Formaldehyde → Acetoacetic Acid

Participants

Reaction Steps

To a solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-6-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (I-54) (70.0 mg, 0.11 mmol), in acetonitrile (1.0 mL), was added formaldehyde (37% solution in water, 42 μL, 0.56 mmol) and sodium cyanoborohydride (28.8 mg, 0.46 mmol). A few drops of MeOH were added and the reaction was allowed to stir for 1 h. Saturated NaHCO3 solution was added and the mixture was extracted with EtOAc (2×). The combined organic solutions were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography and then further purified by HPLC (250 mm C18 column) eluting with acetonitrile containing 30% to 100% 10 mM ammonium acetate in water (20 min gradient), to give N-[4-chloro-3-(trifluoromethyl)phenyl]-6-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yl]-oxy}-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (I-11) as the diacetate salt (12 mg, 17%). 1H NMR (300 MHz, CD3OD): δ 8.58 (d, 1H), 8.17 (d, 1H), 7.85-7.81 (m, 1H), 7.62 (d, 1H), 7.55 (d, 1H), 7.26 (d, 1H), 7.16-7.13 (m, 1H), 6.99-6.97 (m, 2H), 4.07 (d, 1H), 4.04 (s, 4H), 3.71 (d, 1H), 3.46-3.41 (m, 1H), 3.24-3.06 (m, 2H), 2.53 (s, 3H), and 1.91 (s, 6H). LCMS: (FA) ES+ 530.3, ES− 528.2.

Provenance & Evidence