Patent GB-603533-A (GB)
Title: Process for the manufacture of acridine compounds
IPC: C07D219/10
Filed: 1945-10-23
Abstract: 9-Amino substituted acridine compounds of the formula <FORM:0603533/IV(b)/1> are prepared by reacting a 9-halo or a 9-aryloxy acridine compound with an aminomethylaminophenol under acidic conditions.  The phenol and the acridine compound are such as have substituents in appropriate positions such as to give a final product of the formula above.  The acidic conditions comprise the use of either an acid addition salt of the aminomethylaminophenol or the use of an aqueous acidic or a non-aqueous phenolic medium.  In the above formula R and R1 are hydrogen, lower alkyl or lower alkoxy. R2 is hydrogen, halogen or -CN, R3 is hydrogen or halogen, the group <FORM:0603533/IV(b)/2> or a hydroxy, lower alkyl, lower alkylene, lower alkoxy, or a phenyl radical.  R4 is hydrogen or a saturated or unsaturated alkyl radical containing from 1-8 carbon atoms, and R5 is a saturated or unsaturated alkyl radical containing from 1-8 carbon atoms.  R4 and R5 taken together with -N< may form a saturated keterocyclic ring system such as pyrollidine, piperidine or morpholine.  The reaction is carried out in an aqueous or aqueous-organic, or organic solvent. Solvents mentioned include methanol, ethanol, propanol, dioxane, acetone and acetic acid. Instead of using the free amino phenol, there may be employed the corresponding acylamino compound.  The acyl group is split off under the acidic conditions of the condensation.  Examples are given of the preparation of the compounds of the invention by refluxing together in one or other of the solvents mentioned above the appropriate aminomethylaminophenol and the appropriate acridine compound. Compounds whose preparation is described in detail in the particular examples are (1) 2-methoxy-6-chloro-9 - (31-diethylaminomethyl - 41 - hydroxyanilino) acridine; (2) 2-methoxy-6-chloro-(31-hydroxy-41 - diethylamino - methylanilino) acridine; (3) 2 - methoxy - 6 - chloro - 9 - (31-ethylaminomethyl-41-hydroxyanilino) acridine; (4) 9-(31-diethylaminomethyl-41-hydroxyanilino) acridine; (5) 2 - methoxy - 6 - chloro - 9 - (31-di - n - butylaminomethyl - 41 - hydroxyanilino) acridine; (6) 2 - methoxy-6-chloro-9-(31-di-n-hexylaminomethyl-41 -hydroxyanilino) acridine; (7) 2 : 3-dimethyl-6-chloro-9-(31-diethylaminomethyl-41-hydroxy anilino) acridine; (8) 2 - methoxy - 6 - chloro - 9 - (31 - diallylaminomethyl - 41 - hydroxyanilino) acridine; (9) 2 - methoxy - 6 - cyano - 9 - (31 - N a  : a 1 - dimethylpyrrolidylmethyl - 41 - hydroxy - anilino) acridine; (10) 2 - methoxy - 6 - chloro - 9 - (31-N-piperidylmethyl-41-hydroxyanilino) acridine; (11) 2-methoxy-6-chloro-9-(21-hydroxy - 31 - diethylaminomethyl - 51 - tert. - butylanilino) acridine; (12) 2 - methoxy - 6 - bromo - 9 - (31 - N - morpholinylmethyl - 41 - hydroxyanilino) acri - dine; (13) 2-methoxy-6-chloro-9-(21-hydroxy-31-diethylaminomethyl -51-phenylanilino) acridine; (14) 2-methoxy-6-chloro-9-(31-diethylaminomethyl - 41 - hydroxy - 5 - allylanilino) acri - dine; (15) 2 : 3-dimethoxy-9-(21-41-dihydroxy-51 - n - propylaminomethyl) acridine; (16) 2 - methoxy-6-chloro-9-(31-N-piperidylmethyl-41-hydroxy - 51 - allylanilino) acridine; (17) 2 - methoxy-6-chloro-9-(31-diallylaminomethyl-41-hydroxy - 5 - allylanilino) acridine; (18) 2 - methoxy-6-chloro-9-(31-diethylaminomethyl-41-hydroxy - 61 - chloroanilino) acridine; (19) 2-methoxy-6-chloro-9-[31 : 51-bis-(diethylaminomethyl)-21-hydroxyanilino] acridine.  The substitute acylaminophenols are prepared from the corresponding acylaminophenols by reacting them with formaldehyde and a secondary amine.ALSO:9-Amino-substituted acridine compounds of the formula <FORM:0603533/IV (c)/1> are prepared by reacting a 9-halo or a 9-aryloxy acridine compound with an aminomethylaminophenol under acidic conditions.  The phenol and the acridine compound are such as have substituents in appropriate positions such as to give a final product of the formula above.  The acidic conditions comprise the use of either an acid addition salt of the aminomethylaminophenol or the use of an aqueous acidic or a non-aqueous phenolic medium.  In the above formula R and R1 are hydrogen, lower alkyl or lower alkoxy. R2 is hydrogen, halogen or -CN, R3 is hydrogen or halogen, the group <FORM:0603533/IV (c)/2> or a hydroxy, lower alkyl, lower alkylene, lower alkoxy, or a phenyl radical.  R4 is hydrogen or a saturated or unsaturated alkyl radical containing from 1-8 carbon atoms, and R5 is a saturated or unsaturated alkyl radical containing from 1-8 carbon atoms.  R4 and R5 taken together with -N may form a saturated heterocyclic ring system such as pyrollidine, piperidine or morpholine.  The reaction is carried out in an aqueous, or aqueous-organic, or organic solvent. Solvents mentioned include methanol, ethanol, propanol, dioxane, acetone and acetic acid. Instead of using the free amino phenol, there may be employed the corresponding arylamino compound.  The aryl group is split off under the acidic conditions of the condensation.  Examples are given of the preparation of the compounds of the invention by refluxing together in one or other of the solvents mentioned above the appropriate aminomethylaminophenol and the appropriate acridine compound. Compounds whose preparation is described in detail in the particular examples are (1) 2-methoxy-6-chloro-9-(31-diethyl-aminomethyl-41 -hydroxyanilino) acridine; (2) 2-methoxy-6-chloro-(31-hydroxy-41 - diethylamino - methylanilino) acridine; (3) 2-methoxy-6-chloro-9-(31-ethylaminomethyl-41 -hydroxyanilino) acridine; (4) 9 - (31-diethylaminomethyl-41-hydroxyanilino) acridine; (5) 2-methoxy-6-chloro-9-(31-di-n-butylaminomethyl - 41 - hydroxyanilino) acridine; (6) 2-methoxy-6-chloro-9-(31-di-n-hexylaminomethyl-41 -hydroxyanilino) acridine; (7) 2 : 3-dimethyl-6-chloro-9-(31-diethylaminomethyl-41-hydroxy anilino) acridine; (8) 2-methoxy-6-chloro-9-(31 - diallylaminomethyl - 41 - hydroxyanilino) acridine; (9) 2-methoxy-4-cyano-9-(31-N-dimethylpyrrolidylmethyl - 41 - hydroxyanilino) acridine; (10) 2-methoxy-6-chloro-9-(31-N-piperidylmethyl-41 -hydroxyanilino) acridine; (11) 2-methoxy - 6 - chloro - 9 - (21-hydroxy-31-diethylaminomethyl-51-tert. -butylanilino) acridine; (12) 2 - methoxy - 6 - bromo - 9 - (31 - N - morpholinylmethyl - 41 - hydroxyanilino) acridine; (13) 2-methoxy-6-chloro-9-(21-hydroxy-31 - diethylaminomethyl - 51 - phenylanilino) acridine; (14) 2-methoxy-6-chloro-9-(31-diethylaminomethyl - 41 - hydroxy - 5 - allylanilino) acridine; (15) 2 : 3-dimethoxy-9-(21-41-dihydroxy - 51 - n - propylaminomethyl) acridine; (16) 2-methoxy-6-chloro-9-(31-N-piperidyl-methyl-41-hydroxy -51-allylanilino) acridine; (17) 2-methoxy-6-chloro-9-(31-diallylaminomethyl-41-hydroxy -5-allkylanilino) acridine; (18) 2-methoxy-6-chloro-9-(31-diethylamino-methyl-41-hydroxy -61-chloroanilino) acridine; (19) 2-methoxy-6-chloro-9-[31 : 51-bis-(diethylaminomethyl)-21-hydroxyanilino] acridine.