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Synthesis method of epinastine hydrochloride

A technology for the synthesis of epinastine hydrochloride and its synthesis method, which is applied in the field of synthesis of epinastine hydrochloride, can solve the problems of not being suitable for large-scale industrial production, low yield of reduction steps, and many preparation steps, etc. Short, high purity and yield, simple reaction steps

Active Publication Date: 2018-07-31
千辉药业(安徽)有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But this method has many preparation steps, takes too long, and uses highly toxic sodium cyanide and expensive and flammable lithium aluminum hydride or aluminum hydride, and the yield in the reduction step is not high, so it is not suitable for large-scale There are also 6-cyano-6,11-1H-dibenzo[b,e]azepine as the starting material, which is reduced by sodium borohydride and converted into fumarate for refining to obtain 6- (Aminomethyl)-6,11-dihydro-1H dibenzo[b,e]azepine Then cyclization with cyanogen bromide gives 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine Hydrobromide, which is converted into epinastine with sodium hydroxide, and then salted by hydrochloric acid ethanol solution. In this process, sodium borohydride is used as the reducing agent to generate boron, which will introduce impurity phases, and in the reduction step The yield is not high

Method used

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  • Synthesis method of epinastine hydrochloride

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Embodiment 1

[0023] A kind of synthetic method of epinastine hydrochloride proposed by the present invention comprises the following steps:

[0024] S1, with 6-cyano-6,11-1H-dibenzo[b,e]azepine As a raw material, in the presence of Raney-Ni, using methanol solution of ammonia as a solvent, passing through hydrogen for reduction reaction to obtain 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e] Aza

[0025] S2, 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e]azepine Cyclization with cyanogen bromide to generate 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine Hydrobromide, neutralized with base, to give 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine

[0026] S3, 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine Salt with hydrochloric acid, that is.

Embodiment 2

[0028] A kind of synthetic method of epinastine hydrochloride proposed by the present invention comprises the following steps:

[0029] S1, 100 parts of 6-cyano-6,11-1H-dibenzo[b,e]azepine Put it into a high-pressure reactor, then add 4 parts of Raney-Ni and 400 parts of methanol solution of ammonia, pass in hydrogen, control the pressure in the high-pressure reactor to 2.5MPa, stir and react at 25°C for 4h, filter, and concentrate the filtrate to recover methanol , adding dichloromethane for extraction, the extract was washed with saturated brine and dried to obtain 6-(aminomethyl)-6,11-1H-dibenzo[b,e]azepine Purified by chromatographic column, the yield was 90.1%. Among them, the methanol solution of ammonia was prepared as follows: under ice bath, ammonia gas was passed into methanol until saturated to obtain the product;

[0030] S2, 100 parts of 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e]azepine Dissolve with 300 parts of dichloromethane, add 30 parts of cyanogen br...

Embodiment 3

[0033] A kind of synthetic method of epinastine hydrochloride proposed by the present invention comprises the following steps:

[0034] S1, 100 parts of 6-cyano-6,11-1H-dibenzo[b,e]azepine Put it into the autoclave, then add 5 parts of Raney-Ni and 420 parts of methanol solution of ammonia, pass in hydrogen, control the pressure in the autoclave to 2.6MPa, stir and react at 27°C for 5h, filter, and concentrate the filtrate to recover methanol , adding dichloromethane for extraction, the extract was washed with saturated brine and dried to obtain 6-(aminomethyl)-6,11-1H-dibenzo[b,e]azepine Purified by chromatographic column, the yield was 91.8%. Among them, the methanol solution of ammonia was prepared as follows: under ice bath, ammonia gas was passed into methanol until saturated to obtain the product;

[0035] S2, 100 parts of 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e]azepine Dissolve with 320 parts of dichloromethane, add 32 parts of cyanogen bromide, stir and react ...

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Abstract

The invention discloses a synthesis method of epinastine hydrochloride and relates to the technical field of medicines. The synthesis method comprises the following steps of: adopting 6-cyano-6,111H-dibenzo[b,e]azacycloheptatriene as a raw material, under the existence of RaneyNi, adopting methanol solution of ammonia as a solvent, introducing hydrogen to generate reduction reaction, and then obtaining 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e]azacycloheptatriene; leading the 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e]azacycloheptatriene and cyanogen bromide to generate cyclization reaction, then using alkaline for neutralization, and obtaining 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5a]azacycloheptatriene; leading the 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5a]azacycloheptatriene and hydrochloric acid to form a salt, and obtaining the epinastine hydrochloride. The synthesis method disclosed by the invention has the beneficial effects that in the reduction step, the RaneyNi is adopted as a catalyst, catalytic hydrogenation reaction is carried out in the methanol solution of the ammonia, the reaction conditions are moderate, the reaction time is shorter, the yield of reduction products can reach 90% or more, the whole synthesis process is stable, the reaction steps are simple, the consumed time is short and the prepared epinastine hydrochloride is high in purityand yield.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing epinastine hydrochloride. Background technique [0002] Epinastine hydrochloride is called epinastine hydrochloride in English, and its chemical name is 3-amino-9,13-dihydro-1H-dibenzo[c,f]-imidazo[1,5-a]azepine Hydrochloride, whose structure is shown in the following formula, is an orally effective antihistamine successfully developed by Boehringer Ingelheim in Germany. It cooperated with Japan Sankyo Pharmaceutical Co., Ltd. to further jointly develop the market. It was first listed in Japan in 1994 , trade name "Alesion". [0003] [0004] Epinastine hydrochloride is used for the treatment of bronchial asthma, allergic dermatitis, urticaria, eczema, dermatitis and common psoriasis (psoriasis), has a strong inhibitory effect on the bronchoconstriction caused by histamine and bradykinin, and It has no inhibitory effect on bronchoconstriction caus...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 孙学喜杨会来毛杰
Owner 千辉药业(安徽)有限责任公司
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