Patent GB-667770-A (GB)
Title: Improvements in or relating to quinoline compounds
Inventor: GREEN MAURICE BERKELEY
IPC: C07D215/40
Filed: 1948-10-18
Abstract: 8 - (5 - Hydroxy - amylamino) - 6 - alkoxyquinolines are made by heating a carboxylic ester of a 5-chloro or 5-bromo-pentane-1-ol with an 8-amino-6-alkoxyquinoline in which the alkoxy group contains not more than 8 C atoms.  The primary reaction product, an 8 - (5 - acyloxy-amylamino) - 6 - alkoxyquinoline with a further mol. of the aminoquinoline forms the corresponding 5-hydroxyamylamino and acylamino quinoline compounds.  Preferably the reaction mixture is treated with an acid hydrolysing agent to ensure complete conversion to the required 5-hydroxyamino-compound and, to facilitate the isolation of the products, to hydrolyse the acylamino quinoline compound.  A temperature of 140-200 DEG  C. is given.  Preferably an excess of quinoline reagent is used so that the reaction mixture contains the above indicated components.  Thus at about 150 DEG  C. p one mol. of the ester and four mols. of the quinoline are reacted, the crude product hydrolysed with HCl at 90 DEG  C., the hydrochloride of the 8-amino-6-alkoxyquinoline filtered off and the required compound isolated by fractional distillation under reduced pressure.  The invention has particular reference to 8-(5-hydroxyamylamino)-6-methoxy quinoline which is an intermediate in the production of a compound of strong antimalarial activity.  The hydroxyamylamino quinolines are halogenated and heated under pressure with a mono- or dialkylamine, preferably isopropylamine, in which the alkyl group or groups, contains or contain, respectively, not more than 5 C atoms to provide 8-(5-alkylamino-amylamino)6-alkoxyquinolines. Preferably halogenation is effected in solution, e.g. chloroform, with the theoretical quantity of thionyl chloride at low temperatures and subsequently heating on the steam bath for several hours with the addition of a little pyridine.  Excess pyridine and higher temperatures favour the formation of bis-[8-(5-chloroamylamino)-6-alkoxyquinolyl] sulphides as by-products.  The reaction with an alkylamine is preferably effected at 80-150 DEG  C. in an autoclave.  Desirably 2 mols. and preferably 5 mols. of alkylamine are used per mol. of quinoline reagent.  The reaction mixture generally contains some 8-piperidino-6-alkoxyquinoline.  The required product is preferably isolated by dissolving the crude product in aqueous HCl, adding NaOH and sodium acetate to a pH of about 5.0, extracting the piperidino by-product and allowing the mono-chloride of the desired product to crystallize.  The free base may be obtained in conventional fashion and converted to its mono-phosphate with phosphoric acid in ethyl alcohol.  In examples: chloroamyl acetate and 8-amino-6-methoxyquinoline are heated for 8 hours at 150 DEG  C., poured into water, made alkaline with NaOH, extracted with CHCl3, and the crude 8-(5-hydroxyamylamino) - 6 - methoxyquinoline thus obtained is purified via the hydrochloride; (2) the product of (1) dissolved in CHCl3 is treated with thionyl chloride in an ice-salt bath, heated at 90 DEG  C. with pyridine and the product isolated after passing into iced potassium carbonate solution before reaction with isopropylamine for seven hours in an auto-clave at 120 DEG  C. to yield 8-(5-isopropylamino-amylamino)-6-methoxyquinoline, isolated as the hydrochloride by the method outlined above, the 8-piperidino-6-methoxyquinoline by-product being extracted with benzene, and the free base formed, dissolved in boiling alcohol, and converted to the mono-phosphate by adding thereto an alcoholic solution of phosphoric acid.  A sample has been furnished under Sect. 2 (5) of 8 - (5 - n - butylamino-amylamino) - 6 - methoxyquinoline monophosphate made by treating 8 - (5 - hydroxyamylamino) - 6 - methoxyquinoline with thionyl chloride to produce the corresponding (5-chloroamylamino) compound which is converted to the phosphate and reacted in an auto-clave at 120 DEG  C. with n-butylamine to give the (5-n-butylaminoamylamino) derivative which is converted to the monophosphate.