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Preparation method of benzothiophene compound intermediate

A technology of compound and thiophene, which is applied in the field of preparation of benzothiophene compound intermediates, can solve the problems of high industrialization cost, unfriendly environment, harsh reaction conditions, etc., and achieve the effects of simple operation, low cost and low environmental pollution

Inactive Publication Date: 2019-03-05
SHANGHAI SHYNDEC PHARMA CO LTD
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Problems solved by technology

[0017] The purpose of the present invention is to provide a new ebiprazole intermediate in order to overcome the problems of expensive process raw materials, high industrialization costs, harsh reaction conditions, and unfriendly environment in the preparation of ebiprazole intermediates in the prior art. The preparation method of the body, the preparation method is low in cost and price, less environmental pollution, easy to operate, and can be applied to industrialized industries

Method used

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  • Preparation method of benzothiophene compound intermediate
  • Preparation method of benzothiophene compound intermediate
  • Preparation method of benzothiophene compound intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Add 5g 4-bromobenzo[b]thiophene (23.5mmol, 1.0eq), 6g anhydrous piperazine (70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V) into a 100ml three-necked flask , 2.7g L-proline (23mmol, 1.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq). Under the protection of N2, keep warm at 110°C and stir for 10h, drop in 75ml of water, filter out the solid, extract the mother liquor once with 200ml of dichloromethane, concentrate to dryness under reduced pressure, add 75ml of toluene, add about 3ml of concentrated hydrochloric acid dropwise at 0-10°C, A white solid precipitated, stirred at 0-10°C for 1 h, filtered out the solid, and dried at 45°C to obtain 4.8 g of off-white solid with a yield of 80.54%.

[0034] 1H-NMR (DMSO-d6, 400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H,m),7.42~7.38(1H,t,J=16Hz),7.06~7.01(1H,d,J=8Hz),3.44(4H,s),3.39( 4H,s).MS / ES: m / z:219.09[M+H]+

Embodiment 2

[0036] Add 5g 4-bromobenzo[b]thiophene (23.5mmol, 1.0eq), 6g anhydrous piperazine (70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V) into a 100ml three-necked flask , 0.27g L-proline (2.3mmol, 0.1eq), 3.2g K2CO3 (23.5mmol, 1.0eq), under N2 protection, keep warm at 110°C and stir for 10h, drop into 75ml of water, filter out the solid, and use 200ml of dichloromethane for the mother liquor Methane was extracted once, 3ml of concentrated hydrochloric acid was added dropwise at 0-10°C, a white solid was precipitated in the system, and 3.0g of off-white solid was obtained by column chromatography, with a yield of 50.34%.

[0037] 1H-NMR (DMSO-d6, 400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H,m),7.42~7.38(1H,t,J=16Hz),7.06~7.01(1H,d,J=8Hz),3.44(4H,s),3.39( 4H,s).MS / ES: m / z:219.09[M+H]+

Embodiment 3

[0039] Add 5g 4-bromobenzo[b]thiophene (23.5mmol, 1.0eq), 6g anhydrous piperazine (70mmol, 3.0eq), 0.45g CuI (2.3mmol, 0.1eq), 25mlDMF (5V) into a 100ml three-necked flask , 27g L-proline (230mmol, 10.0eq), 3.2g K2CO3 (23.5mmol, 1.0eq), under N2 protection, keep warm at 110°C and stir for 10h, drop into 75ml of water, filter out the solid, and extract the mother liquor with 200ml of dichloromethane Once, concentrate to dryness under reduced pressure, add 75ml of toluene, add about 3ml of concentrated hydrochloric acid dropwise at 0-10°C, a white solid precipitates in the system, stir at 0-10°C for 1h, filter out the solid, and dry at 45°C to obtain 3.5g of off-white solid , yield 58.73%.

[0040]1H-NMR (DMSO-d6, 400MHz): 9.54 (2H, s), 7.85~7.83 (1H, d, J=8.0Hz), 7.79~7.77 (1H, d, J=8.0Hz), 7.62~7.61 (1H,m),7.42~7.38(1H,t,J=16Hz),7.06~7.01(1H,d,J=8Hz),3.44(4H,s),3.39( 4H,s).MS / ES: m / z:219.09[M+H]+

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Abstract

The invention provides a preparation method of a novel brexpiprazole intermediate. The method is as below: in the presence of a cuprous catalyst and a ligand, carrying out a coupling reaction on witha compound 4-halobenzo[b]thiophene and N-protecting piperazine through alkali. Compared with the prior art, the method replaces precious metal palladium with cheap copper iodide under the suitable ligand, and obtains the brexpiprazole intermediate compound with high conversion rate; and the method has the advantages of safer and more convenient reaction, low cost, less environmental pollution andeasy operation, and can be applied to industrialized production.

Description

technical field [0001] The invention relates to a preparation method of a benzothiophene compound intermediate. Background technique [0002] Brexpiprazole (Brexpiprazole) is a dopamine D2 and 5-HT jointly developed by Otsuka Pharmaceutical of Japan and Lundbeck of Denmark 2A Receptor modulator, chemical name is 7-(4-(4-(benzo[B]thiophen-4-yl-piperazin-1-yl)butoxy)-1H-quinolin-2-one, this The product is used 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] Patents CN101155804B, CN101155804A, and CN105461703A report that the chemical name of Brexpiprazole (Brexpiprazole) is 7-(4-(4-(benzo[B]thiophen-4-yl-piperazin-1-yl)butoxy)- 1H-quinolin-2-one is obtained through the coupling and condensation of the key intermediate 4-(1-piperazinyl)benzo[b]thiophene. The structural formula is as follows: [0004] [0005] Among them, compound 1 is used as a key intermediate, and there...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/54
CPCC07D333/54
Inventor 占轶鹏张旭李春刚李卉李倩
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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