Patent GB-1267091-A (GB)
IPC: C07F9/14
Filed: 1969-05-12
Abstract: 1,267,091. Preparing (cis-1,2-epoxypropyl)- phosphonic acid and derivatives thereof. MERCK & CO. Inc. 12 May, 1969 [15 May, 1968; 16 Dec., 1968], No. 23988/69. Heading C2P. (cis-1,2-Epoxypropyl)phosphonic acid and its salts and esters and the phosphonamidate, phosphonothioate, phosphonamidothioate, phosphonodithioate, thiophosphonoamidate and diamide derivatives and analogues thereof are obtained by treating an appropriate phosphinyl- or phosphinothioyl methylide having a suitable leaving group at the methylide carbon with acetaldehyde. The methylide compound may have the formula wherein M is a sulphonium cation (R<SP>2</SP>) 2 S#, a sulphoxonium cation (R2) 2 SO#-, a phosphonium cation of the formula (R<SP>2</SP>) 3 P# or an ammonium cation (R<SP>3</SP>) 3 N#- where R<SP>2</SP> is alkyl, aryl or aralkyl, R<SP>3</SP> is alkyl or aralkyl, Z is O or S, and each of R and R<SP>1</SP> is alkoxy, alkenyloxy, mono-, di-, or tri-haloalkoxy, dialkylaminoalkoxy, aryloxy, aralkoxy, phthalimidoalkoxy, dialkylamino, alkylthio, N-alkyl- N-arylamino, or acyloxymethoxy, R and R<SP>1</SP> being the same or different, or R and R<SP>1</SP> together are arylenedioxy, the reaction product having the formula The phosphinyl methylide may also have the formula wherein Z, R and R<SP>1</SP> are as defined above, M A # is a cation, and M<SP>1</SP> is halo, di-(C 1 -C 5  alkoxy)- phosphinyl, diaryloxyphosphinyl, or diaralkyloxyphosphinyl. The compounds IIa may be formed, if desired in situ, by reacting a halomethylphosphonic derivative of the formula wherein X is halo with an appropriate sulphide, amine, sulphoxide or phosphine to form a cationic intermediate which is then reacted with a base such as a sulphonylmethylide or sodium hydride. The compounds IIb in which M<SP>1</SP> is the specified phosphinyl group may be obtained by treating III with an appropriate phosphite triester and then treating the resulting intermediate with a base, e.g. as specified above. When M<SP>1</SP> in compounds IIb is halogen the starting compound may be obtained by treating III with a base. The halomethyl derivatives (III) may be obtained by treating HalCH 2 P(O)(Hal) 2  wherein Hal is halogen, e.g. ClCH 2 P(O)Cl 2 , with an appropriate alcohol, phenol, arylene diol, mercaptan, dialkyl amine, or dialkylaminoalkanol in one or more steps according to the product required. When a fluoromethyl phosphonic derivative (X = F in III) is required it may be obtained by treating POCl with an alcohol or other appropriate compound as defined above in the presence of a base, e.g. triethylamine, to form a chlorophosphonic derivative, reacting the latter with NaF to form the corresponding fluorophosphonic compound and finally reacting the latter with diazomethane to yield the fluoromethyl phosphonic derivative. When the ester radicals in III are derived from an aralkanol such as benzyl alcohol the compound III may be obtained by treating a triaralkyl phosphite with methylene halide, generally with heating. The products I may be converted to (cis-1,2- epoxypropyl)phosphonic acid or its salts by various methods, e.g. as disclosed in Specification 1,236,955. The ()(cis-1,2-epoxypropyl)- phosphonic acid and its salts, e.g. Na or Ca salts, have therapeutic and antiseptic properties and for therapeutic use they may be administered orally in the form of a capsule, tablet, liquid solution or suspension, or parenterally by injection in a sterile excipient.