反应详情

3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethylbenzonitrile (0.055 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.050 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from boiling IPA, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.021 g, 0.048 mmol, 26.8% yield) as a white solid. The mother liquor was concentrated to dryness and purified on an XTerra™ C-18 column eluted with 5 to 75% CH3CN/H2O (0.2% NH4OH buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give additional 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.043 g, 0.099 mmol, 54.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (br. s., 1H), 8.30 (br. s., 1H), 7.76 (s, 1H), 7.43-7.54 (m, 2H), 7.29-7.42 (m, 1H), 7.18 (m, 2H), 4.53 (d, J=5.22 Hz, 2H), 2.64 (q, J=7.23 Hz, 2H), 1.15 (t, J=7.48 Hz, 3H). LC-MS (ES−) m/z 431.16, 433.15 [M−1]. LC-MS (ES+) m/z 433.08, 435.07 [M+H].

1. concentrationThe reaction mixture was concentrated to dryness
2. dissolutiondissolved in DCM
3. washwashed with water
4. dry with materialdried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated to dryness
7. dissolutionThe residue was dissolved in DCM (2.5 mL)
8. additiontreated with TFA (2.5 mL) at 25° C. for 3 days
9. concentrationThe reaction mixture was concentrated to dryness
10. dissolutiondissolved in DCM
11. washwashed with saturated aqueous NaHCO3
12. dry with materialdried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated to dryness
15. customThe resultant solid was recrystallized
16. temperaturecooled in an ice bath
17. filtrationfiltered