Chemical synthetic method of azepine derivate

A synthesis method and azepine technology are applied in the field of chemical synthesis of azepine derivatives, can solve the problems of large amount of sulfuric acid waste water, cumbersome treatment process, difficult recovery of acetic acid, etc., and achieve reasonable process conditions, simple and quick operation, and reaction Productivity improvement effect

Active Publication Date: 2008-11-12
浙江瑞博制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The route first step bromination (synthetic of I → II) used NBS (N-bromosuccinimide), the cost is very high, and the process is more loaded down with trivial details, in addition in the final hydrolysis step (VI → The synt

Method used

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  • Chemical synthetic method of azepine derivate
  • Chemical synthetic method of azepine derivate
  • Chemical synthetic method of azepine derivate

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Preparation of Example 1.5-cyano-10-bromo-10,11-dihydro-5H-diphenyl[b,f]azepine (II)

[0026] 10g of 5-cyano-10,11-dihydro-5H-diphenyl[b,f]azepine (I), 60mL of chlorobenzene was stirred and dissolved, and 10mL of purified water was added, the temperature was raised to 85°C, and the solution was slowly added dropwise A mixture of bromine 8g / 60mL chlorobenzene, the temperature is controlled at 85-90°C, after 8 hours of dripping, continue to keep warm for 0.5 hours. After the reaction, the reaction solution was allowed to stand for stratification, and the temperature was controlled not lower than 50°C to avoid solid precipitation. The organic phase was taken, and 60 mL of solvent was evaporated under reduced pressure, and the solid was precipitated by cooling, recrystallized from acetone to obtain a yellow solid 5-cyanide 11.8 g of 10-bromo-10,11-dihydro-5H-diphenyl[b,f]azepine (II). (HPLC: 97.83%), yield 87%.

Embodiment 2

[0027] Preparation of Example 2.5-cyano-10-bromo-10,11-dihydro-5H-diphenyl[b,f]azepine (II)

[0028] 10g (I), 60mL of chlorobenzene were stirred and dissolved, and 8g Na 2 CO 3 , the temperature was raised to 85°C, and a mixture of liquid bromine 8g / 60mL chlorobenzene was slowly added dropwise, the temperature was controlled at 95°C, the dripping was completed after 7h, and the temperature was continued for 0.5h. After the reaction, filter while hot, rinse the filter cake with 10mL of chlorobenzene, evaporate 60mL of solvent from the reaction solution under reduced pressure, cool and precipitate a solid, and recrystallize from acetone to obtain a yellow solid 5-cyano-10-bromo-10,11-di Hydrogen-5H-diphenyl[b,f]azepine(II) 10.9g (HPLC: 97.51%), yield 80%.

Embodiment 3

[0029] Preparation of Example 3.5-cyano-10-bromo-10,11-dihydro-5H-diphenyl[b,f]azepine (II)

[0030] Dissolve 10g (I) and 60mL dichloroethane with stirring, add 8g Na 2 CO 3 , the temperature was raised to 85°C, and a mixture of 8g of liquid bromine / 60mL of dichloroethane was slowly added dropwise, under total reflux, the temperature was at 83°C, after 7h of dropping, the temperature was continued for 0.5h. After the reaction, filter while hot, rinse the filter cake with 10mL of dichloroethane, distill off 60mL of solvent from the reaction solution under reduced pressure, cool to precipitate a solid, and recrystallize from acetone to obtain a yellow solid 5-cyano-10-bromo-10,11 -Dihydro-5H-diphenyl[b,f]azepine (II) 11.1 g (HPLC: 98.12%), yield 82%.

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Abstract

The invention discloses a synthesis method for an azepine derivative, in particular relating to a chemical synthesis method for 10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepin-5-formylamino. The method of the invention is as follows: 10-cyano-10,11-dihydro-5H-dibenzo[b,f]azepin-5- formylamino undergoes bromination at the benzyl position to give a bromide. The bromide undergoes hydrolysis to give a hydrolysate which is oxidized under the condition of NaClO/TEMPO to give a carboxide. And finally a cyan in the carboxide is hydrolyzed by H2O2 in an alkaline condition to give the resultant. The method has the advantages of reasonable process condition, cheap materials, convenient and rapid operation, highly improved resultant yield, giving far more environment-friendly process due to the hydrolysis of cyan with hydrogen peroxide compared with that with concentrated sulphuric acid, having large advantages for industrial production. The method can be widely used in pharmaceutical industry.

Description

technical field [0001] The present invention relates to a chemical synthesis method of azapine derivatives, specifically a kind of 10-oxa-10,11-dihydro-5H-diphenyl[b,f]azepine-5-carboxamide chemical synthesis method. technical background [0002] 10-oxa-10,11-dihydro-5H-diphenyl[b,f]azepine-5-carboxamide, that is, Oxcarbazepine (Oxcarbazepine,), the structural formula is as follows: [0003] [0004] It is a voltage-sensitive sodium channel blocker developed by Novartis, Switzerland. It was first launched in Denmark in 1990 and has been marketed in more than 70 countries so far. It is a relatively new type of antiepileptic drug, and because of its exact efficacy and safety, it has gradually become a global first-line broad-spectrum antiepileptic drug with a broad market. There are many reports on the synthesis of oxcarbazepine and its intermediates, classified by starting materials, mainly containing three categories: 1) the carbamazepine method invented by Kawashima K ...

Claims

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Application Information

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IPC IPC(8): C07D223/22
Inventor 韩卫华陈崇华凌波
Owner 浙江瑞博制药有限公司
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