Patent GB-388087-A (GB)
Title: Improvements in and relating to the manufacture of quinoline derivatives
IPC: C07D215/18
Filed: 1931-08-25
Abstract: Substances containing the quinoline nucleus, of the general formula <FORM:0388087/IV/1> where R2 to R8 may be hydrogen, halogens, amino, hydroxy or carboxylic groups or organic radicles of an aliphatic, alicyclic, aromatic or heterocyclic nature, or combinations of the foregoing such as aromatic amino radicles, chain derivatives and fused ring derivatives, whilst R5 to R8 may be additionally nitro or sulphonic groups and the organic radicles referred to above may contain nitro or sulphonic groups, are manufactured by condensing an aromatic amino compound, substituted or not but containing at least one free ortho position to the amino group, simultaneously or successively with a carboxylic compound not containing any carbonyl group other than that in the carboxyl group and a carbonyl compound containing a methylene group adjacent to the carbonyl group. Alternatively an anilide, substituted or not but containing at least one free ortho position to the acidylamino group and not containing any carbonyl group other than that in the acidyl group, is condensed with a carbonyl compound containing a methylene group adjacent to the carbonyl group.  In either case the final stage of condensation involving ring closure may be performed in a separate operation.  The condensations may be effected in solution and in the presence of a dehydrating agent, and may be performed at atmospheric temperature and pressure or at elevated temperatures and pressures.  In examples: (1) aniline, formic acid, and paraldehyde are heated together to produce quinoline; (2) formanilide is refluxed with paraldehyde, producing quinoline; (3) p-formanisidide is refluxed with acetone with addition of freshly ignited calcium chloride, yielding p-methoxylepidine; (4) p-formanisidide is heated with excess of pyruvic acid to produce quininic acid; (5) 2-formaminophenol is heated with excess of paraldehyde, producing 8-oxyquinoline; (6) N-formyl-p-phenylenediamine is heated with excess of paraldehyde to yield 6-aminoquinoline; (7) N-formyl-o-phenylenediamine (obtained by heating together equimolecular proportions of o-phenylenediamine and formic acid) similarly yields 8-aminoquinoline; (8) 1 : 3 : 5-triaminobenzene hydrochloride is heated with formic acid and the monoformyl derivative obtained is refluxed with excess of paraldehyde to produce 5 : 7-diaminoquinoline; (9) phenyloxamic acid is heated with excess of paraldehyde, yielding quinaldic acid; (10) 4-chloro-2-nitraniline is melted with formic acid and the anilide is heated with excess of paraldehyde to yield 6-chloro-8-nitroquinoline; (11) m-nitro-p-formaminophenol (prepared from m-nitro-p-aminophenol and formic acid) is refluxed with excess of paraldehyde, producing 6-oxy-8-nitroquinoline; (12) 3-nitro-4-aminoanisole is heated with formic acid and the anilide produced is heated with excess of paraldehyde, yielding 6-methoxy-8-nitroquinoline; (13) p-methoxy-o-nitroformanilide is refluxed with acetone with addition of freshly ignited calcium chloride; (14) the same compound is heated with pyruvic acid in excess, producing 6-methoxy-8-nitroquinoline-4-carboxylic acid; (15) benzanilide is heated with excess of pyruvic acid, yielding 2-phenylquinoline-4-carboxylic acid; (16) benz-p-toluidide similarly yields 6-methyl-2-phenylquinoline-4-carboxylic acid; the product yields with alcohol and hydrochloric acid the ethyl ester, which may also be produced by condensing benz-p-toluidide with pyruvic acid ethyl ester; (17) aniline and piperonylic acid are heated together and the anilide formed is heated with excess of pyruvic acid to produce 2-piperonylquinoline-4-carboxylic acid, which with methyl alcohol and hydrochloric acid yields the methyl ester; (18) 4-oxybenzene-1 : 3-dicarboxylic acid (obtainable by heating three molecular proportions of sodium phenate and one of potassium phenate with carbon dioxide) is refluxed in alcoholic solution with aniline and the anilide is directly heated with excess of pyruvic acid, yielding 2-(p-oxy-m-carboxylphenyl)-quinoline-4-carboxylic acid; (19) benzanilide is heated with excess of paraldehyde to produce 2-phenylquinoline (flavine); (20) benzanilide is heated with acetone to yield 2-phenyl-4-methylquinoline (flavoline); (21) aniline is heated with anthranilic acid and the anilide is heated with excess of paraldehyde, producing mainly 2-o-aminophenylquinoline; (22) aniline is mixed with anthranilic acid and the resulting anilide is heated with excess of acetone to produce 4-methyl-2-(o-amino)-phenylquinoline (isoflavaniline); (23) aniline is heated with gallic acid and the anilide is heated with excess of acetone with addition of calcium chloride, yielding 4-methyl-2-gallylquinoline; (24) gallic acid is heated with phosphorus pentachloride and the chloride condensed with 3 : 4 : 5-trioxyaniline (obtainable by reduction of 3 : 4 : 5-trioxynitrobenzene or from gallic acid by the Hofmann reaction); the anilide produced is heated with excess of acetone with addition of calcium chloride to yield 4-methyl-5 : 6 : 7-trihydroxy-2-(3<1> : 4<1> : 5<1>-trihydroxyphenyl)-quinoline; (25) sulphanilic acid is heated with anthranilic acid and the anilide is dissolved in paraldehyde and heated, producing 2 - o - aminophenylquinoline-6 - sulphonic acid; (26) the anilide of (25) is heated with acetone in excess and calcium chloride to produce 4-methyl-6-sulpho-2-(2<1>-aminophenyl)-quinoline; the product may be further condensed with gallic acid and acetone; (27) aniline is heated with anthranilic acid and the anilide is heated with excess of paraldehyde; the 2-(2<1>-amino)-phenylquinoline produced is heated with anthranilic and then with excess of paraldehyde, and the product is heated with gallic acid and then with excess of paraldehyde, yielding a compound of the formula <FORM:0388087/IV/2> (28) 4-aminophenyloxamic acid is heated with excess of paraldehyde to produce 6-aminoquinoline-2-carboxylic acid, which on heating loses CO2 to yield 6-aminoquinoline; (29) oxanilide is heated in alcohol with excess of glycollic acid, yielding 3 : 3<1>-dioxy-4 : 4<1>-diethoxy-2 : 2<1>-diquinolyl. The following examples describe further reactions which can be carried out with the products of some of the preceding examples: (30) the product of (3) is heated in the presence of freshly ignited calcium chloride with an amino ketone of the formula CH3.CO.CH2.CH2.CH2.N (C2H5)2 (obtainable by heating together acetone, ethylene dichloride, diethylamine and aluminium chloride, or by heating calcium acetate with the calcium salt of 4-diethylaminobutyric acid) to produce a compound of the formula <FORM:0388087/IV/3> (31) the product of (5) is sulphonated and iodinated to yield 5-sulpho-7-iodo-8-oxyquinoline; (32) the product of (10) is reduced by means of stannous chloride and hydrochloric acid to 6-chlor-8-aminoquinoline, which may be condensed with the acetal obtained by treating the aminoketone of (30) with orthoformic ester, alcohol, and a trace of sulphuric acid; the resulting ketonanilide is reduced by means of zinc powder and caustic soda and the product treated with sodium methylate to produce 6-methoxy-8-(1-diethylamino-4-methylbutyl)-aminoquinoline; (33) the product of (11) is reduced by means of stannous chloride to 6-oxy-8-aminoquinoline; (34) the product of (20) is nitrated to produce 4<1>-nitroflavine, which on reduction yields 4-methyl-2-(p-amino)-phenylquinoline; (35) the product of (21) is diazotized and coupled with dimethylaniline; (36) the product of (22) is heated with anthraquinone with the addition of freshly ignited calcium chloride, then with dimethylaniline in the presence of nitrobenzene, and the product is diazotized and coupled with dimethylaniline to produce a dyestuff of the <FORM:0388087/IV/4> formula (37) the product of (23) is condensed with anthraquinone and dimethylaniline as in (36) <FORM:0388087/IV/5> to yield a dyestuff of the formula (38) the product of (24) similarly yields a dye <FORM:0388087/IV/6> stuff of the formula (39) the product of (25) is diazotized and coupled with dimethylaniline; (40) the product of (26) is condensed with anthraquinone and dimethylaniline, producing a dyestuff of the <FORM:0388087/IV/7> formula (41) the product of (28) is heated with the product of (9) in the presence of sulphuric acid to produce the quinoline analogue of b -aminoanthraquinone, of the formula <FORM:0388087/IV/8> this compound may be sulphonated and the product converted by fusion with caustic potash to the corresponding hydroxyl compound; on fusing this product with caustic potash, dissolving in water and oxidizing with chromic acid, a dyestuff analogous to indanthrene blue is produced; (42) the product of (29) is dissolved in hydrochloric acid, filtered, rendered alkaline, heated with dilute caustic soda, the alcohol is removed and the vat obtained is oxidized with potassium chromate and acetic acid to the quinoline analogue of indigo, of the formula <FORM:0388087/IV/9>