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Process for preparing aripiprazole

一种阿立哌唑、哌嗪的技术，应用在制备阿立哌唑领域，能够解决DMF回收困难等问题

Inactive Publication Date: 2007-02-14
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

DMF recovery is also very difficult

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: the preparation of crude aripiprazole

[0028] BBQ (10 Kg), DCP-HCl (9.85 Kg) and potassium carbonate (9.3 Kg) were mixed with acetonitrile (80 L) in a jacketed reactor equipped with a mechanical stirrer and reflux condenser to form a reaction mixture. The reaction mixture was heated to reflux for two hours until the reaction was complete (less than 2% BBQ in the reaction mixture when measured by HPLC). 50 L of acetonitrile was distilled off from the reaction mixture and the reaction was cooled to 70°C. 50 L of water was added to the reaction mixture and the reaction mixture was stirred for half an hour. The reaction mixture was cooled to 40°C and stirred overnight at this temperature. A precipitate formed and was collected by filtration, washed with water. 50 L of water was added to the washed precipitate and stirred for half an hour. The precipitate was collected again by filtration and washed with water. 18 Kg of wet crude aripiprazole was obtained...

Embodiment 2

[0029] Embodiment 2: the preparation of crude aripiprazole

[0030] BBQ (1 Kg), DCP-HCl (986 g) and potassium carbonate (927 g) were mixed with acetonitrile (6 L) in a jacketed reactor equipped with a mechanical stirrer and reflux condenser to form a reaction mixture. The reaction mixture was heated to reflux for three hours until the reaction was complete (less than 1% BBQ in the reaction mixture when measured by HPLC). 3 L of acetonitrile was distilled off from the reaction mixture and the reaction was cooled to 70°C. 5 L of water was added to the reaction mixture and the reaction mixture was stirred for half an hour. The reaction mixture was cooled to 40°C and stirred overnight at this temperature. A precipitate formed and was collected by filtration, washed with water. 3.5 L of water was added to the washed precipitate and stirred for half an hour. The precipitate was collected again by filtration and washed with water. 1.8 Kg of wet crude aripiprazole was obtained (9...

Embodiment 3

[0031] Example 3: Preparation of Aripiprazole Using Sodium Lauryl Sulfate as Phase Transfer Catalyst

[0032] 7-(4-bromobutoxy)-3,4-dihydroquinolone (BBQ) (4g, 13.88mmol, 1 equivalent), 1-(2,3-dichlorophenyl)piperazine hydrochloride ( DCP) (3.95g, 17.17mmol, 1.2 equiv), Na 2 CO 3 (2.65g, 25mmol, 1.8eq), dodecyl sulfate, sodium salt (0.7g, 2.4mmol, 0.17eq) was suspended in acetonitrile (40ml). The mixture was heated to reflux for 4 hours. The volume of the suspension was reduced to about a quarter of said volume, poured into 70 ml of water and stirred for 15 minutes. The white precipitate formed was filtered and washed twice with water (50ml). Crude aripiprazole (6.4 g, 90% yield) was obtained.

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PUM

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Abstract

The invention includes the synthesis of aripiprazole from BBQ and DCP, and comprises mixing 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (BBQ) and 1-(2,3-dichlorophenyl)piperazine hydrochloride (DCP) in the presence of at least one base and at least one organic solvent to form a reaction mixture; heating the reaction mixture for a sufficient amount of time to effect the reaction; and isolating aripiprazole. The invention also includes the use of phase transfer catalysts in synthesizing aripiprazole from BBQ and DCP.

Description

[0001] Relevant US filing data [0002] This application claims the benefit of US Provisional Application No. [Attorney Docket No. 1662 / 78203] filed January 18, 2005 and US Provisional Application No. 60 / 542412 filed February 5, 2004. field of invention [0003] The present invention relates to the preparation of arginine using intermediates BBQ (7-(4-bromobutoxy)-3,4-dihydroquinolone) and DCP (1-(2,3-dichlorophenyl)piperazine hydrochloride) Ripiprazole (aripiprazole) method. The method of preparing aripiprazole may include the use of a phase transfer catalyst. Background of the invention [0004] Schizophrenia is the most common type of neurological disease caused by excessive neurotransmission activity of the dopaminergic nervous system in the central nervous system. Several drugs have been developed that have the activity of blocking neurotransmission from dopaminergic receptors in the central nervous system. F...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22A61K31/4706C07D215/227
CPCC07D215/22C07D215/227A61P25/18
Inventor B·-Z·多利茨基O·莱尔曼
Owner TEVA PHARMA IND LTD
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