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Improved synthesis and isolation of Aripiprazole crystal Disclosure Number: IPCOM000185659D
Publication Date: 2009-Jul-30
Document File: 2 page(s) / 57K

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7- hydroxy -3,4-dihydro -2(1H)-quinolinone reacts with 1,4- dibromobutane in presence of potassium carbonate water or PTC with base to forms crude 7-(4-bromobutoxy )-3,4-dihydro-2(1H) quinolinone , which upon purification by treatment of silica gel: charcoal mixture in methylene dichloride, gives pure 7-(4-bromobutoxy)-3,4-dihydro -2(1H)-quinolinone. which, on reaction with 1-(2, 3-dichlorophenyl) piperazine hydrochloride in presence of triethylamine and sodium iodide in acetonitrile at reflux temperature, gives crude Aripiprazole, which on recrystalization by ethanol followed by treatment with cyclohexane at desired temperature gives a pure aripiprazole crystalline form.

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Aripiprazole is synthesized with anhydrate crystalline form according to the following depicted scheme-I:

The synthesis may involve reaction of 7-hydroxy-3, 4-dihydro-2 (1H)-quinolinone (II) with 1, 4-dibromobutane (III), in water using potassium carbonate as base at reflux temperature.  The product may then be isolated by extraction of reaction mixture with methylene chloride or by hexane and cooled to 10 ºC to yield product (IV).  The isolated product (IV) may then be purified by charcoal:silica gel in methylene dichloride  at -5 to 10 ºC to yield pure 7-(4-bromobutoxy)-3, 4-dihydro-2 (1H)-quinolinone (IV).  Further, 7-(4-bromobutoxy)-3, 4-dihydro-2 (1H)-quinolinone (IV) may be recrystallized from ethanol and hexane and condensed with 1-(2, 3-dichlorophenyl) piperazine (V), optionally as the hydrochloride salt in acetonitrile using sodium iodide as catalyst and triethylamine as base to obtain crude Aripiprazole.  The crude Aripiprazole may be further taken in water with pH 8-9 by liq. Ammonia and the reaction mass stirred at 50-55oC for 30 minutes and extracted by methylene chloride. Methylene chloride layer is concentrated to get the solid of aripiprazole followed by double recrystallization from ethanol to form pure Aripiprazole.  Further, pure aripiprazole (wet solid, purified in alcohol) may be taken in 5-15 parts of cyclohexane, heated to reflux temperature for 5-15 minutes followed by distillation of 1-10 parts of cyclohexane at atmospheric pressure.  The react...