Reaction Steps
To a 0° C. solution of N,N-dibutyl-4-chloro-5-(2-hydroxyethyl)-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamide (Example 170, 20 mg, 0.026 mmol) in CH2Cl2 (0.5 mL) was added trichloroacetyl isocyanate (4 μl, 0.031 mmol). After stirring at 0° C. for 30 min, K2CO3 (2 mg, 0.014 mmol) and MeOH (0.5 mL) were added. The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with water and EtOAc. The aqueous layer was extracted with EtOAc (2×), and the combined organic extracts were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo to afford a colorless oil. The oil was dissolved in MeOH (3.0 mL) and water (3.0 mL) and K2CO3 (120 mg, 0.84 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and then partitioned between EtOAc and H2O. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (10 mg, 44%) as a white solid. 1H NMR (CD3OD, 1.5:1 mixture of amide rotamers) δ 8.73 (br s, 1H), 8.13-8.04 (m, 4.5H), 8.02-7.95 (m, 2H), 7.78-7.64 (m, 3H), 7.23-7.08 (m, 4H), 7.02-6.88 (m, 0.5H), 4.94-4.89 (m, 1H), 4.67-4.41 (m, 1H), 4.25 (t, J=6.5 Hz, 2H), 4.18-4.05 (m, 1.5H), 4.01-3.71 (m, 1.5H), 3.65-3.46 (m, 4H), 3.37-3.34 (m, 2H), 3.02 (t, J=6.5 Hz, 1.5H), 2.92-2.77 (m, 1.5H), 1.68-1.53 (m, 2H), 1.31-1.25 (m, 3H), 1.20-1.17 (m, 1H), 0.99 (t, J=7.4 Hz, 2H), 0.94-0.86 (m, 3H), 0.78-0.73 (m, 2H), 0.68 (t, J=6.4 Hz, 1H); MS(ESI+) m/z 813.5 (M+H)+.
