反应详情

3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethenyl)benzonitrile (0.068 g, 0.215 mmol), 4-chloro-1H-imidazole-5-carboxylic acid (0.040 g, 0.273 mmol), and DIPEA (0.075 mL, 0.429 mmol) were combined in THF (6 mL) and treated with EDC (0.082 g, 0.429 mmol) at 50° C. for three days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and brine. The organic phase was isolated, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 40 to 100% EtOAc/hexanes to give impure product. This material was repurified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(1-methylethenyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.013 g, 0.029 mmol, 13.60% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br. s., 1H), 8.30 (br. s., 1H), 7.73-7.78 (m, 2H), 7.50 (d, J=8.52 Hz, 1H), 7.43 (s, 1H), 7.36 (t, J=7.76 Hz, 1H), 7.26 (s, 1H), 5.57 (s, 1H), 5.25 (s, 1H), 4.52 (d, J=5.36 Hz, 2H), 2.10 (s, 3H). LC-MS (ES−) m/z 443.08, 445.16 [M−1]. LC-MS (ES+) m/z 445.07, 447.07 [M+H].

1. concentrationThe reaction mixture was concentrated to dryness
2. custompartitioned between EtOAc and brine
3. customThe organic phase was isolated
4. washwashed with saturated aqueous NaHCO3
5. dry with materialdried over MgSO4
6. filtrationfiltered
7. concentrationconcentrated to dryness
8. customThe residue was purified on 40 g silica gel
9. washeluted with 40 to 100% EtOAc/hexanes
10. customto give impure product
11. customThis material was repurified by mass-directed HPLC on a SunFire prep C-18 column
12. washeluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer)
13. concentrationconcentrated to dryness
14. customto remove residual water