Key clozapine intermediate synthesis method

A synthesis method and intermediate technology, applied in the field of pharmaceutical synthesis, can solve the problems of many types of raw materials, low yield, complicated reaction steps, etc., and achieve the effects of simple steps, avoiding environmental pollution, and avoiding cost increase.

Active Publication Date: 2016-12-14
CHANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In order to solve the above problems, namely cumbersome reaction steps, many types of raw and auxiliary materials, and low yield,

Method used

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  • Key clozapine intermediate synthesis method
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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0022] Under argon protection, add 20.5 g of N-(2-chloro-5-chlorophenyl) carbamic acid, 82 mL of aniline, 13.8 g of potassium carbonate and 0.02 g of cuprous chloride to the four-necked flask in sequence, raise the temperature to 153°C, and stir React for 2-3 hours. TLC followed the reaction, the reaction was completed, cooled slightly, filtered, the filtrate was distilled under reduced pressure, and the excess aniline solvent was evaporated, and the remaining solid was washed with water three times and dried to obtain 8-chloro-5,10-dihydro-11H-dibenzo[ b,e][1,4]-Diazepam -11-one 21.2g, yield 86.8%.

example 2

[0024] Under argon protection, add 20.5g of N-(2-chloro-5-chlorophenyl)carbamate, 102.5mL of aniline, 12.7g of sodium carbonate and 0.13g of cuprous bromide to the four-necked flask in sequence, and heat up to 153°C , stirring the reaction for 2-3 hours. TLC followed the reaction, the reaction was completed, cooled slightly, filtered, the filtrate was distilled under reduced pressure, and the excess aniline solvent was evaporated, and the remaining solid was washed with water three times and dried to obtain 8-chloro-5,10-dihydro-11H-dibenzo[ b,e][1,4]-Diazepam -11-one 21.7g, yield 88.9%.

example 3

[0026] Under argon protection, add 25.0 g of N-(2-bromo-5-chlorophenyl) carbamic acid, 150 mL of aniline, 7.4 g of lithium carbonate and 0.02 g of cuprous chloride to the four-necked flask in sequence, raise the temperature to 153°C, and stir React for 2-3 hours. TLC followed the reaction, the reaction was completed, cooled slightly, filtered, the filtrate was distilled under reduced pressure, and the excess aniline solvent was evaporated, and the remaining solid was washed with water three times and dried to obtain 8-chloro-5,10-dihydro-11H-dibenzo[ b,e][1,4]-Diazepam -11-one 21.8g, yield 89.3%.

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Abstract

The invention discloses a key clozapine intermediate synthesis method and belongs to the field of drug synthesis. The key clozapine intermediate synthesis method comprises the steps that N-(2-halogenated-5-chlorphenyl) amino formic acid and aniline are used as starting raw materials, the aniline serves as a solvent, and 8-chlorine-5,10-dihydro-11H-dibenzo [b,e][1,4]-dinitrogen(shown in the description)-11-ketone is obtained through reaction under the effects of a catalyst and alkali. The key clozapine intermediate synthesis method has the positive and progressive advantages that the novel method for synthesis of the 8-chlorine-5,10-dihydro-11H-dibenzo [b,e][1,4]-dinitrogen(shown in the description)-11-ketone overcome lots of shortcomings in the prior art, adopts simple steps and only needs one-step reaction, the yield is up to 90% or above; the aniline is a reaction solvent and is also a raw material, can not only make reaction of the raw material (2-halogenated-3-pyridyl) carbamic acid complete, but also increase the yield of reaction, cost increase and environmental pollution brought by usage of other solvents are further avoided, the excessive aniline can be continuously used after being poste-treated and evaporated out, the cost is greatly saved, the environment is protected, and the key clozapine intermediate synthesis method has a good industrialized prospect.

Description

technical field [0001] The present invention relates to a key intermediate of antipsychotic clozapine 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepine The invention discloses a method for synthesizing 11-ketone, which belongs to the field of drug synthesis. Background technique [0002] Clozapine is effective on positive symptoms of psychosis and also has some 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. At present, the method for synthesizing clozapine (Chinese Journal of Pharmaceutical Industry, 20...

Claims

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Application Information

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IPC IPC(8): C07D243/38
CPCC07D243/38
Inventor 殷乐唐龙李正义孙小强
Owner CHANGZHOU UNIV
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