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Preparation of 3-(3-chlorine propyl)-7, 8-di methoxy-1, 3-dihydrogen-2H-3-benzo aza -ketone

A technology of dimethoxy and chloropropyl, applied in 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine -The field of preparation of 2-ketones can solve the problems of difficult storage, high water absorption, easy explosion and so on

Inactive Publication Date: 2009-01-14
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, apart from the fact that sodium hydride and dimethylformamide are also highly hygroscopic and difficult to store, there is a major disadvantage of being prone to explosion at lower temperatures

Method used

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  • Preparation of 3-(3-chlorine propyl)-7, 8-di methoxy-1, 3-dihydrogen-2H-3-benzo aza -ketone
  • Preparation of 3-(3-chlorine propyl)-7, 8-di methoxy-1, 3-dihydrogen-2H-3-benzo aza -ketone
  • Preparation of 3-(3-chlorine propyl)-7, 8-di methoxy-1, 3-dihydrogen-2H-3-benzo aza -ketone

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Experimental program
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Effect test

Embodiment 1

[0025] 1.5g (6.8mmol) 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine -2-Kone, 1.5g (9.5mmol) of 1,3-bromochloropropane and 6ml of DMF were placed in a flask, the temperature of the reaction mixture was raised to 40°C, and 0.8g of 40% sodium hydroxide (8mmol) solution was added. The mixture was then heated to 60°C and stirred for 2 hours; 30 ml of ice water was added and stirred for 1 hour under cooling in an ice-water bath. The solid precipitate was filtered off, washed and dried. The yield of the title compound was obtained in 85%.

Embodiment 2

[0027] 1.5g of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine -2-Kone, 1.5g of 1,3-bromochloropropane and 5ml of N-methylpyrrolidone were placed in a flask, the temperature of the reaction mixture was raised to 40°C, and 0.8g of 40% sodium hydroxide solution was added. The mixture was then heated to 60°C and stirred for 2 hours; 30 ml of ice water was added and stirred for 1 hour under cooling in an ice-water bath. The solid precipitate was filtered off, washed and dried. The yield of the title compound was obtained in 83%.

[0028] Synthesis of 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine in the presence of potassium carbonate -2-one

Embodiment 3

[0030] 1.5g (6.8mmol) 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine -2-Kone, 2.7g (19.5mmol) of potassium carbonate and 8ml of DMF were mixed, stirred at 80°C for 1 hour, 1.9g (12.2mmol) of 1,3-bromochloropropane was added at the same temperature, and stirred for 2 hours. Add 50ml of ice water, extract with dichloromethane, concentrate the obtained oil, add appropriate amount of isopropyl ether and ethyl acetate, stir overnight, and filter to obtain the title compound with a yield of 80%.

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Abstract

The invention relates to the technique field of a preparation method of an intermediate compound of Ivabradine. The preparation method of 3-(3-chloropropyl)-7, 8-dimethoxy-1, 3-dihydro-2H-3-benazepine-2-ketone comprises: making 7, 8-dimethoxy-1, 3-dihydro-2H-3-benazepine-2-ketone and 1, 3-chlorobromide have the alkylation reaction. The preparation method unexpectedly selects an alkaline reagent used commonly, and has advantages of mild reaction conditions, safety and reliability, and rather high yield, and the method fully overcomes the defects of strong water absorption, easy deterioration, or easy explosion under rather low temperature of the alkylation reagent used in the prior art, and is extremely applied to the industrialized big-production.

Description

technical field [0001] The present invention relates to 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine The preparation method of -2-ketone. Background technique [0002] Ivabradine and its pharmaceutically acceptable salts, especially its hydrochloride, have very important pharmacological and therapeutic properties, especially heart rate-lowering properties, so that these compounds can be used for the treatment or prophylaxis of various Clinical myocardial ischemic conditions, such as angina pectoris, myocardial infarction and related rhythm disturbances, also include various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances. [0003] The preparation and therapeutic use of ivabradine and its pharmaceutically acceptable salts (especially hydrochloride) have been described in the specification of European patent EP0534859. The synthesis of ivabradine hydrochloride as a compound of formula (I), i.e. 3-(3-chloropropyl)-7...

Claims

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Application Information

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IPC IPC(8): C07D223/16A61K31/55A61P9/10
Inventor 岑均达郭珩
Owner SHANGHAI INST OF PHARMA IND
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