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Preparation method of epinastine hydrochloride and intermediate thereof

A technology of epinastine hydrochloride and intermediates, which is applied in the field of preparation of pharmaceutical compounds, can solve the problems of many side reactions, many impurities generated, and easy to be oxidized, and achieve simple preparation methods, high product purity, and few by-products Effect

Inactive Publication Date: 2014-01-15
YAOPHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In this route, due to 6-aminomethyl-11-hydrogen-dibenzo[ b, e ] Azapine is unstable, not easy to store, easy to be oxidized, resulting in more side reactions in the next step reaction, more impurities are generated, not easy to separate and purify, and affect the yield
In addition, ammonia gas is easy to run out of the reaction system, which causes great pollution and is not conducive to environmental protection.

Method used

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  • Preparation method of epinastine hydrochloride and intermediate thereof
  • Preparation method of epinastine hydrochloride and intermediate thereof
  • Preparation method of epinastine hydrochloride and intermediate thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0037] In the reaction flask, drop in the starting material 6-chloromethyl-11-dihydro-dibenzo[ b,e ] Azepine 10g, 150 milliliters of ethanol, add N - 11.2 g of fluorenylmethoxycarbonyl ammonia, 4.2 g of triethylamine was added dropwise, and reacted at 60 ° C for 10 hours. After the reaction was completed, the solid was removed by filtration, distilled to dryness under reduced pressure, 15 ml of water was added, and extracted with 20 ml of dichloromethane. The solvent is recovered to obtain the product 6- N -Fmoxycarbonylaminomethyl-11-dihydro-dibenzo[ b,e ] Azepine 16.2g (HPLC purity 98.4%, yield 91%).

[0038]

Embodiment 2

[0040] In the reaction flask, drop in the starting material 6-chloromethyl-11-dihydro-dibenzo[ b,e ] Azepine 20g, 280 milliliters of acetonitrile, add N - 22.4 g of fluorenylmethoxycarbonyl ammonia, 8.4 g of triethylamine was added dropwise, and reacted at 80 ° C for 6 hours. After the reaction was completed, the solid was removed by filtration, distilled to dryness under reduced pressure, 30 ml of water was added, extracted with 50 ml of dichloromethane, The solvent is recovered to obtain the product 6- N -Fmoxycarbonylaminomethyl-11-dihydro-dibenzo[ b,e ] Azepine 30.1g (HPLC purity 98.8%, yield 84.6%).

[0041]

Embodiment 3

[0043] In the reaction bottle, drop into raw material 6- N -Fmoxycarbonylaminomethyl-11-dihydro-dibenzo[ b,e] Azapine 15g, methyl alcohol 150 milliliters, sodium borohydride 4.0g room temperature conditions, reacted 24 hours, and reaction was completed, and the control internal temperature was lower than 25 ℃, and 2% dilute hydrochloric acid solution was added dropwise to make its pH value to 5~6, with Dichloromethane 150ml×2 extracted, the organic layer was washed with saturated brine, concentrated to dryness, added 20ml of 18% dimethylamine acetonitrile solution, heated to an internal temperature of 26-30°C, stirred for 0.5 hours, distilled under reduced pressure, added 35ml of acetonitrile was stirred and filtered with suction. After beating with 40ml of isopropyl ether for 10min, filter with suction, add 20ml of purified water to the filter cake, extract with 100ml of dichloromethane×2, wash the organic layer with saturated brine, dry over anhydrous magnesium sulfate, fi...

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Abstract

The invention relates to a method preparing an epinastine hydrochloride intermediate and epinastine hydrochloride. The method comprises the following steps: reacting 6-chloromethyl-11-dihydro-dibenzo[b,e]azepine and an amino reagent under protection to generate an amino-protective compound; carrying out reduction reaction and deprotection reaction to generate 6-aminomethyl-6,11-dihydro-dibenzo[b,e]azepine; and finally, carrying out cyanogen bromide cyclization on the 6-aminomethyl-6,11-dihydro-dibenzo[b,e]azepine, neutralizing with alkali, and reacting with hydrochloric acid to generate the epinastine hydrochloride. The preparation method has the advantages of accessible reaction raw materials, fewer byproducts and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a novel intermediate for preparing epinastine hydrochloride and a preparation method of epinastine hydrochloride. Background technique [0002] Allergic diseases are common clinical diseases and have been threatening human health for a long time. Especially in recent decades, with the progress of industrialization and the aggravation of environmental pollution, the incidence of allergic diseases has been increasing year by year. Such diseases include allergic bronchial asthma, allergic rhinitis, allergic skin diseases, and measles. Moreover, allergic reactions are involved in the occurrence and development of many diseases, making antiallergic drugs one of the most commonly used drug categories in the world. [0003] The chemical name of Epinastine Hydrochloride is 3-amino-9,13-dihydro-1 H -Dibenzo[ c, f ]-imidazo[1,5-a]azepine hydrochloride (Ⅲ), its structu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D223/20
CPCC07D487/04C07D223/20
Inventor 孟文学裴东冉咏梅宋显根
Owner YAOPHARMA CO LTD
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