Patent ES-373715-A1 (ES)
Title: Acylation of 6-aminopenicillanic acid and 7-aminocephalosporanic acid
IPC: C07D499/12
Filed: 1969-11-20
Abstract: An improved process for the preparation of compounds of the formulae and the pharmaceutically acceptable salts thereof, wherein R 3 is hydrogen, hydroxy, or acetoxy, R 1 is thienyl, furyl, pyridyl, phenyl, or substituted phenyl, wherein the substituent is (lower)alkyl, chloro, bromo, (lower)alkoxy, di(lower)alkylamino or trifluoromethyl wherein "lower" denotes from 1 to 6 carbon atoms, and R 2 is phenyl or substituted phenyl wherein the substituent is at least one of chloro, bromo, fluoro, (lower)- alkyl, (lower)alkoxy, (lower)alkanoyl, carbo(lower)alkoxy, nitro, or di(lower)alkyl amino wherein "lower" denotes from 1 to 6 carbon atoms furyl quinolyl methyl substituted quinolyl phenazinyl 9,10-anthraquinolyl phenanthrenequinolyl anthracenyl phenanthryl (1,3-benzodioxylyl) 3-(2-methyl-4-pyronyl) 3-(4-pyronyl) or N-(methylpyridyl) wherein Y 2 is -CR=CH-O-- -CH=CH-S-- -CH 2 -CH 2 -S- -CH=N-CH=-CH- -CH=CH-CH =CH- -C(O)-CH=CH-C(O)-or -C(O)-C(O)-CH=CH- wherein Z1 is -(CH 2 ) 3 - or -(CH 2 ) 4 -, and substituted derivatives thereof wherein the substituent is methyl, chloro or bromo benzyl, or substituted benzyl wherein the substituent is chloro, bromo, fluoro, (lower)alkyl, (lower)- alkoxy, (lower)alkanoyl, carbo(lower) alkoxy, nitro, or di(lower) alkylamino wherein "lower" denotes from 1 to 6 carbon atoms phthalimidomethyl benzohydryl trityl cholesteryl alkenyl having up to 8 carbon atoms alkynyl having up to 8 carbon atoms (1 -indanyl)methyl (2-indanyl)methyl furylmethyl pyridylmethyl (2-pyrrolidono)methyl (4-imidazolyl)methyl [2,2-di(lower alkyl)-1,3-dioxolon-4-yl]methyl cycloalkyl and (lower alkyl) substituted cycloalkyl having from 3 to 7 carbon atoms in the cycloalkyl moiety and "lower" denotes from 1 to 6 carbon atoms bicyclo[4. 4 .0]decyl thujyl fenchyl isofenchyl 7-adamantanyl ac-indanyl and substituted derivatives thereof wherein the substituent is methyl, chloro or bromo ac-tetrahydronaphthyl and substituted derivatives thereof wherein the substituent is methyl, chloro or bromo alkyl and substituted C 1 -C 6 alkyl wherein the substituent is at least one of: chloro bromo fluoro nitro carbo (C 1 -C 6 alkoxy) C 1 -C 6 alkanoyl C 1 -C 6 alkoxy, or cyano -CH 2 -CH 2 -NR 5 R 6 -CH 2 -CH 2 -CH 2 -NR 5 R 6 -CH 2 -CH(CH 3 )-NR 5 R 6 or -CH(CH 3 )-CH 2 -NR 5 R 6 wherein -NR 5 R 6 is -NH(C 1 -C 6 alkanoyl), groups may be alike or different and -N(C 1 - C 6 alkyl)anilino and -(lower alkylene)-Y 1 wherein (lower alkylene) contains from 1 to 3 carbon atoms and Y1 is azetidino aziridino pyrrolidino piperidino morpholino thiomorpholino N-(C 1 -C 6 alkyl) piperazino pyrrolo imidazolo 2-imidazolino 2,5-dimethylpyrrolidino 1,4,5,6 -tetrahydropyrimidino 4-methylpiperidino or 2,6-dimethylpiperidino which comprises (a) reacting at a temperature of from - 10 to 50 C. in a reaction-inert solvent, an aryl-malonic acid half-ester having the formula wherein R 1 and R 2 are as defined above, with hexachlorocyclotriphosphatriazine or hexabromocyclotriphosphatriazine, and (b) thereafter reacting the product thus produced with an amino acid compound having the formulae or the alkali metal, alkaline earth metal, or amine salts thereof, wherein R 3 is as defined above, at a temperature of from - 10 to 50 C. in a reaction-inert solvent at a pH of from 5 to 9.