8-chloro-1-methyl-4,5-dihydro-1h-benzo[d]azepine-2(3H)-one preparation method

A methyl, dihydrogen technology, applied in the direction of organic chemistry, etc., can solve the problems of cumbersome post-processing, many impurities, large amount of catalyst aluminum trichloride, etc.

Inactive Publication Date: 2015-09-02
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This reaction has the disadvantages of large amount of catalyst aluminum trichloride, high reaction temperature, difficult stirring, more impurities, complicated post-treatment, etc., and the yield is low, only 54%.

Method used

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  • 8-chloro-1-methyl-4,5-dihydro-1h-benzo[d]azepine-2(3H)-one preparation method

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Experimental program
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Effect test

Embodiment 1

[0020] 8-Chloro-1-methyl-4,5-dihydro-1H-benzo[d]azepine Synthesis of -2(3H)-ketone (I)

[0021] Add anhydrous aluminum trichloride (21.7g, 0.165mol) and 70mL of anhydrous 1,2-dichlorobenzene into a 500ml eggplant-shaped bottle, and dissolve IV (20g, 0.082mol) in 80mL of anhydrous 1 , 2-dichlorobenzene, dropwise added to the reaction system. After dropping, stir at 25°C for 15 minutes, then raise the temperature to an internal temperature of 140°C, stir and react for 6 hours, then cool to room temperature, and TLC detects that the reaction is complete. Slowly add 105 mL of 4 mol / L hydrochloric acid solution to the reaction mixture, stir well to dissolve all the solids, let stand, separate the organic layer, and extract the aqueous layer twice with 300 mL of dichloromethane. The organic layers were combined, washed with saturated NaCl solution, decolorized with activated carbon, and suction filtered. The filtrate was dried with anhydrous sodium sulfate, and suction filtered. ...

Embodiment 2

[0025] 8-Chloro-1-methyl-4,5-dihydro-1H-benzo[d]azepine Synthesis of -2(3H)-ketone (I)

[0026] Add anhydrous aluminum trichloride (28.0 g, 0.206 mol) and 80 mL of anhydrous 1,2-dichlorobenzene into a 500 ml eggplant-shaped bottle, dissolve IV (20 g, 0.082 mol) in 80 mL of anhydrous 1 under nitrogen protection, 2-Dichlorobenzene was added dropwise to the reaction system. After dropping, stir at 25°C for 15 minutes, heat up to an internal temperature of 145°C, stir for 5.5 hours, then cool to room temperature, and TLC detects that the reaction is complete. Slowly add 125 mL of 5 mol / L hydrochloric acid solution to the reaction mixture, stir well to dissolve all the solids, let stand, separate the organic layer, and extract the aqueous layer twice with 300 mL of dichloromethane. The organic layers were combined, washed with saturated NaCl solution, decolorized with activated carbon, and suction filtered. The filtrate was dried with anhydrous sodium sulfate, and suction filter...

Embodiment 3

[0028] 8-Chloro-1-methyl-4,5-dihydro-1H-benzo[d]azepine Synthesis of -2(3H)-ketone (I)

[0029] Add anhydrous aluminum trichloride (21.7 g, 0.165 mol) and 80 mL of anhydrous 1,3-dichlorobenzene into a 500 ml eggplant-shaped bottle, and protect under a nitrogen atmosphere. Dissolve IV (20 g, 0.082 mol) in 90 mL of anhydrous 1,3-dichlorobenzene and add it dropwise to the reaction system. After dropping, stir at 25°C for 20 minutes, raise the temperature to 150°C, react for 6 hours, and cool to room temperature. TLC detects that the reaction is complete. Slowly add 100 mL of 4 mol / L hydrochloric acid solution to the reaction mixture, stir well to dissolve all the solids, let stand, separate the organic layer, and extract the aqueous layer twice with 400 mL of dichloromethane. The organic layers were combined, washed with saturated NaCl solution, decolorized with activated carbon, and filtered with suction. The filtrate was dried with anhydrous sodium sulfate, and filtered with...

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Abstract

The present invention relates to the pharmaceutical synthesis field, particularly to a preparation method of an lorcaserin intermediate 8-chloro-1-methyl-4,5-dihydro-1H-benzo[d]azepine-2(3H)-one. The preparation method is characterized in that in an intramolecular Friedel-Crafts alkylation reaction, aluminum trichloride is adopted as a catalyst and anhydrous dichlorobenzene is adopted as a solvent so as to increase the reaction at the step to 73%, such that the method has advantages of low catalyst consumption, low reaction temperature, convenient post-treatment, easy scale-up, and the like.

Description

technical field [0001] The invention relates to the field of drug synthesis. Specifically related to green caserin intermediate 8-chloro-1-methyl-4,5-dihydro-1H-benzo[d]azepine - Preparation method of 2(3H)-one (I). Background technique [0002] 8-Chloro-1-methyl-4,5-dihydro-IH-benzo[d]azepine -2(3H)-ketone (I) is a key intermediate for the preparation of Lorcaserin. Green caserin acts on 5-HT in the brain 2C receptors to control appetite and regulate metabolism. The structural formulas of compound I and greencaserin are as follows: [0003] [0004] Green caserin hydrochloride is obtained from the racemate of green caserin after resolution and salt formation. There are three main synthetic routes of green caserin racemate (II) reported in the literature. [0005] Route 1 (WO2005042490, WO2005042091 and WO2006071740) uses 2-(4-chlorophenyl)ethylamine (III) as raw material to prepare compound II through six steps, including selective iodination, Heck coupling reac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
Inventor 徐云根聂凤卞学国姚魏何广卫
Owner CHINA PHARM UNIV
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