New synthesis method of aripiprazole

Abstract

A preparation method of aripiprazole comprises the following steps: reacting a raw material tetrahydrofuran with paratoluensulfonyl chloride under the catalysis of zinc chloride to obtain 4-chlorobutyl paratoluenesulfonate in a rapid mild high-output manner; reacting 4-chlorobutyl paratoluenesulfonate with 7-hydroxyquinolinone under the action of a solvent and an alkali to generate 4-chlorobutoxyquinolinone; and reacting chlorobutoxyquinolinone with piperazine hydrochloride in the certain solvent and the alkali to generate aripiprazole. Each of the intermediate 4-chlorobutoxyquinolinone and the finally obtained product aripiprazole contains a low content of dimer, so the tedious low-efficiency time-consuming removal process of the dimer can be avoided. The method has the advantages of simple process, high output, safety and low cost.

Description

Technical field: [0001] The invention belongs to the technical field of medicine and relates to a preparation method of an antipsychotic drug aripiprazole. technical background: [0002] Aripiprazole (aripiprazole, formula I), the chemical name is 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro -2(1H)-quinolinone, developed by Otsuka Corporation in 1988, was approved by the US FDA on November 15, 2002, for the treatment of schizophrenia, and is the first third-generation atypical antipsychotic new drug. The mechanism of action of aripiprazole is completely different from the typical and atypical antipsychotic drugs that are currently on the market. It is a partial agonist of dopamine D3 receptors, a partial agonist of 5-HT1A receptors and an antagonist of 5-HT2A receptors. Studies have shown that the drug is a dopamine-serotonin system stabilizer; compared with typical and atypical antipsychotics that have been marketed, it has better efficacy on negative sym...

AI Technical Summary

Problems solved by technology

[0008] The content of the dimer is usually greater than 10%. Because the dimer is very difficult to remove, this not only reduces the yield and purity of the intermediate 4-bromobutoxyquinolinone, but also affects the yield of the final product aripiprazole. efficiency and purity, the purification process is also extremely cumbersome and inconvenient

[0013] Although the use of 1-chloro-4-bromobutane and 4-bromo-1-butanol can effectively reduce the generation of dimers, 1-chloro-4-bromobutane and 4-bromo-1-butanol Expensive, especially 4-bromo-1-butanol is unstable and easily cyclized to tetrahydrofuran under alkaline reaction conditions

Generally speaking, the existing production process either generates a large number of dimers, which are difficult to remove, affecting the purity of the product aripiprazole, or the reagents are expensive and unsuitable for large-scale industrial production

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