New method for preparing 4-(1-piperazinyl)benzo[b]thiophene

A technology of protecting groups and leaving groups, which is applied in the field of medicinal chemistry, can solve problems such as difficult to completely remove by-products, increase reaction costs, and difficult to separate by-products, so as to reduce environmental pressure and post-processing difficulty, and reduce by-products. The formation of products, the effect of facilitating refining and purification

Inactive Publication Date: 2015-04-22
HANGZHOU XINBOSI BIOMEDICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

On the one hand, because the palladium catalyst is expensive, the reaction cost is greatly increased; on the other hand, the palladium catalyst is easily deactivated, resulting in relatively high requirements for the reaction, which increases the difficulty of the reaction; and, as a heavy metal, palladium is harmful to the environment, In particular, the pollution of water bodies is relatively serious, and it is also toxic to the human body, making it difficult to treat the three wastes.
At the same time, ligands are inevitably used in the process of using palladium catalysts, such as (R)-(+)2,2'-bis(diphenylphosphino)-1,1'-biphenyl (BINAP) , tri-tert-butyltetraphenylphosphonium borate, and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos), and these ligands are relatively A large amount of by-products that are difficult to separate will be produced. Although column purification is performed to increase the purity of compound (2a) in Patent Document 1, it is very difficult to completely remove by-products even through column chromatography purification, resulting in compound (2a) Purity is thus inevitably reduced

Method used

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Embodiment 1

[0034] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene hydrochloride

[0035] A mixture of 2.00g 4-bromobenzo[b]thiophene, 3.23g piperazine, 4.21g potassium tert-butoxide and 10ml xylene was stirred in a nitrogen atmosphere, and reacted at 120-130°C for 30 hours (TLC monitored the end of the reaction). After the reaction solution is cooled, add 40ml of saturated saline and 20ml of xylene, separate layers, take the xylene layer, wash it once again with saturated saline, and slowly add 1ml of concentrated hydrochloric acid dropwise to the system for 3 minutes or longer. The pH is 3-4. Filter and dry under reduced pressure at 60°C to obtain 0.53 g of off-white powder. The crude product was further subjected to silica gel column chromatography to obtain 4-(1-piperazinyl)benzo[b]thiophene hydrochloride with a purity of 98.8%.

[0036] 1 H-NMR (DMSO-d 6 ) δppm:

[0037] 3.30(8H, s), 6.96(1H, d, J=7.6Hz), 7.30(1H, t, J=7.8Hz), 7.52(1H, d, J=5.5Hz), 7.69(1H, d, J=5.5Hz) =8.0...

Embodiment 2

[0039] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene hydrochloride

[0040] A mixture of 2.13g of 4-bromobenzo[b]thiophene, 4.3g of piperazine, 24g of sodium hydride and 10ml of xylene was reacted at 120°C for 14 hours in a nitrogen atmosphere (monitored by TLC at the end of the reaction). Add 30ml of ethanol dropwise to the reaction solution to quench excess sodium hydride in an ice-water bath, distill off excess ethanol under reduced pressure, add 20ml of xylene and 50ml of saturated saline and stir at 60°C for 0.5 hours, then separate layers, and the xylene layer is again After washing once with saturated brine, drop it into a container containing 10 ml of methanol and 1 ml of concentrated hydrochloric acid. After the dropwise addition, continue stirring for 1 hour in an ice-water bath, filter, and dry the solid under reduced pressure to obtain 0.74 g of off-white powder. The crude product was further subjected to silica gel column chromatography to obtain 4-(1-pip...

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Abstract

The invention relates to a new preparation method of 4-(1-piperazinyl)benzo[b]thiophene compound shown by a formula (2) or salt thereof, wherein R1 is a hydrogen atom or a protecting group. The method is realized in a way that the compound expressed by a formula (3) in which X1 is a leaving group reacts with the compound expressed by a formula (4) in which R1 is defined above or salt thereof to generate the compound expressed by the formula (2) or salt thereof in an inert solvent and under the effect of a certain amount of alkaline compounds. The method provided by the invention is safer and more environment-friendly since the use of usually adopted expensive palladium catalyst and complex is avoided.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new method for preparing 4-(1-piperazinyl)benzo[b]thiophene compound or a salt thereof. Background technique [0002] brexpiprazole (compound represented by formula (1), chemical name 7-(4-(4-(benzo[b]thiophen-4-yl-piperazin-1-yl)butyl) jointly developed by Lundbeck Pharmaceutical and Otsuka Pharmaceutical Oxy)-1H-quinolin-2-one,) is a serotonin-dopamine activity modulator (SDAM) for the adjunctive treatment of schizophrenia and major depressive disorder. July 14, 2014, Dan Ling Bei Pharmaceutical announced that Japan's Otsuka Pharmaceutical has submitted a new drug application (NDA) for brexpiprazole to the US Food and Drug Administration (FDA). In terms of schizophrenia, brexpiprazole has comparable efficacy to aripiprazole, but in improving negative symptoms and cognitive function and depression.Brexpiprazole has a unique pharmacological targeting, compared with tradition...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/54
CPCY02P20/55C07D333/54
Inventor 杜焕达叶鑫杰罗瑾丁建圣王万青刘艳华
Owner HANGZHOU XINBOSI BIOMEDICAL CO LTD
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