Processes for making alkylated arylpiperazine and alkylated arylpiperidine compounds including novel intermediates
View Patent ↗Novel processes, and intermediates, for making alkylated arylpiperazine and alkylated arylpiperidine compounds of the general formulas (I) and (VII), respectively wherein, R 1 and R 2 are individually selected from hydrogen, alkyl, substituted or alkyl; n=0, 1, or 2; Y=NR 3 R 4 , OR 5 , or SR 5 , where R 3 and R 4 are individually selected from acyl or sulfonyl, and where R 5 is aryl or heteroaryl, or heterocyclic; and Ar is an aryl, heteroaryl, or heterocyclic compound.
1. A process for preparing lurasidone comprising the steps of:
(i) alkylating (3aR,4S,7R,7aS)-hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione by reacting it with (5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine-3,3-dioxide in the presence of K 2 CO 3 to form potassium ((1R,2R)-2-(((3aR,4S,7R,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol -2-yl)methyl)cyclohexyl)methyl sulfate;
(ii) hydrolyzing potassium ((1R,2R)-2-(((3 aR,4S,7R,7 aS)-1,3 -dioxooctahydro-2H-4,7-methanoisoindol -2-yl)methyl)cyclohexyl)methyl sulfate to form (3aR,4S,7R,7aS)-2-(((1R,2R)-2-(hydroxymethyl) cyclohexyl)methyl) hexahydro-1H-4,7-methanoisoindole-1,3 (2H)-dione;
(iii) reacting (3aR,4S,7R,7aS)-2-(((1R,2R)-2-(hydroxymethyl)cyclohexyl)methyl) hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione with methanesulfonyl chloride to form ((1R,2R)-2-(((3 aR,4S,7R,7aS)-1,3-dioxooctahydro-2H-4,7-methanoisoindol-2-yl) methyl)cyclohexyl)methyl methanesulfonate; and
(iv) reacting 3-(piperazin-l-yl)benzo[d]isothiazole with ((1R,2R)-2-(((3aR,4S,7R,7aS)- 1,3-dioxooctahydro-2H-4,7-methanoisoindol-2-yl)methyl)cyclohexyl)methyl methanesulfonate to form (3 aR,4S,7R,7aS)-2(((1R,2R)-2-((4-(benzo[d]isothiazol-3-yl)piperazin-1- yl) methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione (Lurasidone).