Sodium Carbonate → (R)-{1-[4-(2-chloro-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester

Participants

Reaction Steps

To a solution of (R)-1-(4-bromophenyl)ethylamine (1.0 g, 5 mmol) in methanol (10 ml) was added sodium hydrogen carbonate (1.26 g, 15.0 mmol) and di-tert-butyl dicarbonate (1.2 g, 5.5 mmol). The reaction mixture was sonicated for 4 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure to give (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.8 g, 6.0 mmol, 120%) as a white solid. To a solution of (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.73 g, 2.4 mmol) in 1,2-dimethoxyethane (10 ml) was added tetrakis (triphenylphosphine) palladium (0.14 g, 0.12 mmol), 2-chloropyridine-3-boronic acid (0.77 g, 4.9 mmol) and 2 M sodium carbonate. The reaction mixture was heated to reflux for 16 h and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was chromatographed over silica gel eluting with 3:1 heptane/ethyl acetate and the solvent removed under reduced pressure to give (R)-{1-[4-(2-chloro-pyridin-3-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.56 g, 1.7 mmol, 71%) as an off white solid. A mixture of (R)-{1-[4-(2-chloro-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester (100 mg, 0.3 mmol), sodium ethoxide (61 mg, 0.9 mmol) and tetrahydrofuran (5 ml) was heated under reflux under an argon atmosphere for 16 h. The solvent was evaporated and the residue purified on a SCX column (eluted with 2M ammonia in methanol) chromatography to give (R)-1-[4-(2-ethoxy-pyridin-3-yl)-phenyl]-ethylamine (66 mg, 0.27 mmol, 90%) as a yellow gum. To a solution of (R)-1-[4-(2-ethoxy-pyridin-3-yl)-phenyl]-ethylamine (13 mg, 0.05 mmol) in dichloromethane (1 ml) was added triethylamine (17 mg, 0.16 mmol) followed by 2-(trifluoromethoxy)benzenesulfonyl chloride (17 mg, 0.065 mmol). The reaction mixture was stirred for 16 h and the solvent evaporated under reduced pressure. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (6 mg, 0.013 mmol, 26%). 1H NMR (400 MHz, DMSO-d6): δ 8.42 (d, 1H), 8.13 (dd, 1H), 7.81 (dd, 1H), 7.63 (m, 2H), 7.39 (m, 4H), 7.24 (d, 2H), 7.05 (m, 1H), 4.48 (q, 1H), 4.36 (q, 2H), 1.35 (d, 3H), 1.29 (t, 3H) ppm; MS (ESI) m/z: 467 [M+H]+.

Provenance & Evidence