Patent GB-1239986-A (GB)
Title: (-) (cis-1,2-epoxypropyl) phosphonic acid derivatives
Inventor: CHIRNSTENSEN BURTON GRANT
IPC: C07F9/655
Filed: 1968-10-24
Abstract: 1,239,986. (-)(Bis - 1,2 - epoxypropyl)phosphonic acid derivatives. MERCK & CO. Inc. 24 Oct., 1968 [15 May, 1968; 28 Aug., 1968], No. 50631/68. Heading C2C. [Also in Division A5] The invention comprises (a) esters of (-)(cis- 1,2 - epoxypropyl)phosphonic acid of the formula  wherein R is a substituted or unsubstituted hydrocarbyl or heterocyclic group, R 1  is H or an equivalent of a salt-forming cation, or a substituted or unsubstituted hydrocarbyl or heterocyclic group or R and R 1  together form a hydrocarbylene e.g. methylene, ethylene, propylene or arylene bridge, and (b) derivatives of (-) (cis - 1,2 - epoxypropyl)phosphonic acid of the formula in which Y is an -OR 2  group or a halogen atom where R 2  is C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, aryl, substituted aryl, aralkyl, or substituted aralkyl and Y<SP>1</SP> is a halogen atom. The hydrocarbyl or substituted hydrocarbyl radicals may be substituted or unsubstituted alkyl radicals, or alkenyl, alkynyl, cycloaliphatic, araliphatic or aromatic radicals. The esters (I) may be prepared (a) by reacting a heavy metal (preferably silver) salt of (-)(cis - 1,2 - epoxypropyl)phos. phonic acid with a halide (R Hal); (b) by reacting the free phosphonic acid with a diazoalkane or diazoaralkane, (c) by reacting (-)(cis - 1,2- epoxypropyl)phosphonic dichloride with an alcohol or phenol (ROH) conveniently in the presence of a tertiary amine, this reaction being operable to prepare mono- or di-esters by using appropriate molar proportions of the reactants, (d) by reacting a salt of the phosphonic, e.g. an alkali metal or amine salt with an alcohol or thiol in the presence of an activating agent e.g. a carbodiimide such as dicyclohexyl carbodiimide, an arylsulphonyl halide, e.g. 2,4,6- trimethylsulphonyl chloride or trichloroacetonitrile. Monoesters may also be obtained by reacting a diester with a dilute base e.g. NaOH or KOH at a pH of 8-13 to remove one ester residue. Mixed esters may be prepared (a) by reacting a (-)(cis - 1,2 - epoxypropyl)monoester phosphonohalidate with an alcohol or thiol in the presence of an acid binding agent, e.g. a tertiary amine, or (b) by converting a monoester mono-alkali metal salt to the free acid and then to the mono-silver salt by reaction with a soluble silver salt and then reacting the monosilver salt monoester with a hydrocarbyl halide the hydrocarbon residue of which is different from that of the monoester radical. Diesters may also be obtained by treatment of a 1 - chloro - 2- hydroxypropyl phosphonic acid diester with a base. The (-)(cis - 1,2 epoxypropyl)phosphonic dihalides may be obtained by reacting the free phosphonic acid with a halogenating agent, preferably a thionyl halide such as thionyl chloride. The ester and ester salt products have antibacterial properties and the diester products may be converted to monoamide derivatives of (-)(cis - 1,2 - epoxypropyl)phosphonic acid salts thereof, e.g. by hydrolysing with alkali to form a monoester which is reacted with thionyl chloride to form the monoester chloride, the latter being then reacted with an amine to form the monoester monoamide which on hydrolysis with an alkali, e.g. NaOH, forms a salt of the monoamide. The diesters may be converted to the free phosphonic acid or salts thereof by various methods e.g. as disclosed in Specification No. 1,236,955/68. Di - n - butyl cis propenylphosphonate is obtained by hydrogenation of di - n - butyl propynyl phosphonate and is converted to cispropenyl phosphonic acid by treatment with concentrated HC1 followed by the addition of water and the free acid after neutralization with NB 4 OH to pH 5À5 is epoxidized to form the ammonium salt of, ()(cis - 1,2 - epoxypropyl)- phosphonic acid which is then resolved by use of (+ )α - phenethylamine to form the (+)α- phenylethylamine salt of (-)(cis - 1,2 - epoxypropyl)phosphonic acid from which the free phosphonic acid is obtained by passing a solution of the salt over an ion exchange resin on the H<SP>+</SP> cycle. Di - n - butyl propynylphosphonate is obtained by reacting methylacetylene magnesium bromide with di - n - butyl chlorophosphonate, a detailed example being given.