Patent GB-601768-A (GB)
Title: Process for the manufacture of derivatives of acridine
IPC: C07D403/12
Filed: 1945-10-11
Abstract: Acridine derivatives having antiplasmodial properties and of the formula <FORM:0601768/IV(b)/1> wherein either or both Bz rings of the acridine nucleus may contain one or more substituents, e.g. alkyl, alkoxy, nitro, disubstituted amino or halogen, and wherein the pyrimidine nucleus may also contain one or more additional substituents, e.g. halogen atoms or alkyl, arylalkoxy, aryloxy, hydroxy, nitro, amino or substituted amino groups, are manufactured by heating a 5-aminopyrimidine with a mesohalogenated acridine in the presence of a phenol, or with a meso-phenoxyacridine (preferably also in the presence of a phenol, or without isolation from the reaction mixture obtained by heating a meso-halogenated acridine with a phenol).  The phenol (e.g. phenol itself, a cresol or a higher alkylated phenol, or a mixture of alkylphenols) is preferably present in excess, and the resulting solution may be poured into a normally liquid ether or ketone (e.g. diethyl ether or acetone) to isolate the product in the form of its hydrohalide (from which the free base may be obtained, e.g. by trituration with aqueous alkali), or the free base may be directly isolated by pouring the reaction mixture into aqueous alkali.  In examples: (1) 2-methoxy-6 : 9-dichloroacridine is heated with 2 : 5-diaminopyrimidine in phenol, the reaction mixture is poured into ether and the resulting precipitate is ground with cold dilute caustic soda to liberate 51-(2-methoxy-6-chloroacridyl-9) -amino-21-aminopyrimidine; (2) the same product is prepared by heating 2-methoxy-6-chloro-9-phenoxyacridine (obtained by heating 2-methoxy-6 : 9-dichloroacridine with phenol) with 2 : 5-diaminopyrimidine in phenol and pouring the reaction mixture into excess of cold dilute caustic soda; (3) the 2 : 5 - diamino-pyrimidine in (1) is replaced by 5-amino-pyrimidine, producing 51-(2-methoxy-6-chloroacridyl-9)-aminopyrimidine. Additional starting materials specified are, on the one hand, 9-chloro-, 9-bromo-, 2-methoxy-9-chloro-, 2-and 3-cyano-9-chloro-, 2-methoxy-6-cyano-9-chloro-, 2-methoxy-6 : 9-dibromo-, 2-dimethyl-amino-6 : 9-dichloro- and 2-methoxy - 7 - cyano-9-chloro-acridine; and, on the other hand, 2 : 4-dihydroxy-, 2 : 4 : 6-trihydroxy-, 2 : 4-dihydroxy - 6 - methyl-, 2 : 4 - dihydroxy - 6 - phenyl-, 2 : 6 - dimethyl - 4 - hydroxy - and 2 : 6 - dimethyl - 4 - chloro - 5 - aminopyrimidine, and 4 - hydroxy - 6 - methyl-, 4 : 6-dimethyl- and 4 : 6-dichloro-2 : 5-diaminopyrimidine.ALSO:Acridine derivatives having antiplasmodial properties and of the formula <FORM:0601768/IV (c)/1> wherein either or both Bz rings of the acridine nucleus may contain one or more substituents, e.g. alkyl, alkoxy, nitro, disubstituted amino or halogen, and wherein the pyrimidine nucleus may also contain one or more additional substituents, e.g. halogen atoms or alkyl, aryl, alkoxy, aryloxy, hydroxy, nitro, amino or substituted amino groups, are manufactured by heating a 5-aminopyrimidine with a meso-halogenated acridine in the presence of a phenol, or with a meso-phenoxy acridine (preferably also in the presence of a phenol or without isolation from the reaction mixture obtained by heating a meso-halogenated acridine with a phenol).  The phenol (e.g. phenol itself, a cresol or a higher alkylated phenol, or a mixture of alkylphenols) is preferably present in excess, and the resulting solution may be poured into a p  normally liquid ether or ketone (e.g. diethyl ether or acetone) to isolate the product in the form of its hydrohalide (from which the free base may be obtained, e.g. by trituration with aqueous alkali), or the free base may be directly isolated by pouring the reaction mixture into aqueous alkali.  In examples: (1) 2-methoxy-6 : 9-dichloroacridine is heated with 2 : 5-diaminopyrimidine in phenol, the reaction mixture is poured into ether and the resulting precipitate is ground with cold dilute caustic soda to liberate 51-(2-methoxy-6-chloroacridyl-9) -amino-21-aminopyrimidine; (2) the same product is prepared by heating 2-methoxy-6-chloro-9-phenoxyacridine (obtained by heating 2-methoxy-6 : 9-dichloroacridine with phenol) with 2 : 5-diaminopyrimidine in phenol and pouring the reaction mixture into excess of cold dilute caustic soda; (3) the 2 : 5-diaminopyrimidine in (1) is replaced by 5-aminopyrimidine, producing 51-(2-methoxy-6-chloroacridyl-9)-aminopyrimidine. Additional starting materials specified are, on the one hand, 9-chloro-, 9-bromo-, 2-methoxy-9-chloro-, 2- and 3-cyano-9-chloro-, 2-methoxy-6-cyano-9-chloro-, 2-methoxy-6 : 9-dibromo-, 2-dimethylamino-6 : 9 - dichloro- and 2 - methoxy - 7 - cyano - 9 - chloro-acridine, and, on the other hand, 2 : 4-dihydroxy-, 2 : 4 : 6 - trihydroxy-, 2 : 4 - dihydroxy-6-methyl-, 2 : 4-dihydroxy-6-phenyl-, 2 : 6-dimethyl-4-hydroxy- and 2 : 6-dimethyl-4-chloro-5-aminopyrimidine, and 4-hydroxy-6-methyl-, 4 : 6-dimethyl- and 4 : 6-dichloro-2 : 5-diaminopyrimidine.