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

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).

1. temperatureThe mixture was subsequently cooled to 0° C.
2. waitAfter 1 hr
3. stirringto stir for 24 hours at RT
4. customThe solvents were evaporated
5. customthe residue was purified

ORD record

ord-8a08f26cd1b34620a04bb5cedf8305e7

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09133224B2