Patent GB-597816-A (GB)
Title: Improvements in or relating to a process of preparing new quinoline antimalarials
IPC: C07D215/40
Filed: 1944-12-08
Abstract: 2-Methyl-6-methoxy-8-[21-dialkylamino) -ethylamino]-quinolines, useful as antimalarials, of the general formula <FORM:0597816/IV/1> wherein each of R and R1 represents an acyclic, non-tertiary alkyl radical containing not more than four carbon atoms, are prepared by condensing 2-methyl-8-aminoquinoline or its hydrohalide with a dialkylaminoethyl halide of the general formula <FORM:0597816/IV/2> or its hydrohalide, wherein Ha represents chlorine or bromine and R and R1 have the significance indicated above, for example, by refluxing in a solvent, e.g. methanol or ethanol, at a temperature between 90 DEG  C. and 130 DEG  C. from one to three days. The products may be isolated by adding water and making the solution alkaline and converted into salts by the addition of acids.  In examples: (1) 2 - methyl - 6 - methoxy - 8 - aminoquinoline is refluxed in ethanol with 2-(isobutyl-sec-butyl-amino) - ethylchloride to yield 2 - methyl - 6 - methoxy-8-[21-(isobutyl-sec-butylamino) -ethyl-amino]-quinoline and is converted to its dihydrochloride; (2) 2-(diisobutylamino)-ethyl-chloride hydrochloride similarly yields 2-methyl-6 - methoxy - 8 - [21 - (diisobutylamino) - ethyl - amino]-quinoline and its dihydrochloride; (3) 2 - (isopropyl - isobutylamino) - ethylchloride hydrochloride yields as in (1) 2-methyl-6-methoxy - 8 - [21 - isopropyl - isobutylamino) - ethylamino]-quinoline; (4) the corresponding hydrobromide salts of the ethylbromides, substituted as in (1), (2) and (3), are similarly reacted and the products are converted into their hydrobromide salts; (5) the bases obtained in (1) to (4) are converted into their sulphate, nitrate, phosphate, lactate or propionate salts. Dialkylaminoethy halides of the general formula given above are obtained, in the form of their hydrohalides from which the free base may be liberated if desired, by the action of a halogenating agent, e.g. thionyl chloride, phosphorus trichloride or tribromide, preferably at about -5 DEG  C. in the presence of a dispersing agent which is desirably a solvent for both reactants, e.g. benzene, chloroform or carbon tetrachloride, on the corresponding dialkylaminoethanols, which are prepared by introducing the group D1 and, if necessary a b -hydroxyethyl group into a amine R2NHR (in which R2 represents hydrogen or a b -hydroxyethyl group).  The preparation of the dialkylaminoethanols is preferably effected: (a) when at least one of R and R1 is secondary by introducing one of these radicals into a primary alkylamine containing the other by the action of the appropriate aldehyde or ketone and hydrogen in the presence of a hydrogenation catalyst, e.g. Raney nickel or Adams platinum oxide and treating the product with ethylene oxide in a solvent; (b) when both R and R1 are primary, by treating an alkylamino-ethanol containing one of these radicals with the alkyl halide corresponding to the other in a solvent, e.g. methanol or ethanol.  In examples: (1) isobutylamine, methylethylketone and hydrogen are reacted in the presence of Raney nickel to give isobutyl-sec-butylamine, which is converted to 2-(isobutyl-sec-butylamino)-ethanol-1 by treatment with ethylene oxide and then to the desired 2-(isobutyl-sec-butylamino)-ethyl-chloride by reacting with thionyl chloride in chloroform, and treating the resulting hydrochloride with sodium hydroxide solution; (2) 2 - (diisobutylamino) - ethylchloride - 1 hydro - chloride is obtained from diisobutylamine as in (1); (3) 2 - (isopropylisobutylamino) - ethyl-chloride-1 hydrochloride is obtained as in (1) from isopropylisobutylamine which is prepared as in (1) from isobutylamine and acetone.  The Specification as open to inspection under Sect. 91 refers generally to the preparation of 2-, 3- and 4-methyl-6-methoxy-8-[2-(dialkyl-amino)-ethylamino]-quinolines of the general formula <FORM:0597816/IV/3> where in each of R and R1 represents an acyclic, non-tertiary lower alkyl radical, by condensing 2-, 3- or 4-methyl-8-aminoquinoline or their hydrohalides with a dialkylaminoethyl halide of the general formula <FORM:0597816/IV/4> or its hydrohalide, wherein Ha represents chlorine or bromine and R and R1 have the significance indicated above.  In examples: (1) 3 - methyl - 6 - methoxy - 8 - [21 - (diisobutylamino)-ethylamino]-quinoline is obtained by condensing 3 - methyl - 6 - methoxy - 8 - amino - quinoline with 2 - (diisobutylamino) - ethyl - chloride; (2) 4-methyl-6-methoxy-8-[21-(ethyl-111-methylhexylamino) -ethylamino]-quinoline is prepared by condensing 4-methyl-6-methoxy-8 - aminoquinoline with 2-(ethyl-11-methyl-hexylamino) - ethylchloride - 1.  The dialkyl-aminoethyl halides are prepared by the methods described above and in an additional example, ethyl-1-methylhexylamine is prepared, convered to 2 - (ethyl - 11 - methylhexylamino) - ethanol-1 and then to the desired 1-(ethyl-11-methylhexylamino) - ethylchloride - 1.  This subject-matter does not appear in the Specification as accepted.