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Preparation method of Brexpiprazole intermediate and Brexpiprazole intermediate

A technology for intermediates and compounds is applied in the field of preparation of Brexpiprazole intermediates, which can solve the problems of heavy metal pollution, increase production costs and the like, and achieve the effects of simple operation, cost reduction, and avoidance of heavy metal pollution.

Inactive Publication Date: 2016-07-06
SUZHOU PENGXU PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are few reports on the synthesis of 4-(1-piperazinyl)benzo[b]thiophene at home and abroad
Route 2 uses cheap and easy-to-get 2,6-dichlorobenzaldehyde as a raw material, and each step of the reaction has a high yield, but the use of palladium-catalyzed coupling reaction will always greatly increase the production cost and bring heavy metal pollution

Method used

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  • Preparation method of Brexpiprazole intermediate and Brexpiprazole intermediate
  • Preparation method of Brexpiprazole intermediate and Brexpiprazole intermediate
  • Preparation method of Brexpiprazole intermediate and Brexpiprazole intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1, the synthesis of 2-(4-acetylpiperazin-1-yl)-6-fluorobenzaldehyde

[0052]

[0053]Add N-acetylpiperazine (6.40g, 50mmol), 2,6-difluorobenzaldehyde (7.46g, 52.5mmol), potassium carbonate (8.28g, 60mmol) and 96mL DMF into a 250mL three-necked flask. The system was heated to 80°C and reacted at this temperature for 18 hours. Stop the reaction, cool to room temperature, add 300mL water, extract three times with ethyl acetate (3×150mL), combine the organic phases, wash with 150mL water, 150mL saturated NaCl solution once, and dry over anhydrous sodium sulfate. After filtration and concentration, the crude product was obtained, which was purified by column chromatography (developer polarity: petroleum ether / ethyl acetate=1 / 2) to obtain 10.21 g of the product, a light yellow solid, with a yield of 82% and a purity of 98%.

[0054] Product NMR data: 1 HNMR (400MHz, DMSO-d 6 )δ10.19(s,1H),7.67–7.55(m,1H),7.00(d,J=8.3Hz,1H),6.94(dd,J=10.7,8.4Hz,1H),3.63(brs,4H...

Embodiment 2

[0055] Embodiment 2, the synthesis of 2-(4-acetylpiperazin-1-yl)-6-chlorobenzaldehyde

[0056]

[0057] 2-Chloro-6-fluorobenzaldehyde (1.00g, 6.3mmol), potassium carbonate (1.74g, 12.58mmol), N-acetylpiperazine (0.89g, 6.92mmol) and 12mL DMF were added to a 25mL single-necked bottle. Stir for 5min. The reaction solution was heated to 100° C. for 15 hours. Stop the reaction, cool to room temperature, add 80 mL of water, extract three times with ethyl acetate (40 mL×3), combine the organic phases, wash with 40 mL of water and 40 mL of saturated NaCl solution once, and dry over anhydrous sodium sulfate. After filtration and concentration, the crude product was obtained, which was purified by column chromatography (developer polarity: petroleum ether / ethyl acetate=1 / 1) to obtain 1.40 g of a yellow solid with a yield of 84% and a purity of 99%.

[0058] Product NMR data: 1 HNMR(400MHz,DMSO)δ10.24(s,1H),7.55(t,J=8.1Hz,1H),7.21(d,J=2.5Hz,1H),7.19(d,J=2.9Hz,1H) ,3.68–3.54(m,4H)...

Embodiment 3

[0059] Embodiment 3, the synthesis of 2-(4-Boc piperazin-1-yl)-6-fluorobenzaldehyde

[0060]

[0061] Add 2,6-difluorobenzaldehyde (4.00g, 28.2mmol), N-Boc piperazine (4.98g, 26.8mmol), potassium carbonate (4.44g, 32.2mmol) and 60mL DMF into a 100mL three-necked flask. The system was heated to 80°C for 15 hours. Stop the reaction, cool to room temperature, pour the reaction solution into 200mL water, extract three times with ethyl acetate (80mL×3), combine the organic phases, wash once with 60mL water, 60mL saturated NaCl solution, and dry over anhydrous sodium sulfate. After filtration and concentration, the crude product was obtained, which was purified by column chromatography (developer polarity: petroleum ether / ethyl acetate=20 / 1) to obtain 5.81 g of a yellow solid with a yield of 70% and a purity of 98%.

[0062] Product NMR data: 1 HNMR (400MHz, CDCl 3 )δ10.32(s,1H),7.47(td,J=8.3,6.4Hz,1H),6.87–6.73(m,2H),3.75–3.56(m,4H),3.12–2.96(m,4H) ,1.49(s,9H).

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Abstract

The invention relates to a preparation method of a Brexpiprazole intermediate and a novel Brexpiprazole intermediate. Raw materials required in the preparation method are low in price and easy to get, and the method is simple in reaction steps and operation. A palladium-catalyzed coupling reaction is not required; the preparation cost is greatly reduced; and heavy metal pollution is avoided. Besides, the intermediate can be obtained just through simple post-treatment, and an overall reaction yield can reach a relatively ideal level.

Description

technical field [0001] The invention belongs to the technical field of preparation of Brexpiprazole intermediates, in particular to a preparation method of 4-(1-piperazinyl)benzo[b]thiophene and novel Brexpiprazole intermediates. Background technique [0002] The incidence of mental diseases such as depression and schizophrenia is getting higher and higher, seriously affecting people's physical and mental health. Brexpiprazole, a psychotropic drug jointly developed by Lundbeck Pharmaceuticals of Denmark and Otsuka Pharmaceuticals of Japan, is an experimental serotonin-dopamine activity modulator (SDAM), which can act on dopamine D2 and 5-HT2A receptors. The drug can be used as an adjuvant treatment for schizophrenia and severe depression. It has shown good therapeutic effect and tolerance in Phase III clinical studies, and has a good application prospect. [0003] The chemical name of Brexpiprazole is 7-(4-(4-(benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy)-1H-quinolin-2-one. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/70C07D333/54
CPCY02P20/55
Inventor 王鹏李丕旭刘远华程文杜强强
Owner SUZHOU PENGXU PHARM TECH CO LTD
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