Patent GB-498752-A (GB)
Title: The manufacture of quinoline derivatives
IPC: C07D215/40
Filed: 1937-07-07
Abstract: 6 - Oxy - 8-aminoquinolines in which the nitrogen atom of the 8-amino group is connected by a chain of three carbon atoms with the nitrogen atom of an aliphatic or cycloaliphatic amine or of a saturated heterocyclic compound are prepared by (1) hydrolysing the corresponding 6-alkoxy, -aralkoxy or -aryloxy compounds; (2) saponifying the corresponding 6-acyloxy compounds; (3) diazotizing the corresponding 6-amino compound; (4) reducing and then diazotizing the corresponding 6-nitro compound; (5) reacting a 6-hydroxy-8-aminoquinoline with an aliphatic amine containing a reactive ester group in which three carbon atoms separate the two groups; (6) reacting a 6-hydroxy-8-aminoquinoline according to the method described in Specification 433,625 with an amino-alcohol in which the amino and hydroxy groups are connected by a chain of three carbon atoms; (7) treating with ammonia or an aliphatic amine a 6-hydroxy-8-alkylaminoquinoline which contains a halogen atom or a sulphonic ester or alkylene oxide group separated from the amino group by a chain of three carbon atoms; (8) submitting to Skraup's synthesis a 1 : 2-diamino-4-hydroxybenzene the 2-amino group of which is appropriately substituted.  The products, which may also contain alkyl or hydroxy groups attached to any of the three carbon atoms, possess enhanced therapeutic properties.  They may be used in the form of their salts with mineral or organic acids, or with such acids as methylene-bis-salicylic acid and methylene-bis-(21-hydroxynaphthalene-3-carboxylic acid). According to the examples: (1) 6-methoxy-8-(41-dimethylaminobutyl-21-amino) -quinoline is heated with hydrobromic acid to give the 6-hydroxy compound; the same compound is obtained by heating the corresponding 6-ethoxy compound in benzene with aluminium chloride, the 6-benzyloxy compound with hydrobromic acid, the 6-phenoxy compound in xylene with aluminium chloride, or the 6-acetoxy compound with caustic soda; (2) 6-methoxy-8-(41-diethylaminobutyl - 21 - amino) - quinoline is heated with hydrobromic or hydriodic acid to split off the methyl group; (3) 6-methoxy-8-dimethyl- or diethyl-aminopropylamino-quinoline is boiled with hydrobromic acid to effect hydrolysis of the methoxy group; (4) 6-nitro-8-(31 - dimethylamino - 21 : 21 - dimethylpropylamino)-quinoline is reduced with stannous chloride and the 6-amino product then diazotized and boiled to form the corresponding 6-hydroxy compound; (5) 6-methoxy-8-(31-phthalimidopropylamino)-quinoline is heated with hydrazine hydrate and then with hydrobromic acid, producing 6-hydroxy-8-(31-propylamino) - quinoline; (6) 6 - hydroxy - 8 - aminoquinoline is treated with 4-dimethylamino-2-bromobutane to give 6-hydroxy-8-(41-dimethyl-aminobutyl - 21 - amino) - quinoline; (7) 6-hydroxy-8-acetylaminoquinoline is reacted with sodium dissolved in 3-dimethylaminobutane-1-ol and then heated with dilute hydrochloric acid; the same product, 6 - hydroxy - 8 - (31-dimethylaminobutyl - 11 - amino) - quinoline is also obtained by hydrolysing the 6-methoxy compound; (8) 6 - hydroxy - 8 - (41 - dimethyl-aminobutyl - 21 - amino) - quinoline is prepared by heating 6-methoxy-8-(41-hydroxybutyl-21-amino)-quinoline with hydrobromic acid and then with methylalcoholic dimethylamine; (9) 4-amino-5-[methyl-(31-dimethylamino-21 : 21-dimethylpropyl)-amino] - 1 - hydroxybenzene is heated with paraldehyde and concentrated hydrochloric acid to give 2-methyl-6-hydroxy-8-[methyl - (31 - dimethylamino - 21 : 21 - dimethylpropyl) - amino] - quinoline. Specifications 267,169, 282,453, 295,656, and 301,401, [all in Class 2 (iii)], also are referred to.  The samples furnished under Sect. 2 (5) consist of (1) 6-hydroxy-8-(31-piperidino-21 : 21-dimethylpropylamino) - quinoline, and (2) 6-hydroxy-8-(31-pyrrolidino-21 : 21-dimethylpropylamino)-quinoline, prepared in each case by hydrolysing the corresponding 6-methoxy compound with hydrobromic acid.  6-Methoxy-, ethoxy-, benzyloxy-, phenoxy- and acetoxy - 8 - (41 - dimethylaminobutyl - 21 - amino)-quinolines are prepared by treating the corresponding 6-substituted-8-aminoquinoline with 4-dimethylamino-2-bromobutane.  6 - Methoxy - 8 - (41 - diethylaminobutyl - 21-amino)-quinoline is obtained by reacting 6-methoxy-8-aminoquinoline with 4-diethylamino-2-bromobutane.  6 - Methoxy - 8 - dimethyl- and diethylamino-propylamino-quinolines are prepared by interaction of 6 - methoxy - 8 - aminoquinoline with 1-chloro-3-dimethyl- or diethyl-aminopropane.  6 - Nitro - 8 - (31 - dimethylamino - 21 : 21-dimethylpropylamino)-quinoline is formed by converting 2 : 4 - dinitraniline by Skraup's method into 6 : 8-dinitroquinoline, partially reducing to 6-nitro-8-aminoquinoline and reacting with 1 - chloro - 2 : 2 - dimethyl - 3 - dimethylaminopropane.  6 - Methoxy - 8 - (31 - phthalimidopropylamino)-quinoline results when 6 - methoxy - 8 - aminoquinoline is melted with 3-bromopropyl-phthalimide. 6-Hydroxy-8-aminoquinoline is prepared by boiling the corresponding 6-methoxy compound with hydrobromic acid.  6 - Methoxy - 8 - (31 - dimethylaminobutyl - 11-amino)-quinoline is obtained by heating 6-methoxy - 8 - aminoquinoline with 1 - chloro-3-dimethylaminobutane. 6 - Methoxy - 8 - (41 - hydroxybutyl-21-amino)-quinoline results from the treatment of 6-methoxy - 8 - aminoquinoline with 2 - chloro-4-hydroxy-butane.  6 - Methoxy - 8 - (31 - piperidino- and pyrrolidino - 21 : 21 - dimethylpropylamino) - quinoline are obtained by reacting 6-methoxy-8-aminoquinoline with 1-chloro-2 : 2-dimethyl-3-piperidino- or pyrrolidino-propane.  4 - Amino - 5 - [methyl - (31 - dimethylamino-21 : 21 - dimethylpropyl) - amino] - 1 - hydroxybenzene is prepared by condensing isobutylaldehyde with formaldehyde and dimethylamine, reducing the resulting 1-oxo-2 : 2-dimethyl - 3 - dimethylamino - propane to the 1-hydroxy compound, and converting the latter by means of thionyl chloride into the 1-chloro compound; by reacting with monomethylaniline there is formed methyl-(3-dimethylamino - 2 : 2 - dimethylpropyl) - aniline which, by the action of nitrous acid, splits up to 1-methylamino - 2 : 2 - dimethyl - 3 - dimethylaminopropane, which is then reacted with 3-chloro-4-nitrophenol and finally reduced.  1-Chloro-2 : 2-dimethyl-3-dimethylamino-piperidino- and pyrrolidino-propane are produced when isobutylaldehyde is condensed with formaldehyde and dimethylamine, piperidine or pyrrolidine, and the product first reduced and then treated with thionyl chloride.  4-Dimethyl- and diethyl-2-bromobutane are obtained by condensing acetone with formaldehyde and dimethyl- or diethyl-amine, reducing the product and treating it with hydrobromic acid.  1-Chloro-3-dimethylaminopropane is prepared by the addition of hydrogen chloride to dimethyl-allylamine.  3-Bromopropyl-phthalimide is prepared from 1 : 3-dibromopropane and potassium phthalimide. 3-Dimethylaminobutane-1-ol is obtained by the addition of hydrogen chloride to crotonaldehyde, treatment with dimethylamine to form b -dimethylaminobutyraldehyde, followed by reduction. 1-Chloro-3-dimethylaminobutane is produced by reacting the corresponding 1-hydroxy compound with thionyl chloride. 2-Chloro-4-hydroxybutane is obtained by treating 2 : 4-dihydroxybutane with hydrogen chloride.