Patent GB-634531-A (GB)
Title: New quinoline derivatives
IPC: C07D403/04
Filed: 1947-08-22
Abstract: Pyrimidylaminoquinoline derivatives of general formula Pq-NH-Qq, wherein P represents a 2-, 4- or 6-amino-substituted pyrimidine nucleus attached to the linking -NH-group at another of the 2-, 4- or 6-positions and which may be substituted in the remaining 2-, 4- or 6-positions by an alkyl radicle of not more than 5 carbon atoms or an amino group, Q stands for a quinoline nucleus substituted in the 2- or 4-position by an amino group and may be substituted by an alkyl group or groups of not more than 5 carbon atoms and contains the -NH- link in the 6-position, and the symbols q indicate that the preceding nuclei, P and Q, are present in the form of quaternary salts, are obtained by reacting one or more of the substances P-NH-Q, Pq-NH-Q and P-NH-Qq with a quaternary salt-forming agent such as dimethyl sulphate and methyl iodide and p-toluene sulphonate.  The reaction may be effected by heating the reactants together conveniently in a solvent such as ethyl alcohol, acetonitrile or nitrobenzene.  It is often possible and advisable in separations to convert one disalt into another thus a di-(metho-methyl sulphate) may be converted to a dimethochloride with e.g. sodium chloride.  The products are trypanocides having both curative and prophylactic properties.  In examples: (1) 4-amino-6-(21-amino-61-methyl-pyrimidyl - 41 - amino) - quinaldine is heated with methyl iodide in ethyl alcohol at 100-110 DEG  C. to give a complex of 4-amino-6-(21-amino - 61 - methylpyrimidyl - 41 - amino)-quinaldine - 1 : 11 - dimethiodide and the corresponding 1-methiodide hydriodide which is treated with hot dil-hydrochloric acid and filtered, the solid being dissolved in sodium carbonate and sodium chloride added to yield the corresponding quinaldine-1 : 11-dimethochloride; (2) 4 - amino - 6 - (41 - amino - 61-methyl - pyrimidyl - 21 - amino) - quinaldine is heated at 115-120 DEG  C. with methyl iodide in methyl alcohol to give the 1 : 11-dimethiodide; (3) 4 - amino - 6 - (21 - aminopyrimidyl - 41-amino)-quinaldine is boiled under reflux with methyl iodide and acetonitrile to give the 1 : 11-dimethiodide; (4) 4 - amino - 6 - (21 - amino-61 - methylpyrimidyl - 41 - amino) - quinaldine-11 - methiodide in nitrobenzene is heated at 100 DEG  C. dimethyl sulphate added and a solid precipitated with acetone which is treated with brine to yield the required quinaldine 1 : 11-dimethochloride; (5) the quinaldine of example (1) is heated in nitrobenzene at 100 DEG C. dimethyl sulphate added and the corresponding 1 : 11-dimethomethylsulphate isolated which may be converted to the 1 : 11-dimethochloride or -dimethiodide by treatment with sodium chloride or iodide respectively; (6) 4-amino-6-(21 - amino - 61 - methylpyrimidyl - 41 - amino) quinaldine 1-methomethylsulphate in nitrobenzene at 100 DEG  C. is treated with dimethyl sulphate to give the 1 : 11-dimethomethylsulphate; (7) 4 - amino - 6 - (21 - amino - 61-ethylpyrimidyl - 41 - amino) - quinaldine in nitrobenzene at 110 DEG  C. is treated with dimethyl sulphate, the solid obtained treated with excess sodium iodide and the latter product crystallized from aqueous hydrochloric acid to give the desired 1 : 11-dimethochloride; (8) 4 - amino - 6 - (21 - amino - 61 - pentylpyrimidyl - 41 - amino) - quinaldine is heated with dimethyl sulphate in nitrobenzene at 120 DEG  C., treated with excess water, and brine added to the aqueous alkaline extract to give the 1 : 1-dimethochloride; (9) 4-amino-6-(21 : 61 - diaminopyrimidyl - 41 - amino)-quinaldine is heated with dimethyl sulphate at 120 DEG  C. in nitrobenzene and the corresponding 1 : 11-dimethiodide obtained on treating an aqueous extract with sodium iodide and in (10) 2 - amino - 6 - (21 - amino - 61 - methylpyrimidyl - 41 - amino) - lepidine is heated with methyl p-toluenesulphonate in nitrobenzene at 120 DEG  C. and the solid obtained on adding acetone is treated with aqueous sodium iodide to give the 1 : 11-dimethiodide.  The starting materials are obtained by condensing the appropriately substituted diaminoquinaldine or lepidine and 2-chloro- or 4-chloro-substituted pyrimidine in aqueous hydrochloric acid and precipitating the desired base with alkali. In (1) the starting compound is also obtained by refluxing 6-amino-4-hydroxy-quinaldine hydrochloride with 4-chloro-2-amino-6-methylpyrimidine treating with ammonia and separating 4 - hydroxy - 6 - (21 - amino - 61-methylpyrimidyl - 41 - amino) - quinaldine which is converted to the corresponding 4-chloro and 4-amino-compound by treatment with phosphorus oxychloride and ammonia respectively. The starting methiodide of (4) is obtained by condensing 4 : 6-diaminoquinaldine with 4 - chloro - 2 - amino - 6 - methylpyrimidine 1 - methiodide in aqueous hydrochloric and treating the 4-amino-6-(21-amino-6 - (21 - amino - 61 - methylpyrimidyl - 41-amino) - quinaldine - 11 - methiodide hydriodide thus obtained with aqueous alkali and the methosulphate of (6) is obtained by treating the free base in cold p-ethoxy-ethanol with dimethyl sulphates.