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Synthesis method for epinastine intermediate

A synthesis method and technology of borane tetrahydrofuran complexes, which are applied in the field of medicinal chemistry, can solve problems such as unsuitable for industrial production, and achieve the effects of easy industrial production, high yield, and simple reaction operation

Inactive Publication Date: 2015-06-10
YAOPHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] This route requires the use of highly toxic and explosive sodium azide, which is not suitable for industrial production

Method used

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  • Synthesis method for epinastine intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Preparation of 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine?

[0030] Add 276ml of borane tetrahydrofuran complex (1mol / L, 0.276mol) into a 1L three-necked flask, stir and cool down to below 0°C in an ice-salt bath. Dissolve 60g (0.276mol) of 6-cyano-11H-dibenzo[b,e]azepine in 120ml of tetrahydrofuran, transfer it to a dropping funnel, and add it slowly, keeping the temperature below 0°C. After the dropwise addition, the temperature was raised to 30-40°C for 2 hours. The ice-salt bath cooled the temperature below 0°C, and slowly added dilute hydrochloric acid dropwise to pH=1 to quench the reaction. After the dropwise addition was completed, stirring was continued for 10 min. Suction filtration, the filter cake was washed with 600ml tetrahydrofuran until it was nearly white, and the filtrate was rotary evaporated under reduced pressure to nearly dryness. Add 300ml of ethyl acetate and 300ml of purified water to the concentrate, stir, and slowly add 30% sodium hy...

Embodiment 2

[0032] Preparation of 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine?

[0033] Add 553ml of borane tetrahydrofuran complex (1 mol / L, 0.553mol) into a 1L three-necked flask, stir and cool down to below 0°C in an ice-salt bath. Dissolve 60g (0.276mol) of 6-cyano-11H-dibenzo[b,e]azepine in 120ml of tetrahydrofuran, transfer it to a dropping funnel, and add it slowly, keeping the temperature below 0°C. After the dropwise addition, the temperature was raised to 30-40°C for 2 hours. The temperature was cooled to 0°C in an ice-salt bath, and dilute hydrochloric acid was slowly added dropwise to pH=1 to quench the reaction. After the dropwise addition was completed, stirring was continued for 10 min. Suction filtration, the filter cake was washed with 600ml tetrahydrofuran until it was nearly white, and the filtrate was rotary evaporated under reduced pressure at 60°C to nearly dryness. Add 300ml of ethyl acetate and 300ml of purified water to the concentrate, stir, and slowly a...

Embodiment 3

[0035] Preparation of 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine?

[0036] Add 1.1L borane tetrahydrofuran complex (1 mol / L, 1.1mol) into a 2L three-necked flask, stir and cool down to below 0°C in an ice-salt bath. Dissolve 60g (0.276mol) of 6-cyano-11H-dibenzo[b,e]azepine in 120ml of tetrahydrofuran, transfer it to a dropping funnel, and add it slowly, keeping the temperature below 0°C. After the dropwise addition, the temperature was raised naturally to 20-30°C for 3 hours. The temperature was cooled to 0°C in an ice-salt bath, and dilute hydrochloric acid was slowly added dropwise to pH=1 to quench the reaction. After the dropwise addition was completed, stirring was continued for 10 min. Suction filtration, the filter cake was washed with 600ml tetrahydrofuran until it was nearly white, and the filtrate was rotary evaporated under reduced pressure at 60°C to nearly dryness. Add 300ml of ethyl acetate and 300ml of purified water to the concentrate, stir, and slow...

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Abstract

The invention relates to a synthesis method for an epinastine intermediate 6-aminomethyl-6, 11-dihydro-5H-dibenzo[b, e]azepine. The synthesis method includes: taking 6-cyano-11h-dibenzo[b, e]azepine as the raw material, conducting reduction by a borane tetrahydrofuran complex, then carrying out dilute hydrochloric acid quenching, alkali dissociation and other routine technique aftertreatment so as to obtain the 6-aminomethyl-6, 11-dihydro-5H-dibenzo[b, e]azepine. The synthesis method has the characteristics of cheap and easily available raw materials, no need for pretreatment of the raw materials and solvent needed in the whole process, no need of high pressure reaction equipment, simple reaction operation and mild conditions, and the prepared product has the advantages of high purity, good safety, high yield, and easy industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing an epinastine intermediate 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine. Background technique [0002] Epinastine is histamine H 1 Receptor antagonists are second-generation antihistamines, which are not only suitable for skin allergic reactions, but also have good curative effects on allergic rhinitis and allergic bronchial asthma, and are widely used in clinical practice. Epinastine has a stronger anti-allergic effect than traditional drugs, has multiple anti-allergic mechanisms, eliminates allergic symptoms more thoroughly, and has a rapid onset of action, which can quickly relieve the pain of patients. Its market prospect is very promising. [0003] The published patents and documents all use 6-aminomethyl-6,11-dihydro-5H-dibenzo[b,e]azepine as the key intermediate in the synthesis of epinastine. [0004] German patent DE3008944 discloses a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/20
CPCC07D223/20
Inventor 张贝周鸿睿张毅崔波卿勇裴东
Owner YAOPHARMA CO LTD
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