Patent GB-1315269-A (GB)
Title: 6-alpha-aryl substituted-2-amino-2-carboxyacylamino penicillanic acids and derivatives thereof
IPC: C07D499/00
Filed: 1971-10-12
Abstract: 1315269 Penicillins PFIZER Inc 12 Oot 1971 [9 July 1971] 47539/71 Headings C2A and C2C Novel penicillins of general Formula (I) and salts thereof, wherein R 1  is thienyl, phenyl or phenyl substituted with C 1 -C 4  alkyl, C 1 -C 4  alkoxy, trifluoromethyl or di-(C 1 -C 4  alkyl)- amino; R 2  is hydrogen or acyloxy C 1 -C 4  alkyl in which the acyloxy moiety is C 1 -C 4  alkanoyloxy, benzoyloxy or benzoylox substituted with chloro, bromo, fluoro, trifluoromethyl, C 1 -C 4  alkyl or C 1 -C 4  alkoxy; R 3  is hydrogen, C 1 -C 4  alkyl or benzyl; R 4  is hydrogen or carbobenzoxy; and n is zero or 1; are prepared by acylating 6-aminopenicillanic acid or a salt or ester thereof with an acid of Formula (III) wherein R 1  is as defined above, R<SP>1</SP> is an amino protective group and R<SP>11</SP> is hydrogen or an appropriate carboxy protective group, or with an acylating derivative thereof, and if required, removing the protective groups. The 6-aminopenicillanic acid may be reacted in the form of an alkali metal or amine salt or an appropriate ester. The acid (III) may be used as the free acid, preferably in the presence of a condensing agent, or as an acylating derivative, e.g. the anhydride or mixed anhydride, halide, azide, or the active ester (for example with N-hydroxy-phthalimide or -succinimide, or a phenol or thiophenol). The reaction may be carried out in water, organic solvent or an aqueous emulsion or mixture of a waterimmiscible or -miscible organic solvent. The compounds (I) wherein R 2  is acyloxyalkyl may be obtained by esterifying the compounds wherein R 2  is hydrogen, e.g. by treatment of a salt thereof with acyloxyalkyl halide. Diethyl carbobenzoxyaminomalonate is prepared by treating diethyl aminomalonate hydrochloride with carbobenzoxy chloride, and is then converted to its sodio-derivative with sodium hydride and condensed with ethyl α- bromophenylacetate to give 3-carbobenzoxyamino - 3,3 - bis - (ethoxycarbonyl) - 2 - phenylpropionic acid ethyl ester, which is subsequently hydrolysed to give 3-carbobenzonyamino-3-carboxy-2-phenylpropionic acid. This compound is cyclized with acetic anhydride giving α-phenyl- α<SP>1</SP>-carbobenzoxyamino-succinic anhydride and the latter is then treated with benzyl alcohol to provide 3 - carbobenzoxyamino - 3 - carbobenzoxy- 2-phenylpropionic acid. Ethyl α-bromo-(substituted)-phenyl acetates of general formula wherein R 1  is as defined above are prepared by brominating a corresponding substituted mandelic acid ethyl ester, either with bromine under irradiation with U.V. light, or with PBr 5  in chloroform medium. Ethyl α-aryl-#-acetoxycyanoacetates in which the aryl radical is R 1  as defined above are prepared by reacting the corresponding ethyl arylglyoxylate (R 1 COCOOC 2 H 5 ) with acetone cyanohydrin and potassium cyanide to give ethyl α-R 1 -α-hydroxy-cyanoacetate, which is treated with acetic acid and pyridine to give the required product. This product is subsequently catalytically hydrogenated in ethanolic HCl to give ethyl - α - R 1  - # - aminopropionate hydrochloride, which is hydrolysed to the corresponding α-R 1 - #-aminopropionic acid. This is cyclized by treatment with sodium nitrite in acetic acid, to the α-R 1 -#-propiolactone, which is hydrolysed with hydrogen chloride in acetic acid to afford an α-aryl-#-bromopropionic acid of formula R 1  being as defined above. Pharmaceutical compositions having broadspectrum antibacterial activity comprise a penicillin of Formula (I) as hereinbefore defined together with a pharmaceutical carrier.