Methods for preparing brexpiprazole intermediate and brexpiprazole with cheap metal copper

Abstract

Methods for preparing a brexpiprazole intermediate and brexpiprazole with cheap metal copper are disclosed. The method for preparing the brexpiprazole intermediate includes dissolving 4-halogen benzo[b]thiophene and piperazine into a solvent under nitrogen protection, and adding an alkali, a ligand and a copper-based catalyst; stirring and reacting the mixture until TLC detection shows that the reaction is finished; after the reaction is finished, subjecting the system to extraction with ethyl acetate or dichloromethane; combining organic phases, and spin-drying the mixture; adding methanol todissolve solid; adding dropwise a hydrochloric acid methanol solution with a concentration of 2M to adjust the pH to 1-7 so that a target product forms a salt and then is precipitated; performing suction filtration to obtain white solid; and drying the white solid to obtain 4-piperazinyl benzothiophene hydrochloride. The methods have advantages of few side reactions, high product quality, low production cost, and the like, are suitable for industrial production and have good promotion and application prospects. The invention further provides a brexpiprazole bulk pharmaceutical chemical prepared from the brexpiprazole intermediate obtained with a low-cost technique, with the bulk pharmaceutical chemical having high purity.

Description

technical field [0001] The invention relates to a synthesis method for preparing a high-purity ebiprazole intermediate 4-piperazinylbenzothiophene hydrochloride through Ullmann reaction catalyzed by cheap metal copper and using the intermediate to further prepare ebiprazole bulk drug. [0002] technical background [0003] Brexpiprazole (Brexpiprazole), chemical name 7-[4-(4-benzo[B]thiophen-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone, from Denmark Developed by Lundbeck and Otsuka, Japan. In July 2015, it was approved for marketing by the US Food and Drug Administration (FDA). Ebiprazole is effective, safe and well tolerated in the adjuvant treatment of schizophrenia and depression. Ebiprazole is mainly synthesized by the following two routes. [0004] Route A: From 4-bromo (chloro) benzo [b] thiophene (a) as raw material, coupled with piperazine (b) to obtain 1- (benzo [B] thiophen-4-yl) piperazine (c) , (c) undergoes a nucleophilic substitution reaction with 7-(4-chloro...

AI Technical Summary

Problems solved by technology

However, there are some disadvantages in the use of precious metal palladium catalysts in large-scale industrial production: (1) because the palladium catalyst is expensive, the reaction cost is greatly increased; High, increased the difficulty of reaction; (3) palladium, as heavy metal, pollutes the environment, especially the water body, is relatively serious, also has certain toxicity to the human body, and it is relatively difficult to treat the three wastes; (4) in the use of palladium catalyst In the process, ligands are inevitably used, such as (R)-(+)2,2'-bis(diphenylphosphine)-1,1'-biphenyl (BINAP), tri-tert-butyltetraphenyl phosphonium borate, and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos), both of which are relatively expensive and produce large amounts of inseparable by-products of

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