Patent GB-1236955-A (GB)
Title: Preparation of (cis-1,2-epoxypropyl)phosphonic acid and salts thereof
Inventor: SLETZINGER MEYER
IPC: C12P17/02
Filed: 1968-05-15
Abstract: 1,236,955. Converting (cis 1,2-epoxypropyl)- phosphonic acid derivatives to the free phosphonic acid or salts thereof. MERCK & CO. Inc. 17 April, 1969, No. 23137/68. Heading C2C. A (cis 1,2-epoxypropyl) phosphonic or phosphonothioic acid halide, ester-halide, guanidide, hydrazide, imide, azide, ureide, ester, thioester amide, ester-amide, anhydride, N-substituted amide derivative, or salt thereof is converted to (cis-1,2-epoxypropyl) phosphonic acid or a salt thereof by subjecting said derivative to at least one process as defined below using at least one agent capable of effecting such conversion. The invention also includes the conversion of (1) a cyclic dianhydride of the formula wherein X and X<SP>1</SP> are an O or S atom and (2) of a pyrophosphonic acid derivative of the formula wherein each of X and X<SP>1</SP> is an O or S atom and Q is OR 3  or SR 3  wherein R 3  is H or a hydrocarbyl group to (cis-1,2-epoxypropyl)- phosphonic acid or a salt thereof by subjecting the dianhydride or the pyrophosphonic acid derivative to at least one process as defined below using at least one agent capable of effecting such conversion. The derivatives which are converted can be a mixture of enantiomers or a particular enantiomeric form and representative derivatives of the first mentioned type are compounds of the formula wherein X is O or S and each of Y and Z is an -OR, -SR, -NR.R 2 , -NRCH(R)COOH, -NROR, -NR-NR 1 R 2 , NR-N =CR 1 R 2 , -NR-C(: NR)-NR 1 R 2 , -NR-C(X).XR, -NHC(: X)NR 1 R 2 , -NC=X, -O-C(: O)R or -N 3  group or a halogen atom, R is H or a hydrocarbyl or heterocyclic radical either of which may be substituted and each of R 1  and R 2  is H or a substituted or unsubstituted hydrocarbyl radical or an alkoxy or acyl radical, (with the proviso that Y and Z may not both be OH) or NR 1 R 2  is the residue of a heterocyclic secondary amine, or Y and Z are joined together by the residue of a polyfunctional hydrocarbyl compound, e.g. an alkylene, aralkylene or arylene polyamine, monoethanolamine, catechol, salicylic acid or succinic acid. Specified processes are hydrolysis and/or reduction or treatment with a photochemical, displacement or oxidizing agent, thermal cleavage, and interesterification followed by hydrolysis, according to the derivative to be converted and more than one process is necessary in the case of certain derivatives. Hydrolysis may be effected with water, an aqueous base or acid, or an enzyme, or by photochemical means and salts may be obtained, e.g. by the addition of a base, metal oxide or metal salt to the acid formed. In the case of the C 1 -C 5  alkyl esters they can be converted to the silane mono- or di-esters by reaction with a halo-trialkyl silane and the resulting silane esters then hydrolysed with water to form the phosphonic acid. Several hydrolysis agents are specified and when the halide derivative is a fluoride the hydrolysis is preferably effected with hydroxylamine in aqueous medium at a pH of 5 to 8. Alkaline hydrolysis is generally preferred and is suitable, e.g. for cleaving the halide and amide derivatives and mixed anhydrides of the type covered by Formula (I) and for the conversion of the pyrophosphonic derivatives of Formula (III). The dianhydrides of Formula (II) (e.g. where X and X<SP>1</SP> are each S) may be converted to the epoxyphosphonic acid by aqueous hydrolysis in the presence of an inorganic base, e.g. CaO, as catalyst. When a dialkyl ester of Formula (I) type is used alkaline hydrolysis usually yields the monoalkyl ester which is then further hydrolysed, e.g. by photochemical means or by acidic agents to remove the remaining ester group. Carboxylic acids or water may be used for hydrolysing the halide derivatives and organic and mineral acids may be used for removing hydrocarbyl and substituted hydrocarbyl ester groups. The thioesters (where X and/or Y is SR) may be cleaved by treatment with aqueous mineral acid or by reaction with an aqueous heavy metal salt, e.g. mercury or silver acetate or carbonate, and the latter may also be used to convert the cyclic dianhydrides of Formula (II) where X is O and X<SP>1</SP> is S to form the free phosphonic acid which is recovered as a salt. Pyrophosphonic acids of Formula (III) may also be converted by treatment with acids. Amides of type (I) may also be converted by means of water or an aqueous mineral acid or by treatment with a strongly acidic ion-exchange resin and primary and secondary amide sub - stituents may also be replaced by OH groups by reaction with nitrous acid. Enzymatic hydrolysis is suitable for converting the C 1 -C 5  alkyl and C 2 -C 5  alkenyl mono-esters and amides, suitable enzyme sources being homogenized cotton leaf worm and mammalian tissue, mammalian plasma, aliesterases derived from animal tissues, plants, yeasts and molds, acid phosphatases derived from animal tissues, plants, yeasts and bacteria, phosphodiesterases and phosphotriesterases. Catalytic hydrogenolysis is useful for converting various esters and for the conversion of cyclic dianhydrides of Formula (II) (e.g. where X and X<SP>1</SP> = oxygen) to the free acid or salt. An ester group may be replaced by a more easily removable ester group, by ester interchange, thus the diethyl ester may be reacted with benzyl bromide to form the dibenzyl ester which is then converted by hydrogenolysis. Chemical reduction may also be used, e.g. by using activated Zn/Cu, Raney nickel and alkali metal/base systems such as sodium in ammonia or an amine, e.g. trimethylamine. When a photochemical reagent such as U.V. light is used to effect the conversion the process is preferably conducted in a basic medium, e.g. aqueous ammonia, methylamine or a tertiary base. Certain mono esters, e.g. methyl or benzyl esters may be converted by the use of displacement agents which may be ionic salts or tertiary amines. Oxidizing agents may be used to cleave cyclic esters, e.g. the cyclic o-phenylene ester which may be converted by oxidation using a bromine-water solution, a reducing agent such as sodium bisulphite being used to reduce excess bromine. Oxidizing agents are also used to convert derivatives of Formula (I) wherein X is sulphur to the corresponding phosphonic acid derivatives and for the conversion of pyrophosphonothioates of Formula (III) in which X is sulphur, Q<SP>1</SP> is oxygen and Q is OR 3 . Compounds of Formula (III) in which X and X<SP>1</SP> are sulphur and Q is SR 3  where R 3  is H or hydrocarbyl may be converted to the epoxyphosphonic acid or salt thereof by first using a hydrolysing agent and then an oxidizing agent. The () and ( - ) forms of (cis-1,2-epoxypropyl) phosphonic acid and salts thereof are useful antimicrobial agents. Bis - (2 - nitroethyl)( - )(cis 1,2 - epoxy. propyl)-phosphonic acid is prepared by adding racemic bis-(2-aminoethyl)(cis 1,2-epoxypropyl)- phosphonate to (+) tartaric acid in isopropanolwater, cooling, filtering off the precipitated (- )(cis 1,2 - epoxypropyl) - phosphonyl- O,O<SP>1</SP> - bis - 2 - ethylammonium (+) tartrate, purifying the latter and then treating with a solution of sodium nitrite and sodium cobaltinitrite in water and benzene to form bis (2- nitroethyl)(- )(cis 1,2 - epoxypropyl) phosphonate. N,N<SP>1</SP> - bis - [(+) - α - phenethyl](-)(cis-1,2- epoxypropyl) - phosphonodiamidate is prepared by treating (cis - 1,2 - epoxypropyl) phosphonic dichloride with N-methyl morpholine and (+ )-α-phenethylamine in benzene and filtering off the N-methylmorpholine hydrochloride formed. Mono - ( - )menthyl ( - )(cis - 1,2 - epoxypropyl) phosphonate is obtained by passing a methanol solution of racemic monobenzylammonium (cis - 1,2 - epoxypropyl) phosphonate through a strongly acidic polystyrene ion exchange resin on the acid cycle, dropping the effluent into pyridine, and after washing with methanol and vacuum concentration treating with (- ) menthol in the presence of a further amount of pyridine and toluene in which N,N<SP>1</SP>-dicyclohexylcarbodiimide is dissolved. When enantiomeric mixtures of the (cis 1,2- epoxypropyl) phosphonic acid or salt thereof are produced the mixture can be resolved or separated, e.g. by forming salts with optically active bases. The (cis 1,2 - epoxypropyl) phosphonic acid ester and amide derivatives can be obtained by epoxidation of the corresponding cis-propenyl phosphonic acid compound or by ring closure (e.g. by treatment with a base) of a 1,2-disubstituted ethyl phosphonic acid wherein one substituent is an OH radical or functionally equivalent oxy substituent, e.g. acyloxy, and the second substituent is one which can be removed under the ring closing conditions, several such substituents being specified. The cis-1-propenyl phosphonic acid derivatives may be obtained by reacting cis-1-propenyl phosphonic dihalide with an appropriate reagent, e.g. with an alcohol, thiol, amine, in one or more steps, or with silver acetate. Cyclic dianhydrides of Formula (II) where X and X<SP>1</SP>=O are obtained by reacting one mole of the dihalide with an equimolar amount of water at below - 10 C. and epoxidizing and when X and X<SP>1</SP> are sulphur the dianhydride is obtained by reducing the cis-1-propenyl phosphonic dihalide with lithium aluminium hydride, then heating with sulphur and finally epoxidizing. The pyrophosphonic acid derivatives of Formula (III), e.g. wherein X<SP>1</SP> is O, one X is O and the other is S, are obtained by reacting 2 moles of a propenyl phosphonic halidate with H 2 S, and epoxidizing the product. Cis - 1,2 - epoxypropyl phosphonothioic dichloride is obtained by reacting cis-1-propenyl phosphonic dichloride with P 2 S 5  followed by epoxidation of the product. It may be reacted with methanol in the presence of triethylamine to form the dimethyl ester. Bis - (cis - 1,2 - epoxypropyl) - pyrophosphonic acid is obtained by heating cis-propenyl phosphonic acid under