1,2-Dichloroethane → 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide

Participants

Reaction Conditions

Reaction Steps

Combined 6-chloronicotinic acid (2.0 g, 12.69 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (2.193 g, 19.04 mmol) and EDC (4.87 g, 25.4 mmol) in CH2Cl2 (100 mL) then added Hunig's base (6.65 mL, 38.1 mmol) and the mixture stirred at 20° C. for 24 h. More (tetrahydro-2H-pyran-4-yl)methanamine (1 g, 0.7 equiv), Hunig's base (2.2 mL, 1 equiv.) and DMAP (ca. 10 mg) were added and the reaction was heated at 45° C. for 18 h. More Hunig's base (3 mL) and DMAP (80 mg) was added and heating continued at 50° C. for 5 h. The reaction was then concentrated in vacuo to give a residue which was taken up in EtOAc (100 mL) and washed with saturated aqueous ammonium chloride (100 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on an 80 g silica gel column eluted with 0 to 100% EtOAc in hexanes, then filtered and dried in the lyophilizer to give the title compound (0.985 g, 30.5% yield) as a white solid. MS m/z 255, 257 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.28 (m, 2 H) 1.60 (dd, J=12.9, 1.8 Hz, 2 H) 1.78 (td, J=7.4, 3.7 Hz, 1 H) 3.13-3.20 (m, 2 H) 3.26 (td, J=11.7, 2.1 Hz, 2 H) 3.84 (dd, J=11.4, 2.5 Hz, 2 H) 7.64 (dd, J=8.3, 0.5 Hz, 1 H) 8.23 (dd, J=8.3, 2.5 Hz, 1 H) 8.74 (t, J=5.6 Hz, 1 H) 8.82 (dd, J=2.5, 0.8 Hz, 1 H).

Provenance & Evidence