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Preparation method of 7,8-dimethoxy-1,3-dihydro-2h-3-benzazepin-2-one

A technology of -2H-3- and dimethoxy, which is applied in the direction of organic chemistry, can solve the problems of equipment corrosion, environmental pollution, unfavorable industrial production, and reduced production efficiency, so as to avoid high-temperature vacuum distillation and shorten the reaction The effect of simple time and production conditions

Inactive Publication Date: 2011-12-14
QILU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In the route of the above-mentioned document, due to the presence of thionyl chloride during the reaction, a large amount of hydrogen chloride gas will be produced during the preparation of 3,4-dimethoxyphenylacetyl chloride, which is highly corrosive to equipment and can pollute the environment, and In the post-treatment process, operations such as high-temperature and vacuum distillation are required to obtain relatively pure products, which is very unfavorable for industrial production, reduces production efficiency, and has disadvantages such as serious environmental pollution, long production cycle, low yield and high cost.

Method used

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  • Preparation method of 7,8-dimethoxy-1,3-dihydro-2h-3-benzazepin-2-one

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Experimental program
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Effect test

Embodiment 1

[0033] 2,4-dimethoxy-6-chloro-1,3,5-s-triazine (210.6g) was dissolved in 2L of dichloromethane, and 3.4-dimethoxyphenylacetic acid (196g) was added to In the above dichloromethane solution, stir and lower the temperature to 0-10°C, add N-methylmorpholine (121.2g) dropwise to the above system, continue stirring for 3 hours after the addition, and then analyze the raw material 3,4-dimethoxy by TLC Phenylacetic acid basically disappeared, and 2,2-dimethoxyethylamine (105 g) was added dropwise to the reaction solution. Stirring was continued for 2 h after addition, and the intermediate active ester disappeared according to TLC analysis. Suction filtration, the filtrate was successively washed with saturated NaHCO 3 solution, NaCl solution washing, anhydrous Na 2 SO 4 Dry it, filter it with suction, and evaporate it below 45°C under reduced pressure to obtain 261 g (compound IV) as a light yellow blocky solid, with a yield of 92.3%.

Embodiment 2

[0035]Dissolve N,N-dicyclohexyldiimine (250g) in 2L of dichloromethane, then add 2,2-dimethoxyethylamine (130g), and then lower the temperature to 0-20°C. Add 3.4-dimethoxyphenylacetic acid (250 g) in batches, stir and lower the temperature by 10-20° C., and stir until the raw material disappears. After suction filtration, the filter cake was washed with a small amount of dichloromethane, and then the filtrate was placed at 0-5°C for 12 hours, a little white precipitate was precipitated, filtered, and the filtrate was evaporated to dryness to obtain 206 g of (Compound IV), with a yield of 74%.

Embodiment 3

[0037] 2,4-dimethoxy-6-chloro-1,3,5-s-triazine (5.25kg) was dissolved in 30L of dichloromethane, and 3.4-dimethoxyphenylacetic acid (5kg) was added to In the above dichloromethane solution, stir and lower the temperature to 0-10°C, add N-methylmorpholine (3.0kg) dropwise to the above system, continue stirring for 3 hours after the addition, and then analyze the raw material 3,4-dimethoxy by TLC Phenylacetic acid basically disappeared, and 2,2-dimethoxyethylamine (2.6kg) was added dropwise to the reaction solution. Stirring was continued for 2 hours after the addition, and the intermediate active ester disappeared according to TLC analysis. Suction filtration, the filtrate was successively washed with saturated NaHCO 3 solution, NaCl solution washing, anhydrous Na 2 SO 4 Dry it, filter it with suction, and evaporate it below 45° C. to obtain 6.579 kg (compound IV) as a light yellow lumpy solid, with a yield of 93.0%.

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Abstract

The invention belongs to the field of medicinal preparations and provides a method for preparing a key intermediate of ivabradine, namely 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one. The method is characterized in that: a form of active ester is obtained by activating a carboxyl group of 3,4-dimethoxyphenylacetic acid under the catalysis of alkali, and then the active ester and 2,2-dimethoxyethylamine are ammoniated and cyclized to form a target product, so that the conditions such as adoption of thionyl chloride, high-temperature distillation and the like which are not suitable for industrialized production are avoided, the yield of the reaction is remarkably improved and reaches 75 to 80 percent, and the method is more suitable for large-scale industrialized production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for preparing a key intermediate of ivabradine, 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one . Background technique [0002] 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one is a key intermediate for the synthesis of ivabradine, a drug for treating angina pectoris, and its structural formula is as follows: [0003] [0004] US4584293A, CN101607939A and literature Spec I f Ic Bradycard I cAgents.1.Chem I stry, Pharmacology, and Structure-Ac I v I ty Relat I onshI ps of Subst I tuted Benzazep I nones, a New Class of Compounds ExertIng Ant II scheme I c Propert I es (Novel compound with anti-ischemic properties as a drug for slowing heart rate and its chemistry, pharmacology and structure-activity relationship) J.Med.Chem.1990, 33 (5), all in 1496-1504 A preparation method of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one is disclosed. In the above-mentioned docu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
Inventor 王晶翼林栋张占涛倪刚范传文朱屹东
Owner QILU PHARMA CO LTD
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