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Preparation method for synthesizing brexpiprazole

A technology of ebiprazole and compounds, applied in a new field of preparation, can solve the problems of increased risk of industrial production, difficulty in large-scale production, long reaction steps, etc., and achieve low implementation cost, strong industrial application value, and high product quality Good results

Inactive Publication Date: 2017-06-13
ZHEJIANG LIAOYUAN PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0021] The method selects relatively easy-to-get 4-hydroxybenzo[b]thiophene as the starting raw material, but the reaction steps are long, which reduces the yield, and a lot of auxiliary raw materials are added in the reaction process, which increases the cost. The use of sodium hydride, a dangerous chemical that explodes in contact with water, increases the risk of industrial production and is difficult for large-scale production

Method used

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  • Preparation method for synthesizing brexpiprazole
  • Preparation method for synthesizing brexpiprazole
  • Preparation method for synthesizing brexpiprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] (a) Put 80g (0.446mol) of 4-nitrobenzene[b]thiophene into a 500mL autoclave, 4g (0.05g / g) of 5% palladium carbon, and 320mL of methanol. 3 times, fill with hydrogen to a pressure of 0.3 MPa, stir, heat up to 50°C and react for 6 hours, keep warm until no hydrogen is absorbed in the kettle, keep warm for 30 minutes, cool down to room temperature, take out the reaction solution, and filter under nitrogen protection. The filtrate was concentrated under reduced pressure until the remaining volume was 150 mL to obtain compound (II) with a weight of 60 g and a yield of 90%.

[0068] (b) Under nitrogen protection, 81.6g (0.5mol) of 7-hydroxyl-1H-quinolin-2-one, 103g (0.6mol, 1.2ep) of bromochlorobutane, 103.5g (0.75 ep) of potassium carbonate were put into the flask mol, 1.5ep), acetone 816mL, stirred and heated to 60°C, and reacted for 8 hours. After the reaction is completed, cool down to 20°C, filter, concentrate the filtrate to recover a part of acetone, add water dropwis...

Embodiment 2

[0074] (a) drop into 4-nitrobenzene [b] thiophene 80g (0.446mol) in 500ml autoclave, Raney nickel 8g (0.1g / g), ethanol 400ml, feed intake complete, nitrogen replacement 3 times, then hydrogen replacement 3 times Once, fill in hydrogen gas to a pressure of 1MPa, stir, raise the temperature to 80°C and react for 5 hours, keep the temperature until the hydrogen is no longer absorbed in the kettle, keep the temperature for 30 minutes, cool down to room temperature, take out the reaction solution, and suction filter under the protection of nitrogen. Concentrate under reduced pressure until the remaining volume is 200ml, stir and crystallize to obtain compound (II) with a weight of 58g and a yield of 87%.

[0075](b) under nitrogen protection, put into the flask 80.6g (0.5mol) of 7-hydroxy-1H-quinolin-2-one, 86g (0.5mol, 1ep) of bromochlorobutane, 53g (0.5mol, 1ep) of sodium carbonate ), 484 ml of N,N-dimethylformamide, and stirred at 100°C for 6 hours. After the reaction is comple...

Embodiment 3

[0081] (a) 80g (0.446mol) of 4-nitrobenzene[b]thiophene, 2.4g (0.03g / g) of 10% palladium on carbon, 500ml of ethanol were put into a 500ml autoclave, the feeding was completed, nitrogen was replaced 3 times, and then hydrogen Replaced 3 times, filled with hydrogen to a pressure of 0.2 MPa, stirred, heated at 20 °C for 8 hours, kept the reaction at a temperature until no more hydrogen was absorbed in the kettle, kept the reaction for another 30 minutes, cooled to room temperature, took out the reaction solution, and suction filtered under nitrogen protection , the filtrate was concentrated under reduced pressure until the remaining volume was 200ml, and the mixture was stirred and crystallized to obtain compound (II) with a weight of 59g and a yield of 88%.

[0082] (b) under nitrogen protection, put into the flask 80.6g (0.5mol) of 7-hydroxy-1H-quinolin-2-one, 103g (0.6mol, 1.5ep) of bromochlorobutane, 106g (1mol, 1.5ep) of sodium bicarbonate 2ep), 645 ml of N,N-dimethylacetam...

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Abstract

The invention provides a preparation method for synthesizing brexpiprazole. The preparation method comprises the following specific steps of using 4-nitrobenzo[b]thiophene as a raw material to carry out a hydrogenation reaction to synthesize an intermediate compound (II), and using 7-hydroxy-1H-quinolin-2-one as a raw material to carry out a reaction to synthesize and obtain a compound (III) at a first step and to obtain an intermediate compound (IV) at a second step; afterwards, condensing the intermediate compound (II) and the intermediate compound (IV) to make a target compound (I), namely the brexpiprazole. Raw materials of the entire synthetic route of the preparation method are both obtained easily; the operation is simple and convenient; the operation cost is low; the preparation method is green and environment-friendly; further, the yield of each step is high; the preparation method is quite suitable for industrialized production, and has extremely high industrial application value.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis of medicines, and in particular relates to a brand-new preparation method for synthesizing ebiprazole. Background technique [0002] Ibiprazole (brexpiprazole), trade name Rexulti, is the first dopamine, partial 5-HT1A receptor agonist and 5-HT2A receptor antagonist compound developed by Otsuka Pharmaceutical Co., Ltd. Best-selling drug - another blockbuster after aripiprazole. The drug was approved by the U.S. FDA on July 11, 2015 as an adjuvant drug for the treatment of major depressive disorder (MDD) in adults and a drug for the treatment of schizophrenia in adults. [0003] Epirazole has a wide range of activities in multiple monoamine systems, the partial agonist activity of dopamine D2 receptors is reduced, and the activity of specific 5-HT receptors (such as 5-HT1A, 5-HT2A, 5-HT7) Improved affinity, better efficacy and tolerability, can reduce adverse reactions such as akathisia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/12
CPCC07D409/12
Inventor 宋志刚杨敏华崔建丰陈伟军
Owner ZHEJIANG LIAOYUAN PHARM CO LTD
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