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Novel method for preparing new antipsychotic drug brexpiprazole

A technology of epipiprazole and a new method is applied in the field of electrochemical preparation of the new antipsychotic drug epipiprazole, and can solve the problems of not being a green process route, reducing atom utilization, being unfriendly to the environment, etc. Yield and purity improvement, process controllable effect

Active Publication Date: 2020-12-25
湖南省湘中制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The preparation method of this patent [WO2018172463A1] uses protection and deprotection methods to improve the selectivity and yield of the reaction, but adds a two-step synthesis reaction, and there is a problem that the total yield needs to be removed due to the need to remove the protecting group
The utilization of atoms in the synthesis process is reduced, and the pressure on environmental protection is high
The method of protection and deprotection is not an atom-economical preparation method, nor is it a green process route (environmentally unfriendly)

Method used

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  • Novel method for preparing new antipsychotic drug brexpiprazole
  • Novel method for preparing new antipsychotic drug brexpiprazole
  • Novel method for preparing new antipsychotic drug brexpiprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Preparation of 1-(4-bromobutoxy)-3-nitrobenzene

[0061]

[0062] Add 20mmol 3-nitrophenol and 24mmmol potassium carbonate to 30ml N,N-dimethylformamide, stir at room temperature for 1h, then add 32mmol 1,4-dibromobutane to the mixture and react for 16.0h; the reaction solution is poured into 200ml of water, 100ml of dichloromethane extracted 3 times, combined organic phase, washed 3 times with 100ml of 2% sodium hydroxide solution, washed 2 times with 100ml of water; dried with anhydrous sodium sulfate; recovered solvent by rotary evaporation, and used petroleum ether-ethyl acetate Esters (V 石油醚 :V 乙酸乙酯 =50:1) column chromatography, purified to obtain 3.70g 1-(4-bromobutoxy)-3-nitrobenzene, yield 67.5%; 1 H NMR (400MHz, CDCl 3 )δ: 7.88—7.84 (m, 1H, C 6 h 4 ), 7.76(t, J=2.3Hz, 1H, C 6 h 4 ), 7.47(t, J=8.2Hz, 1H, C 6 h 4 ), 7.25 (dd, J = 8.6Hz, 2.1Hz, 1H, C 6 h 4 ), 4.12(t, J=6.4Hz, 2H, OCH 2 ), 3.54(t, J=6.4Hz, 2H, CH 2 ), 2.15—2.02 (m, 4H, CH 2 CH 2 )...

Embodiment 2

[0064] Preparation of 1-(4-chlorobutoxy)-3-nitrobenzene

[0065]

[0066] Add 20mmol 3-nitrophenol and 24mmmol potassium carbonate to 30ml N,N-dimethylformamide, stir at room temperature for 1h, then add 20mmol 1-bromo-4-chlorobutane to the mixture for overnight reaction for 16h; Pour the solution into 200ml water, extract three times with 100ml dichloromethane, combine the organic phases, wash three times with 100ml of 2% sodium hydroxide solution, and wash twice with 100ml water; dry the organic phase with anhydrous sodium sulfate; Solvent, using petroleum ether: ethyl acetate = 50:1 column chromatography, purified to obtain 3.26g 1-(4-chlorobutoxy)-3-nitrobenzene, yield 71.0%; 1 H NMR (400MHz, CDCl 3 )δ: 7.88—7.84 (m, 1H, C 6 h 4 ), 7.76(t, J=2.3Hz, 1H, C 6 h 4 ), 7.47(t, J=8.2Hz, 1H, C 6 h 4 ), 7.25 (dd, J = 8.6Hz, 2.1Hz, 1H, C 6 h 4 ), 4.12(t, J=6.4Hz, 2H, OCH 2 ), 3.54(t, J=6.4Hz, 2H, CH 2 ), 2.15—2.02 (m, 4H, CH 2 CH 2 ).

Embodiment 3

[0068] Preparation of 1-(Benzo[b]thiophen-4-yl)-4-(4-(3-nitrophenoxy)butyl)piperazine

[0069]

[0070] 10mmol 1-(4-bromobutoxy)-3-nitrobenzene, 10mmmol1-(2,3-dichlorophenyl)piperazine hydrochloride and 12mmol potassium carbonate were added to 25ml acetonitrile, and refluxed for 48h. Inorganic matter is removed, the filtrate is washed, the filtrate is concentrated, and the organic solvent is recovered. Add 30ml of dichloromethane and 10ml of water to the concentrate, extract the aqueous layer 3 times with 20ml of dichloromethane, combine the organic phases, and wash with water until neutral. Dry the organic phase with anhydrous sodium sulfate, filter with suction; use V 石油醚 :V 乙酸乙酯 =10:1 column chromatography, 2.41g of 1-(benzothienyl)-4-(4-(3-nitrophenoxy)butyl)piperazine was obtained; the yield was 58.6%; 1 H NMR (400MHz, CDCl 3 )δ: 7.86 (d, J=9.2Hz, 1H, C 6 h 4 ), 7.78(t, J=2.1Hz, 1H, C 6 h 4 ), 7.60 (d, J=8.0Hz, 1H, C 6 h 4 ), 7.49~7.45(m, 2H, SCH=CH), 7.43(d,...

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Abstract

The invention discloses a new electrochemical preparation method of a new antipsychotic drug brexpiprazole. The preparation method specifically comprises the following steps of: preparing a key intermediate, namely -1-(benzo [b] thiophene-4-yl)-4-(4-(-3nitrophenoxy) butyl) piperazine, and carrying out electric reduction on the key intermediate to prepare 3-[4-[4-(benzo [b] thiophene-4-yl) piperazine-1y-l] butoxy] aniline; and carrying out acylation reaction with cinnamyl chloride and intramolecular Friedel-Crafts acylation reaction to prepare brexpiprazole.

Description

technical field [0001] The invention relates to a new electrochemical preparation method of ebiprazole, a new antipsychotic drug. Specifically, via 1-(benzo[b]thiophen-4-yl)-4-(4-(3-nitrophenoxy)butyl)piperazine and 3-[4-[4-(benzo[ b] A method for preparing ebiprazole from two key intermediates of thiophen-4-yl)piperazin-1-yl]butoxy]aniline. Background technique [0002] Ebiprazole (1), chemical name 7-(4-(4-(benzo[b]thiophen-4-yl)-piperazin-1-yl)butoxy)-1H-quinoline-2 -ketone: [0003] [0004] Ebiprazole compound patent: WO 2006112464A1, filed on April 12, 2006. It was launched in the United States on July 10, 2015, under the trade name Rexulti; in July 2015, the U.S. FDA approved ebiprazole for the treatment of schizophrenia, and as an adjuvant drug for antidepressants [Medical Report, 2016, 35 (1) :3-6]. [0005] Yamashita Bosi et al [CN200680011923.0, 2006.4.12 application] select quinolinone compound 2 and 1-bromo-4-chlorobutane to etherify intermediates 4, 4 a...

Claims

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Application Information

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IPC IPC(8): C07D409/12C25B3/04
CPCC07D409/12
Inventor 胡斯登何嘉宸杨贞皓曾顺胡艾希何湘宁
Owner 湖南省湘中制药有限公司
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