 g containing 3-difluoromethyl-1-methyl-pyridine and 5-difluoromethyl-1-methyl-pyridine in a ratio of 4:1 (GC retention time: 5- isomer: 7.6 minutes; 3-isomer: 9.2 minutes). The overall yield of 3-difluoromet...

specific Embodiment 3

[0028] At 22°C, in 45g of acetic acid solution containing 80% of 1,1-difluoro-4-ethoxy-3-buten-2-one (0.24mol), add dropwise to 460ml of methylhydrazineacetic acid solution (99% pure, 14.4 g, 0.31 mol). Under these conditions, the reaction was incubated for 19 hours. The mixture was freed of acetic acid under reduced pressure. The residual oily mixture was dissolved in methyl tert-butyl ether (MTBE, 300ml) and washed with water (250ml). The aqueous phase was extracted once with MTBE (150ml). The collected organic solutions were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue (23.5 g) was subjected to fractional distillation to isolate the product. The main fraction was distilled under reduced pressure to obtain 21.5 g containing 3-difluoromethyl-1-methyl-pyridine and 5-difluoromethyl-1-methyl-pyridine in a ratio of 4:1 (GC retention time: 5- isomer: 7.6 minutes; 3-isomer: 9.2 minutes). The overall yield of 3-difluoromet...

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Abstract

The invention relates to a preparation method of 3-difluoromethyl-1-methyl-pyridine-4-carbonyl chloride. The method comprises the following steps: (A) 3-difluoromethyl-1-methyl-pyridine is prepared from 1,1-difluoro-4-ethoxy-3-buten-2-one and methylhydrazine in presence of an acid and an organic solvent by a reaction at subzero 10-60 DEG C for 3-8 h; (B) 3-difluoromethyl-4-trichloromethyl-1-methyl-pyridine is prepared from 3-difluoromethyl-1-methyl-pyridine and carbon tetrachloride in presence of aluminium chloride and zeolite by a reaction at subzero 10-60 DEG C for 1-5 h; (C) 3-difluoromethyl-1-methyl-pyridine-4-carbonyl chloride is prepared from 3-difluoromethyl-4-trichloromethyl-1-methyl-pyridine and water under the action of Lewis acid by a hydrolysis reaction at 50-100 DEG C for 1-4h. Influence of different reaction steps and refining conditions on the preparation route of 3-difluoromethyl-1-methyl-pyridine-4-carbonyl chloride is explored, and wastewater pollution is reduced while yield is increased.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of 3-difluoromethyl-1-methyl-pyridine-4-carbonyl chloride. Background technique [0002] 3-(Difluoromethyl)-1-methyl-1H-pyridine-4-carbonyl chloride, CAS: carbonyl chloride, the structural formula is as follows [0003] [0004] It is an intermediate unit for the synthesis of various fungicides and insecticides. [0005] CN200480031203.1 describes that 3-(difluoromethyl)-1-methyl-1H-pyridine-4-carbonyl chloride can be prepared by N,N-dimethylaminoacrylate successively with difluoroacetyl chloride, and then with methyl Hydrazine and reaction prepare 3-(dichloromethyl)-1-methyl-1H-pyridine-4-carboxylate, which is then subjected to hydrolysis and acidification. However, the synthesis steps are many, the operation is complicated, and the synthesis yield is low. [0006] CN 102731402A describes the synthesis of 3-polyflu...

Claims

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Application Information

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IPC IPC(8): C07D231/14
CPCC07D231/14
Inventor 余永志吴政杰顾海宁谢文明孔富强
Owner ZHEJIANG BENLI TECH CO LTD
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