Epinastine hydrochloride intermediate and synthesis method thereof

A synthesis method and epilastine technology are applied in the field of epilastine hydrochloride intermediate and its synthesis, which can solve the problems of not meeting environmental protection and safety production requirements, threatening operator safety, odorous hydrogen sulfide gas, etc. Conducive to safe production and environmental protection, improve safety, and ensure the effect of drug safety

Active Publication Date: 2020-07-17
重庆美莱德生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] This method will also produce highly toxic and foul-smelling hydrogen sulfide gas during ring closure, which

Method used

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  • Epinastine hydrochloride intermediate and synthesis method thereof
  • Epinastine hydrochloride intermediate and synthesis method thereof
  • Epinastine hydrochloride intermediate and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1N-methoxycarbonyl-3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine (formula II-1 compound) synthesis

[0041] The reaction scheme is as follows:

[0042]

[0043] In the above method, the solvent used is water, lower alcohols with 1-4 carbon atoms (methanol, ethanol, n-propanol, isopropanol, n-butanol, etc.), N,N-dimethylformamide, N, One or more of N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, acetone, and acetonitrile.

[0044] Studies have found that in the above method, the pH and reaction temperature of the reaction solution have a very important impact on the reaction. Once the control is not good, the reaction will hardly occur or the by-products will increase significantly. Preferably, the pH of the reaction solution of the present invention is 2-5 (more preferably 2.5-4), and the reaction temperature is 40°C-100°C (more preferably 60°C-90°C).

[0045] The specific operation is:

[0046] 6-Aminomethyl-6,11-dihydro-5H-diben...

Embodiment 2

[0047] Example 2N-tert-butoxycarbonyl-3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine (compound of formula II-2) synthesis

[0048] The reaction scheme is as follows:

[0049]

[0050]Reference Example 1, 6-Aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine (26.5g) with 400ml of tert-butanol as solvent, add tert-butyl cyanocarbamate (31.5g), heated to reflux for 3h, cooled, and distilled to dryness to obtain a light brown oily substance, namely N-tert-butoxycarbonyl-3-amino-9,13b-dihydro-1H-dibenzo[c,f ]imidazo[1,5-a]azepine 25.8g, purity 96.7%, yield 87%. m / z 350[M+1] + .

Embodiment 3

[0051] Synthesis of Example 3N-benzyloxycarbonyl-3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine (compound of formula II-3)

[0052] The reaction scheme is as follows:

[0053]

[0054] Referring to Example 1, 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine (20.8g) was used as solvent in 400ml of tetrahydrofuran, and benzyl cyanocarbamate (22.5g ), heated to reflux for 10h, cooled, and distilled to dryness to obtain a light brown oily substance, namely N-benzyloxycarbonyl-3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[ 1,5-a]azepine 29.2g, purity 97.7%, yield 82%; m / z 384[M+1] + .

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Abstract

The invention provides a compound shown in the formula II; the compound is used as a raw material or an intermediate for synthesizing epinastine hydrochloride, cyanogen bromide is not needed in the synthesis process, hydrogen sulfide or/and methyl mercaptan is/are not generated in the synthesis process, the operation safety is improved, the environmental protection pressure is reduced, and safetyproduction and environmental protection requirements are met. The synthetic method disclosed by the invention is short in time, the reaction can be completed within 10 hours in total in two steps, andthe synthetic method has obvious advantages in industrial production, is high in yield and is suitable for industrial production.

Description

technical field [0001] The invention relates to epinastine hydrochloride, in particular to an epinastine hydrochloride intermediate and a synthesis method thereof. Background technique [0002] Epinastine hydrochloride, whose English name is epinastine hydrochloride, is a histamine H that was jointly developed by Boehringer Ingelheim and Japan Sankyo Pharmaceutical Co., Ltd. and listed in Japan in 1994. 1 receptor antagonists. The chemical name of epinastine hydrochloride is 3-amino-9,13b-dihydro-1H-diphenyl[c,f]imidazo[1,5-a]azepine hydrochloride, and its structural formula is as follows: [0003] [0004] Epinastine has inhibitory effects on histamine, leukotriene C4, PAF, and serotonin, and can inhibit the release of histamine and slow-reacting substance A (SRS-A) chemical mediators. Allergic rhinitis, urticaria, allergic dermatitis, pruritus, prurigo, psoriasis vulgaris with pruritus, and allergic bronchitis. Epinastine is the most potent non-sedating histamine H a...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 刘颜夏彪罗绪张健陈大海王涛
Owner 重庆美莱德生物医药有限公司
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