Patent GB-1226472-A (GB)
IPC: C07F9/38
Filed: 1969-05-12
Abstract: 1,226,472. Epoxidizing optically active derivatives of cis-propenyl phosphonic and thiophosphonic acids. MERCK & CO. Inc. 12 May, 1969 [15 May, 1968], No. 23965/69. Heading C2C. An optically active derivative of cis-propenyl phosphonic or thiophosphonic is reacted with an epoxidizing agent and a derivative of an optical form of (cis-1,2-epoxypropyl)phosphonic or thiophosphonic acid is recovered from the reaction product. The invention also includes reacting an optically active derivative of cispropenyl-phosphonic or thiophosphonic acid with an epoxidizing agent to form a mixture of diastereoisomers of a derivative of (cis-1,2- epoxypropyl)phosphonic or thiophosphonic acid, said mixture containing a preponderance of one of the diastereoisomers. The optically active derivative used as starting material may have an optically active phosphorus centre and have the general formula CH 3 CH = CH-P( :X)(Y)(Z) wherein X is O or S, Y and Z are different, Y is OR, SR, NRR 1  or halogen, Z is OR<SP>1</SP>, SR<SP>1</SP>, NR<SP>1</SP>R 1  or halogen, R is a univalent substituted or unsubstituted hydrocarbyl or heterocyclic group and R 1  and R<SP>1</SP> are hydrogen or a univalent substituted or unsubstituted hydrocarbyl or heterocyclic group. The optically active starting materials may alternatively have attached to the phosphorus atom a substituent containing an optically active centre or may contain an optically active centre substituted on the terminal methyl group of the acid. Compounds of the latter type may have the formula CH 2 (B)CH 2  = CH-P(:X)(Y)(Z) wherein X, Y and Z are as defined above and B is a group containing an optically active centre which is convertible to hydrogen. Thus diphenyl propenyl phosphonate may be brominated to produce diphenyl 3-bromopropenyl phosphonate which is then reacted with an optically active amino acid derivative, e.g. with sodium L-N-acetyl ethyl cysteinate in ethanol to form S-[3-(diphenoxyphosphinyl)allyl]-N- acetyl-L-cysteine ethyl ester which is then epoxidized and the resulting epoxide treated with Raney nickel to yield a mixture from which an optically active form of diphenyl (cis-1,2- epoxypropyl)phosphonate is recovered. Similarly when the D-cysteine derivative is used the other optically active form of diphenyl (cis-1,2- epoxypropyl)phosphonate is recovered. When the derivative contains an optically active phosphorus atom the (+) and ( - ) enantiomers of such derivative can be separated by forming a diastereoisomer of such derivative, e.g. by reaction of a derivative containing a basic or acidic ester-forming group with an optically active acid or base respectively, or by forming the OR group from an optically active alcohol and separating the diastereoisomers in each case. Thus, the diastereoisomers of (1) the (+) 10- camphorsulphonic acid salt of benzyl 2-aminoethyl cis-propenyl phosphonate, (2) benzyl L- (2 - carbobenzyloxyamine - 2 - ethoxycarbonyl)- ethyl cis-propenyl phosphate, (3) methyl ( - ) menthyl cis-propenyl phosphonate and (4) the (+) phenethylamine salt of benzyl carboxymethyl cis-propenyl phosphonate, may be separated. In the case of (1) the separated diastereoisomers are converted to the (+) and ( - ) antipodes of benzyl 2-aminoethyl cispropenyl phosphonate which are then separately epoxidized and the ester groups in the products cleaved to form the ( + ) and ( - ) enantiomers of (cis - 1,2 - epoxypropyl)phosphonic acid. The diastereoisomers of (2), (3) and (4) are separately epoxidized and the epoxides converted to ( + ) and ( -) (cis-1,2-epoxypropyl)phosphonic acid or salt derivative. Other optically active derivatives which can be used for the epoxidation include, (a) the ( + ) α-phenethylamine salt of cis-propenyl phosphonic acid and (b) optically active cyanoalkyl esters of cis-propenyl phosphonic acid, e.g. ( + ) and ( - ) benzyl cyanomethyl cis-propenyl phosphonic acid which are epoxidized with H 2 O 2  in the presence of methanol containing sodium bicarbonate to form the (+) and ( - ) benzyl carbamoylmethyl (cis-1,2- epoxypropyl)-phosphonates which are then converted to ( + ) and ( -) (cis-1,2-epoxypropyl) phosphonic acids by hydrogenolysis followed by passage through a cation exchange resin on the hydrogen cycle. In another example benzyl cis-propenylphosphonochloridate is treated with H 2 S and triethylamine added to yield the corresponding phosphonothioic acid which is then treated with ( - ) quinine to form diastereoisomeric quinine salts which are separated and converted to the two optically active antipodes of the free phosphonothioic acid, these antipodes are then separately epoxidized and converted to (+) and ( - ) benzyl (cis-1,2- epoxypropyl) phosphonochloridates by treatment of the sodium salt of each epoxidized product with phosgene in hexane solution at -40 to - 60 C. and then warming to room temperature, the resulting phosphonochloridate ester being finally converted to the benzylamine salts of (+) and ( - ) (cis-1,2-epoxypropyl)- phosphonic acid by hydrogenolysis followed by the addition of benzylamine hydrochloride. Cis-propenyl phosphoric dichloride is obtained by adding the free phosphonic acid dissolved in tetrahydrofuran to a suspension of PCl 5  in CCl 4 . Benzyl cis - propenylphosphonochloridate is obtained by reacting the dichloride dissolved in benzene with benzyl alcohol in the presence of triethylamine and the product is converted to benzyl 2-amino ethyl cis-propenyl phosphonate by reaction with ethanolamine hydrochloride in tetrahydrofuran in the presence of pyridine. Benzyl [(2 - tetrahydropyranyloxy)- carbonyl]- methyl cis-propenyl phosphonate is obtained by reacting benzyl cis-propenylphosphonochloridate with hydroxy acetic acid tetrahydropyranyl ester in the presence of triethylamine and is converted to benzyl carboxymethyl cispropenyl phosphonate by acidification with 1NHCl. Diphenyl propenyl phosphonate is obtained by reacting propenyl phosphonic acid with phenol in CH 2 Cl 2  in the presence of dicyclohexylcarbodiimide and is converted to diphenyl 3-bromo propenyl phosphonate by reacting with N-bromosuccinimide in CCl 4  under irradiation with U.V. light. Methyl cis - propenylphosphonochloridate is obtained by reacting the dichloride with methanol in benzene in the presence of triethylamine and is converted to methyl ( - ) menthyl cispropenyl phosphonate by reacting with ( - ) menthol in benzene in the presence of triethylamine, the product being separated into the ( + ) and ( - ) diastereoisomeric forms by fractional crystallization from ethyl acetate-hexane. (+)(cis - 1,2 - Epoxypropyl)phosphonic acid is converted to cis-propenyl phosphonic acid by heating with potassium thiocyanate in aqueous methanol and the product may be converted to ( - )(cis-1,2-epoxypropyl)phosphonic acid by the epoxidation procedure of the invention.