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Preparation method of aripiprazole intermediate 1-(2,3-dichlorophenyl)piperazine hydrochloride

A technology of aripiprazole and dichlorophenyl is applied in the field of preparation of aripiprazole intermediate 1-piperazine hydrochloride, and can solve the problems of unsuitability for large-scale production, long reaction time, low yield and the like , to achieve the effect of low cost, simple operation and less waste liquid

Active Publication Date: 2017-08-04
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In Chinese patent CN102807536A, 2,3-dichloroaniline and bis(2-chloroethyl)amine hydrochloride are prepared by cyclization reaction in different solvents; the raw materials of this method are economical and easy to obtain, but the reaction time is long and the yield is low. Low, produces a large amount of acid waste gas and waste liquid, not suitable for large-scale production

Method used

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  • Preparation method of aripiprazole intermediate 1-(2,3-dichlorophenyl)piperazine hydrochloride
  • Preparation method of aripiprazole intermediate 1-(2,3-dichlorophenyl)piperazine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0019] In a 500ml reaction bottle, add 10g 2,3 dichloronitrobenzene, 9.3g bis(2-chloroethyl)amine hydrochloride, add 100ml diethylene glycol ether, 8.7g iron powder, 14.0g ammonium chloride , 125ml purified water, 0.90g potassium iodide, 1.68g tetrabutylammonium bromide, heat up to 130°C, keep warm for 20h, stop heating, cool down to room temperature and filter with suction, add 100ml of acetone to the mother liquor and stir for 1.5h, crystallize, and filter with suction to obtain The crude product was dried to obtain 9.47g of solid, purity (HPLC): 99.0%, yield 68.0%; ESI (m / z): 266.01.

Embodiment 2

[0021] In a 500ml reaction flask, add 10g 2,3 dichloronitrobenzene, 9.8g bis(2-chloroethyl)amine hydrochloride, add 100ml diethylene glycol ether, 10.5g iron powder, 14.0g ammonium chloride , 125ml of purified water, 1.0g of potassium iodide, 1.92g of tetrabutylammonium bromide, heat up to 130°C, keep warm for 20h, stop heating, cool down to room temperature and filter with suction, add 100ml of acetone to the mother liquor and stir for 1.5h, crystallize, and filter with suction to obtain The crude product was dried to obtain 9.52 g of solid, purity (HPLC): 99.2%, yield 68.3%; ESI (m / z): 266.01.

Embodiment 3

[0023] In a 500ml reaction bottle, add 10g 2,3 dichloronitrobenzene, 10.2g bis(2-chloroethyl)amine hydrochloride, add 100ml diethylene glycol ether, 12.0g iron powder, 14.0g ammonium chloride , 125ml purified water, 1.10g potassium iodide, 2.14g tetrabutylammonium bromide, heat up to 130°C, keep warm for 20h, stop heating, cool down to room temperature and filter with suction, add 100ml of acetone to the mother liquor and stir for 1.5h, crystallize, and filter with suction to obtain The crude product was dried to obtain a solid 9.67g, purity (HPLC): 99.4%, yield 69.4%; ESI (m / z): 266.01.

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Abstract

The invention discloses a preparation method of an aripiprazole intermediate 1-(2,3-dichlorophenyl)piperazine hydrochloride. The preparation comprises the step of reacting by taking 2,3-dichloronitrobenzene and bis(2-chloroethyl)amine hydrochloride as starting materials and utilizing a one-pot method. The method is simple in operation, and acidic hydrogen chloride generated in the reaction process is dissolved into an ammonium chloride solution to participate in reduction of nitryl, so that the cost is saved, and energy conservation and environment protection are achieved; and furthermore, the method is simple in operation, high in cost, relatively low in cost and suitable for industrial production.

Description

Technical field [0001] The invention belongs to the field of medical technology, and more specifically relates to a preparation method of aripiprazole intermediate 1-(2,3-dichlorophenyl)piperazine hydrochloride. Background technique [0002] Aripiprazole Tablets, chemical name is: 7-{4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy}-3,4-dihydro- 2(1H)-Quinolinone, molecular formula: C 23 H 27 N 3 O 2 Cl 2 ;Molecular weight: 448, structural formula is as follows: [0003] [0004] Aripiprazole is a quinolinone derivative invented by Otsuka Corporation of Japan and later jointly developed with Bristol-Myers Squibb Company of the United States for the treatment of atypical psychosis in schizophrenia; it was approved in November 2002. Marketed in the United States, this product is used to treat schizophrenia. It is a dihydroquinolinone antipsychotic. It is different from other antipsychotics in terms of chemical structure and pharmacological mechanism of action. It is th...

Claims

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Application Information

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IPC IPC(8): C07D295/073
CPCC07D295/073
Inventor 高大龙杨庆坤吴柯周学文杨波勇江海平吴兆申
Owner 山东安信制药有限公司
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