Patent GB-1382267-A (GB)
Title: Phenylalkanoic acid derivatives
IPC: C07C57/58
Filed: 1971-12-10
Abstract: 1382267 Phenylalkanoic acid derivatives WILLIAM H RORER Inc 10 Dec 1971 [10 March 1971 11 June 1971 (4) 21 July 1971 (2) 4 Nov 1971] 57510/71 Addition to 1355681 Heading C2C Novel phenylalkanoic acid derivatives of the general formula  wherein R is a C 1-7  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkenyl, aryloxy, arylthio, arylamino, aroyl, heterocyclic, aryl or Y (not H)- substituted aryl group; Y is a hydrogen or halogen atom or a C 1-7  alkyl, nitro, amino, acylamino, mono- or di-C 1-7  alkylamino, mercapto, acylthio, C 1-7  alkylthio, C 1-7  alkylsulphinyl, C 1-7  alkylsulphonyl, hydroxy, C 1-6  alkoxy, C 1-7  acyloxy, C 1-7  haloalkyl, cyano or acetyl group, n is 0, 1 or 2, m is 0, 1 or 2, the sum of n and m is 0, 1 or 2, each of Rx, R# and Rγ is a hydrogen atom or C 1-7  alkyl group; X is a halogen atom or a hydroxy, C 1-6  alkoxy, C 1-7  acyloxy, C 2-7  carbalkoxy oxycarbamoyloxy, mono- or di-C 1-7  alkylcarbamoyloxy, C 1-7  alkanesulphonyloxy, benzenesulphonyloxy, toluenesulphonyloxy, carboxyacyloxy, mercapto, C 1-7  alkylthio, acylthio, sulpho, sulphino, C 1-7  alkylsulphinyl, C 1-7  alkylsulphonyl, thioacylthio, thiosulphato (of formula S 2 O 3 M where M is a cation), thiocyanato, amidinothio, carbamoylthio, mono- or di-C 1-7  alkylcarbamoylthio, C 1-6  alkoxy-thiocarbonylthio, C 1-6  alkoxy - carbonylthio, di-C 1-7  alkyl-thiocarbamoylthio, ar-C 1-5 -alkoxy-carbonylthio or carboxyacylthio group; and Z is a hydrogen atom or a hydroxy, C 1-6  alkoxy, ar-C 1-6  alkoxy, amino, mono- or di-C 1-7  alkylamino, C 3-7  cycloalkylamino, -NA (A is a C 2-6  alkylene group or a C 2-5  alkylene group having at least one atom selected from O, N and S in the chain), -NHOH, -NHNH 2  or -OM group, where M is an alkali or alkaline earth metal or Al atom or an ammonium or quaternary ammonium salt group; with the proviso that when n is  0 and m is 0, then X is a said oxy group and is other than a hydroxy, alkoxy or alkanoyloxy group; when n is 0 and m is 1 and Rx is an alkyl group and R is a cycloalkyl group, then X is other than a hydroxy group; and when n is 1 and m is 1 or n is 0 and m is 2 and Rx, R# and Rγ are hydrogen atoms, then X is other than a hydroxy group if R is a phenyl group, are prepared, e.g. (a) when X is a hydroxy group R# is a hydrogen ato m and Z is a hydroxy, alkoxy or aralkoxy group, by reduction of the corresponding compound in which -CXR 13 - is -CO-; (b) when X is a hydroxy group, R 13  is an alkyl group and Z is an alkoxy or aralkoxy group, by reaction of the corr esponding compound in which -CXR 13 - is -CO- with a Grignard reagent of the general formula R 13 Mghalogen; (c) when n is 0, m is 1, X is a hydroxy group, Rx is a hydrogen atom, and Z is an alkoxy or aralkoxy group, by reaction of the corresponding phenyl alkyl ketone with a haloalkanoic acid ester of the general formula halogen -CH 2 COOR<SP>11</SP> in the presence of zinc; (d) when each of X and Z is a hydroxy group, by acid hydrolysis of the corresponding nitrile; (e) by conversion of a Y substituent in the compound of the first general formula above into another such substituent by a known method; (f) when X is other than a hydroxy group, by conversion of a corresponding compound of the first general formula above to the desired compound having a different value of X by a known method; (g) by interconversion of acids, esters and amides of the first general formula above by known methods; (h) when Z is -OM, by salification of the corresponding free acid; and (i) by resolution of a racemic mixture of compounds of the first general formula above to give the optical isomers.  The keto-ester starting materials of (a) above (in which n is 0) may be prepared by reaction of the corresponding benzene derivative with a suitable carboxylic acid chloride in the presence of AlC 3 . γ-(Y, R-Substituted phenyl)-α-hydroxybutyronitriles are prepared by reaction of an R,Y-substituted benzaldehyde with malonic acid or an alkyl derivative thereof, catalytic hydrogenation of the resulting cinnamic acid derivative, treatment of the resulting #-phenylpropionic acid with thionyl chloride, treatment of the resulting acid chloride with lithium tri-tbutoxyaluminium hydride and reaction of the resulting #-phenyl-propionaldehyde with sodium bisulphite and sodium cyanide. 4-(R,Y-substituted phenyl)-butan-2-ones are prepared by reaction of the corresponding #-phenyl-propionic acid chloride with methylmagnesium bromide in ether, followed by ammonium chloride solution. #-(R,Y-Substituted phenyl)-pyruvic acids are prepared (a) by bromination of the corresponding #-phenyl-cinnamic acid and treatment of the resulting α,#-dibromo-#-phenyl-propionic acid with piperidine, followed by acid hydrolysis, and (b) by reaction of the corresponding benzaldehyde with hippuric acid in the presence of sodium acetate and acetic anhydride and base hydrolysis of the resulting 2-phenyl-4-benzylidenyl-5-oxazolone, and may be esterified to give the corresponding alkyl esters. #-(R,Y-Substituted phenyl)-cinnamic acids are prepared by dehydration of the corresponding alkyl #-phenyl #-hydroxy-propionate with phosphorus oxychloride. #-Hydroxy-γ-(R,Y-substituted phenyl) - butyronitriles are prepared by reaction of an R,Y-substituted phenyl magnesium bromide with epichlorohydrin and reaction of the resulting 1 -chloro-3-(R,Y-substituted phenyl)-2- propanol with aqueous sodium cyanide. (RSubstituted bromo-, chloro- or nitro-phenyl) - glyoxylates are prepared-by bromination, chlorination or nitration, respectively, of the corresponding (R-substituted phenyl)-glyoxylate. Pharmaceutical compositions having analgesic, antipyretic and anti-inflammatory activity comprise, as active ingredient, a phenylalkanoio acid derivative of the first general formula above, together with an acceptable carrier therefor, and may be administered orally, topically, parenterally or rectally.