Diisopropyl Phosphorochloridate → 5-((4-(3-Acrylamidophenyl)-5-Chloropyrimidin-2-Yl)Amino)-2-Morpholinophenyl Diisopropyl Phosphate

Participants

Reaction Steps

n-Butyl lithium (0.14 mL, 2.5 M solution in hexane) was diluted 10-fold in THF (1.4 mL), and the resulting mixture added dropwise to a rapidly stirring solution of N-(3-(5-chloro-2-((3-hydroxy-4-morpholinophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide (100 mg, 0.221 mmol) in THF (5 ml) that was under argon gas and the reaction vessel was immersed in a salt-ice bath (bath temperature about −10° C. to −5° C.). The resulting white suspension was stirred for 5 min, followed by addition of diisopropyl phosphorochloridate (178 mg, 0.885 mmol) to the reaction mixture in a single portion. The suspension became a clear solution within about 5 min, and then reaction mixture was stirred at ambient temperature for about 18 h. Then reaction mixture was evaporated to dryness on a rotary evaporator. The resulting crude residue was purified by silica gel flash chromatography using a mixture of 3% methanol and DCM as eluting solvent to provide the title compound (50 mg, 0.078 mmol, 35.2% yield) as a syrup. 1HNMR (400 MHz, CDCl3): δ 8.52 (bs, 1H), 8.49 (d, 1H, J=8.0 Hz), 8.37 (s, 1H), 7.98 (s, 1H), 7.78 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.38 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 6.77 (d, 1H, J=8.0 Hz), 6.45 (m, 2H), 5.68 (t, 1H, J=6.0 Hz), 4.74 (m, 2H), 3.81 (m, 4H), 2.96 (m, 4H). Mass: 616.2 [M+H]+.

Provenance & Evidence