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Preparation method for Ivabradine

A technology of compound and addition salt, applied in the field of preparation of ivabradine

Inactive Publication Date: 2010-07-07
BEIJING D VENTUREPHARM TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The two-step reactions of the above-mentioned route all use precious metal palladium-carbon as a catalyst, and both use autoclave reaction. Although the total yield is high, there are disadvantages in this route in terms of cost and industrialization.

Method used

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  • Preparation method for Ivabradine
  • Preparation method for Ivabradine
  • Preparation method for Ivabradine

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Example 1: 3-(3-hydroxypropyl)-7,8-dimethoxy-4,5-dihydro-1H-benzazepine-2(3H)-one 2.3g3-(3- Hydroxypropyl)-7,8-dimethoxy-1H-benzazepine-2(3H)-one and 1.8g 10% Pd / C were added to 20mL methanol, and then slowly introduced into the system h 2 , so that the bubbles in the system are uniform. Heat the system to react at 40°C for 24h. Pd / C was recovered by suction filtration, and the filtrate was rotary evaporated to obtain 1.97 g of white solid, yield: 85%, melting point 102.5°C. 1H-NMR (CDCl 3 , 400MHz), δ1.72-1.75(t, 2H), 3.05-3.08(t, 2H), 3.48-3.51(t, 2H), 3.58-3.61(t, 2H), 3.71-3.74(q, 2H) , 3.84-3.85 (d, 8H), 6.57-6.60 (d, 2H). The NMR picture is attached figure 1

Embodiment 2

[0036] Embodiment 2: the hydrochloride preparation of ivabradine

[0037] 0.4g 3-(3-hydroxypropyl)-7,8-dimethoxy-4,5-dihydro-1H-benzazepin-2(3H)-one and 0.3g (S)-( 4,5-dimethoxy-1,2-dihydrobenzocyclobutyl-1-yl)-N-methylmethanamine was added to 10 mL of acetone, and then 0.2 g KI and 0.5 g K 2 CO 3 , started stirring and heated to reflux. The reaction was stopped after 24 h of reaction. Suction filtration, the filtrate was spin-dried to obtain a viscous solid, the solid was dispersed in water, and a filter cake was obtained by suction filtration, and the filtrate was discarded. It was then dissolved in ethyl acetate, washed with 3N HCl solution, adjusted to pH 7-8 with sodium hydroxide solution, dried over anhydrous magnesium sulfate, and rotary evaporated under reduced pressure to obtain an oily substance. The oil was dispersed in ethyl acetate to form monohydrochloride, and recrystallized from methanol and acetone to obtain 0.5 g of white crystalline powder with a yield o...

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Abstract

The invention discloses a preparation method for Ivabradine. Catalytic hydrogenation is carried out on a formula (II) compound to obtain a formula (III) compound, reaction is carried out between the formula (III) compound and a formula (IV) compound under the action of base catalysis, and a catalyst is removed through filtration and separated to obtain the target compound.

Description

technical field [0001] The present invention relates to the synthesis of ivabradine of formula (I), i.e. 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octane-1,3,5-tri En-7-yl]-methyl}(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine- A method for preparing 2-ketone, and a pharmaceutically acceptable acid addition salt thereof. [0002] Background technique [0003] Ivabradine and its addition salts with pharmaceutically acceptable acids, more particularly its hydrochloride, possess extremely valuable pharmacological and therapeutic properties, especially bradycardic properties, making these compounds For the treatment or prophylaxis of various clinical conditions of myocardial ischemia such as angina pectoris, myocardial infarction and related arrhythmias, as well as various pathological conditions involving arrhythmias, especially supraventricular arrhythmias and heart failure. [0004] The preparation method of ivabradine and its hydrochloride has bee...

Claims

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Application Information

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IPC IPC(8): C07D223/16
Inventor 王春霞卢文张志强
Owner BEIJING D VENTUREPHARM TECH DEV
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