Patent GB-610055-A (GB)
Title: Process for the manufacture of acridine and quinoline compounds
IPC: C07D215/44
Filed: 1945-10-23
Abstract: Heterocyclic compounds of the general formula <FORM:0610055/IV(b)/1> are prepared by reacting an aminomethyl phenol of the formula <FORM:0610055/IV(b)/2> with a heterocyclic compound of the formula YX under acidic conditions, where R is hydrogen, halogen, hydroxy, or a saturated or unsaturated alkyl radical, X is a chlorine or bromine atom, or an anyloxy radical when Y is a 9-acridyl radical.  Y may also be a 4-quinolyl radical.  The quinolyl radical may be substituted by halogen, -CN, -COOH, -COO alkyl, alkyl or alkoxy, and the acridyl radical may be substituted alkyl, alkoxy or cyano.  The reaction is carried out in an aqueous, or aqueous-organic, or organic solvent.  Solvents mentioned include methanol, ethanol propanol, dioxone and acetone.  The acidic conditions comprise either the use of an acid addition salt of the aminomethylaminophenol, or, where the free aminomethyl phenol base is employed, carrying out the reaction in an aqueous acidic or a non-aqueous phenolic medium.  Instead of using the free amino phenol, there may be employed the corresponding mono- or di-acylamino compound, and the free base regenerated after the condensation.  Where the di-acylamino compound is used, the acyl group attached to the amino group concerned in the condensation is hydrolysed by the acidic reaction conditions, the other amino group is more stable and requires to be separately hydrolysed.  In examples: (1a) 4 : 7-dichloroquinoline and 2-aminomethyl-4-aminophenol hydrochloride are reacted in aqueous ethanol to give 4-(31-aminomethyl-41-hydroxyanilino) -7-chloro-quinoline; (1b) as in (1a) but using 2-benzamido-methyl-4-aminophenol as starting material and including a final hydrolysis step; (2) 4-chloro-6-methoxy-quinoline is reacted with 2-aminomethyl-4-aminophenol dihydrochloride in aqueous alcohol to give 4-(31-aminomethyl-41-hydroxyanilino)-6-methoxy quinoline.  As starting materials also 2-methyl-4-chloro-6 methoxyquinoline 2-methyl-4-chloro-6-ethoxy quinoline and 4-chloro-6 : 7-dimethoxyquinoline may also be used; (3) 4-chloroquinoline and 2-aminomethyl-6-aminophenol dihydrochloride are reacted in aqueous solution to give 4-(21-hydroxy-31-aminomethylanilino)-quinoline; (4) 2 - acetylaminomethyl - 4 - acetylaminophenol is treated with HCl and then reacted with 4-chloro-7-bromoquinoline to give 4-(31-amino-methyl-41-hydroxyanilino)-7-bromoquinoline; (5) 2-aminomethyl-4-aminophenol hydrochloride and 3-carbethoxy-4 : 7-dichloroquinoline are reacted in ethanol to give 3-carbethoxy-4-(31-aminomethyl - 41 -hydroxyanilino) - 7 -chloroquinoline; (6) 2-aminomethyl-5-aminophenol dihydrochloride and 4-chloro-7-cyanoquinoline are reacted in acetone methanol solution to form 4-(31-hydroxy-41-aminomethylanilino)-7-cyanoquinoline; (7) 2-methoxy-6 : 9-dichloroacridine and 2-aminomethyl-4-amino-6-chlorophenol dihydrochloride are refluxed in dioxane to form 2-methoxy-6-chloro-9-(31-aminomethyl-41-hydroxy -51-chloroanilino)-acridine; (8) 2-ethoxy-6 : 9-dichloroacridine and 2-aminomethyl-4-amino-6-allyl phenol hydrochloride are refluxed in aqueous ethanol to form 2-ethoxy-6-chloro-9-(31-aminomethyl-41-hydroxy -allylanilino)-acridine; (9) 2-aminomethyl-4-acetylamino-6-methylphenol is treated with aqueous HCl and then reacted with 2 : 3-dimethyl-9-chloro-acridine to give 2 : 3-dimethyl - 9 - (31 - aminomethyl - 41 - hydroxy - 51-methylanilino)-acridine; (10) 2-aminomethyl-4-aminophenol and 2 : 3-dimethoxy-6-bromo-9-chloro-acridine is refluxed in ethanol solution to give 2 : 3-dimethoxy-6-bromo-9-(31-aminomethyl-41-hydroxy -anilino)-acridine; (11) a phenol solution of 9-chloro-acridine is treated with 2-aminomethyl-4-amino-5-hydroxyphenol to give 9-(21 : 41-dihydroxy-51-amino-methylanilino)-acridine.  The aminophenols used in the process are prepared by catalytic reduction of the corresponding aminomethylnitrophenols. Specification 584,917 is referred to.ALSO:Heterocyclic compounds of the general formula <FORM:0610055/IV (c)/1> are prepared by reacting an aminomethyl phenol of the formula <FORM:0610055/IV (c)/2> with a heterocyclic compound of the formula YX under acidic conditions, where R is hydrogen, halogen, hydroxy, or a saturated or unsaturated alkyl radical, X is a chlorine or bromine atom, or an aryloxy radical when Y is a 9-acridyl radical.  Y may also be a 4-quinolyl radical.  The quinolyl radical may be substituted by halogen, -CN, -COOH, -COO alkyl, alkyl or alkoxy, and the acridyl radical may be substituted alkyl, alkoxy or cyano.  The reaction is carried out in an aqueous, or aqueous-organic, or organic solvent, solvents mentioned include methanol, ethanol, propanol, dioxene and acetone.  The acidic conditions comprise either the use of an acid addition salt of the aminomethylaminophenol, or, where the free aminomethylphenol base is employed, carrying out the reaction in an aqueous acidic or a non-aqueous phenolic medium.  Instead of using the free amino phenol, there may be employed the corresponding mono- or diacylamino compound, and the free base regenerated after the condensation. Where the di-acylamino compound is used, the acyl group attached to the amino group concerned in the condensation is hydrolysed by the acidic reaction conditions.  The other amino group is more stable and requires to be separately hydrolysed. Examples are furnished.  The aminophenols used in the process are prepared by catalytic reduction of the corresponding aminomethylnitrophenols.  Specification 584,917 is referred to.