Patent GB-1227077-A (GB)
IPC: C07F9/653
Filed: 1969-05-12
Abstract: 1,227,077. Preparing cis-(1,2 - epoxypropyl) phosphonic acid and intermediates therefor. MERCK & CO. Inc. 12 May, 1969 [15 May, 1968], No. 23978/69. Heading C2C. (Cis- 1 ,2-epoxypropyl) phosphonic acid or an ester or salt thereof is obtained by eliminating S0 2 , S0 3 , CO or N 2  from a cis-compound of the formula wherein each R is H or a substituted or unsubstituted aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbyl or heterocyclic radical, the two R groups being similar or dissimilar and Z is or from a salt of such a compound in which at least one of R is H. Suitable salts are e.g. the mono- and di- Na or K salts, Ca, Mg, Ag, Fe and NH 4  salts, and amine salts including salts of biologically active amines such as erythromycin or novobiscin. The elimination of Z may be effected by pyrolyzing or heating, e.g. at above 80 C., or by U.V. light. In carrying out the pyrolysis the starting material can be heated directly or may be dissolved in an inert solvent or suspended in a suspending agent, e.g. a mineral oil and the reaction is generally complete when no more S0 2 , S0 3 , CO or N 2  is evolved from the reaction mixture. The treatment with U.V. light such as that produced by a mercury vapour lamp may be conducted on a solution or suspension of the starting material which may have been sensitized to U.V. light by the addition of a photosensitizing agent such as benzophenone or acetophenone and the irradiation is suitably conducted at from -10 to 50 C. The starting material may be the () cis isomer or a cis/trans mixture and the corresponding product isomer is obtained. A mixture of the cis and trans isomers of the starting material can be separated into the cis and trans isomers by known techniques and any () trans isomer of the product can be converted to the () cis isomer by U.V. light. If the starting material is an ester the resulting ester product can be converted to the free acid or salt thereof by acid or base hydrolysis, by enzymatic or light catalysed hydrolysis, by hydrolysis via a trimethyl silyl derivative, or by hydrogenolysis or by treatment with a sodium tertiary amine. The racemic end mixture may be resolved into the optically active forms. The () compounds have antibacterial properties being especially useful in salt form. The starting materials (I) in which Z is -SO 2 - can be obtained by reacting a compound of the formula with a sulphide, e.g. sodium sulphide, to form a compound of the formula which is then oxidized, e.g. with potassium permanganate or H 2 0 2  to form the desired product. Compounds (I) in which Z is -O-SO 2 - can be obtained by reacting CH 3 CH(OH)S0 3 Na with O=CH-P(O)(OR) 2  in the presence of acetic anhydride followed by addition of a base. Compounds (I) in which Z is CO and R is H can be obtained by converting phosphonoacetic acid e.g. by treatment with thionyl chloride and then with bromine to form Cl 2 -P(O)CHBrCOCl which is diazotized with diazoethane to form the 3-diazo compound Cl 2 P(O)CHBrCOC(CH 3 ) = N 2  which is then cyclized by treatment with an aqueous solution of a carbonate and an acid, e.g. acetic acid. Compounds (I) in which Z is N=N are obtained by reacting acetaldehyde with a hydroxymethyl phosphonic acid compound and a chlorinating agent to form CH 3 CHClOCH 2 P(O)(OR) 2 , reacting the latter with a free radical halogenating agent such as t-butyl hypochlorite at about 40 C. to form CH 3 CHClOCH(Cl)P(O)(OR) 2  which is reacted with hydrazine to yield a product of the formula and finally oxidizing the latter, e.g. by treatment with mercuric oxide or cupric chloride in a solvent such as an ether or hydrocarbon. The formyl - phosphonate compounds O = CHP(O)(OR) 2  may be obtained by ozonizing vinyl phosphonic acid or ester or salt thereof.