Diethyl Ether → Diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

Participants

Reaction Steps

1.0 M Zinc dichloride in ether (4.07 mL, 4.07 mmol) was added to a solution of the commercially available 2,4-dichloro-5-trifluoromethylpyrimidine (0.8 g, 3.70 mmol) in 1,2-dichloroethane (6.7 mL) and t-BuOH (6.7 mL). After 30 minutes diethyl (4-amino-3-methoxybenzyl)phosphonate (Compound 1F, 1.01 g, 3.70 mmol) was added followed by triethylamine (0.567 mL, 4.07 mmol) while keeping the temperature at ˜25° C. The reaction mixture was allowed to stir at rt overnight before quenching with sat. aq. NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (15 mL) and the organic layer was washed with brine (10 mL), dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to afford a yellow oil. This crude material was initially purified using a Teledyne ISCO CombiFlash® Rf system eluting with 0-5% MeOH in DCM followed by preparative HPLC (MDP) to afford 1.09 g of the title compound (70%). 1H NMR (CD3OD, 400 MHz): δ 1.28 (t, J=7.1 Hz, 6H), 3.23-3.29 (m, 2H), 3.90-3.95 (m, 3H), 4.01-4.13 (m, 4H), 6.90-6.96 (m, 1H), 7.03 (m, J=2.0 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 8.62 (s, 1H).

Provenance & Evidence