Preparation of diphenyl chloromethyl phosphate_industrial additives

Background and overview^[1]

Diphenyl chloromethyl phosphate is a pharmaceutical intermediate. There are reports in the literature that diphenyl chloromethyl phosphate can be used to prepare a water-soluble form of alcohol- and phenol-containing drugs such as camptothecin and propylene glycol. phenol.

Preparation^[1-2]

Report 1,

In 20 minutes, add dibenzyl phosphate to the refluxing solution of chloroiodomethane (25g, 97%, 0.14mol) in toluene (HPLC-Cabot silica grade, 30mL) in several portions. Ester silver salt (7.0g, 0.018mol). Continue refluxing for 1 hour. After the reaction mixture was cooled to room temperature, it was filtered, and the solvent was evaporated under reduced pressure. The oily residue was purified by silica gel flash column chromatography (7:3 hexanes/ethyl acetate) to afford 3.63 g (62% yield) of the title compound as a yellow oil. FABMS+(NBA):[M+H]⁺, m/z 327. ¹H NMR (300MHZ, CDCl₃, δ): 5.10 (d, J=8.0Hz, 4H), 5.63 (d, J=15.7Hz, 2H), 7.36 (s, 10H). 13C vulcanizing agent NMR (75MHz, CDCl3, δ): 69.68, 69.75, 73.33, 73.42, 127.93, 128.51, 128.63, 135.07.

Report 2,

Install a mechanical stirrer and a thermometer on a 500mL four-neck round-bottom flask, and add dibenzyl phosphate (20g), sodium bicarbonate (5.9g), dipotassium hydrogen phosphate (50g), and hydrogen sulfate into the nitrogen flow. Tetrabutylammonium (2.4g), tert-butyl methyl ether (94mL) and water (72mL) were stirred while cooling in an ice bath. A solution obtained by dissolving chloromethyl chlorosulfonate (17.8 g) in tert-butyl methyl ether (16 mL) at an internal temperature of 15° C. was added dropwise over 2 hours at an internal temperature of 30° C. or lower. After the dripping was completed, the mixture was stirred for 12 hours. Water (72 mL) and tert-butyl methyl ether (104 mL) were placed in a separatory funnel, and the above reaction liquid was added. Separate the lower layer, and wash the organic layer with 2M dipotassium hydrogen phosphate aqueous solution (72mL), N-methylmorpholine aqueous solution (prepared from 0.8g N-methylmorpholine and 72mL water), water, and brine. Add 0.8g N-methylmorpholine, add MgSO₄, set the bath temperature to 35°C, and concentrate the organic layer under reduced pressure to obtain 20.1g of the title compound (yield 86%).