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Method for synthesizing Ivabradine

A synthetic route and compound technology, applied in the fields of drug combination, cardiovascular system diseases, organic chemistry, etc., can solve the problems of chlorinated alkanes prone to side reactions, unreasonable reaction sequence, and cannot be placed for a long time, and achieves easy purification and production. High rate and convenient post-processing effect

Inactive Publication Date: 2010-06-09
QILU PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] This method solves the problem of high cost in route 1 and route 2, and is suitable for industrial production, but this route first forms N-chloropropane-7,8-dimethoxy-1,3-dihydro-2H- 3-benzazepine-2-ketone (A), the method of reduction still has high cost, the problem of unreasonable reaction sequence, and chloroalkane is also prone to side reactions in the reduction process
Simultaneously, the free base of compound (II) is unstable and cannot be placed for a long time. It is generally sold in the form of salt or stored in the form of salt in the market.

Method used

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  • Method for synthesizing Ivabradine
  • Method for synthesizing Ivabradine
  • Method for synthesizing Ivabradine

Examples

Experimental program
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Effect test

Embodiment 1

[0041] 1. In 20mlDMSO, add 2.21g (10mmol) of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (III) at room temperature Stir to dissolve, add potassium tert-butoxide 1.2g (10.3mmol) in batches, stir at room temperature for 30min, add in batches 1.7g (10.8mmol) of 1-bromo-3-chloropropane in 20ml MDSO solution, react at room temperature for 2h, use Extract with 200ml of water and 200ml of dichloromethane, separate and dry. Distilled under reduced pressure to obtain 2.47 g of oil (IV), with a yield of 83%.

[0042] 2. In 20ml of acetone, add N-(3-chloropropyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2 -Kone 2.47g (8.3mol), (1S)-4,5-dimethoxy-1-(methylaminomethyl) benzocyclobutane (II) 1.72g (8.3mol), sodium iodide 1.26 g (15mmolmol), potassium carbonate 2.76g, heated to reflux for 24h, cooled, filtered with suction, and the filtrate was evaporated to dryness under reduced pressure. After separation by column chromatography, 3.38 g of off-white solid (I) was obt...

Embodiment 2

[0044] 1. Intermediate N-(3-chloropropyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 3g ( 10mmol) was added to 30ml of acetone, 1.26g (15mmolmol) of sodium iodide, heated to reflux for 48h, and filtered with hot suction. The filtrate was distilled under reduced pressure to obtain N-(3-iodopropyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one (IV) 3.78g, yield 97%.

[0045] 2. In 25ml of acetone, add N-(3-iodopropyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2 -Kone 3.4g (8.7mmol), (1S)-4,5-dimethoxy-1-(methylaminomethyl) benzocyclobutane formula (II) 1.8g (8.7mmol), potassium carbonate 2.5 g, heated to reflux for 18h, cooled, filtered with suction, and the filtrate was evaporated to dryness under reduced pressure. Purified by column chromatography to obtain 3.38 g of off-white solid (I), with a yield of 83%.

Embodiment 3

[0047] In 25ml of acetone, add N-(3-iodopropyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 3.89g (10mmol), (1S)-4,5-dimethoxy-1-(methylaminomethyl)benzocyclobutane (II) hydrochloride 2.41g (9.9mol), sodium carbonate 4.14g , Heated to reflux for 24h, cooled, filtered with suction, and the filtrate was evaporated to dryness under reduced pressure. Separated by column chromatography, 3.71 g of off-white solid (I) was obtained with a yield of 91%.

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Abstract

The invention relates to a method for synthesizing Ivabradine or salts thereof, which is prepared by two steps of synthesizing an intermediate N-(3-substitutedpropyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-ketone by 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-ketone, and further reacting with (1S)-4,5-dimethoxy-1-[(methylamino)methyl] benzocyclobutane. By using the method in the invention for preparing the Ivabradine or salts thereof, the reaction post-treatment is simple, the product purity is high, the yield is high, and the method is favor of industrialized production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a synthesis method of ivabradine (ivabradine, I) or an addition salt thereof. Background technique [0002] Ivabradine (I) [0003] [0004] And their pharmaceutically acceptable acid addition salts, especially the hydrochloride, have very important pharmacological and therapeutic properties, especially the property of slowing the heart rate, so that these compounds are used for the prevention or treatment of various clinical Myocardial ischemic conditions such as angina, myocardial infarction and related rhythm disturbances. [0005] A method for synthesizing ivabradine shown in route 1 is disclosed in US5296482: [0006] [0007] Route 1 [0008] In this method, the hydrogenation double bond that involves the last step has only 40% yield, and (1S)-4,5-dimethoxy-1-(methylaminomethyl) benzocyclobutane (II) preparation Difficult, higher prices, resulting in hi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16A61P9/10
Inventor 林栋王丽娟范传文朱屹东冷传新张明会王晶翼
Owner QILU PHARMA
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