Synthetic method of key intermediate for preparing clozapine

A synthetic method, the technology of chlorophenyl, applied in the field of drug synthesis, can solve the problems of long reaction time, difficult industrial production, complex processing, etc., achieve good industrialization prospects, avoid cost increase, and avoid environmental pollution effects

Inactive Publication Date: 2018-11-23
唯智医药科技(北京)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It can be found by observation that 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepine -11-ketone is the key intermediate for the synthesis of clozapine. In the traditional synthetic route, the cyclization step uses xylene and polyphosphoric acid system to reflux and separate the hydration ring, but there are long reflux time at high temperature, high energy consumption, and product development. Black and other issues
At the same time, Applied Radiation and Isotopes 55 (2001) 789–791, me

Method used

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  • Synthetic method of key intermediate for preparing clozapine
  • Synthetic method of key intermediate for preparing clozapine
  • Synthetic method of key intermediate for preparing clozapine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 15 g of 2-((2-amino-4-chlorophenyl) amino)benzoic acid into a three-necked reaction flask, add 100 g of sulfuric acid aqueous solution (mix 85 g of purified water with 15 g of sulfuric acid), and raise the temperature to reflux temperature (100-104 ℃), stirred for 4 hours. TLC followed the reaction. After the reaction was complete, the temperature was lowered to 58°C, filtered, washed with 3% sodium hydroxide solution until alkaline; washed with hot water at 58°C until nearly neutral, and dried; dried to obtain 8-chloro-5, 10-Dihydro-11H-dibenzo[b,e][1,4]-diazepine -11-one 12.5g, yield 89.5%, purity 99.111%.

Embodiment 2

[0029] 15 g of 2-((2-amino-4-chlorophenyl) amino) benzoic acid was added into a three-necked reaction flask, 100 g of hydrochloric acid aqueous solution (70 g of purified water mixed with 30 g of concentrated hydrochloric acid), and the temperature was raised to reflux temperature (100 -104°C), stirring for 4 hours. TLC followed the reaction. After the reaction was complete, the temperature was lowered to 58°C, filtered, washed with 3% sodium hydroxide solution until alkaline; washed with hot water at 58°C until nearly neutral, and dried; dried to obtain 8-chloro-5, 10-Dihydro-11H-dibenzo[b,e][1,4]-diazepine -11-one 11.8g, yield 84.5%, purity 96.0%.

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Abstract

The invention discloses a synthetic method of a key intermediate for preparing clozapine, and belongs to the field of drug synthesis. The method comprises the step that 2-((2-amino-4-chlorphenyl)amino)benzoic acid is taken as a raw material to be cyclized under backflow of a sulfuric acid water solution, and 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]-dinitro-11-ketone. The formula is shown in thedescription. The synthetic method utilizes the sulfuric acid water solution to conduct cyclization, and overcomes the multiple defects in the prior art, the reaction is simple, convenient and rapid,the impurities introduced by the raw material can be effectively removed, the product with the higher purity is obtained, and the waste liquid is easy to treat. Meanwhile, increasing cost and environmental pollution caused by using of other solvents are avoided, and the synthetic method has the good industrialized prospect.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method for preparing a key intermediate of clozapine. Background technique [0002] Clozapine is a light yellow crystalline powder, odorless and tasteless, effective for positive symptoms of psychosis, and also has a certain effect on negative symptoms. It is suitable for all subtypes of acute and chronic schizophrenia, and has a good effect on hallucination, delusional and youthful schizophrenia. It may also reduce affective symptoms (eg, depression, guilt, anxiety) associated with schizophrenia. For some patients who are ineffective or poorly cured by traditional antipsychotic drugs, it may be effective to switch to this product. It is also used to treat agitation, hallucinations and delusions in mania or other psychotic disorders. [0003] At present, the synthetic method of clozapine (Wang Fuxiang, Peng Zhenyun. The synthesis of clozapine, Chinese Jour...

Claims

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Application Information

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IPC IPC(8): C07D243/38
CPCC07D243/38
Inventor 张建楼左伟初野赵卫国
Owner 唯智医药科技(北京)有限公司
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