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Novel preparation method for ivabradine

A compound and hydrogenation reaction technology, applied in the field of medicine and chemical industry, can solve the problems of complicated preparation operation of compound I, unsuitable for industrial scale-up production, low yield of docking reaction, etc., achieve good industrialization basis and application value, reduce synthesis difficulty, The effect of high product yield

Active Publication Date: 2013-04-03
江苏宇田医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] As can be seen from the existing ivabradine synthetic methods, no matter which method, the yield of the docking reaction is low, and an autoclave needs to be used in the synthetic process, multi-step recrystallization is required, and the solvent consumption is large, resulting in The preparation of Compound I is cumbersome and costly
It directly leads to the high preparation cost and difficulty of preparation of ivabradine hydrochloride, which is not suitable for industrial scale-up production

Method used

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  • Novel preparation method for ivabradine
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  • Novel preparation method for ivabradine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Take 2.96g of compound III, wherein R is Cl, 2.44g of compound IV, 1.38g of potassium carbonate and 1.50g of sodium iodide in 50mL of methyl isobutyl ketone for reflux reaction for 6h, cool, add 50mL of 1N hydrochloric acid, separate layers, Collect the aqueous layer, adjust the aqueous layer to pH = 10 with sodium hydroxide, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to dryness to obtain 4.5 g of the intermediate, namely 7,8-dimethoxy -3-(3-[[(1S)(4,5-dimethoxybenzocyclobutan-1-yl)methyl]-methylamino]propyl)-1,3,-dihydrogenated-2 Hydrogen-benzazepin-2-one;

[0030] In a 50 mL reaction flask, add 2.0 g 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutane-1-yl)methyl ]-methylamino]propyl)-1,3,-dihydro-2hydro-benzazepin-2-one, 20 mL of methanol, 0.3 g of ammonium formate, 0.2 g of palladium on carbon, hydrogenation reaction pressure of 1 atm, Raise the temperature to 30°C and stir for 4 hours, filt...

Embodiment 2

[0032] Take 3.40g of compound III, where R is Br, 2.44g of compound IV, 0.69g of potassium carbonate and 1.50g of potassium iodide in 50mL of acetone for 12h under reflux, filter, concentrate the filtrate, add 50mL of 1N hydrochloric acid to the residue, and wash with sodium hydroxide Adjust to pH=9, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to dryness to obtain 4.6g of intermediate, namely 7,8-dimethoxy-3-(3-[[(1S )(4,5-dimethoxybenzocyclobutan-1-yl)methyl]-methylamino]propyl)-1,3,-dihydro-2hydro-benzazepine-2- ketone;

[0033] In a 50 mL reaction flask, add 2.0 g 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutane-1-yl)methyl ]-methylamino]propyl)-1,3,-dihydro-2hydro-benzazepin-2-one, 20 mL ethanol, 0.6 g ammonium formate, 0.5 g palladium carbon, hydrogenation reaction pressure is 3 atm, Raise the temperature to 60°C and stir for 5 hours, filter, and concentrate the filtrate to dryness to obtain 1.9...

Embodiment 3

[0035] Take 3.86g of compound III, where R is I, 2.44g of compound IV, 0.69g of potassium carbonate and 1.50g of potassium iodide in 50mL of methyl ethyl ketone for 12h under reflux, filter, concentrate the filtrate, add 50mL of 1N hydrochloric acid to the residue, and Adjust the pH to 11 with sodium, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to dryness to obtain 4.4 g of the intermediate, namely 7,8-dimethoxy-3-(3-[[( 1S)(4,5-dimethoxybenzocyclobutan-1-yl)methyl]-methylamino]propyl)-1,3,-dihydro-2hydro-benzazepine-2 -ketone;

[0036] In a 50 mL reaction flask, add 2.3g 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutane-1-yl)methyl ]-methylamino]propyl)-1,3,-dihydro-2hydro-benzazepine-2-one, 23 mL ethanol, 3.1 g ammonium formate, 2.3 g palladium carbon, hydrogenation reaction pressure is 1 atm, Raise the temperature to 80°C and stir for 1.5 hours, filter, and concentrate the filtrate to dryness to ob...

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Abstract

The invention belongs to the field of pharmaceutical chemical engineering, and relates to a novel synthesis method for ivabradine. The novel synthesis method for ivabradine comprises the following steps of: reacting a compound III with a compound IV in a reaction solvent under the catalysis of an alkali, performing post-treatment to obtain a compound II, and performing hydrogenation reaction under a system containing a catalyst and ammonium formate to obtain a compound I, namely, ivabradine. The method is short in synthesis route, simple to operate, greatly lowered in the difficulty of synthesis for ivabradine, low in cost and high in product yield; and most importantly, the method is good in safety, not involved with high-pressure hydrogenation, free from the use of an inflammable gas, namely, hydrogen, and great in industrialization base and application value.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to the preparation of a group of benzocyclobutane compound ivabradine shown in formula I. Background technique [0002] Ivabradine, the compound shown in formula I, chemical name: 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutane-1 -base)methyl]-methylamino]propyl)-1,3,4,5-tetrahydro-2hydro-benzazepine-2-one, which can be used clinically to treat various myocardial ischemia, For example, angina pectoris, myocardial infarction and related rhythm disorders are a new generation of cardiovascular drugs with very broad treatment prospects. [0003] I [0004] At present, the synthesis of ivabradine mainly includes the following types: [0005] method one: [0006] [0007] The R group represents halogen, dioxolane, dioxane, and the like. [0008] Method Two: [0009] [0010] The R group represents halogen, dioxolane, dioxane, and the like. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
Inventor 洪承杰陈言德刘德龙朱万里
Owner 江苏宇田医药有限公司
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