Synthetic method of 3-chloro-5-(difluoromethoxy)benzylamine

A technology of difluoromethoxy and synthetic methods, which is applied in the field of pharmaceutical chemical synthesis, can solve problems such as no synthetic methods reported in literature, and achieve the effects of easy control, reasonable process design, and simple operation

Active Publication Date: 2020-03-17
埃法姆(常州)生命科学技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mainly solve the technical problems that there is no synthesis method reported in the literature

Method used

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  • Synthetic method of 3-chloro-5-(difluoromethoxy)benzylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] 3-Chloro-5-hydroxybenzonitrile (23.5g, 150mmol, 1eq.) was dissolved in 450ml N,N-dimethylformamide, and sodium difluorochloroacetate (57.2g, 375mmol, 2.5eq. ), cesium carbonate (74.1g, 225mmol, 1.5eq.) and 45g of water, under the protection of nitrogen, the temperature was raised to 100°C, and the reaction was kept for 5 hours.

[0021] After the reaction was finished, 900ml of water was added to the reaction solution and stirred. Extract with ethyl acetate, separate the layers, and concentrate the organic phase. After purification by column chromatography, 28.4 g of yellow oily substance 3-chloro-5-(difluoromethoxy)benzonitrile was obtained, with a yield of 93%.

[0022] 3-Chloro-5-(difluoromethoxy)benzonitrile (28.4g, 139.5mmol, 1eq.) was dissolved in 300ml of anhydrous tetrahydrofuran and cooled to 0°C. Under nitrogen protection, borane dimethyl sulfide (41.9ml, 418.5mmol, 3eq.) was added dropwise to the above reaction system, the temperature was raised to 65°C, an...

Embodiment 2

[0026] 3-Chloro-5-hydroxybenzonitrile (18.8g, 120mmol, 1eq.) was dissolved in 400ml N,N-dimethylacetamide, and sodium difluorochloroacetate (36.6g, 240mmol, 2eq.) was added successively , potassium carbonate (33.5g, 240mmol, 2eq.) and 35g of water, under the protection of nitrogen, the temperature was raised to 80°C, and the reaction was kept for 10 hours.

[0027] After the reaction was finished, 800ml of water was added to the reaction solution and stirred. Extract with ethyl acetate, separate the layers, and concentrate the organic phase. After purification by column chromatography, 20.5 g of yellow oil 3-chloro-5-(difluoromethoxy)benzonitrile was obtained, with a yield of 84%.

[0028] 3-Chloro-5-(difluoromethoxy)benzonitrile (20.5 g, 100.8 mmol, 1 eq.) was dissolved in 200 ml of anhydrous tetrahydrofuran and cooled to 0°C. Under nitrogen protection, borane dimethyl sulfide (30.2ml, 302.4mmol, 3eq.) was added dropwise to the above reaction system, the temperature was rai...

Embodiment 3

[0032] 3-Chloro-5-hydroxybenzonitrile (28.2g, 180mmol, 1eq.) was dissolved in 600ml of dimethyl sulfoxide, and sodium difluorochloroacetate (41.2g, 270mmol, 1.5eq.) and sodium carbonate ( 19.3g, 180mmol, 1eq.) and 55g of water, under the protection of nitrogen, the temperature was raised to 148°C, and the reaction was kept for 1 hour.

[0033] After the reaction was finished, 1200ml of water was added to the reaction solution and stirred. Extract with ethyl acetate, separate the layers, and concentrate the organic phase. After purification by column chromatography, 26.8 g of yellow oil 3-chloro-5-(difluoromethoxy)benzonitrile was obtained, with a yield of 73%.

[0034] 3-Chloro-5-(difluoromethoxy)benzonitrile (26.8g, 131.4mmol, 1eq.) was dissolved in 300ml of anhydrous tetrahydrofuran and cooled to 0°C. Under nitrogen protection, borane dimethyl sulfide (39.4ml, 394.2mmol, 3eq.) was added dropwise to the above reaction system, the temperature was raised to 30°C, and the reac...

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Abstract

The invention provides a synthetic method of 3-chloro-5-(difluoromethoxy)benzylamine, and belongs to the field of chemical synthesis of medicines. According to the method, 3-chloro-5-hydroxybenzonitrile is used as a raw material, and under the protection of nitrogen, the final product 3-chloro-5-(difluoromethoxy)benzylamine is obtained through difluoromethylation and reduction. The method is reasonable in process design, short in route, simple to operate and easy to control.

Description

technical field [0001] The invention relates to a method for synthesizing difluoromethoxy compounds, in particular to a method for synthesizing 3-chloro-5-(difluoromethoxy)benzylamine, and belongs to the field of pharmaceutical chemical synthesis. Background technique [0002] Because fluorine-containing drugs have better fat solubility, high drug efficacy and strong metabolism, they are widely used in the field of medicine. Difluoromethoxy is one of the important pharmacophore groups, and the use of difluoromethoxy to replace other groups on the benzene ring can improve drug activity. At present, there are many kinds of drugs containing difluoromethoxy in the domestic market. Such as the inhibitor roflumilast of phosphodiesterase 4 (PDE4), its key intermediate is 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid; treatment of duodenal and gastric ulcer and Pantoprazole, which relieves severe reflux esophagitis, has a pharmaceutical intermediate of 2-mercapto-5-difluorome...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/02C07C215/50
CPCC07C213/02C07C253/30C07C215/50C07C255/54
Inventor 史建云许义波史红亮戴红升顾云龙
Owner 埃法姆(常州)生命科学技术有限公司
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