Diisopropylethylamine → 5-((5-((6-Bromobenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)methyl)-5-methylimidazolidine-2,4-dione

Participants

Reaction Conditions

Reaction Steps

To a solution of 2-(6-bromobenzo[d]thiazol-2-yl)acetohydrazide (1.0 g, 3.5 mmol) (prepared as described in WO 2011/074560) in dioxane (10 mL) was added 2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetic acid (0.80 g, 4.2 mmol), T3P (50% in EtOAc, 5.20 mL, 8.74 mmol) and DIPEA (3.1 mL, 17.5 mmol). The reaction mixture was stirred at 90° C. for 6 h. Additional DIPEA (3.1 mL, 18 mmol) and T3P (50% in EtOAc, 3.1 mL, 1.8 mmol) were added. The reaction mixture was heated at 95° C. for 12 h. The reaction mixture was diluted with DCM, and the organic portion washed with 1.5 M K3PO4, 1.0 M HCl solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO silica gel chromatography eluting with 0-15% MeOH/DCM over 30 min gradient to give racemic material (811 mg, 1.92 mmol, 55.0% yield) as a yellow solid. The enantiomers were separated by preparative chiral SFC (Kromasil 5-Cellucoat 21×250 mm ID, 5 μm, 65 mL/min, 150 bar, 35° C., 25% MeOH/77% CO2) to afford isomer A as Example 23A (Rt=7.8 min, 37% yield), LCMS (method B) Rt=1.6 min, m/z=423.9 (M+H)+; and isomer B as Example 23B (Rt=11.2 min, 35% yield), LCMS (method B) retention time=1.6 min, m/z=423.9 (M+H)+. For Example 23B: 1H NMR (400 MHz, CDCl3) δ 8.26 (br. s., 1H), 8.01 (d, J=1.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.60 (dd, J=8.8, 2.0 Hz, 1H), 6.54 (s, 1H), 4.71 (d, J=2.0 Hz, 2H), 3.40-3.21 (m, 2H), 1.59 (s, 3H).

Provenance & Evidence