Patent GB-1239988-A (GB)
Title: Cis-propenyl phosphonic acid and derivatives thereof
Inventor: CHRISTENSEN BURTON GRANT
IPC: C07F9/6571
Filed: 1968-10-24
Abstract: 1,239,988. Cis - propenyl phosphonic acid and derivatives thereof. MERCK & CO. Inc. 24 Oct., 1968 [30 Oct., 1967; 15 May, 1968], No. 50636/68. Heading C2C. The invention comprises cis - propenyl phosphonic acid and derivatives thereof of the formula wherein X is an O or S atom, Y is -OR, -SR, halo, or -NR 1 R 2  or other substituted amino group, Z is -OR, SR, halo, or -NR 1 R 2  or other substituted amino group, and each of R, R 1  and R 2  is a hydrogen atom or a substituted or unsubstituted hydrocarbyl or heterocyclic radical, or an acyl radical, and organic or inorganic salts of such compounds in which one or both of Y and Z is an OH group. The invention also includes such compounds but in which NR 1 R 2  is a heterocyclic ring and also such compounds in which Y and Z together from a bridged arylene or substituted or unsubstituted alkylene radical which may contain an interrupting, hetero atom e.g. -S- or -NH- and also compounds in which Y and Z together for an alkylene or arylene bridge and one of Y and Z is nitrogencontaining. When the radical NR 1 R 2  is a heterocyclic radical it may be e.g. morpholinyl, thiomorpholinyl or piperidinyl. The acid, salt and ester products may be obtained by the selective hydrogenation of cis - propynyl phosphonic acid or ester or salt thereof in the presence of a solvent e.g. an inert organic solvent such as a C 1 -C 6  alkanol, ether, benzene, toluene, ethyl acetate or methylene chloride. The hydrogenation is suitably effected in the presence of a hydrogenation catalyst such as Pd, e.g. palladium on calcium carbonate, or a Raney nickel catalyst, and is preferably stopped when one mole of hydrogen has been taken up per mole of the propynyl compound. A small amount of a poisoning agent, e.g. lead acetate for the Pd catalyst, and zinc acetate and/or an organic base for the Raney nickel catalyst, may be added. The dihalides wherein Y and Z are halo are prepared by treating the free phosphonic acid with 2 molecular proportions of a halogenating agent e.g. a thionyl halide, PCl 5  or phosphonyl fluoro bromide in an organic solvent and the compounds where Y and/or Z are -OR or -OR are obtained by treating the dihalide with an appropriate molar amount of a hydroxy compound or mercaptan to yield the diester or monoester halide. The amides (Y and/or Z are NR 1 R 2 ) are prepared by reacting the dihalide with 1 or 2 moles of ammonia or a primary or secondary amine or other amino compound preferably in the presence of a tertiary base to give the phosphonohalidic amides or the diamides. The amide esters or amide thioesters may be obtained by reacting the phosphonohalidic amides with an appropriate hydroxy compound or thiol. Compounds in which X is sulphur may be obtained analogously by using cis-propenyl phosphonothioic dihalide as starting material, the latter being obtainable by reacting cis-propenyl phosphonic dihalide with P 2 S 5 . The products (I) which are halides, phosphonamides or thioates may also be obtained by catalytic hydrogenation of the corresponding propynyl phosphonic halide, phosphonoamide or phosphonothioate, the starting propynyl compounds being obtainable by reacting a metal acetylene Grignard reagent such as a metal acetylene magnesium bromide with the appropriate chlorophosphonic halide, chlorophosphonothioate or chlorophosphonicamide. Di-t-butyl cis-propenyl phosphonate may also be obtained by hydrogenating di-tbutyl-propodienyl phosphonate in the presence of a Pd or carbon catalyst and in the presence of a solvent. The products in which at least one of Y and Z is other than OH may be hydrolysed, e.g. with acid, to produce cis-propenylphosphonic acid or salt thereof. The products (I) may be epoxidized to form the corresponding ()(cis - 1,2 - epoxypropyl)phosphonic acid compounds which may then be resolved, or if Y and/or Z is other than OH they may be hydrolysed prior to epoxidation. Bis - (cis - propenyl)pyrophosphonic acid is obtained by heating cis-propenyl phosphonic acid to 200 C. under a nitrogen atmosphere at 200 mm. Hg. pressure. Cic - propenyl phosphonic acid cyclic dianhydride is obtained by adding water to cispropenyl phosphonic dichloride at below 10 C. and then heating to 120 C. under 50 mm. pressure. Cis - propenylisohypophosphoric acid is obtained in the form of its sodium salt by reacting diethylchlorophosphate with ethyl cis-propenyl phosphonate in ethanol and then adding NaOH. When X in Formula I is a sulphur atom the S atom may be replaced by O by treating the sulphur-containing compound with peroxytrifluoroacetic acid or with bromine water and when Y and/or Z are -SR the products may be converted to phosphonates by treatment with silver nitrate. The ()(cis - 1,2 - epoxypropyl)phosphonic acid salts obtainable from the products (I) have antibacterial properties and may be resolved into the optical enantiomers by forming a salt with an optically active amine, separating the diastereomers and regeneration of the enantiomeric salts.