Patent GB-1268708-A (GB)
Title: Acylation process
IPC: C07C49/80
Filed: 1969-05-08
Abstract: 1,268,708. Acylation process. PFIZER Inc. 8 May, 1969 [23 Jan., 1969], No. 23618/69. Heading C2A. 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 Z<SP>1</SP> 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 Y<SP>1</SP> 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.