[Synthesis]
General procedure for the synthesis of tert-butyl [(1R)-1-(4-bromophenyl)ethyl]carbamate from di-tert-butyl dicarbonate and 1-(4-bromophenyl)ethylamine:
1. 1-(4-Bromophenyl)ethylamine (1.0 g, 5 mmol) was dissolved in methanol (10 ml) and sodium bicarbonate (1.26 g, 15.0 mmol) and di-tert-butyl dicarbonate (1.2 g, 5.5 mmol) were added.
2. The reaction mixture was sonicated for 4 hours.
3. The solvent was evaporated and the residue partitioned between ethyl acetate and water.
4. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to afford tert-butyl [(1R)-1-(4-bromophenyl)ethyl]carbamate (1.8 g, 6.0 mmol, 120%) as a white solid.
5. tert-Butyl [(1R)-1-(4-bromophenyl)ethyl]carbamate (0.73 g, 2.4 mmol) was dissolved in 1,2-dimethoxyethane (10 ml), tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol), 2-chloro-pyridinyl-3-boronic acid (0.77 g, 4.9 mmol), and 2 M sodium carbonate solution were added.
6. The reaction mixture was heated to reflux for 16 h. The solvent was removed under reduced pressure.
7. The residue was partitioned between ethyl acetate and water.
8. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure.
9. The residue was separated by chromatography on silica gel, eluting with 3:1 heptane/ethyl acetate, and the solvent was removed under reduced pressure to afford tert-butyl (1R)-1-[4-(2-chloropyridin-3-yl)phenyl]ethylcarbamate (0.56 g, 1.7 mmol, 71%) as an off-white solid.
10. tert-Butyl (1R)-1-[4-(2-chloropyridin-3-yl)phenyl]ethylcarbamate (100 mg, 0.3 mmol), sodium ethoxide (61 mg, 0.9 mmol) and tetrahydrofuran (5 ml) were heated and refluxed under argon atmosphere for 16 hours.
11. The solvent was evaporated and the residue was purified on a SCX column eluting with a methanol solution of 2M ammonia to give (1R)-1-[4-(2-ethoxypyridin-3-yl)phenyl]ethylamine (66 mg, 0.27 mmol, 90%) as a yellow gel.
12. (1R)-1-[4-(2-ethoxypyridin-3-yl)phenyl]ethylamine (13 mg, 0.05 mmol) was dissolved in dichloromethane (1 ml), triethylamine (17 mg, 0.16 mmol) and 2-(trifluoromethoxy)benzenesulfonyl chloride (17 mg, 0.065 mmol) were added.
13. The reaction mixture was stirred for 16 hours and the solvent was evaporated under reduced pressure.
14. The crude product was dissolved in dimethyl sulfoxide (1 ml) and purified by preparative LCMS.
15. The solvent was evaporated under reduced pressure to give the title compound (6 mg, 0.013 mmol, 26%).
1H NMR (400MHz, 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]+. |