Patent GB-1227119-A (GB)
IPC: C07D323/04
Filed: 1969-05-12
Abstract: 1,227,119. Preparing (cis-epoxypropyl)phosphonic acid, derivatives thereof and novel intermediates therefor. MERCK & CO. Inc. 12 May, 1969 [15 May, 1968], No. 23980/69. Heading C2C. A cis compound of the formula wherein R is H or a substituted or unsubstituted hydrocarbyl or heterocyclic radical and the two R's are the same or different or a salt of such a compound in which at least one R is H is obtained by reacting a novel compound of the formula wherein X is halogen and R is as defined above or a salt of such a compound in which at least one R is H with a metallic coupling agent which is defined as being any metallic substance which will eliminate the two halogen atoms and C0 2  from the starting material with the production of a metal halide and can be any metal or combination of metals in Group I A , IIA I B  or II B  of the Periodic Table and/or aluminium. The metallic coupling agent can, for example, be Mg, Li or Na or a mixture of metals, e.g. of Zn and Cu. The products when in the form of salts may be. inorganic metallic salts, e.g. mono- and di-Na or K salts or the Ca, Mg, Ag, Fe or NH 4  salts or may be organic base salts, several such bases being specified. The reaction is preferably carried out in an inert organic solvent and is generally effected at from room temperature to about 100 C., preferably 30-80 C., and generally continued until no more C0 2  is evolved. The starting compound is preferably the cis form but a cis/trans mixture can be used in which case the product is a cis/trans mixture from which the cis isomer can be separated by fractional crystallization or by vapour phase chromatography. Any trans isomer can be converted to the cis isomer by subjecting a solution thereof to short wave U.V. light. The cis product of the main process is a racemic mixture which can be resolved into the optically active forms, especially to recover the ( - )(cis 1,2-epoxypropyl)phosphonic acid compound, the latter as well as the () product mixture having antibacterial properties. The starting materials of Formula I can. be prepared by the following reaction sequence This process comprises ozonizing the 1-propenyl phosphonic acid or ester or salt thereof (IV) to form the ozonide (V) which is then reacted with an appropriate di- or poly-halogenated hydrocarbon (or substituted derivative thereof) capable of inserting a carbene radical across the double bond, the latter reaction being generally carried out in the presence of a base such as an anhydrous alkali metal alkoxide or phenoxide. Cis-propenyl phosphonic acid is obtained by reacting PCl 3  with t-butanol in the presence of triethylamine to form a reaction mixture containing di-t-butyl phosphorochloridite which is then reacted with propargyl alcohol in the presence of triethylamine to form a mixture containing di - t - butyl - 2 - propynyl phosphite which on heating under reflux yields di-t.butyl propadienyl phosphonate. A benzene solution of the latter is then hydrogenated to form di-tbutyl-cis-propenyl phosphonate which is then heated under reflux in benzene solution which also contains cis-propenyl phosphonic acid, the heating being continued until the calculated amount of isobutene is formed. Cis-propenyl phosphonic acid remains as residue on removing the solvent and may be converted to mono or disalts by treatment with a base in ethanol.