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Synthesis method of brexpiprazole intermediate 4-bromo-benzo[B]thiophene

A technology of epipiprazole and a synthesis method is applied in the field of synthesis of 4-bromobenzo[B]thiophene, an intermediate of epipiprazole, and can solve the problems of poor product selectivity, influence on product quality, multiple by-products and the like, and achieve The effect of high reaction yield, simple post-processing operation and high product purity

Active Publication Date: 2019-04-05
THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] This route has long steps, poor product selectivity, and low yield; nitration reaction is easy to produce pollution emissions; diazotization reaction requires low temperature control, often produces more by-products, which affects product quality

Method used

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  • Synthesis method of brexpiprazole intermediate 4-bromo-benzo[B]thiophene
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  • Synthesis method of brexpiprazole intermediate 4-bromo-benzo[B]thiophene

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Experimental program
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Effect test

Embodiment 1

[0033] The synthetic method of 4-bromobenzo [B] thiophene, comprises the following steps:

[0034] 1) Mix benzothiophene, acetic acid and catalyst, pass in argon, control the pressure to 3 atmospheres, control the temperature to 78°C, add 30% hydrogen peroxide dropwise at a constant speed, and control the dropping time of hydrogen peroxide to 30min. When the added hydrogen peroxide reached 15% of its total volume, start to drop the mixture A consisting of sodium bromide, water and tetrabutylammonium bromide at a constant speed, and control the time of adding the mixture A to 40min. Raise the reaction temperature to 120°C, raise the pressure to 9.5 atmospheres, and then continue the reaction for 20 hours to complete the reaction;

[0035] The preparation method of the catalyst is as follows: grind the 10Z type molecular sieve, pass it through 600 mesh, and activate it at 530°C.

[0036] The mol ratio of benzothiophene and acetic acid is 1:20, the mol ratio of benzothiophene an...

Embodiment 2

[0039] The synthetic method of 4-bromobenzo [B] thiophene, comprises the following steps:

[0040] 1) Mix benzothiophene, butyric acid and the catalyst, feed nitrogen, control the pressure to 2 atmospheres, control the temperature to 60°C, add 30% hydrogen peroxide dropwise at a constant speed, and control the dropping time of hydrogen peroxide to 25 minutes. When the added hydrogen peroxide reached 10% of its total volume, start to drop the mixture A consisting of magnesium bromide, water and activator at a constant speed, control the time of adding the mixture A for 35min, after the dropwise operation finished, raise the reaction temperature to 110°C, raise the pressure to 8 atmospheres, then continue to react for 15 hours and the reaction ends;

[0041] The preparation method of the catalyst is as follows: grind the 13Z type molecular sieve, pass it through 500 mesh, and activate it at 450°C.

[0042] The molar ratio of benzothiophene to butyric acid is 1:18, the molar rat...

Embodiment 3

[0045] The synthetic method of 4-bromobenzo [B] thiophene, comprises the following steps:

[0046] 1) Mix benzothiophene, propionic acid and catalyst, pass in argon, control the pressure to 4 atmospheres, control the temperature to 85°C, add 30% hydrogen peroxide dropwise at a constant speed, and control the dropping time of hydrogen peroxide to 35min, when When the hydrogen peroxide added dropwise reached 18% of its total volume, start to add dropwise the mixture A consisting of brominating agent, water and activating agent at a constant speed, and control the dropwise addition time of mixture A for 45 minutes. After the dropwise addition operation was finished, raise the reaction temperature To 125 ° C, raise the pressure to 10 atmospheres, then continue to react for 22 hours and the reaction ends;

[0047] The preparation method of the catalyst is as follows: grind the 10Z type molecular sieve, pass it through 700 mesh, and activate it at 600°C.

[0048] The molar ratio of...

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Abstract

The invention discloses a synthesis method of a brexpiprazole intermediate 4-bromo-benzo [B] thiophene. According to the synthesis method, benzothiophene, metal bromide, organic acid and hydrogen peroxide are enabled to react to obtain the 4-bromo-benzo[B]thiophene under the action of a catalyst. A reaction process includes: 1) mixing the benzothiophene, the organic acid and the catalyst, introducing protection gas, controlling pressure within a range from 2 to 4 barometric pressure and temperature within a range from 60 to 85 DEG C, dripping the hydrogen peroxide at a constant speed for 25-35minutes, starting to drip a mixture A composed of the metal bromide, water and an active agent at a constant speed when the hydrogen peroxide accounts for 10-18% of the total volume, controlling dripping time of the mixture A within 35-45 minutes, after operation is over, heating the temperature to 110-125 DEG C, enlarging the pressure to 8-10 barometric pressure, and continuing the reaction for15-22 hours before reaction is over; 2) cooling a system, adding the system into water which is as 2-4 times as the system in volume, extracting with a solvent B, drying an extracting solution with adrying agent, and concentrating by evaporating the solvent to obtain the product. The synthesis method is short in process, low in cost and barely free from production of three wastes.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a method for synthesizing an ebiprazole intermediate 4-bromobenzo[B]thiophene. Background technique [0002] The incidence of adult schizophrenia (Schizophrenia) and major depressive disorder (MDD) is increasing year by year worldwide. According to the statistics of the World Health Organization (WHO), about 1 million people lose their lives every year because of this, and about 1% of people are affected by it so far. In recent years, psychopharmacotherapeutics has gradually become one of the fastest-growing disciplines in the field of clinical medicine, and a large number of new antipsychotic drugs with different structures have come out. On July 10, 2015, the U.S. Food and Drug Administration (FDA) approved the listing of Brexpiprazole (Brexpiprazole), jointly developed by Lundbeck Pharmaceuticals of Denmark and Otsuka Co., Ltd. of Japan. Ebiprazole is an experimental sero...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/54
CPCC07D333/54
Inventor 谭回李维平黄贤键刘文兰唐爱发赵华福
Owner THE SECOND PEOPLES HOSPITAL OF SHENZHEN
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