Patent GB-1092702-A (GB)
Title: Substituted azaindole-3-acetic acid compounds and methods for their preparation
IPC: C07D471/04
Filed: 1965-08-06
Abstract: Novel azaindole compounds of the general formula <FORM:1092702/C2/1> wherein R1 may be hydrogen, C1- 5 alkyl, C1- 5 substituted alkyl such as diethylaminoethyl, or aralkyl, R5 may be hydrogen, C1- 4 alkoxy, aralkyloxy, or dimethylamino, and R6 is an aromatic radical of one or two fused rings having 5 or 6 atoms in the ring, in which rings any heteroatoms present are oxygen, nitrogen or sulphur, there being not more than three such heteroatoms present in not more than one of the said rings and which aromatic radicals are unsubstituted or have any substituents from among halogen atoms, C1- 5 alkyl, C1- 5 alkylthio, C1- 5 alkoxy, trifluoromethyl, phenoxy, (C1- 5 alkyl) phenoxy, (C1- 5 alkoxy) phenoxy, halogeno phenoxy, trifluoroacetyl, difluoroacetyl, monofluoroacetyl, di (C1- 5 alkyl) sulfamoyl, C1- 6 alkanoyl, di (C1- 5 alkyl) carboxamido, cyano, C1- 6 carbo-alkoxy, aldehydo, trifluoromethylthio, C1- 5 alkyl sulphinyl, C1- 5 alkyl sulphonyl, benzylthio, (C1- 5 alkyl) benzylthio, (C1- 5 alkoxy) benzylthio, halogenobenzylthio, mercapto, nitro, amino, di(C1- 5 alkyl) amino, C1- 5 alkyl amino, C1- 6 alkanoylamino, hydroxy, C1- 6 alkanoyloxy, trifluoroacetoxy, difluoroacetoxy, benzyloxy, (C1- 5 alkyl) benzyloxy, (C1- 5 alkoxy) benzyloxy and halogenobenzyloxy, are prepared by admixing a 7-azaindole compound of formula <FORM:1092702/C2/2> where R5 is as defined above, with dimethylamine hydrochloride, and paraformaldehyde in an inert solvent to form a 7-azagramine compound, treating said compound with an alkali metal cyanide, in water, an aqueous alcohol or dimethyl formamide with a small amount of mineral acid to form a 7-azaindole-3-acetonitrile compound, admixing the acetonitrile compound with a hydrohalic acid to form a 7-azaindole-3-acetic acid compound, treating the said 3-acetic acid compound with a C1- 5 alkanol or aryl substitute C1- 5 alkanol and a mineral acid to form a 7-azaindole-3-acetate compound or with a 1,1,2-tri (C1- 5) alkyl ethylene in an inert solvent to form a t-lower alkyl-7-azaindole-3-acetate and acylating said compound with a substituted benzoyl chloride or the p-nitro phenyl ester of a substituted benzoic acid in dimethyl formamide in the presence of an alkali metal hydride to form compounds of the invention and if desired, when R1 is t-lower alkyl, heating to form the free acid.  The free acids may be esterified as required or converted into a salt with an alkali or alkaline earth metal base.  2 - Methyl - 5 - dimethylamino - 7 - azaindole is prepared from 2-methyl-7-azaindole by hydrogenation with Raney nickel and the 2-methyl-7-azaindoline formed, when nitrated with fuming nitric acid gives 2 - methyl - 5 - nitro - 7 - azaindoline. Treatment with benzoic anhydride in an inert solvent at elevated temperature gives 1-benzoyl-2 - methyl - 5 - nitro - 7 - azaindoline which when reduced and simultaneously alkylated with Raney nickel in glacial acetic acid and formaldehyde gives 1 - benzoyl - 5 - dimethyl-amino - 7 - azaindoline which on dehydrogenation with palladium on carbon and deacylation gives the required product 2-methyl-5-methoxy-azaindole is prepared by the reaction of 2-methyl-7-azaindoline and ethyl chloroformate to give the corresponding 1-carbethoxy compound. This compound is treated with per-acetic acid to form 2-methyl-7-azaindoline-7-oxide. The 7-oxide is reacted with acetic anhydride to give 1-acetyl-2-methyl-7-azaindoline-5-ol-5-acetate which when reacted with methanol and sodium methoxide, at room temperature gives 1 - acetyl - 2 - methyl - 7 - azaindoline - 5-ol which can be converted to the corresponding 5-methoxy compound by reaction with sodium hydride in benzene followed by methyl iodide and this compound is dehydrogenated to form the required azaindole.  The corresponding benzyloxy compound may also be prepared by reacting 1 - acetyl - 2 - methyl - 7 - azaindoline with phenyldiazomethane to obtain 1-acetyl-2-methyl - 5 - benzyloxy - 7 - azaindoline which may then be dehydrogenated and treated with acid to obtain 2 - methyl - 5 - hydroxy - 7 - azaindole which on reaction with phenyldiazomethane gives the required 2-methyl-5-benzyloxy-7-azaindole.  Pharmaceutical compositions having anti-inflammatory, analgesic and antipyretic activity and which may be administered orally or topically in the form of tablets or capsules or as ointments contain a compound of the first general formula above as the active ingredient.