Metrifonate is easily synthesized in a one-step spontaneous exothermic condensation of equimolar amounts of chloral hydrate with dimethylhydrogenphosphite, which in turn is accessible by reacting PCl3 with methanol. Contrary to similar reactions described earlier (1950-1952) in two Soviet papers and a U.S. process patent, no catalyst is needed if the aldehyde compound is chloral. Therefore, metrifonate can be readily crystallized directly from the reaction mixture.

Metrifonate is totally unique among the acetylcholinesterase inhibitors currently used or proposed for the treatment of Alzheimer's disease because it is an inactive prodrug. The active compound dichlorvos, (2,2-dichlorovinyl dimethylphosphate; DDVP), is formed in a nonenzymatic reaction by hydrolysis and elimination of HCl followed by rearrangement of an intermediate according to Scheme.

Metrifonate is easily synthesized in a one-step spontaneous exothermic condensation of equimolar amounts of chloral hydrate with dimethylhydrogenphosphite, which in turn is accessible by reacting PCl3 with methanol. Contrary to similar reactions described earlier (1950-1952) in two Soviet papers and a U.S. process patent, no catalyst is needed if the aldehyde compound is chloral. Therefore, metrifonate can be readily crystallized directly from the reaction mixture.

Metrifonate is totally unique among the acetylcholinesterase inhibitors currently used or proposed for the treatment of Alzheimer's disease because it is an inactive prodrug. The active compound dichlorvos, (2,2-dichlorovinyl dimethylphosphate; DDVP), is formed in a nonenzymatic reaction by hydrolysis and elimination of HCl followed by rearrangement of an intermediate according to Scheme.