Hydrochloric Acid → Triethyl Phosphate

Participants

Reaction Conditions

Reaction Steps

A solution of pyridine (16.1 L, 0.2 kmol) in acetonitrile (160 L) is cooled to −10° C. Ethyl chloroformate (19.1 L, 0.2 kmol) is added at such a rate that the temperature does not rise above 0° C. The suspension is then stirred at −10 to 0° C. for 2 hours to ensure complete N-acylation. The batch is cooled to −30° C., and triethyl phosphite (34.3 L, 0.2 kmol) is added at such a rate that the temperature does not rise above −20° C. (ranging from −30 to −20° C.). The solution is stirred in this range for 2 hours, and then warmed to ambient temperature over several hours (or overnight). The acetonitrile is stripped under Sihi vacuum to a temperature not exceeding 80° C. and the residual liquid is cooled to 30° C. Dichloromethane (140 L) is added, followed by a mixture of water (60 L) and concentrated HCl (10 L). The mixture is stirred at ambient temperature for 1 hour, and the lower organic phase is pumped to a separate vessel and washed with water (100 L). After pumping back to the original (water-washed) vessel, it is washed with 1% potassium carbonate solution and finally with water to neutrality. The dichloromethane is then stripped to leave crude (about 92% pure) diethyl N-ethoxycarbonyl-1,4-dihydropyridine-4-phosphonate containing about 5% 1,2-isomer and traces of triethyl phosphate (oxidation of corresponding phosphite). The yield is about 48.4 kg of a light yellow liquid which is stored under nitrogen because it is slightly unstable to air.

Provenance & Evidence