Patent GB-1200204-A (GB)
Title: Substituted phenyl acetic acids and esters, processes for their production and preparations containing them
IPC: C07D207/327
Filed: 1967-10-30
Abstract: 1,200,204. Substituted phenyl acetic acids. J. R. GEIGY A.G. 30 Oct., 1967 [31 Oct., 1966; 18 Jan., 1967; 7 Aug., 1967], No. 49151/67. Heading C2C. Novel compounds of the general formula I wherein R 1  represents hydrogen of a C 1-6  alkyl group, C 2-4  alkenyl group or C 2 _ 4  alkynyl group, R 2  represents hydrogen, a C 1-4  alkyl group, C 1-4  alkoxy group or a halogen atom and R 3  and R 4  each independently of the other represent hydrogen or a C 1-3  alkyl group and R 5  is C 1-6  alkyl or H, and salts of the carboxylic acids having general Formula I with inorganic and organic bases, are prepared by one of the following methods: (a) by reacting a compound of the general Formula II wherein R 1 , R 2  and R 5  have the above meanings with a monomeric or polymeric saturated aliphatic gamma-dioxo compound with at most 10 carbon atoms or with an open chain or cyclic reactive functional derivative thereof and, if desired, converting any free carboxylic acid so obtained into a salt with an inorganic or organic base, preferably where the gammadioxo compound has the general formula wherein at most two of the substituents R in each unit represent low alkyl groups and the rest represent hydrogen atoms, X and X<SP>1</SP> independently of each other represent radicals of the formulas R 6 -O- and R 6 -CO-O, wherein R 6  represents an optionally halogensubstituted hydrocarbon radical having 1 to 6 carbon atoms or chlorine or bromine atoms, or X<SP>1</SP> together with Y<SP>1</SP> is also the oxo radical = O, Y and Y<SP>1</SP> independently of each other represent radicals of the above-defined formulas R 6 -O- or R 6 -CO-O or both together the epoxy radical -O-, or each together with Z or Z<SP>1</SP>, respectively, represents an extra bond corresponding to the dotted lines, and Z and Z<SP>1</SP> represent hydrogen atoms, provided they do not have the above given meaning (b) by reacting a compound of general Formula II above with a compound of formula (c) by heating a compound of the general Formula V until an equally molar amount of carbon dioxide is split off; (d) by reacting a compound of general formula in the presence of the substantially double or equal molar amount of an alkaline condensing agent depending on whether R 5  is hydrogen or a lower alkyl group with a substantially equimolar amount of a reactive ester of the hydroxy compound of the general formula R<SP>1</SP> 1 -OH in which R<SP>1</SP> 1  is an alkyl, alkenyl or alkynyl radical, optionally liberating the carboxylic acid from any resulting alkali salt so obtained; (e) by reacting a compound of the general Formula VII wherein A 1  represents a low alkoxycarbonyl group (-CO-O-alkyl) containing up to 7 carbon atoms of the cyano group and A 2  represents a low alkoxycarbonyl or a low alkoxalyl group (-CO.COOAlkyl) each having up to 7 carbon atoms, the cyano group or the acetyl group, with an alkali metal hydroxide in an organic, organic aqueous or aqueous medium or, if neither A 1  nor A 2  is a cyano group, reacting with an alkali metal alkanoate in anhydrous media, or if A 2  is not an acetyl group, reacting with an aqueous mineral acid liberating the free acid from the alkali metal salt of a dicarboxylic acid or a dicarboxylic monoalkyl ester obtained when an alkali metal hydroxide is used, and heating the so obtained or otherwise acid of the general formula wherein m means 0 or 1 and R 1 , R 2 , R 3 , R 4  and R 5  have the above meanings until substantially an equimolar amount of carbon dioxide, and as the case may be, carbon moxoxide is split off; (f) by reacting a compound of the general formula in the presence of a silver salt, silver oxide, copper or platinum as catalyst with water with an alcohol or other hydroxy compound, hydrolysing the ester so obtained if desired, and in any case hydrolysing an ester with another hydroxy compound; (g) by treating a compound of the general formula wherein R 8  and R 7  represent hydrogen or C 1 -C 4  alkyl groups, with catalytically activated hydrogen or nascent hydrogen until substantially the equimolar amount has been taken up and if desired converting the resulting acid into a salt; (h) a modification of the last process described by reducing a compound of the general formula (k) by hydrolysing a compound of the general Formula X wherein A 3  represents the cyano group, an optionally substituted carbamoyl group or a carboxylic acid ester group or imido ester group, in an alkaline or acid medium and, if desired, liberating the carboxylic acid from any salt so obtained optionally carrying out the process wherein A 3  is a cyano group by prior treatment with alkaline hydrogen perioxide to convert it into the corresponding amide; (1) by heating a compound of the general formula according to the methods of Willgerodt or Willgerodt-Kindler, with ammonium polysulphide or with ammonia or with a primary or secondary amine and sulphur, hydrolysing the resulting amide or as the case may be, mono- or disubstituted thioamide, if desired, liberating the carboxylic acid from the salt of such acid so obtained; (m) by reacting a compound of the general Formula XIII wherein R<SP>1</SP> 5  represents an alkyl group R 5 , with a compound of the general formula so as to obtain a reaction product of the general formula and subsequently treating with an alkali metal hydroxide, if desired liberating the carboxylic acid from the resulting alkali salt so obtained; (n) by subjecting a nitrile of the general formula to alcoholysis; (o) in the case of the compounds wherein R 5  is alkyl by esterification of the corresponding free acid for example with diazomethane or an alcohol and sulphuric acid; or (p) a process for the production of the (+ ) or the (-) optically active enantiomer and wherein R 1  represents a low alkyl group, low alkenyl group or low alkynyl group from a racemic mixture which process comprises resolving said racemic mixture or by preparing the required enantiomer directly by any of the above processes using the appropriate optically active starting materials. Salts of resulting free carboxylic acids may be formed with inorganic and organic bases. Dicarboxylic acid esters of the Formula VII above wherein A 1  and A 2  represent C 1-7  alkoxy carbonyl groups are prepared from the corresponding compound A 1  and R 1  = hydrogen and A 2  = alkoxy carbonyl by reaction with a dialkyl carbonate optionally followed by reaction with firstly an alkali metal and secondly with a halide of the formula R 1 X wherein X is a halogen atom. The corresponding free dicarboxylic acids are prepared by hydrolysis of the diesters. Compounds of the general Formula XIII above are prepared from the corresponding para-amino compounds by reaction with thionyl chloride. Amides of the general Formula X above wherein A 3  represents the carbamoyl group are prepared by action of ammonia on the corresponding compounds A 3  being alkoxy carbonyl. Compounds of the general Formula V above are prepared by reaction of the amine of Formula II above with a 2, 5-dimethoxy-2-alkoxy carbonylpyrrole. p(1 - Pyrryl) - benzoic acid is prepared by hydrolysis of its ethyl ester which is prepared by condensation of 2,5 - dimethoxytetrahydrofuran and 4 - aminobenzoic acid ethyl ester. [p - (1 - Pyrryl) - phenyl] - acetonitrile is prepared by reaction of (p - aminophenyl) - acetonitrile and 2,5 - dimethoxy - tetrahydrofuran and is then converted into 2 - [p - (1 - pyrryl) - phenyl] - butyronitrile by reaction with ethyl bromide. 41 (1 - Pyrryl) - acetophenone and its 31- bromo-, 3<SP>1 </SP>- methyl-, 2<SP>1</SP>- chloro- and 3<SP>1</SP> - methoxy - derivatives are prepared by reacting 2,5 - dimethoxytetrahydrofuran and the appropriate 4<SP>1</SP>-amino-acetophenone. 4<SP>1</SP>- Amino - 3<SP>1</SP>- methoxy - acetophenone is prepared by reduction of the 4<SP>1 </SP> -  nitro - 3<SP>1</SP>  -  methoxy - acetophenone which is itself prepared from 3 - methoxy - 4 - nitrobenzoyl chloride by action of malonic acid ethyl ester and Mg. (4 - Amino - 3 - chlorophenyl) - acetic acid is prepared by action of HCl and sodium chlorate on [p - (acetoamido)phenyl] - acetic acid. Pharmaceutical compositions, in conventional forms for oral, rectal or parenteral administration and having analgesic, antipyretic and antiphlogistic activity, comprise an above novel compound and a carrier therefor, optionally with other inert additives.