Formaldehyde → Trifluoroacetic acid

Participants

Reaction Steps

tert-Butyl 4-phenyl-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methoxy)methyl)piperidine-1-carboxylate was treated with trifluoroacetic acid: water (9:1, 3 ml) at ambient temperature for 15 min at which time LC-MS analysis revealed completion of the reaction (HPLC method 10: tR=2.5 min, 520(MH)+). The volatiles were evaporated and dried under vacuo. The residue was treated with formaldehyde (0.1 mL, 3.6 mmol), acetic acid (cat.) and sodium cyanoborohydride (25 mg, 0.4 mmol) at ambient temperature for 2 h. The reaction was complete by LC-MS analysis (HPLC method 9: tR=2.7 min, 534(MH)+). The solvent was evaporated and the residue was treated with trifluoroacetic acid /dichloromethane (1:1, 4 ml) at ambient temperature for 3 h. LC-MS analysis (HPLC method 1: tR=2.0 min, 404(MH)+). The solvent was evaporated and the residue was purified by Prep HPLC (HPLC method 15). Fractions containing required product were combined and evaporated to give the title compound as a TFA salt. (6 mg, yield for 5 steps from (6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methanol, 13.2% yield). 1H-NMR (CD3OD, 500 MHz) δ 8.85 (s, 1H), 7.99 (s, 2H), 7.57 (s, 1H), 7.43-7.27 (m, 5H), 4.85 (s, 2H), 3.52 (s, 2H), 3.45 (m, 2H), 2.85 (m, 2H), 2.75 (s, 3H), 2.69-2.66 (m, 2H), 2.19 (m, 2H); 19F NMR (471 MHz, CD3OD) δ −62.9, −77.6; LC/MS (HPLC method 1): tR=2.1 min, 404(MH)+.

Provenance & Evidence