Patent GB-1259798-A (GB)
Title: Preparation and separation of diastereoisomers of (cis-1,2-epoxypropyl)-phosphonic acid derivatives
Inventor: SHUMAN RICHARD FERRIS
IPC: C07F9/655
Filed: 1969-05-12
Abstract: 1,259,798. Preparing and separating (cis-1,2- epoxypropyl) phosphonic acid derivatives. MERCK & CO. Inc. 12 May, 1969 [15 May, 1968], No. 23987/69. Heading C2P. Diastereoisomers of (cis - 1,2 - epoxypropyl) phosphonic (or thiophosphonic) acid derivatives are separated by (a) forming a diastereoisomeric mixture of (1) an ester or amide of (cis- 1,2 - epoxypropyl) - phosphonic (or thiophosphonic) acid containing an optically active ester or amide group or (2) of a salt of an optically active acid or base with an ester or amide of (cis - 1,2 - epoxypropyl)phosphonic or thiophosphonic acid containing a basic or acidic group respectively, the (cis-1,2-epoxypropyl)- phosphonic or thiophosphonic acid residue being present in the diastereoisomeric mixture in both its optically active forms by starting from a mixture of enantiomers of (cis-1,2-epoxypropyl)phosphonic or thiophosphonic acid or a salt or an ester or amide thereof, and (b) separating a diastereoisomer from the diastereoisomeric mixture. The diastereoisomers may be compounds of the formula wherein X is O or S, Y is halo, OR, SR or NRR, and Z is OR<SP>1</SP>, SR<SP>1</SP> or NR<SP>1</SP>R 1  wherein R is a substituted or unsubstituted hydrocarbyl or heterocyclic group containing an optically active centre and each of R<SP>1</SP> and R 1  is H or a substituted or unsubstituted hydrocarbyl or heterocyclic group with the proviso that whenY is halo, R<SP>1</SP> is a substituted or unsubstituted hydrocarbyl or heterocyclic group containing an optically active centre. The optically active consituent of the ester group or groups may be derived from an optically active alcohol and the optically active amides may be derived from an optically active primary or secondary amine. The diastereoisomers after separation can be converted to the (+) or (-) enantiomer of cis-1,2-epoxypropyl phosphonic acid or its salts. The individual diastereoisomeric esters can be separated from the mixture thereof by fractional crystallization, chromatography, ion exchange resin procedures or by inclusion or cloth rate compounds. When the diastereoisomers are salts of optically active acids or bases with an ester or amide of (cis-1,2,-epoxypropyl)phosphonic or thiophosphonic acid containing a basic or acidic group respectively the acidic group may be a carboxy, sulphonic, sulphinic, phosphonic or phosphonous acid group and such ester or amide compounds can be prepared (1) by reacting anhydrides (including mono- and dihalides) of (cis-1,2-epoxypropyl) phosphonic acid with strong acids with appropriate alcohols, thio-alcohols, amines, metal alcoholates or thioalcoholates, which also carry an acidic group or a group convertible to an acidic group, (2) by reacting (cis-1,2-epoxypropyl) phosphonic acid or basic salt thereof with an alcohol, thioalcohol or amine carrying such acidic group, or (3) by reacting a metal salt of the phosphonic acid with an appropriate ester of a strong acid (e.g. chloroacetic acid) or with another derivative, the ester or said other derivative also carrying an acidic group or group convertible to an acid group, or (4) by reacting (cis-1,2- epoxypropyl)phosphonic acid or metal salt thereof with alkenes or alkynes in which one of the carbons bearing the unsaturation is also substituted with an electron withdrawing or electronegative atom or group and which also carries an acid group or a group convertible to an acid group. When the diastereoisomers are salts of optically active acids with an ester or amide of (cis-1,2-epoxypropyl) phosphonie acid the said ester or amide may be obtained by a method as in (1) to (4) above but using the corresponding organic reactant containing a basic (e.g. amino) group instead of an acid group. A list of optically active amines (a) and acids (b) suitable for forming the optically acid salts is given and several optically active alcohols (c) and amines (d) suitable for preparing the esters or amides are also specified. In the examples given the optically active amines (a) used include (+) and (-) α-phenethylamine for (a) and (+) α-phenethylamine for (d), (+) tartaric acid for (b) and (-) menthol for (c), the ester used in conjunction with the (+) tartaric acid being racemic bis(2-aminoethyl)(cis-1,2-epoxypropyl) phosphonic acid which is obtained by passing racemic monobenzylammonium (cis- 1,2-epoxypropyl) phosphonate in methanol through a strongly acidic ion exchange resin on the H<SP>+</SP> cycle, collecting the effluent in pyridine, removing the methanol and then adding ethyleneimine and stirring the mixture at 50‹ C., the pyridine being finally removed to leave the racemic diester. By using ethylene episulphide instead of ethyleneimine in the above process racemic - bis(2 - mercaptoethyl)(cis - 1,2 - epoxypropyl) phosphonate is obtained which may be  reacted with H 2 O 2  and NaHCO 3  in water to form a solution containing racemic disodium  (cis - 1,2 - epoxypropyl) - phosphonyl - O,O<SP>1</SP>- bis(2 - ethylsulphonate) which on treatment with (+) phenethylamine hydrochloride in aqueous solution gives a mixture of diastereoisomeric salts which is recovered by filtering the hot aqueous slurry and the salts then separated by cooling the filtrate to 0‹ C. and filtering. The following compounds (inter alia) are also prepared in various steps in the examples given: (1) bis-(2-nitroethyl)(-)(cis-1,2-epoxypropyl) phosphonate by adding a solution of sodium nitrate and sodium cobaltinitrate to (cis - 1,2 - epoxypropyl) phosphonyl - O,O<SP>1</SP>- bis - 2 - ethyl ammonium (+) tartrate; (2) N- benzoyl - N - (+) - α - phenethyl (-) (cis - 1,2- epoxypropyl)-phosphors chloridate from racemic (cis-1,2-epoxypropyl) phosphonic dichloride, (+)-α-phenethylamine and benzoyl chloride, (3) N - methyl - N(+) - α - phenethyl - S- ethyl(-)(cis - 1,2 - epoxypropyl) - thiophosphoramidate from the phosphonic dichloride and N-methyl-(+)-α-phenethylamine with subsequent reaction with potassium ethane thiolate, (4) sodium 2-nitroethyl - (-) (cis - 1,2 - epoxypropyl) phosphonate from sodium nitrite, sodium cobaltinitrite and 2-aminoethyl(-)(cis- 1,2 - epoxypropyl) - phosphonate. The (-)- (cis - 1,2 - epoxypropyl) phosphonic acid and salts thereof obtainable by the invention have antibiotic and antiseptic properties and may be administered orally or parenterally in admixture with suitable diluents and other usual pharmaceutical additives.