Methods for preparing brexpiprazole intermediate and brexpiprazole with cheap metal copper

A technology for epipiprazole and intermediates, which is applied in the field of synthesis of epipiprazole bulk drugs, can solve the problems of high difficulty, high relevant requirements, and increased reaction costs, and achieves low environmental pollution, high economic benefits, and reduced The effect of reaction cost

Active Publication Date: 2019-07-05
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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

Method used

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  • Methods for preparing brexpiprazole intermediate and brexpiprazole with cheap metal copper
  • Methods for preparing brexpiprazole intermediate and brexpiprazole with cheap metal copper
  • Methods for preparing brexpiprazole intermediate and brexpiprazole with cheap metal copper

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1: Under nitrogen protection, 4-bromobenzo[b]thiophene (10.7g, 0.05mol), piperazine (4.3g, 0.05mol), cuprous oxide (0.36g, 0.0025mol) were added to a 500mL single-necked bottle ), potassium hydroxide (4.2g, 0.075mol), 1,10-phenanthroline (1.8g, 0.01mol) and N,N'-dimethylformamide (30mL), stirred at 100°C for 24 hours, and the reaction was completed Finally, spin the reaction solution to dry the solvent, add water to the obtained solid and extract it with ethyl acetate, combine the organic phases and spin dry, dissolve the obtained solid in methanol, add 2M hydrochloric acid methanol solution dropwise to adjust the pH to 4, and the target product becomes a salt The precipitated salt was washed with acetone, suction filtered to obtain a white solid, and dried to obtain 9.0 g of 4-piperazinylbenzothiophene hydrochloride, with a yield of 82.6% and a purity of 99.6%. The data characterization of the 4-piperazinylbenzothiophene hydrochloride prepared in embodiment 1: ...

Embodiment 2

[0082] Example 2: Under nitrogen protection, 4-bromobenzo[b]thiophene (10.7g, 0.05mol), piperazine (21.5g, 0.25mol), cuprous oxide (0.72g, 0.005mol) were added to a 500mL single-necked bottle ), potassium hydroxide (4.2g, 0.075mol), 1,10-phenanthroline (1.8g, 0.01mol) and N,N'-dimethylformamide (30mL), stirred at 100°C for 24 hours, and the reaction was completed Finally, spin the reaction solution to dry the solvent, add water to the obtained solid and extract it with ethyl acetate, combine the organic phases and spin dry, dissolve the obtained solid in methanol, add 2M hydrochloric acid methanol solution dropwise to adjust the pH to 4, and the target product becomes a salt The precipitated salt was washed with acetone, suction filtered to obtain a white solid, and dried to obtain 9.4 g of 4-piperazinylbenzothiophene hydrochloride, with a yield of 86.2% and a purity of 99.4%.

Embodiment 3

[0083] Example 3: Under nitrogen protection, 4-bromobenzo[b]thiophene (10.7g, 0.05mol), piperazine (43.1g, 0.5mol), cuprous oxide (2.15g, 0.015mol) were added to a 500mL single-necked bottle ), potassium hydroxide (4.2g, 0.075mol), 1,10-phenanthroline (1.8g, 0.01mol) and N,N'-dimethylformamide (30mL), stirred at 100°C for 24 hours, and the reaction was completed Finally, spin the reaction solution to dry the solvent, add water to the obtained solid and extract it with ethyl acetate, combine the organic phases and spin dry, dissolve the obtained solid in methanol, add 2M hydrochloric acid methanol solution dropwise to adjust the pH to 4, and the target product becomes a salt The precipitated salt was washed with acetone, suction filtered to obtain a white solid, and dried to obtain 9.5 g of 4-piperazinylbenzothiophene hydrochloride, with a yield of 87.2% and a purity of 99.6%.

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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/66C07D409/12
CPCC07D333/66C07D409/12
Inventor 翁意意杨婷
Owner ZHEJIANG UNIV OF TECH
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