Potassium Hydroxide → N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-carboxamide

Participants

Reaction Steps

A solution of ethyl 4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-carboxylate (0.201 g, 0.49 mmol) in 6N KOH (0.10 mL, 0.6 mmol) and ethanol (1.5 mL) was stirred at RT for 30 mins and evaporated to dryness. The residue was stirred with 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.10 g, 0.32 mmol), HATU (0.203 g, 0.53 mmol) and DIEA (0.085 mL, 0.49 mmol) in DMF (3 mL) at RT overnight. Sat'd NaHCO3 was added and the aqueous layer was extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-50% EtOAc/hex) to afford N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-carboxamide (0.13 mg, 58%) as a brown oil and as a mixture of the expected two isomers. This material was stirred in TBAF (2 mL of a 1N solution in THF, 0.2 mmol) for 1 h. Sat'd NaHCO3 was added and the aqueous layer was extracted with CH2Cl2. The residue was stirred with TFA (0.4 mL) in EtOH (0.02 mL) and CH2Cl2 (0.8 mL) for 8 h and the solution was evaporated and purified by silica gel chromatography (0-100% EtOAc/hexs, then 0-5% MeOH (2M NH3)/CH2Cl2) to provide the title compound (0.0163 g, 20%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (t, J=1.51 Hz, 1H), 7.35-7.43 (m, 2 H), 7.28 (t, J=2.06 Hz, 1H), 7.22-7.26 (m, 1H), 7.15 (br. s., 1H), 4.64 (s, 2H), 4.57 (s, 2H). ES-LCMS: m/z 435.1, 437.0 (M+1).

Provenance & Evidence