Reaction Steps
To a solution of Compound 31b (613 mg, 2.22 mmol) in dioxane (10 mL) was added 2-(6-phenylbenzo[d]thiazol-2-yl)acetohydrazide (723 mg, 2.22 mmol), (described in WO 2011/074560), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (3.30 mL, 5.55 mmol) and DIPEA (1.0 mL, 5.55 mmol). The reaction mixture was stirred at 90° C. for 3 h. 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in EtOAc) (3.30 mL, 5.55 mmol) and DIPEA (1.0 mL, 5.55 mmol) were added. The reaction mixture was heated at 90° C. for 14 h. The reaction mixture was diluted with DCM, and the solution washed with 1.5 M potassium phosphate solution and 1.0 M HCl and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude residue. The crude residue was dissolved in DCM, loaded on CELITE, charged to a 80 g silica gel cartridge which was eluted with a 40 min gradient from 0-10% MeOH/DCM to give racemic 5-methyl-5-((5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)methyl)imidazolidine-2,4-dione (943 mg, 1.88 mmol, 85% yield) as a brown solid. The enantiomers were separated by SFC separation (Berger Prep SFC; column: Lux Cellulose-4, 30×250 mm ID, 5 μm; Flow rate: 100 mL/min, 150 bar BP, 40° C.; Mobile Phase: 25% Isopropanol/75% CO2; Wavelength: 220 nm) to afford Isomer A as Compound 31c (414 mg, 0.817 mmol, 36.8%). LCMS=2.0 min using analytical method (B), 502.1 (M+H). Analytical SFC RT=7.8 min (Instrument, Berger SFC; Column: Lux Cellulose-4, 4.6×250 mm ID, 5 μm; Flow rate: 3 mL/min, 150 bar BP, 35° C.; Mobile Phase: 20% Isopropanol/80% CO2; 220 nm). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.83 (dd, J=8.5, 1.8 Hz, 1H), 7.78-7.68 (m, 2H), 7.54-7.46 (m, 2H), 7.44-7.34 (m, 1H), 4.86 (d, J=1.3 Hz, 2H), 4.10 (q, J=9.2 Hz, 2H), 3.34 (t, J=15.6 Hz, 2H), 1.46 (s, 3H) and Isomer B (Rt=12.8 min, 45 mg, 13% yield), LCMS=1.77 min using analytical method (B), 440.9 (M+H).
