Synthetic method of ivabradine midbody

A technology of ivabradine and synthesis method, which is applied in chemical instruments and methods, preparation of organic compounds, organic chemistry and other directions, and can solve the problems of harsh reaction conditions, low yield and purity, and difficult operation process.

Active Publication Date: 2012-05-23
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Aiming at the harsh reaction conditions commonly existing in the prior art, the need for special experimental equipment, difficulties in the operation process, low yield and purity, etc., after extensive and in-depth research and exploration, the inventor provides a method that is easy and safe to operate, and has the advantages of The method of higher yield (yield is greater than 75%) and purity (more than 99%), this method is suitable for the production application of industrial scale

Method used

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  • Synthetic method of ivabradine midbody
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  • Synthetic method of ivabradine midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Under the protection of nitrogen, add 70ml of tetrahydrofuran and 60ml of n-butyllithium cyclohexane solution (2.0mol / L) into the reaction flask, stir and cool down to -30°C, then control the temperature at -30°C and add 10ml of diethylamine dropwise , the dropwise addition was completed and the reaction was stirred for 0.5-1h, and 40ml of a tetrahydrofuran solution dissolved in 10g of 3-(2-bromo-4,5-dimethoxyphenyl)propionitrile was added dropwise, and the temperature was controlled at -30°C. After the dropwise addition was completed, Stir the reaction for 0.5-1h, TLC detection (developing agent is petroleum ether: ethyl acetate = 4: 1), after the reaction is complete, dropwise add 60ml of 15% hydrochloric acid to quench the reaction, stir after 5min for liquid separation, and wash the organic layer with water once. Dry with anhydrous magnesium sulfate for 5-8h, filter, and evaporate to dryness to obtain the crude product, which is recrystallized with anhydrous ethanol ...

Embodiment 2

[0034] Under the protection of nitrogen, add 70ml tetrahydrofuran and 80ml cyclohexane solution (1.5mol / L) of lithium diisopropylamide into the reaction flask, stir and cool down to -35°C, then control the temperature at -35°C and add 11ml dropwise After the addition of diethylamine, stir the reaction for 0.5-1h, add dropwise 40ml of tetrahydrofuran solution dissolved in 10g of 3-(2-bromo-4,5-dimethoxyphenyl)propionitrile, control the temperature at -35°C, add dropwise After the completion, stir the reaction for 0.5-1h, TLC detection (developing agent is petroleum ether: ethyl acetate = 4: 1), after the reaction is complete, dropwise add 60ml of 15% hydrochloric acid to quench the reaction, stir for 5min and then separate the liquid, the organic layer is water Wash once, dry with anhydrous magnesium sulfate for 5-8h, filter, and evaporate to dryness to obtain the crude product, which is recrystallized with isopropanol (w / v) 3 times the crude product to obtain the compound 4,5-d...

Embodiment 3

[0036] Under nitrogen protection, add 70ml of n-hexane and 60ml of phenyllithium tetrahydrofuran solution (2.0mol / L) into the reaction flask, stir and cool down to -45°C, then add 12.5ml of diethylamine dropwise at -45°C to control the temperature, After the dropwise addition, stir the reaction for 0.5-1h, add dropwise 40ml of tetrahydrofuran solution dissolved with 10g of 3-(2-bromo-4,5-dimethoxyphenyl)propionitrile, control the temperature at -45°C, after the dropwise addition, stir Reaction for 0.5-1h, TLC detection (developing agent is petroleum ether: ethyl acetate=4:1), after the reaction is complete, dropwise add 60ml of 15% hydrochloric acid to quench the reaction, stir for 5min and separate the liquids, the organic layer is washed once with water, and Dry over anhydrous magnesium sulfate for 5-8 hours, filter, and evaporate to dryness to obtain the crude product, which is recrystallized in absolute ethanol (w / v) twice as large as the crude product to obtain the compoun...

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Abstract

The invention belongs to the technical field of medicines and particularly relates to a synthetic method of an ivabradine midbody, i.e. 4, 5 dimethoxy-1-hydrogen radical-benzocyclobutene; the synthetic method comprises the step of leading compound 3-(2-bromine-4, 5-dimethoxy phenyl) and propionitrile serving as raw materials to be subjected to substitution reaction in a non-protonic solvent to generate the compound 4, 5 dimethoxy-1-hydrogen radical-benzocyclobutene under the combined action of organic base and diethylamine; and the synthetic method is simple, convenient and safe in operation, has higher yield (more than 75%) and purity (more than 99%) and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the synthesis of an ivabradine intermediate 4,5-dimethoxy-1-hydrogen-benzocyclohexane. Background technique [0002] Ivabradine and its addition salts with pharmaceutically acceptable acids, especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially heart rate-lowering properties, making these compounds useful in the treatment or prevention of Various clinical manifestations of myocardial ischemia, such as angina pectoris, myocardial infarction and accompanying rhythm disturbances, but also for the treatment or prevention of various conditions involving rhythm disturbances, especially supraventricular rhythm disturbances. [0003] At present, the synthesis of ivabradine generally has the following types: [0004] method one: [0005] [0006] Wherein, the R group of formula (3) represents halogen, dioxolane, dioxane a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/47C07C253/30
Inventor 赵志全卢传广黄维国颜凯
Owner SHANDONG NEWTIME PHARMA
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