反应详情

Oxone (1.33 g, 2.17 mmol) was added to a solution of 1-{[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde (0.86 g, 11.97 mmol) (see following step B for preparation) in DMF (15 mL). The reaction mixture was stirred overnight at room temperature and then cooled down to 0° C. Cyclopropylamine (0.23 g, 0.27 ml, 3.94 mmol) and N,N-diisopropylethylamine (1.02 g, 1.37 ml, 7.88 mmol) were added. Stirring for 20 min, HATU (1.35 g, 3.55 mmol) was added portionwise and the reaction was allowed to warm to room temperature. The reaction mixture was diluted with water (200 mL), and extracted with EtOAc (3×100 mL). The combined organic phases washed with NaCl (2×20 mL) and dried over Na2SO4. The crude product was purified by normal-phase MPLC using EtOAc to provide the title compound as a light brown solid. Yield: 0.70 g (72%). 1H NMR (400 MHz, METHANOL-D4) δ 0.51-0.59 (m, 2 H), 0.68-0.78 (m, 2 H), 1.37-1.54 (m, 5 H), 2.25 (t, J=19.43 Hz, 3 H), 2.68-2.77 (m, 1 H), 3.27 (d, J=2.54 Hz, 1 H), 3.33 (d, J=2.93 Hz, 1 H), 3.84-3.94 (m, 2 H), 4.38 (d, J=7.62 Hz, 2 H), 6.65 (dd, J=3.32, 1.56 Hz, 1 H), 7.30 (dd, J=3.32, 2.34 Hz, 1 H), 7.81-7.84 (m, 1 H), 7.88-7.94 (m, 1 H), 7.94-8.00 (m, 1 H), 8.39 (d, J=1.56 Hz, 1 H); MS (APPI) (M+H)+=493.3; Anal. Calc. for C23H26F2N4O4S+0.8 TFA: C, 50.61; H, 4.63; N, 9.60. Found: C, 50.84; H, 3.87; N, 9.39.

1. temperaturecooled down to 0° C
2. stirringStirring for 20 min
3. temperatureto warm to room temperature
4. extractionextracted with EtOAc (3×100 mL)
5. washThe combined organic phases washed with NaCl (2×20 mL)
6. dry with materialdried over Na2SO4
7. customThe crude product was purified by normal-phase