Patent GB-1063230-A (GB)
Title: (3-indolyl)-aliphatic acids and esters and amides thereof
Inventor: TSUNG-YING SHEN
IPC: C07D209/14
Filed: 1964-06-08
Abstract: Novel compounds of the general formula <FORM:1063230/C2/1> (wherein R1 is an aromatic radical of one ring or two fused rings in which any hetero atoms are nitrogen, sulphur or oxygen and in which any substituent is a halogen atom or a 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- 5 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- 5 alkanoylamino, OH, C1- 5 alkanoyloxy, CF3COO, CHF2COO, CH2FCOO, benzyloxy, (C1- 5 alkyl) benzyloxy, (C1- 5 alkoxy) benzyloxy, phenyl, C2- 5 alkenyloxy or halobenzyloxy group, R2 is H or a C2- 5 alkenyl or C1- 5 alkyl radical, R3 is H or a C1- 5 alkyl or C2- 5 alkenyl radical and R13 is H, or R3 and R13 jointly form an alkylidene radical or, with the carbon atom to which they are attached, a cyclopropane ring, R4 is F or a C1- 5 alkyl, C1- 5 alkoxy or CF3 radical and R5 is H, a halogen atom or a C1- 5 alkyl, C1- 5 alkoxy, aryl, aryloxy, OH, SH, NO2, NH2, acylamino, C1- 5 alkylamino, di-(C1- 5 alkyl) amino, haloalkyl, sulphamoyl, sulphoxide, substituted aminomethyl, COOH, carbalkoxy, C1- 5 alkanoyl, bis-(hydroxy - C1- 5 alkyl) amino, 1-pyrrolidinyl, 4 - methyl - 1 - piperazinyl, 4-morpholinyl, CN, amino - C1- 5 alkyl, di - (C1- 5 alkyl) amino-C1- 5 alkyl, CF3, di-(C1- 5 alkyl) sulphamoyl, benzylthio, (C1- 5 alkyl) benzylthio, (C1- 5 alkoxy) benzylthio, halobenzylthio, benzyloxy, (C1- 5 alkyl) benzyloxy, (C1- 5 alkoxy) benzyloxy, halobenzyloxy, C2- 5 alkenyl, C2- 5 alkenyloxy, 1-azacyclopropyl, cyclopropyl-(C1- 5 alkoxy) methoxy or cyclobutyl-(C1- 5 alkoxy) methoxy radical, or R4 and R5 jointly form a 4,5- or 5,6-methylenedioxy radical, and M is NH2 or OZ, where Z is hydrogen or another cation or a benzyl or C1- 5 alkyl radical) are prepared by reacting an N1-alkali metal salt of a corresponding 1-unsubstituted compound with a halide or a phenolic ester (e.g. the p-nitrophenyl ester) of an acid R1COOH. When M in the product is NH2, benzyloxy or t-alkoxy it may be replaced by OH by, respectively, agitating the product in an inert solvent with a stoichiometric amount of HNO2, hydrogenolysing the product in an inert solvent in the presence of a catalytic amount of palladium, and 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. Interconversions of nuclear substituents, especially NO2 to free or substituted amino groups, and the esterification of 1-benzoyl-4-trifluoromethyl-3-indolylacetic acid with n-propyl alcohol in the presence of cyclohexylcarbodiimide, are also described.  Ester and amide starting materials (M = benzyloxy, alkoxy or NH2) are prepared, when R2 = H or Me, by ring closure of an appropriately substituted phenylhydrazine (obtained from the correspondingly substituted aniline by diazotization and reduction) with an appropriate g -oxocarboxylic acid ester or amide or, when R2 = H, preferably with an acetal thereof. Other methods of preparation described for specific compounds are conversion of methyl esters to benzyl esters by ester intercharge, reaction of acid anhydrides with alcohols, alcoholysis of nitriles, the preparation of methyl 4 - methoxy - 3 - indolylacetate by hydrogenolysis of the corresponding 4-benzyloxy compound and treatment of the resulting 4-hydroxy compound with dimethyl sulphate and caustic soda, the preparation of ethyl a -(2-methyl-7-methoxy-3-indolyl) acrylate by the action of methyltriphenylphosphonium bromide on ethyl (2-methyl - 7 - methoxy - 3 - indolyl) glyoxylate, and the conversion of the product to ethyl a -(2-methyl - 7 - methoxy - 3 - indolyl) - a  - cyclopropanecarboxylate by the action of diiodomethane and a zinc-copper couple in tetrahydrofuran in the presence of a trace of iodine.  (This last reaction is also applicable to compounds already containing the R1CO-group in the 1-position.)  Acid starting materials (M = OH) are prepared by Mannich reaction of a compound of the general formula <FORM:1063230/C2/2> with HCHO and a dialkylamine to produce a substituted gramine, reacting this with an alkali metal cyanide in a C1- 5 alkanol, and subjecting the resulting indolylacetonitrile to alkaline hydrolysis.  The preparation of 4-methoxy-3-indolylacetic acid by the action of ethanolic caustic potash on its methyl ester is also described. 4-Methoxy-2-methylindole is prepared by treating 6 - methoxy - 2 - nitrobenzoyl chloride with diazomethane to form diazomethyl 6-methoxy-2-nitrophenyl ketone, reacting this with silver oxide, sodium thiosulphate and sodium carbonate to produce 6-methoxy-2-nitrophenylacetic acid, converting this to its acid chloride and reacting the latter with ethyl ethoxymagnesium malorate to give ethyl 6-methoxy-2-nitrophenylacetylmalorate, hydrolysing and decarboxylating this to 6-methoxy-2-nitrophenylacetone, and treating this with Raney nickel in ethyl alcohol.  7-Methoxy-5-methylindole is prepared by refluxing 4-methyl-o-anisidine with monochloroacetaldehyde.  p-Methylthiobenzoyl chloride is prepared by heating p-methylthiobenzoic acid with thionyl chloride. p-Nitrophenyl nicotinate is prepared by esterifying nicotinic acid with p-nitrophenol in the presence of dicyclohexylcarbodiimide. Pharmaceutical compositions, e.g. tablets or capsules for oral administration, having antiinflammatory and antipyretic activity, comprise compounds of the first general formula above and a solid or liquid inert pharmaceutical diluent or carrier.