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Piprazole antipsychotic drug key intermediate and electroreduction method thereof

An intermediate and a key technology, applied in the application field of preparing Kang psychiatric drugs, can solve the problems of increasing the two-step synthesis reaction, reducing the total yield, and being unfriendly to the environment.

Active Publication Date: 2020-12-15
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

[0016] The preparation method of this patent [WO2018172463A1] adopts the method of protection and deprotection to prepare the key intermediate of ebiprazole——3-[4-[4-(benzo[b]thiophen-4-yl)piperazine-1- Base] butoxyl] aniline; can improve the selectivity and yield of reaction, but increased two-step synthetic reaction, there is the problem that needs to remove protecting group so that total yield reduces
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, and is not environmentally friendly

Method used

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  • Piprazole antipsychotic drug key intermediate and electroreduction method thereof
  • Piprazole antipsychotic drug key intermediate and electroreduction method thereof
  • Piprazole antipsychotic drug key intermediate and electroreduction method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Preparation of 1-(4-bromobutoxy)-3-nitrobenzene

[0049]

[0050] 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

[0052] Preparation of 1-(4-chlorobutoxy)-3-nitrobenzene

[0053]

[0054] 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

[0056] Preparation of 1-(Benzo[b]thiophen-4-yl)-4-(4-(3-nitrophenoxy)butyl)piperazine

[0057]

[0058] 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, to obtain 2.41g 1-(benzothienyl)-4-(4-(3-nitrophenoxy)butyl)piperazine; yield 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, J=5.6Hz, 1H, ...

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Abstract

The invention discloses a benzo [b] thiophene-4-yl) piperazine derivative shown as a formula I or a salt thereof, an electroreduction method of the benzo [b] thiophene-4-yl) piperazine derivative andapplication of the benzo [b] thiophene-4-yl) piperazine derivative in preparation of antipsychotic drugs. n is selected from 2, 3 or 4; nitro is selected from 2-NO2, 3-NO2 and 4-NO2; and the salt is selected from hydrochloride, hydrobromide, sulfate, nitrate, phosphate, p-toluenesulfonate, benzene sulfonate, mesylate, trifluoromethanesulfonate or trifluoroacetate.

Description

technical field [0001] The present invention relates to a new class of compound, its preparation method and its application in the field of medicine. Specifically, it is benzo[b]thiophen-4-yl)piperazine derivatives and their electroreduction method and their application in the preparation of Kang psychotropic drugs. Background technique [0002] Hiroshi Yamashita et al. [CN102558140A, 2012.7.11] described 1-(benzo[b]thiophen-4-yl)-4-(4-(substituted phenoxy)butyl)piperazine and its preparation. [0003] [0004] Y=H, 4-F, 4-CN, 3-CN, 2-CN, 4-CO 2 H,3-CO 2 H,2-CO 2 H,3-CONH 2 , 3-CONHCH 3 , 4-CONHCH 3 , 3-CON(CH 3 ) 2 , 4-CON(CH 3 ) 2 , 4-CONHC 2 h 5 , 3-CONHC 2 h 5 , 2-CONHC 2 h 5 , 4-CONHCH 2 CF 3 , 3-CONHCH 2 CF 3 , 3-NHCO 2 CH 3 , 4-NHCO 2 CH 3 or 2-OCH 3 -4-COCH 3 [0005] Yang Feipu et al [Bioorganic & Medicinal Chemistry Letters, 2016,26(13):3141-3147] described 1-(benzo[b]thiophen-4-yl)-4-(4-(3-methoxy / methylaminocarbonyl Phenoxy)butyl)pi...

Claims

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Application Information

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IPC IPC(8): C07D333/54C25B3/04
CPCC07D333/54
Inventor 胡斯登何嘉宸杨贞皓曾顺胡艾希何湘宁尹文乐
Owner 湖南省湘中制药有限公司
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