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Method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone

A technology of piperazinyl and quinolinone, which is applied in the field of preparation of quinolinone derivatives, can solve the problems of high production cost, high price, and difficult purchase, and achieve the effect of simple process and easy-to-obtain raw materials

Inactive Publication Date: 2015-03-25
REYOUNG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The shortcoming of this route is that starting raw material 7-hydroxyl-2 (1H) quinolinone price is higher and is not easy to purchase, causes production cost height, has limited its suitability for industrialized production

Method used

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  • Method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone
  • Method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone
  • Method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] (1) Add acetone (50mL) into the three-necked flask, start stirring, add 1,4-dibromobutane (10.8mL, 0.09mol), potassium carbonate (4.2g, 0.03mol) in sequence, and then add 7- Hydroxy-3,4-dihydro-2(1H)-quinolinone (II) (2.5g, 0.015mol), heated to reflux. After the reaction, the acetone was distilled off first, washed twice with cyclohexane (25 mL×2), filtered with suction, and the filter cake was rinsed with cyclohexane. The resulting crude product was recrystallized with a mixture of n-hexane and ethyl acetate at a volume ratio of 2:1 to obtain the product 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinoline Ketone (Ⅲ) 3.8g, yield 85%.

[0027] (2) Add acetonitrile (60mL) into the three-necked flask, start stirring, and add 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (Ⅲ) (3.4g, 0.011mol), potassium iodide (3.3g, 0.022mol), cesium carbonate (7.1g, 0.022mol), heated to reflux for 30min, added 4-(1-piperazinyl)benzo[b]thiophene hydrochloride (Ⅳ)( 3.1g, 0.012mol), reflux rea...

Embodiment 2

[0030] (1) Add acetone (500mL) into the three-necked flask, start stirring, add 1,4-dibromobutane (162mL, 1.35mol), potassium carbonate (41.4g, 0.3mol) in sequence, and then add 7-hydroxyl -3,4-Dihydro-2(1H)-quinolinone (II) (24.5g, 0.15mol), heated to reflux for 30h. After the reaction was completed, the acetone was distilled off first, washed with water and cyclohexane twice (250 mL×2), filtered with suction, and the filter cake was rinsed with cyclohexane. The resulting crude product was recrystallized with a mixture of petroleum ether and ethyl acetate at a volume ratio of 2:1 to obtain the product 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinoline Ketone (Ⅲ) 36.2 g, yield 81%.

[0031] (2) Add acetonitrile (600mL) into the three-necked flask, start stirring, and add 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (Ⅲ) (30g, 0.1 mol), sodium iodide (30g, 0.2mol), potassium carbonate (27.6g, 0.2mol), heated to reflux for 30min, added 4-(1-piperazinyl)benzo[b]thiophene hydrochlo...

Embodiment 3

[0034](1) Add acetone (7.5L) into a 20L reactor, start stirring, add 1,4-dibromobutane (3.24L, 27mol), potassium carbonate (621g, 4.5mol) in sequence, and then add 7- Hydroxy-3,4-dihydro-2(1H)-quinolinone (II) (367.5g, 2.25mol), heated to 65°C for 30h. After the reaction, the acetone was distilled off first, then water was added to wash, and cyclohexane was washed twice (3L×2), and the filter cake was rinsed with cyclohexane. The resulting crude product was recrystallized with a mixture of cyclohexane and ethyl acetate at a volume ratio of 2:1 to obtain the product 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinone Phenone (Ⅲ) 556.5 g, yield 83%.

[0035] (2) Add acetonitrile (10L) into the 20L reactor, start stirring, add 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (Ⅲ) (536g, 1.8mol), sodium iodide (540g, 3.6mol), sodium carbonate (381.6g, 3.6mol), heated to reflux for 30min, and added 4-(1-piperazinyl)benzo[b]thiophene hydrochloride (Ⅳ) (685g, 2.7mol), reflux reaction for 4h...

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Abstract

The invention relates to a method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone, and belongs to the technical field of preparation of quinolinone derivatives. The method comprises the following steps: reacting 7-hydroxy-3,4-dihydro-2(1H)-quinolinone serving as an initial raw material with 1,4-dibromobutane to generate a compound III; reacting the compound III with 4-(1-piperazinyl) benzo[b]thienyl or hydrochloride thereof in an alkaline environment to generate a compound V; reacting the compound V with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a solvent, extracting and drying the reacting product to prepare a crude product of a target product, and recrystallizing the crude product to obtain a competitive product 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone. The method has the advantages of easily available raw materials, simple process, economy and environment friendliness, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone, which belongs to quinolinone The technical field of preparation of derivatives. Background technique [0002] 7-(4-(4-(Benzo[b]thienyl)-1-piperazinyl)butoxy)-2(1H)-quinolinone is the first dopamine, partial 5-HT 1A Agonists and 5-HT 2A Receptor antagonist compounds with broad activity across multiple monoamine systems for dopamine D 2 Receptor partial agonist activity decreased, and specific 5-HT receptors (such as 5-HT 1A , 5-HT 2A , 5-HT 7 ) has improved affinity, has better curative effect and tolerance, and can reduce adverse reactions such as akathisia, restlessness and / or insomnia in patients. At present, this product is in phase III clinical research for the treatment of schizophrenia and the adjuvant treatment of severe depression. In addition, the compound is also in phase II clinical research for attention deficit hypera...

Claims

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Application Information

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IPC IPC(8): C07D409/12
CPCC07D409/12
Inventor 胡清文李乐祥曹燕
Owner REYOUNG PHARMA
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