Patent GB-1063247-A (GB)
Title: (1-aroyl-3-indolyl)-carboxylic acid derivatives
Inventor: TSUNG-YING SHEN
IPC: C07D417/06
Filed: 1964-06-08
Abstract: Novel compounds of the general formula <FORM:1063247/C2/1> (wherein R1 is an aromatic radical of one ring or two fused rings in which any heterocyclic atoms are nitrogen, sulphur or oxygen and which is unsubstituted or carries one or more halogen, C1- 5 alkyl, C1- 5 alkylthio, C1- 5 alkoxy, CF3, phenoxy, (C1- 5 alkyl) phenoxy, (C1- 5 alkoxy) phenoxy, halophenoxy, CF3CO, CHF2CO, CH2FCO, di-(C1- 5 alkyl) sulphamoyl, C1- 6 alkanoyl, di-(C1- 5 alkyl) carbamoyl, CN, C2- 6 carbalkoxy, CHO, CF3S, C1- 5 alkylsulphinyl, C1- 5 alkylsulphonyl, benzylthio, (C1- 5 alkyl) benzylthio, (C1- 5 alkoxy) benzylthio, halobenzylthio SH, NO2, NH2, C1- 5 alkylamino, di-(C1- 5 alkyl) amino, C1- 6 alkanoylamino, OH, or C1- 6 alkanoyloxy substituents, R2 is H or a C1- 5 alkyl or C2- 5 alkenyl group, R3 is H or an alky or alkenyl group and R13 is H, or R3 and R13 jointly form, with the carbon atom to which they are attached, a cyclopropane ring, R5 is a C2- 5 alkenyloxy or a cyclopropyl-C1- 5 alkoxy group, and M is -OZ, where Z is H or another cation or a benzyl or C1- 5 alkyl group) are prepared by reacting the N1-alkali metal salt of the corresponding 1-unsubstituted compound, in an anhydrous inert solvent, with a halide or phenolic ester (especially the p-nitrophenyl ester) of an acid R1COOH.  When M in the product is a benzyloxy or t-alkoxy radical, it may be converted to OH by, in the former case, agitating a solution of the ester in an inert solvent with a catalytic amount of palladium in an atmosphere of hydrogen, or, in the latter case, splitting off an alkene by heating the compound above 210 DEG  C., or at 25-110 DEG  C. in the presence of a catalytic amount of an acid. Ester starting materials (M = benzyloxy or C1- 5 alkoxy) are prepared by ring closure of an appropriately substituted phenylhydrazine with an appropriate g -oxoalkanoic ester (applicable when R2=H or Me, an acetal of the aldehydoacid being preferably used in the former case), or by hydrolysing the methoxy group of a corresponding 5-methoxy compound (R5=MeO) to form the corresponding free 5-OH compound and treating this with a C2- 5 alkenyl halide or a cyclopropyl-C1- 5 alkyl halide in the presence of alkali.  The preparation of t-butyl-(2-methyl-5-allyloxy - 3 - indolyl) - acetate from the corresponding acid via its anhydride, and of the corresponding benzyl ester by ester interchange from the methyl ester, is also described. Free acid starting materials (M=OH) are prepared by Mannich reaction of a 2-R2-5-R5-indole with HCHO and a dialkylamine to produce a substituted gramine, reacting this with an alkali metal cyanide in a lower alkanol to produce a 2-R2-5-R5-3-indolylalkanonitrile and subjecting this to alkaline hydrolysis.  This process is also described for R5=methoxy.  2-Allyl-5-methoxyindole is prepared by the action of methylenetriphenylphosphine on 5-methoxy-2-indolylacetaldehyde, itself prepared by reduction of 5-methoxy-2-indolylacetyl chloride.  p-Nitrophenyl nicotinate is prepared by esterifying nicotinic acid with p-nitrophenol in dry tetrahydrofuran in the presence of dicyclohexylcarbodiimide. Pharmaceutical compositions, e.g. tablets or capsules for oral administration, having antiinflammatory and antipyretic activity, comprise a compound of the general formula above and a solid or liquid pharmaceutic diluent or carrier.