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Preparation method of brexpiprazole

A technology of ebiprazole and compounds, applied in the field of medicinal chemistry, can solve the problems of low purity of intermediates, many by-products, and long reaction time, and achieve the effects of high reaction selectivity, reduced raw material costs, and easy operation

Active Publication Date: 2015-08-19
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In this method, the reaction time is long when preparing the intermediate (3), which takes about 40 hours, and more by-products are produced, with a yield of about 60.0%. The purity of the intermediate is not high, which in turn affects the purity of the final product ebiprazole, And starting material is difficult to obtain; The refinement of crude product adopts salify in the mixed solvent of ethanol and acetic acid, then free prepares ebiprazole, and refining effect is not obvious, and the obtained ebiprazole purity does not meet the requirement of pharmacy

Method used

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Examples

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Embodiment 1

[0026] Example 1 7-(4-chlorobutoxy)-3,4-dihydroquinoline-2(1 H )-Preparation of ketone (formula III)

[0027] Add 10g of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (Formula II), 31.5g of 1-bromo-4-chlorobutane, 30ml of N-methylpyrrolidone, water 5ml, sodium hydroxide 2.9g. After the addition, heat up to 40-50°C, seal and keep warm for 3 hours. After the reaction, add water to crystallize, filter with suction, wash with water twice, and dry the filter cake under reduced pressure to obtain 7-(4-chlorobutoxy)-3. 4-Dihydroquinoline-2(1 H )-ketone 14.6g, yield 94.3%, purity 97.8%.

Embodiment 2

[0028] Example 2 7-(4-chlorobutoxy)-3,4-dihydroquinoline-2(1 H ) - Preparation of ketones

[0029] Add 3,4-dihydro-7-hydroxy-2(1H)-quinolinone 1.0kg, 1-bromo-4-chlorobutane 3.15kg, DMF 3.0L, water 500ml, lithium hydroxide 270 g. After the addition, heat up to 40-50°C, seal and keep warm for 3 hours. After the reaction, add water to crystallize, filter with suction, wash with water twice, and dry the filter cake under reduced pressure to obtain 7-(4-chlorobutoxy)-3. 4-Dihydroquinoline-2(1 H )-ketone dry product 1.48kg, yield 95.0%, purity greater than 98.5%.

Embodiment 3

[0030] Example 3 7-(4-chlorobutoxy)-quinoline-2(1 H )-Preparation of ketone (formula IV)

[0031] Add 700ml of tetrahydrofuran into a 1L three-necked flask, 7-(4-chlorobutoxy)-3,4-dihydroquinoline-2(1 H )-ketone 100g, DDQ 110g, stirred and reacted at 30-40°C for 3-4 hours, after the reaction was completed, pour the reaction solution into an aqueous solution containing 55g of sodium sulfite, stirred for 0.5 hours, then suction filtered, and the filter cake was used Washed three times, dried under reduced pressure to obtain 7-(4-chlorobutoxy)-quinoline-2(1 H )-ketone 97g, yield 98.0%, purity 98.7%.

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Abstract

The invention relates to a preparation method of brexpiprazole and an intermediate thereof; the method includes the steps of carrying out a reaction of a compound represented by the formula II with 1-bromo-4-chlorobutane in a reaction solvent to obtain a compound represented by the formula III, in the presence of 2,3-dicyano-5,6-dichlorobenzoquinone, oxidizing the compound represented by the formula III into a compound represented by the formula IV, carrying out a reaction of the compound represented by the formula IV with a compound represented by the formula V to obtain brexpiprazole, then carrying out hydrochloride formation and refining, adding an alkali, and allowing brexpiprazole to drift away. The purity of brexpiprazole obtained by the method is more than 99.5%, the total yield is more than 80%, the process is simple and the cost is low.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing antipsychotic drug ebiprazole. Background of the invention [0002] The chemical structure of brexpiprazole (brexpiprazole) is shown in the following formula 1 compound, the chemical name is 7-(4-(4-(benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy)- 1 H - Quinolin-2-one. [0003] [0004] Ebiprazole is a serotonin-dopamine activity modulator (SDAM), which has partial dopamine D2 receptor agonism and 5-HT1A receptor agonism, and also has 5-HT2A receptor antagonism. It is manufactured by Japan Otsuka Pharmaceutical Co., Ltd. Jointly developed by the club and Lundbeck. On July 14, 2014, the US NDA was submitted for the adjuvant treatment of severe depression and the treatment of schizophrenia. The FDA accepted the NDA in September 2014, and submitted the EMA New Drug Application in November 2013. [0005] Compared with aripiprazole, ebiprazole...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12
CPCC07D409/12
Inventor 张耀春王兵院兴罗绪左小勇雷皇书
Owner CHONGQING PHARMA RES INST
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