Synthetic method of epinastine hydrochloride

A technology of epinastine hydrochloride and synthesis method, which is applied in the field of chemical substance synthesis, and can solve problems such as long reaction time, unfavorable industrial production, and high price

Active Publication Date: 2017-09-08
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The synthetic starting material of this route is not easy to obtain, the price is expensive, the time required for the synthesis is 7 days, and the reaction time is extremely long, which is not conducive to industrial production

Method used

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  • Synthetic method of epinastine hydrochloride
  • Synthetic method of epinastine hydrochloride
  • Synthetic method of epinastine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] A method for synthesizing epinastine hydrochloride, comprising the following steps: uniformly mixing substance B protected by tert-butoxycarbonyl group with dichloromethane, adjusting the temperature to 15°C, adding dicyclohexylcarbodiimide, stirring for 0.5h, Then add substance A dichloromethane solution dropwise, keep stirring for 12h, add water successively, mass fraction is 3wt% potassium carbonate aqueous solution, saturated sodium chloride aqueous solution, extract and wash once respectively, each extraction and wash all take the organic layer, then concentrate under reduced pressure, drying to obtain substance C, wherein the molar ratio of substance A to substance B is 1:1.2, and the weight ratio of substance B to dicyclohexylcarbodiimide is 1:1;

[0095] Mix substance C with polyphosphoric acid, heat up to 120°C, heat and stir for 2 hours, add dichloromethane to extract the organic layer, wash the organic layer with water, a 3wt% potassium carbonate aqueous solut...

Embodiment 2

[0099] A method for synthesizing epinastine hydrochloride, comprising the steps of: mixing the benzyl-protected substance B with ethyl acetate, adjusting the temperature to 35°C, adding 4,5-dicyanoimidazole, stirring for 1 hour, and then dripping Add substance A ethyl acetate solution, keep stirring for 2 hours, add water, 7wt% sodium carbonate aqueous solution and saturated sodium chloride aqueous solution in sequence to extract and wash once, take the organic layer for each extraction and wash, then concentrate under reduced pressure, and dry Substance C was obtained, wherein the molar ratio of substance A to substance B was 1:1, and the weight ratio of substance B to 4,5-dicyanoimidazole was 1:1.2;

[0100]Mix substance C with polyphosphoric acid, raise the temperature to 160°C, heat and stir for 0.5h, add ethyl acetate to extract the organic layer, wash the organic layer with water, 7wt% sodium carbonate aqueous solution and saturated sodium chloride aqueous solution in seq...

Embodiment 3

[0104] A method for synthesizing epinastine hydrochloride, comprising the following steps: mixing the substance B protected by benzyloxycarbonyl group with dichloromethane, adjusting the temperature to 20°C, adding N,N-carbonyl-diimidazole, stirring for 0.6h, Then add the 1,2-dichloroethane solution of substance A dropwise, keep stirring for 10 hours, add water successively, and extract and wash once with a mass fraction of 4wt% sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution, and extract and wash each time. layer, then concentrated under reduced pressure, and dried to obtain substance C, wherein the molar ratio of substance A to substance B is 1:1.18, and the weight ratio of substance B to N,N-carbonyl-diimidazole is 1:1.13;

[0105] Mix substance C with polyphosphoric acid, heat up to 130°C, heat and stir for 1.5h, add dichloromethane to extract the organic layer, wash the organic layer with water, 4wt% sodium hydroxide aqueous solution, and s...

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Abstract

The invention discloses a synthetic method of epinastine hydrochloride. The synthetic method comprises the following steps: enabling a substance A to react with a substance B to obtain a substance C; enabling the substance C to be subjected to ring closing reaction with polyphosphoric acid to obtain a substance D; enabling the substance D to react with a de-protection reagent to obtain a substance E; enabling the substance E to react with cyanogen bromide to obtain epinastine and then salifying with hydrochloric acids to obtain the epinastine hydrochloride. The synthetic method disclosed by the invention is easily-available in raw materials, mild in reaction conditions, low in energy consumption, low in production cost, simple to operate, short in preparation period and suitable for large-scale industrial production; the prepared epinastine hydrochloride is high in purity and relatively high in yield in each step of reaction.

Description

technical field [0001] The invention relates to the technical field of chemical substance synthesis, in particular to a synthesis method of epinastine hydrochloride. Background technique [0002] Epinastine hydrochloride, the chemical name is 3-amino-9,13-dihydro-1H-dibenzo[c,f]-imidazo[1,5-a]azepine hydrochloride, Molecular formula is C 16 h 15 N 3 HCl, its chemical structure is as follows: [0003] [0004] Epinastine hydrochloride is an orally effective antihistamine successfully developed by Boehringer Ingelheim of Germany. It cooperated with Japan Sankyo Pharmaceutical Co., Ltd. to further jointly develop the market. It was first listed in Japan in 1994 under the trade name "Alesion". 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55
Inventor 高永好陈仕云何勇彭扶云吴宗好
Owner HEFEI HUAFANG PHARMA SCI & TECH
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