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Quinolinenone kind derivative and its accetable salt, its preparation method, application in preparation of alipyrazole and preparation of alipyrazole

A technology of piperazine and compounds, which is applied in the field of preparation of aripiprazole, can solve the problems of high reaction temperature, difficult post-processing, and reduced total yield, and achieve the effects of mild reaction conditions, easy quality control, and few by-products

Inactive Publication Date: 2006-01-11
重庆凯林制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The quality of the finished product is difficult to guarantee. To obtain aripiprazole with "pharmaceutical grade" purity, the obtained crude product needs to be refined many times
Although the total yield of aripiprazole crude product obtained by this synthetic route can reach 50%, after multiple refining methods are used to obtain "pharmaceutical grade" aripiprazole, the total yield will be greatly reduced, and the industrial production of the product Increased costs
[0007] The other four methods for preparing aripiprazole described in the claims of the EP367141 patent are more unfavorable for the industrialization of the product because of the preparation of the piperazine ring; because the reaction temperature is higher than 220 °C during the preparation of the piperazine ring. ℃, and has the characteristics of many side reactions, difficult post-processing, and extremely low yield.

Method used

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  • Quinolinenone kind derivative and its accetable salt, its preparation method, application in preparation of alipyrazole and preparation of alipyrazole
  • Quinolinenone kind derivative and its accetable salt, its preparation method, application in preparation of alipyrazole and preparation of alipyrazole
  • Quinolinenone kind derivative and its accetable salt, its preparation method, application in preparation of alipyrazole and preparation of alipyrazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Preparation of 7-(4-bromo-2-butenyloxy)-3,4-dihydro-2(1H)-quinolinone (D)

[0057] 5g (30mmol) 7-hydroxyl-3,4-dihydro-quinolin-2-one, 7.9g (37mmol) 1,4-dibromo-2-butene, 6.3g (45mmol) were successively dropped into a 1000ml three-necked flask Potassium hydroxide, 80ml of acetonitrile, stirred and reacted at 50°C for 3 hours. After the reaction, filter with suction, filter and wash, recover part of the organic solvent under reduced pressure, add 20ml of dichloromethane, 10ml of distilled water, separate the organic layer, and use 10ml of distilled water for the aqueous layer Chloromethane was extracted three times, the organic layers were combined, washed with half-saturated saline until neutral, dried, suction filtered, and the organic solvent was recovered under reduced pressure, and 30ml of ethanol was added to the residual liquid, frozen, crystallized, and suction filtered to obtain the crude product, which was washed with ethanol Melt in heat, and obtain 6.2 g of wh...

Embodiment 2-6

[0072] Preparation of 7-hydroxy-3,4-dihydro-quinolin-2-one-1,4-dibromo-2-butene (D)

[0073] Dissolve 7-hydroxy-3,4-dihydro-quinolin-2-one (C), 1,4-dibromo-2-butene (F) in the following solvents, use corresponding acid removal agents respectively, and heat Insulation reaction, the reaction is completed, and the product (D) is obtained after post-treatment and recrystallization. See Table 1:

[0074] Example Solvent Deacidifier Temperature (°C) Time (h) Yield (%)

[0075] 2 Tetrahydrofuran Potassium hydroxide 60 4 61.5

[0076] 3 Ethanol Triethylamine 11 0 166

[0077] 4 n-butanol Sodium bicarbonate 50 6 44.3

[0078] 5 N,N-Dimethylformamide Sodium hydride 45 3.5 68

[0079] 6 Dimethyl sulfoxide Potassium carbonate 75 6 54.8

Embodiment 7-11

[0081] 7-[4-[4-(2,3-dichlorophenyl)-1-piperazine]-2-butenyloxy]-3,4-dihydro-2-(1H)-quinolinone ( A) Preparation

[0082] Starting materials 7-(4-bromo-2-butenyloxy)-3,4-dihydro-quinolin-2-one (D), 1-(2,3-dichlorophenyl)-piperazine ( E) Dissolve in the following solvents, respectively adopt corresponding acid removal agents, heat and keep warm for reaction, after the reaction is completed, the product (A) is obtained after aftertreatment and recrystallization. See Table 2:

[0083] Example Solvent Deacidifier Temperature (°C) Time (h) Yield (%)

[0084] 7 Dioxane Potassium hydroxide 120 8 72.3

[0085] 8 Toluene Triethylamine 110 12 70.8

[0086] 9 Isopropanol Potassium hydroxide 70 10 61.6

[0087] 10 N, N-dimethylformamide Potassium carbonate 120 6 73.5

[0088] 11 Dimethyl sulfoxide Sodium hydride 70 6 75.4

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Abstract

A 7-[4-[4-(2,3-dichlorophenyl)-1-piperazine]-2- butenoxy]-3,4-dihydro-2-(1H)-quinoline-2-one and its receptable salt, its preparing process featuring use of high-activity, 1,4-dibromo-2-butene to replace 1,4-bibromobutane, its application in preparing aripiperazole and the process for preparing aripiperazole are disclosed.

Description

technical field [0001] The present invention relates to a kind of 7-[4-[4-(2,3-dichlorophenyl)-1-piperazine]-2-butenyloxy]-3,4-dihydro-2(1H)- Quinolin-2-one and its acceptable salt, its preparation method and as preparation 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3 , Application of 4-dihydro-2 (1H)-quinolinone (aripiprazole) and a preparation method of aripiprazole. Background technique [0002] As we all know, aripiprazole is a quinolinone derivative, which was invented by Otsuka Corporation of Japan in 1988, and then jointly developed with Bristol-Myers Squibb Corporation of the United States. It was approved for marketing by the FDA in 2002. For the treatment of schizophrenia. [0003] Regarding the preparation of aripiprazole, five preparation methods described in the EP367141 patent are known. The specification of this patent describes one of the methods for preparing aripiprazole. The synthetic route is to use 7-hydroxy-3,4-dihydro-quinolin-2-one as raw m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/227
Inventor 李裕林诸葛明邓杰叶文润
Owner 重庆凯林制药有限公司