反应详情

温度

90 °C

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).

1. temperatureThe reaction mixture was heated at 95° C. for 12 h
2. washthe organic portion washed with 1.5 M K3PO4, 1.0 M HCl solution and brine
3. dry with materialThe organic layer was dried over sodium sulfate
4. filtrationfiltered
5. concentrationconcentrated under reduced pressure
6. customThe residue was purified by ISCO silica gel chromatography
7. washeluting with 0-15% MeOH/DCM over 30 min gradient