Patent DE-102005048695-A1 (DE)
Title: Preparation of aripiprazole useful to prepare 7-(4-halobutoxy)-3,4-dihydro-(1H)-quinolinone comprises reacting 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with 1,4-disubstuted-butane followed by reacting with 1-(2,3-dichlorophenyl)piperazine
Inventor: NADDAKA VLADIMIR
IPC: C07D215/20
Filed: 2005-10-11
Abstract: Preparation of aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) (I) and their salts comprises: reacting 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with a 1,4-disubstuted-butane in the presence of a base or in a water-immiscible organic solvent; and reacting 7-(4-halobutoxy)-3,4-dihydro-(1H)-quinolinone and 1-(2,3-dichlorophenyl)piperazine in the presence of a water-soluble base. Preparation of aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) (I) and their salts comprises: reacting 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (7-HQ) with a 1,4-disubstuted-butane (A) in a single-phase solvent in the presence of a base or in a water-immiscible organic solvent and optionally with addition of water to form an heterogeneous biphasic reaction mixture, in the presence of a water-soluble base and optionally a tetra alkyl ammonium phase transfer catalyst and a reaction promoter, for a period of time to completely convert 7-HQ to a 7-(4-halobutoxy)-3,4-dihydro-(1H)-quinolinone (7-HBQ); and reacting a 7-HBQ and 1-(2,3-dichlorophenyl)piperazine (B) or their acid addition preferably in a biphasic reaction mixture that comprises water and a water-immiscible solvent, in the presence of a water-soluble base and optionally also a phase transfer catalyst and a reaction promoter. Independent claims are also included for: (1) preparation of 7-HBQ, comprising: reacting 7-HQ and (A) in an heterogeneous biphasic reaction mixture containing water, isolating the 7-HBQ from the reaction mixture, optionally purifying the obtained 7-HBQ by precipitation from a suitable organic solvent, and optionally further purifying the obtained 7-HBQ by slurrying the 7-HBQ in an organic solvent and isolating the purified 7-HBQ; (2) a method of purifying 7-(4-chlorobutoxy)-3,4-dihydro-(1H)-quinolinone (7-CBQ) by re-crystallizing from an organic solvent comprising: dissolving 7-CBQ in a suitable organic solvent optionally at elevated temperature to obtain a solution of 7-CBQ in the suitable solvent, and isolating the crystals, optionally upon cooling; (3) a process of producing a purified (I) comprising: providing a crude (I) obtained by reacting 7-HBQ and (B), where the 7-HBQ containing at least 10% of the impurity l,4-bis[3,4-dihydro-2(1H)-quinolinone-7-oxy] butane (BQB), partially purifying the crude (I) with a first solvent, isolating the thus obtained partially purified (I), slurrying the partially purified (I) in a second solvent and re-slurrying in a third solvent, and isolating the thus obtained purified (I); and (4) a process for preparing BQB having a purity of at least 98%, preferably of 99.5%, comprising: reacting 7-HQ and a 1,4-dibromobutane in an organic solvent in the presence of a base, isolating the BQB from the reaction mixture by precipitation, and purifying the product.