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Synthesis of Epilastine

A synthetic method and the technology of epinastine, applied in the synthesis of epinastine and the synthesis of histamine H1 receptor antagonists, can solve the problems of unfavorable industrial production, combustion and explosion, etc., and achieve high product yield and good condition Gentle, pure effect

Active Publication Date: 2017-03-22
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this route avoids the use of metal cyanide and ammoniation reagents, sodium azide is used, which may cause combustion and explosion hazards in case of open flame, high temperature, vibration, impact, and friction, which is not conducive to industrial production.

Method used

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  • Synthesis of Epilastine
  • Synthesis of Epilastine
  • Synthesis of Epilastine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1 Synthesis of Epinastine

[0036] (1) Synthesis of quaternary ammonium salt

[0037] 6-Chloromethylmorphopidine (24.1g, 0.1mol), urotropine (28g, 0.2mol), and 150ml of chloroform were added to a three-necked flask for reflux reaction for 3 hours, cooled to room temperature, and suction filtered. The filter cake was washed with chloroform, and dried to obtain 30.1 g of quaternary ammonium salt of 6-chloromethylmorphopinidine, with a yield of 79%;

[0038] (2) Synthesis of 6-aminomethylmorphopidine hydrochloride

[0039] Dried 6-chloromethylmorphophene quaternary ammonium salt (25g, 65mmol), methanol 100ml, concentrated hydrochloric acid 12ml, refluxed for 2 hours, cooled to room temperature, suction filtered, and the filtrate recovered ethanol under reduced pressure to obtain 6-aminomethyl Morphenidine hydrochloride 12.9g, yield 76.3%;

[0040] (3) 6-Aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine Synthesis

[0041]6-Aminomethylmorphopidine hydrochloride (...

Embodiment 2

[0046] Example 2 Synthesis of Epinastine

[0047] (1) Synthesis of quaternary ammonium salt

[0048] Add 6-bromomethylmorphopidine (28.5g, 0.1mol), urotropine (28g, 0.2mol), and 150ml of dichloromethane into a three-necked flask, reflux for 3 hours, cool to room temperature, and filter with suction , the filter cake was washed with dichloromethane, and dried to obtain 33.5 g of quaternary ammonium salt of 6-bromomethylmorphopidine, with a yield of 78.8%.

[0049] (2) Synthesis of 6-aminomethylmorphopidine hydrochloride

[0050] Dry 6-bromomethylmorphophene quaternary ammonium salt (30g, 70mmol), 150ml ethanol, 10ml concentrated sulfuric acid, reflux for 2 hours, cool room temperature, filter with suction, and recover ethanol from the filtrate under reduced pressure to obtain 6-aminomethyl Morphenidine hydrochloride 13.9g, yield 76.4%.

[0051] (3) 6-Aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine Synthesis

[0052] 6-Aminomethylmorphopidine hydrochloride (10g, 38mmol) et...

Embodiment 3

[0057] Example 3 Synthesis of Epinastine

[0058] (1) Synthesis of quaternary ammonium salt

[0059] Add 6-bromomethylmorphopidine (0.1mol), urotropine (0.25mol), and 300ml of dichloromethane into a three-necked flask for reflux reaction for 3 hours, cool to room temperature, filter with suction, and filter the cake with dichloromethane Washed with methane and dried to obtain quaternary ammonium salt of 6-bromomethylmorphophenolidinium with a yield of 87.9%.

[0060] (2) Synthesis of 6-aminomethylmorphopidine hydrochloride

[0061] Dry 6-bromomethylmorphophene quaternary ammonium salt (40g, 94mmol), 200ml ethanol, 16ml concentrated hydrochloric acid, reflux for 2 hours, cool to room temperature, filter with suction, and recover ethanol from the filtrate under reduced pressure to obtain 6-aminomethyl Morphenidine hydrochloride 20.1g, yield 82.7%.

[0062] (3) 6-Aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine Synthesis

[0063] 6-Aminomethylmorphopidine hydrochloride (20g,...

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Abstract

The invention discloses a method for synthesizing epinastine. The method comprises the following steps: (1) reacting 6-halomethylmorphanthridine with hexamine in an organic solvent, thereby obtaining a 6-halomethylmorphanthridine quaternary ammonium salt; (2) dissolving the 6-halomethylmorphanthridine quaternary ammonium salt in the organic solvent to carry out an acid hydrolysis reaction, thereby obtaining 6-halomethylmorphanthridine hydrochloride; (3) reducing the product 6-halomethylmorphanthridine hydrochloride obtained in the step (2) by using a reducing agent, thereby obtaining 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]aza-cycloheptatrien; and (4) adding cyanogen bromide to carry out a ring-closure reaction, thereby obtaining the epinastine. According to the synthetic method disclosed by the invention, use of high-price and flammable lithium aluminum hydride or aluminum hydride is avoided, use of virulent sodium cyanide is avoided, and the security risk and production cost are effectively reduced. The method disclosed by the invention is simple in synthetic process, the reaction conditions are mild, the product is high in yield and high in purity, and industrial production is facilitated.

Description

technical field [0001] The present invention relates to a kind of histamine H 1 A synthesis method of a receptor antagonist, in particular relates to a synthesis method of epinastine, belonging to the field of organic synthesis of epinastine. Background technique [0002] The chemical name of epinastine is 3-amino-9,13b-dihydro-1H-dibenzo[c,f]-imidazo[l,5-a]azepine , is an oral antihistamine. For the treatment of bronchial asthma, allergic dermatitis, urticaria, eczema, dermatitis, and common psoriasis. Epinastine is a non-sedating histamine H that effectively acts around the 1 One of the receptor antagonists. In addition, epinastine also has strong anti-PAF and anti-LT activities, which may enhance the anti-allergic activity. It has a strong inhibitory effect on bronchoconstriction caused by histamine and bradykinin, but has no inhibitory effect on bronchoconstriction caused by other chemical mediators. [0003] The synthetic method of the epinastine of present discl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 何勇陈仕云高永好吴宗好
Owner HEFEI HUAFANG PHARMA SCI & TECH
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