(3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindol-2,1'-piperazin]-2-ium methanesulfonate (Intermediate 4, 28.8 kg, 66.2 mol) and (3aR,4S,7R,7aS)-rel-hexahydro-1H-4,7-bridged methylidene isoindole-1,3(2H)-dione (Intermediate 5. 12.0 kg, 72.8 mol) as raw material and potassium carbonate (11.0 kg, 79.7 mol) as base were suspended in toluene (270 L). The resulting suspension was heated and refluxed at 105 °C for 15 h. The reaction process was monitored by UPLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature and quenched by the addition of water (90 L). The organic and aqueous phases were separated and the organic phase was concentrated to a smaller volume. Subsequently, the concentrated organic phase was treated with hydrochloric acid in isopropanol to afford the target product (3aR,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 hydrochloride ( Lurasidone hydrochloride, 34.4 kg, yield 98.3%, HPLC purity 99.49%).
![(3aR,7aR)-4'-(1,2-Benzisothiazol-3-yl)octahydrospiro[2H-isoindole-2,1'-piperaziniuM] Methanesulfonate](/CAS/20180906/GIF/186204-37-5.gif)
