Synthetic method of ivabradine

A synthetic method and compound technology, applied in the field of medicine and chemical industry, to achieve good practical application value, mild reaction conditions and high yield

Inactive Publication Date: 2018-05-08
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Each step of the method uses palladium-carbon catalyst, and it is high-pressure hydrogenation. Although the total yield is high, there are major disadvantages in this route in terms of cost and industrialization.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] At room temperature, take 10g of compound (II) and 100ml of N,N-dimethylformamide and stir evenly, add 6.2g of potassium tert-butoxide to activate for 30min, then transfer it to a container containing 8.6g of bromochloropropane diluent, Control the temperature at 25±5°C, react for 30 minutes, transfer to 1L of ice water to quench the crystallization for 5 hours after the reaction is completed, filter, and recrystallize the crude product in acetone / water (volume ratio: 1:6) to obtain 9.8 g of white solid.

[0039] Add 8g of compound (III), 80ml of methanol, 14g of ammonium formate, and 1.6g of palladium carbon into the reaction flask, heat up to 60°C under normal pressure and react for 6h, filter, and concentrate the filtrate to dryness to obtain compound (IV).

[0040] Take 7g of compound (IV), 40ml of acetone, and 18g of sodium iodide, raise the temperature and reflux for 24 hours, cool and filter, concentrate to dryness under reduced pressure, add 50ml of dichlorometha...

Embodiment 2

[0043] At room temperature, take 20g of compound (II) and 200ml of N,N-dimethylformamide and stir evenly, add 12.4g of potassium tert-butoxide to activate for 30min, then transfer it to a container containing 17.2g of bromochloropropane diluent, and control Temperature 25±5°C, react for 30min, transfer to 1L of ice water to quench the crystallization for 5h after the reaction is completed, filter, and recrystallize the crude product in acetone / water (volume ratio: 1:6) to obtain 20.1g of white solid.

[0044] Add 15g of compound (III), 200ml of methanol, 32g of ammonium formate, and 3.0g of palladium carbon into the reaction flask, heat up to 60°C under normal pressure and react for 6h, filter, and concentrate the filtrate to dryness to obtain compound (IV).

[0045] Get 12g of compound (IV), 80ml of acetone, 30g of sodium iodide, heat up and reflux for 24h, cool and filter, concentrate under reduced pressure to dryness, add 150ml of dichloromethane at room temperature and stir...

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PUM

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Abstract

The invention provides a synthetic method of ivabradine. The synthetic method of ivabradine comprises following steps: 1, a compound II and bromo chloropropane are subjected to alkylation reaction under the catalytic effect of a first alkali so as to obtain a compound III; 2, the compound III is subjected to hydrogenation reaction in a palladium on carbon and ammonium formate system so as to obtain a compound IV; 3, the compound IV and an iodination reagent are subjected to iodization reaction so as to obtain a compound V; 4, the compound V and the compound VI are subjected to condensation reaction under the catalytic effect of a second alkali so as to obtain a compound I. Operation is simple; reaction conditions are mild; the raw materials are commercially available; the synthetic methodis simple; cost is low; and the ivabradine synthesis difficulty is reduced greatly.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthetic method of ivabradine. Background technique [0002] Ivabradine, as the compound shown in formula (I), chemical name: 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclidine Alk-1-yl)methyl]-methylamino]propyl)-1,3,4,5-tetrahydro-2hydro-benzazepin-2-one: [0003] [0004] Ivabradine (Ivabradine), on November 3, 2005, was approved by the European Medicines Evaluation Agency (EMEA) and launched in 27 countries in Europe. Symptomatic treatment of chronic stable angina pectoris in whom blockers are contraindicated or not tolerated. [0005] Procoralan was developed by Servier and has become one of the most important advances in cardiovascular therapy in the past 20 years. Procoralan is the first pure heart rate-lowering drug that works by selectively inhibiting the If channel responsible for controlling the automatic depolarization of the sinus...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 袁金桥竺来发刘虎陈舟
Owner HARVEST PHARMA HUNAN CO LTD
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