Patent GB-758570-A (GB)
Title: N-substituted 1:2:3:4-tetrahydroquinoline derivatives
IPC: C07D215/06
Filed: 1954-05-21
Abstract: The invention comprises compounds, or isomeric mixtures thereof, of the general formula <FORM:0758570/IV(a)/1> wherein X represents hydrogen or one or more alkyl groups of 1-3 carbon atoms, one Y represents hydrogen and the other a halogen atom, R represents a straight or branched alkylene group of not more than 4 carbon atoms, and R1 represents an unsubstituted or mono- or di-substituted amino group linked to R by its nitrogen atom, which, if tertiary, may be a member of a saturated heterocyclic ring.  These compounds may be prepared by (a) reacting 6-methyl-5- or -7-halo-1 : 2 : 3 : 4-tetrahydroquinoline or its substitution products, or isomeric mixtures thereof, with reactive esters of aminoalcohols, preferably in the presence of condensing agents, or with the aminoalcohols themselves in the presence of condensing agents such as phosphorus pentoxide, vitreous phosphoric acid, boron-phosphoric acids, hydrates of boron phosphate, boron phosphate, zinc chloride or aluminium chloride, or in the presence of basic condensing agents such as basic compounds of alkali or alkaline-earth metals, magnesium or aluminium (in which case preferably at least one of the reactants is in the form of a compound with the metal and the amino compound is advantageously in the form of an acyl derivative); (b) introducing at the ring nitrogen an alkyl or acyl group containing a reactive substituent and converting this into the aminoalkyl radical; (c) introducing at the ring nitrogen an acylaminoalkyl radical and, if desired after alkylation, reducing the acyl group (if derived from an aliphatic carboxylic acid) to an alkyl group or removing it; or (d) aminoacylating the ring nitrogen and reducing the aminoacyl group to an aminoalkyl group.  Examples describe the interaction of: (1) and (2) 5- and 7-chloro - 6 - methyl - 1 : 2 : 3 : 4 - tetrahydroisoquinoline with b  - diethylaminoethyl chloride; (3) a mixture of 5 - and 7 - chloro - 6 - methyl-1 : 2 : 3 : 4 - tetrahydroisoquinoline with (a) b -diethylaminoethyl chloride, (b) b - diethylaminoisopropyl chloride, (c) b  - dimethylaminoisopropyl chloride, (d) b  - di - n - butylaminoethyl chloride, (e) N - b  - chloroethylpyrrolidine, (f) N - b  - chloroethylpiperidine, (g) N - b - chloroethylcyclohexylamine, and (h) N - b  - chloroethylhexahydro - o - toluidine; (4) the same mixture with ethylene chlorhydrin and phosphorus pentachloride followed by reaction of the resulting N-b -chloroethyl compounds with (a) methylamine, (b) ethylamine, (c) n-propylamine, (d) n-butylamine, (e) ethanolamine, (f) diethanolamine, and (g) allylamine; (5) the same mixture with bromobutylphthalimide followed by boiling with hydrazine hydrate in ethanol to remove the phthaloyl radical; (6) the same mixture with acrylonitrile followed by reduction of the b -cyanoethyl group introduced and alkylation of the resulting g -aminopropyl group with isopropyl bromide and potassium carbonate; (7)(A) 5 - chloro - 6 - methyl - N-g  - aminopropyl - 1 : 2 : 3 : 4 - tetrahydroquinoline (obtained as in (6) from the pure 5-chloro starting material) with benzenesulphonyl chloride and the product with ethyl iodide and sodium ethoxide, followed by removal of the benzenesulphonyl group by heating with concentrated sulphuric and glacial acetic acids; (7)(B) the same starting material with acetic acid or acetyl chloride and pyridine, followed by reduction of the acetyl group with LiAlH4; (8) 5 - chloro - 6 - methyl - 1 : 2 : 3 : 4 - tetrahydroquinoline with chloroacetyl chloride and the product with butylamine, followed by reduction of the butylaminoacetyl group with LiAlH4; (9) a mixture of 5- and 7-chloro-2 : 6-dimethyl - 1 : 2 : 3 : 4 - tetrahydroquinoline with (a) b  - diethylaminoethyl chloride, (b) b  - di - n-butylaminoethyl chloride, (c) b  - diethylaminoisopropyl chloride, (d) N - b  - chloroethylhexamethyleneimine, and (e) N - b  - chloroethylpyrrolidine; (10) the same mixture with ethylene chlorhydrin and phosphorus pentachloride and the product with (a) hydroxyethylethylamine, (b) hydroxyethylpropylamine, (c) hydroxethylbutylamine, (d) 2 - hydroxypropylethylamine, (e) 2 - hydroxypropylpropylamine, and (f) 2 - hydroxypropylbutylamine; (11) a mixture of 5 - and 7 - chloro - 4 : 6 - dimethyl-1 : 2 : 3 : 4 - tetrahydroquinoline with (a) b  - diethylaminoethyl chloride, (b) dimethylaminoisopropyl chloride, and (c) b -diethylaminoisopropyl chloride; (12) a mixture of 5- and 7-chloro - 2 : 4 : 6 - trimethyl - 1 : 2 : 3 : 4 - tetrahydroquinoline with (a) b  - diethylaminoethyl chloride, (b) N - b  - chloroethylpyrrolidine, and (c) b -diethylaminoisopropyl chloride.  The products are useful for the treatment of schistosomiasis, especially in the form of their hydrochlorides.  Starting materials.  The mixtures of isomers employed in Examples (3), (9), (11) and (12) are prepared by catalytic reduction of the corresponding mixtures of substituted quinolines, themselves obtainable respectively by the Skraup synthesis from 2-chloro-4-aminotoluene and by modified Skraup syntheses from 2-chloro-4-aminotoluene and crotonaldehyde, from 2-chloro-4-aminotoluene and methyl vinyl ketone, and from the anil of 2-chloro-4-aminotoluene and acetylacetone.  In the first instance the isomeric 5- and 7-chloro-6-methylquinolines may be separated by fractional crystallization of their picrates from alcohol, and the 7-chloro compound reduced to give the starting material of Example (2).  The starting material of Example (1) is prepared by catalytic hydrogenation of 5 - chloro - 6 - methylquinoline, obtainable from 5-amino-6-methylquinoline by the Sandmeyer reaction.  Specification 729,332 is referred to.