Dibenzyl (Chloromethyl) Phosphate

• 2,6-Diisopropylphenol [D0617]
• Dibenzyl (Chloromethyl) Phosphate [D5828]
• Sodium Hydride (60%, dispersion in Paraffin Liquid) [S0481]
• DMF

To a reaction vessel were added 2,6-diisopropylphenol (0.42 g, 2.36 mmol) and DMF (20 mL) under nitrogen atmosphere, cooling with an ice bath. Sodium hydride (60%, dispersed in liquid paraffin) (0.113 g, 2.83 mmol) was added and stirred for 30 min, then (chloromethyl)dibenzyl phosphate (1.0 g, 3.06 mmol) was added. The mixture was stirred for 2 h at room temperature and cooled with an ice bath. Water (20 mL) was added and extracted with diethyl ether. The organic layer was sequentially washed with water and brine, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give 1 (0.8 g, 72% yield) as a colorless liquid.

The reaction mixture was monitored by TLC (hexane:ethyl acetate = 5:1, Rf = 0.3).

¹H NMR (400 MHz, CDCl₃); δ 7.38-7.27 (m, 10H), 7.17-7.09 (m, 3H), 5.42 (d, 2H, J = 9.6 Hz), 5.06-4.95 (m, 4H), 3.33(sep, 2H, J = 6.9 Hz), 1.18 (d, 12H, J = 6.9 Hz).

• Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF1) receptor antagonist BMS-665053 leading to improved oral bioavailability
• R. A. Hartz, V. M. Vrudhula, V. T. Ahuja, J. E. Grace, N. J. Lodge, J. J. Bronson, J. E. Macor, Bioorg. Med. Chem. Lett. 2017, 27, 1360.

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