Reaction Steps
A mixture of 4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine (319 mg, 1.0 mmol) and 1,1-dioxido-2-(4-oxo-pentyl)-1,2-benzisothiazol-3-(2H)-one (267 mg, 1.0 mmol) in isopropanol (0.4 mL) containing titanium (IV) isoproproxide (0.4 mL, 1.3 mmol) was heated at 55° C. under an argon atmosphere for one hour to give a yellow solution. This solution was cooled to room temperature and diluted with absolute EtOH (4 mL). Sodium cyanoborohydride (70 mg, 1.1 mmol) was added and the reaction mixture stirred for 20 hours. Upon dilution of the reaction with water and addition of aq. NaHCO3, the product was extracted into EtOAc, the extract dried (Na2SO4) and evaporated. The crude residue was chromotographed on a column of silica gel and eluted with a gradient of 0.25-1.25% methanol/chloroform to give (±)1,1-dioxido-2-(4-(4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidin-1-yl)pentyl)-1,2-benzisothiazol-3(2H)-one (referred to herein as Compound L) as a viscous oil. 1H NMR (400 mHz, CDCl3): d 8.07 (dd, J=5.5 Hz, J=1.4 Hz, 1H), 7.93 (dd, J=6.5 Hz, J=1.1 Hz, 1H), 7.85 (quintet, 2H), 7.35-7.37 (m, 1H), 7.05 (quintet, 2H), 6.98-7.02 (m, 1H), 4.33-4.38 (m, 1H), 3.93 (q, J=7.1 Hz, 2H), 3.85 (dt, J=7.3 Hz, J=3.6 Hz, 2H), 2.86-2.90 (m, 2H), 2.73 (quartet, J=6.8, 1H), 2.57 (broad t, J =10 Hz, 1H), 2.26-2.49 (overlapping quintets, 3H), 1.97 (quintet, 2H), 1.80 (broad d, J=10 Hz, 2H), 1.61-1.69 (m, 1H), 1.41-1.48 (m, 1H), 1.33 (t, J=7.1 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H). The residual oil was converted to its hydrochloride salt and crystallized from isopropanol to give a white crystalline solid, melting point 176° C. (Compound L). Analysis calculated for C26H32N4O4S.HCl0.3 H2O: C, 57.99; H, 6.29; N, 10.41; found: C, 58.03; H, 6.19; N, 10.38.
