Patent GB-1266611-A (GB)
IPC: A01N57/20
Filed: 1969-05-12
Abstract: 1,266,611. Preparing (cis-1,2-epoxypropyl)- phosphonic acid and derivatives thereof. MERCK & CO. Inc. 12 May, 1969 [15 May, 1968; 27 Aug., 1968; 25 April, 1969], No. 23990/69. Headings C2C and C2P. (Cis-1,2-epoxypropyl)-phosphonic acid or a salt or ester thereof (I) is obtained by treating a 1,2-disubstituted n-propyl phosphonic acid or salt or ester thereof with a reagent capable of effecting epoxide ring closure, at least one of the substituents being OH or functionally equivalent oxygen-containing radical and the other of the said substituents being any leaving group that can be displaced under the reaction conditions. The starting phosphonic compound may have the formula CH 3 CHX<SP>1</SP>CHXP(O)(OR) 2  (II) wherein each R is H or a C 1 -C 5  alkyl, C 2 -C 5  alkenyl, mononuclear aryl or -aralkyl, a metal of Group Ia, IIa, Ib or IIb of the Periodic Table, an amine salt-forming cation, and X and X<SP>1</SP> are halo, hydroxy, azido, C 1 -C 5  alkanoyloxy, trihalomethyl substituted C 1 -C 5  alkanoyloxy, C 1 -C 5  alkylsulphonyloxy, aryl (alkaryl- or aralkyl-) sulphonyloxy, tri-(C 1 -C 5  alkyl) quaternary ammonium salt-forming group, N- cycloalkyl (or N-phenyl) di-(C 1 -C 5  alkyl) quaternary ammonium salt-forming group, di- (C 1 -C 5 ) alkyl sulphonium salt-forming group, aryloxy, aralkoxy, dialkoxyphosphino, N- (alkanesulphonyl) alkylamino or N-alkarylsulphonyl cycloalkylamino with the proviso that at least one of X and X<SP>1</SP> is hydroxy or functionally equivalent oxygen-containing radical. The ring closure may be effected by treating the starting material (which may be formed in situ) with (1) an acid, e.g. H 2 SO 4 , peracetic acid or nitrous acid; with a Lewis acid such as BF 3  or P 2 O 5 ; or with hexafluoroacetone in a protonic acid such as a mineral acid or p-toluene sulphonic acid, (2) with a solution of a metal or metal compound capable of forming metal ions in a neutral or acidic solution, e.g. with silver acetate in a mineral acid, e.g. HCl, (3) with a base having a pH equal to or greater than 7, or (4) by passing a solution of the starting material through an ion exchange column on the basic cycle. Different optically active isomers are obtained according to the particular optically active isomer used as starting material and epoxy formation occurs with a net inversion of the configuration at the carbon atom bearing the leaving substituent X or X<SP>1</SP>. The invention is more particularly directed to the production of () and (-) (cis-1,2-epoxypropyl) phosphonic acid derivatives and when the product is an ester it may be converted to the free acid which may then be converted to a salt especially an alkali metal or alkaline earth metal salt by treatment with a base. The free () and (-) cis-1,2-epoxypropyl phosphonic acid and salts thereof are useful antibacterial agents and may be formulated with diluents and conventional additives. They may be administered orally in capsule or tablet form or in a liquid solution or suspension or parenterally by injection in a sterile excipient. Several methods are described for preparing various types of starting materials of Formula II. Thus, the (1-hydroxy-2-organosulphonyl. oxypropyl) phosphonic compounds may be prepared by treating a compound: wherein R<SP>1</SP> is alkyl, aryl or aralkyl and X<SP>3</SP> is halogen, e.g. Cl or Br, with a phosphite P(OR) 3  and then reducing the resulting intermediate CH 3 CH(OSO 2 R<SP>1</SP>)C(O)P(O)(OR) 2  with a reducing agent, e.g. NaBH 4 . Compounds of Formula II in which X<SP>1</SP> is a dialkylsulphonium salt-forming radical may be obtained by the following reaction scheme: wherein R<SP>2</SP> is C 1 -C 5  alkyl, R<SP>1</SP>Z is an alkyl halide and Z<SP>(-)</SP> is a halogen anion. Starting compounds in which the sulphonium radical is bonded to the 1-carbon atom may be obtained by the following reaction: wherein R<SP>2</SP>SZ is a C 1 -C 5  alkylsulphenyl halide, R<SP>2</SP>X is a C 1 -C 5  alkyl halide, R<SP>3</SP> is C 1 -C 5  alkyl, R<SP>3</SP>COOM is a metal salt of a C 1 -C 5  alkanoic acid, X# is a halogen anion and R, R<SP>2</SP> and Z are as defined above. Compounds of the type in which an oxygen-containing radical is bonded to the 2-C atom, e.g. as in (IIb) below may be obtained by a reaction of the type: wherein R<SP>4</SP> is C 1 -C 5  alkyl, trihalomethyl, or trihalomethyl-substituted C 1 -C 5  alkyl. Compounds in which X is halogen in Formula II may be obtained by either (a) the following reaction: wherein R<SP>5</SP> is a hydrocarbyl radical or an alkali metal or alkaline earth metal and wherein the N-bromo-succinimide may be replaced by other functionally equivalent halogenating agents; or (b) by the following reaction sequences wherein X<SP>4</SP> is a halogen atom, this method being particularly suitable for the preparation of the () threo (1-halo-2-hydroxypropyl) phosphonic acid (IIj) which may then be converted to the (+) threo derivative (IIm) by resolution as shown. Starting compounds in which the leaving group X is a substituted amino radical may be obtained by the following reaction: wherein R<SP>6</SP> is alkyl or mononuclear cycloalkyl, X<SP>2</SP> is a halogenating agent, H+ is the cation derived from an acid, and the chloroform is used as reaction medium for the halogenating agent. In another method the above intermediate compound VI is converted to the compound IIp below by the following reaction: wherein M, R and R<SP>6</SP> are as defined above and wherein other appropriate sulphonyl halides may also be used instead of the reagent shown. Compounds (II) in which the oxygen-containing radical is bonded to the 1-carbon atom may be obtained by the following reaction: with further reaction of the OH group on the 1-carbon atom with an appropriate organic acid halide if required. The starting compounds in which R is C 1 -C 5  alkyl, X is OH and X<SP>1</SP> is tri- (C 1 - 5  alkyl) quaternary ammonium or a di- (C 1 -C 5  alkyl) sulphonium salt forming group may be prepared by the latter reaction using compounds in which X<SP>1</SP> is NH 2  or (C 1 -C 5  alkyl) mercapto and then treating the product with a C 1 -C 5  alkyl halide. Compounds II may also be obtained by reacting a suitably substituted propionyl halide with a phosphite triester to form a (2-X<SP>1</SP>-substituted propionyl) phosphonate and then reducing the latter, e.g. with an alkali metal borohydride: Threo dimethyl - [1 - (phenylamino) - 2 - hydroxyprepyl] phosphonate is obtained by reacting cis-1-propenyl phosphonate with phenyl azide to form (1,2 - N - phenyliminopropyl) phosphonate and then treating the latter with 2N H 2 SO 4  at 40 C. Treatment of the product with methyl iodide in methanol, removal of the methanol, addition of benzene and its evaporation to azeotrope the reaction mixture to dryness, followed by further reaction with methyl iodide in benzene yields the corresponding N-phenyl dimethylammonium iodide derivative. Benzyl-2-tosyloxypropionate is obtained by reacting benzyl lactate (dissolved in benzene) with p-toluene sulphonyl chloride in the presence of pyridine and on hydrogenation over a Pd on charcoal catalyst yields 2-tosyloxypropionic acid which is then treated with thionyl chloride to form 2-tosyloxypropionyl chloride.