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Preparation process of 1-(2,3-difluorophenyl)-2-methyl-1-acetone

A technology for the preparation of difluorophenyl, which is applied in the field of preparation of 1--2-methyl-1-acetone, can solve the problems of unfavorable large-scale production, high cost of raw materials, and many side reactions, and achieve convenient scale The effect of modern production, low cost, and few by-products

Inactive Publication Date: 2018-09-11
苏州莱克施德药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of this invention is to provide a kind of preparation technology of 1-(2,3-difluorophenyl)-2-methyl-1-propanone, solve the existing problems including high cost of raw materials, many side reactions, reaction Repeated heating and cooling in the middle, the operation is cumbersome, which is not conducive to large-scale production

Method used

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  • Preparation process of 1-(2,3-difluorophenyl)-2-methyl-1-acetone
  • Preparation process of 1-(2,3-difluorophenyl)-2-methyl-1-acetone

Examples

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example 1

[0025] Add o-difluorobenzene (100 g, 0.877 mol) and anhydrous tetrahydrofuran (1.0 L) sequentially into a 2.0 L three-neck reaction flask, stir until the system is clear, and cool down to -80°C. Control the temperature of the system at -30~-80°C, add n-butyllithium (315ml, 2.5M cyclohexane solution) dropwise, and continue stirring for 1-2.0h after the dropwise addition is complete. Isobutyryl chloride (84 g, 0.788 mol) was added dropwise to the reaction system, and the temperature of the system was controlled at -30 to -80°C. After the dropwise addition was completed, the stirring reaction was continued for 2.0 h. Keep the temperature of the system below -30°C, and adjust the pH of the system at 3-5 with 3M hydrochloric acid solution.

[0026] The reaction system was filtered, the filtrate was extracted several times with ethyl acetate, and the organic phase was concentrated to obtain the crude product of 1-(2,3-difluorophenyl)-2-methyl-1-propanone, which was purified by disti...

example 2

[0028] Add o-difluorobenzene (100 g, 0.877 mol) and anhydrous diethyl ether (1.0 L) sequentially into a 2.0 L three-neck reaction flask, stir until the system is clear, and cool down to -80°C. Control the temperature of the system at -30~-80°C, add sec-butyllithium (555ml, 1.5M cyclohexane solution) dropwise, and continue stirring for 1-2.0h after the dropwise addition is complete. Isobutyryl chloride (84 g, 0.788 mol) was added dropwise to the reaction system, and the temperature of the system was controlled at -30 to -80°C. After the dropwise addition was completed, the stirring reaction was continued for 2.0 h. Keep the temperature of the system below -30°C, and adjust the pH of the system at 3-5 with 3M hydrochloric acid solution.

[0029] The reaction system was filtered, the filtrate was extracted several times with ethyl acetate, and the organic phase was concentrated to obtain the crude product of 1-(2,3-difluorophenyl)-2-methyl-1-propanone, which was purified by disti...

example 3

[0031] Add o-difluorobenzene (100 g, 0.877 mol) and anhydrous diethyl ether (1.0 L) sequentially into a 2.0 L three-neck reaction flask, stir until the system is clear, and cool down to -80°C. Control the temperature of the system at -30~-80°C, add lithium diisopropylamide (315ml, 2.5M tetrahydrofuran solution) dropwise, and continue stirring for 1-2.0h after the dropwise addition is complete. Isobutyryl chloride (84 g, 0.788 mol) was added dropwise to the reaction system, and the temperature of the system was controlled at -30 to -80°C. After the dropwise addition was completed, the stirring reaction was continued for 2.0 h. Keep the temperature of the system below -30°C, and adjust the pH of the system at 3-5 with 3M hydrochloric acid solution.

[0032] The reaction system was filtered, the filtrate was extracted several times with ethyl acetate, and the organic phase was concentrated to obtain the crude product of 1-(2,3-difluorophenyl)-2-methyl-1-propanone, which was purif...

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Abstract

The invention provides a preparation process of 1-(2,3-difluorophenyl)-2-methyl-1-acetone, and specifically relates to the technical field of drug synthesis. The preparation process specifically includes the following steps: 1,2-difluoride and organic base react under low temperature conditions to generate 2,3-difluorophenyllithium; then isobutyryl chloride is added to obtain a raw product solution of the final product 1-(2,3-difluorophenyl)-2-methyl-1-acetone; pH is regulated to 3-5 by using acid; and finally through extraction, concentration and purification, high-purity 1-(2,3-difluorophenyl)-2-methyl-1-acetone is produced. The process of the invention has advantages of novelty, mild reaction condition, few by-products, simple purification method and high yield. Compared with the existing synthetic process, the process of the invention is low-cost, is simple to operate, and is convenient for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation process of 1-(2,3-difluorophenyl)-2-methyl-1-propanone. Background technique [0002] 1-(2,3-difluorophenyl)-2-methyl-1-propanone is an important API intermediate, which often appears in the synthesis of many new drugs. The prior art discloses the following synthetic route [0003] [0004] This route uses 2,3-difluorobenzonitrile as the starting material, reacts with Grignard reagent isopropylmagnesium chloride at high temperature, then quenches with hydrochloric acid at low temperature, extracts, concentrates and purifies, and prepares 1-(2,3-di Fluorophenyl)-2-methyl-1-propanone. The process has high cost of raw materials, many side reactions, repeated heating and cooling during the reaction, cumbersome operation, and is not conducive to large-scale production. [0005] Therefore, it is necessary to study the synthesis method of 1-(2,3...

Claims

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Application Information

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IPC IPC(8): C07C45/46C07C49/807
CPCC07C45/46C07F1/02C07C49/807
Inventor 汪爱丰卢建庄江俞菊荣
Owner 苏州莱克施德药业有限公司