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Brexpiprazole preparation method

A technology of epipiprazole and compound, applied in the field of preparation of epipiprazole, can solve the problems of difficult separation of impurities, side reactions, poor reaction selectivity, etc., and achieves the effects of high reaction selectivity, easy operation and high product purity

Inactive Publication Date: 2015-08-12
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0008] In this method, the selectivity of the reaction between the compound of formula (2) and 1-bromo-4-chlorobutane is poor, and the two impurities of formula a and formula b are easily produced, resulting in difficulties in post-processing and purification. Moreover, formula (3) The compound reacts with the compound of formula (4), and in the presence of a base, the compound of formula (3) will have a side reaction with ebiprazole, resulting in impurities that are not easy to separate

Method used

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Examples

Experimental program
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Embodiment 1

[0024] The preparation of embodiment 1 formula Ⅳ compound

[0025] Add 4ml of N-methylpyrrolidone, 0.5g of the compound of formula II and 0.53g of the compound of formula III, 0.28g of sodium carbonate, and 0.2g of sodium bromide into a 25ml three-necked flask, heat up to 70-80 degrees and react for 3-5 hours. After completion, cool down to room temperature, add 12ml of water, precipitate a white solid, filter with suction, wash the filter cake twice with water, and dry under reduced pressure to obtain the compound of formula IV, with a dry weight of 0.84g. Yield: 97.8%, purity 98.3%.

Embodiment 2

[0026] The preparation of embodiment 2 formula Ⅳ compound

[0027] Add 400L of N-methylpyrrolidone, 50g of the compound of formula II and 50g of the compound of formula III, 27.6g of sodium carbonate, and 28.6g of potassium iodide into a 2L three-necked flask, heat up to 70-80°C and react for 3-5 hours. After the reaction is completed, cool down After reaching room temperature, 1.2 L of water was added to precipitate a white solid, which was filtered with suction, washed twice with water, and dried under reduced pressure to obtain the compound of formula IV, with a dry weight of 82.3 g. Yield: 95.8%, purity 97.6%.

Embodiment 3

[0028] The preparation of embodiment 3 ebiprazole

[0029] Add 700ml of N-methylpyrrolidone, 100g of the compound of formula IV and 67.7g of DDQ into a 1000ml three-necked flask, and stir and react with 30-40°C for 3-4 hours. In 2.5L aqueous solution, after stirring for 0.5 hour, suction filtration, the filter cake was washed three times with water, and dried under reduced pressure to obtain ebiprazole, off-white powdery solid, 93.6g, yield 94.0%, purity 98.3%.

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Abstract

The present invention relates to a brexpiprazole preparation method, which comprises: (1) carrying out a condensation reaction of a compound represented by a formula III and a compound represented by a formula II in a solvent to prepare a compound represented by a formula IV; and (2) in a solvent, carrying out dehydrogenation on the compound represented by the formula IV with dichloro dicyano benzoquinone to obtain the brexpiprazole. With the method of the present invention, the reaction selectivity can be improved, the impurity generation can be reduced, the low yield problem caused by poor solubility of the key intermediate is avoided, and the total yield of the reaction is higher than 70.0%.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of ebiprazole. Background of the invention [0002] The chemical name of brexpiprazole is 7-(4-(4-(benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy)-1 H -Quinolin-2-one, a serotonin-dopamine activity modulator (SDAM), has partial dopamine D2 receptor agonism and 5-HT1A receptor agonism, and also has 5-HT2A receptor antagonism, developed by Japan Originally developed by Otsuka Pharmaceutical Co., Ltd., jointly developed by Otsuka Pharmaceutical and Lundbeck. On July 14, 2014, the US NDA was submitted (indications for the adjuvant treatment of severe depression and schizophrenia treatment), the FDA accepted the NDA in September 2014, and the EMA new drug application was submitted in November 2013. Its chemical structural formula is as shown in formula I: [0003] [0004] (I) [0005] Compared with aripiprazole, the drug has an increased affin...

Claims

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Application Information

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IPC IPC(8): C07D409/12
CPCC07D409/12
Inventor 罗绪付廷印张华娇张耀春左小勇雷皇书
Owner CHONGQING PHARMA RES INST
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