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

Participants

Reaction Steps

A solution of 2,6-Dichloro-5-trifluoromethylpyrimidine (4.76 gm, 22 mmol) in 20 mL of dichloroethane and t-butanol (1:1) was treated with a 1M solution of zinc chloride in ether (22 mL, 22 mmol) and allowed to stir at RT for 30 minutes. The mixture was subsequently cooled to 0° C. and treated with a solution of (4-amino-3-fluorobenzyl)phosphonic acid diethyl ester (Compound 22D, 3.3 g, 7.94 mmol) in dichloroethane and t-butanol (10 mL, 1:1) over 10 min through an addition funnel. After 1 hr, diisopropylethylamine (2.2 mL, 12.6 mmol) was added and the mixture was allowed to stir for 24 hours at RT. The solvents were evaporated and the residue was purified using flash column chromatography (9:1 DCM:EtOAc) to afford 3.9 g of the title compound (71%). 1H NMR (600 MHz, CDCl3): δ=1.23-1.28 (m, 6H), 3.1 (d, J=22 Hz, 2H), 4.02-4.09 (m, 4H), 7.09-7.25 (m, 2H), 7.63 (s, 1H), 8.24-8.27 (m, 1H), 8.58 (s, 1H).

Provenance & Evidence