Preparation method of ivabradine

A technology of ivabradine and its compound, which is applied in the field of preparation of angina drug ivabradine and its salt, can solve the problems of high cost, complicated preparation process and high cost, and achieve simple method, easy-to-obtain raw materials and large application value effect

Active Publication Date: 2008-10-15
UTOPHARM SHANGHAI +1
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Problems solved by technology

[0013] It is reported in the literature that the yield of this method is 85%, but the two-step reaction of this method all needs to use expensive metal catalysts, and the consumption is relatively large, the cost is extremely expensive, and the raw material compound VIII is not easy to obtain, and its preparation process is relatively complicated and the cost is high , so it is not suitable for industrial production

Method used

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  • Preparation method of ivabradine
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  • Preparation method of ivabradine

Examples

Experimental program
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Effect test

Embodiment 1 7

[0030] Example 1, Synthesis of 7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one:

[0031] 7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzazepine - 2-ketone (15.0g, 50.8mmol), ethanol (80ml) and 5% Pd / C (0.8g) were added to the autoclave, and reacted at 5-10 bar hydrogen pressure at 60°C until no hydrogen was absorbed, and the reaction was terminated , cooled, filtered, concentrated under reduced pressure to about 30ml, cooled and filtered to obtain 7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydro-2H-3-benzene And aza -2-Kone, white solid 13.9g, mp: 93-95°C, yield 92.1%

[0032] MS: 297(M+), 299(M+2), 262(M-Cl)

[0033] 1HNMR (CDCl3): δ2.06 (2H, m), 3.07 (2H, t), 3.56 (2H, M), 3.76 (2H, t), 3.81 (2H, t), 3.84 (3H, s), 3.85 (3H, s), 6.58-6.60 (2H, aromatic hydrogen)

Embodiment 2

[0034] Example two, 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl]-methyl}( Methyl)amino]propyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine Synthesis of -2-ketone (compound 1, ivabradine):

[0035] 7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydro-2H-3-benzazepine -2-Kone (10.0g.33.7mmol), (1S)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane (compound IV, 7.0g, 33.8mmol) , triethylamine (10ml) and acetonitrile (50ml) were added into a three-necked flask, then stirred at room temperature for 20 hours, then concentrated under reduced pressure to 200ml of water, extracted with ethyl acetate (150ml*3), dried over anhydrous magnesium sulfate , filtered, and concentrated under reduced pressure to obtain a yellow oil, namely 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-triene-7 -yl]-methyl}(methyl)amino]propyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine -2-one, about 13.5 g.

[0036] The sample for analysis was obtained by silica gel col...

Embodiment 3

[0039] Example three, 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl]-methyl}( Methyl)amino]propyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine Preparation of -2-one hydrochloride:

[0040] The compound 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl]-methyl}(methyl )amino]propyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine -2-Kone (ivabradine) (13.5g,) was dissolved in acetonitrile (40ml), then heated to 70°C, and under stirring, dry HCl gas was introduced until the pH of the reaction solution was about 2-3, and 1 g of activated carbon was added, Reflux for 10 minutes, filter while hot, cool, filter, and vacuum dry at 60°C to obtain 12.4g of a near-white powder, mp:°C, yield 73.1% (calculated as compound III), and recrystallize the above crude product with acetonitrile to obtain 10.6g of a white powder , yield 85.5%, HPLC > 99.0%, [α] 7.2 (DMSO, 1%)

[0041] MS: 468(M+), 469(M+1), 453(M-CH3), 305(M-163), 262(M-206).

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Abstract

The invention relates to a novel method for preparing angina pectoris medicine Ivabradine (compound I and salt thereof). The method takes a formula II compound as the raw material to obtain a compound III through catalytic hydrogenation, the compound III is made an alkylation reaction with a formula IV compound to produce the compound I. The method is simple and convenient, is easy to obtain raw materials, and is suitable for industrialized production.

Description

Technical field: [0001] The invention relates to medicinal chemistry, in particular to a preparation method of a novel angina drug ivabradine (compound I) and a salt thereof. Background technique: [0002] Ivabradine (Ivabradine), chemical name 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl ]-methyl}(methyl)amino]propyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine -2-ketone, and its pharmaceutically acceptable acid addition salt and its hydrate, compound I of the following formula: [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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
Inventor 罗军芝严益民屠永锐孙永强钱明霞
Owner UTOPHARM SHANGHAI
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