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Novel synthetic method of ivabradine and novel intermediate product of ivabradine

A new and synthetic method technology for ivabradine, which is applied in the field of synthetic methods and its new intermediate products, and can solve the problems of large solvent consumption, high preparation cost and difficult preparation of ivabradine

Active Publication Date: 2012-12-19
江苏宇田医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] As can be seen from the existing synthetic methods of ivabradine, no matter which method, the compound , in the existing methods, the synthesis of this compound is from , that is, starting with 1-cyano-3,4-dimethoxybenzocyclobutane, it needs to undergo hydrogenation reduction, resolution, methylation and other steps. During the synthesis process, autoclave, lithium tetrahydrogen aluminum And other high-risk equipment and dangerous reagents with active chemical properties. In addition, the resolution process also requires multi-step recrystallization, the resolution yield is low, and the solvent consumption is large. All of the above lead to compound The synthetic route shown in the following formula is cumbersome to operate and the preparation cost is high, which indirectly leads to the high preparation cost and difficulty of preparation of ivabradine, which is not suitable for industrial scale-up production

Method used

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  • Novel synthetic method of ivabradine and novel intermediate product of ivabradine
  • Novel synthetic method of ivabradine and novel intermediate product of ivabradine
  • Novel synthetic method of ivabradine and novel intermediate product of ivabradine

Examples

Experimental program
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Effect test

Embodiment 1

[0034] In a 500mL reaction flask, add 30.0g N-methyl-3-chloropropylamine hydrochloride, 200mL dichloromethane, 30mL water, stir for 10min, then add 33.0g sodium carbonate, stir for 30min, filter, and wash with dichloromethane cake, and the filtrate was dried with anhydrous sodium sulfate for later use.

[0035] Add 400mL of dichloromethane to a 1L reaction flask, add 41.6g of (1S)-4,5-dimethoxybenzocyclobutane-1-carboxylic acid, 42.5g of N,N'-dicyclohexyl carbon under stirring Imide (DCC), stir for 10 minutes after addition, cool down in an ice-water bath to below 10°C, add the dichloromethane solution of N-methyl-3-chloropropylamine dropwise, control the feeding rate so that the temperature of the reaction solution does not exceed 10°C After the addition, continue to react at 10°C~15°C, a large amount of white solids are produced, the raw materials are completely reacted in about 2 hours, the reaction solution is filtered, the filter cake is washed with an appropriate amount ...

Embodiment 2

[0037] In a 500 mL reaction flask, add 30.0 g of N-methyl-3-chloropropylamine hydrochloride, 200 mL of dichloromethane, 30 mL of water, stir for 10 min, then add 33.0 g of sodium carbonate, stir for 30 min, filter, The filter cake was washed with dichloromethane, and the filtrate was dried over anhydrous sodium sulfate for later use.

[0038] Add 400 mL of dichloromethane into a 1 L reaction flask, add 41.6 g of (1S)-4,5-dimethoxybenzocyclobutane-1-carboxylic acid while stirring, and cool down to 0°C~5°C in an ice-water bath , began to add 28.5 g of thionyl chloride dropwise, controlled the rate of addition so that the temperature of the reaction solution did not exceed 10°C, removed the ice-water bath after dropping, stirred and reacted at room temperature for 2 h, evaporated the solvent to dryness under reduced pressure to obtain a brown oil, added 250 mL Dichloromethane dissolves, and the solution obtained after dissolving is added dropwise to the mixed solution of the dich...

Embodiment 3

[0040] In a 500 mL reaction flask, under inert gas protection, add 200 mL of anhydrous tetrahydrofuran, 9.8 g of (1S)-[N-(3-chloropropyl)-N-methyl]carbamoyl prepared in Example 1 or 2 -4,5-dimethoxybenzocyclobutane, stir to dissolve, add 6.3 g lithium tetrahydrogen aluminum to the reaction liquid in batches at room temperature, after the addition is complete, stir at room temperature for 1 h, then heat up to reflux for reaction 1 h, the raw material reaction of the sampling point plate is complete, the reaction solution is cooled to room temperature, and 10 mL of water is slowly added dropwise to the reaction solution to quench the reaction, then the reaction solution is transferred to a 2 L beaker, 500 mL of ethyl acetate is added, and then Anhydrous sodium sulfate was stirred and dried for 2 h, the desiccant was filtered off and the solvent was evaporated to dryness under reduced pressure to obtain 9.0 g of white solid, namely compound III: (1S)-[N-(3-chloropropyl)-N-methyl] ...

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PUM

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Abstract

The invention relates a novel synthetic method of ivabradine and a novel intermediate product of the ivabradine. In consideration of huge medicinal value of the ivabradine (compound I) and larger difficulty for synthesizing the ivabradine at present, the invention provides a group of novel benzocyclobutane compounds and a method for synthesizing the benzocyclobutane compounds and a method for synthesizing the ivabradine by the benzocyclobutane compounds, that is, a novel synthetic method of the ivabradine. The method provided by the invention is short in synthetic line, simple to operate, simple in preparation method and low in cost, and the synthetic difficulty of the ivabradine is greatly reduced.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a new synthesis method of ivabradine and a new intermediate product thereof. Background technique [0002] Ivabradine, chemical name: 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutan-1-yl)methyl] -Methylamino]propyl)-1,3,4,5-tetrahydro-2H-benzazepine-2-one, its structure is shown in formula Ⅰ: [0003] [0004] I [0005] Ivabradine can be used clinically to treat various myocardial ischemia, such as angina pectoris, myocardial infarction and related rhythm disorders. It is a new generation of cardiovascular drugs with very broad treatment prospects. [0006] At present, the synthesis of ivabradine mainly includes the following types: [0007] method one: [0008] [0009] Wherein: R group represents halogen, dioxolane, dioxane and the like. [0010] Method Two: [0011] [0012] Wherein: R group represents halogen, dioxolane, dioxane ...

Claims

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Application Information

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IPC IPC(8): C07D223/16C07C235/40C07C231/02
Inventor 刘德龙朱万里
Owner 江苏宇田医药有限公司
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