Patent GB-1283791-A (GB)
Title: Preparation of (cis-1,2,-epoxypropyl)phosphonic acid compounds; also intermediates therefor and their preparation
Inventor: SLETZINGER MEYER
IPC: C07F9/655
Filed: 1970-01-19
Abstract: 1283791 1,2-Epoxyallylphosphonic acid compounds and their conversion to the corresponding epoxypropyl phosphonic compounds MERCK & CO Inc 19 Jan 1970 [23 Jan 1969] 2504/70 Heading C2P A propadienyl phosphonic acid compound (I) is treated with a substantially equimolar quantity of an epoxidizing agent to produce a novel (1,2-epoxyallyl)-phosphonic acid compound (II) which is then reduced to form a (cis-1,2-epoxypropyl) phosphonic acid compound (III), e.g. as illustrated by the following reaction scheme: In the formulµ each of R and R 1  is halogen, OH, OY wherein Y is a metal or other saltforming radical, 0Y 1  where Y 1  is a substituted or unsubstituted hydrocarbon or heterocyclic radical or -NY 3 Y 4  where each of Y 3  and Y 4  is H or a hydrocarbon radical or NY 3 Y 4  is the residue of a cyclic amine and R and R 1  may be the same or different in each compound. A wide variety of epoxidizing agents can be used and when epoxidation of I is complete the product II may, without isolation, be submitted directly to the reduction process. Alternatively the compound II which is formed as a racemate may be resolved into its optically active isomers and either or both of the latter subjected to the reduction process to produce the corresponding optical isomer of III. Resolution may be effected by use of an optically active amine to produce a pair of diastereoisomers, separating the diastereoisomers, e.g. by fractional crystallization, and regenerating the appropriate enantiomer from the diastereoisomer. Suitable optically active amines for use in the resolution are quinine, brucine, and α- phenethylamine. The reduction step is conveniently effected with hydrogen in the presence of a catalyst, e.g. Pt, Pd or Raney nickel, or may be effected by means of an alkali or alkaline earth metal borohydride. The reduction can be carried out so as to form either the (+) or ( - ) isomers of III from the resolved isomers of II. The reduction may be carried out asymmetrically so as to obtain the (+) or (-) isomer of III. This may be done by using in the hydrogenation process a catalyst having adsorbed thereon an optically active amino acid such as d- or l-alanine, d- or l-glutamic acid, d- or l-aspartic acid or d- or l-lysine. Alternatively when () (cis-1,2-epoxypropyl) phosphosphonic acid salts are obtained they may be resolved into their optical isomers by forming diastereoisomers with an optically active amine such as α-phenethylamine followed by separation of the diastereoisomers by fractional crystallization. When the final products are esters of (cis-1,2- epoxypropyl) phosphonic acid they may be converted by various defined methods to the free acid or salt thereof, e.g. by alkaline hydrolysis, hydrogenolysis, U.V. irradiation in the presence of a base, treatment with sodium in a tertiary amine, or enzymolysis, according to the nature of the ester to be converted. Examples are given for the preparation of the d-α-phenethylamine salt of (- )(cis-1,2-epoxypropyl)- phosphonic acid and of various salts and esters of () (cis-1,2-epoxypropyl) phosphonic acid and also for the conversion of various esters of (cis-1,2-epoxypropyl) phosphonic acid to salts thereof. ( -) and ()(cis-1,2-epoxypropyl) phosphonic acid and salts and labile esters thereof have microbial properties and may be used to combat bacteria in man or lower animals. They may be administered orally as capsules or tablets or in liquid solution or suspension and suitable formulations can include diluents, granulating agents, preservatives, binders, flavouring agents and coating agents. They may also be administered parenterally by injection in a sterile vehicle. Propadienyl phosphonic acid is obtained by adding water dropwise to a solution of propadienyl phosphonic dichloride in dioxane containing pyridine and is converted to its sodium salt by the addition of aqueous sodium bicarbonate solution to an aqueous solution of the acid to give a pH of 5À5 to 6.