Patent GB-605870-A (GB)
Title: Improvements in or relating to process of producing substituted acridines and intermediates therefor
Filed: 1945-06-01
Abstract: 2 - Methoxy - 6 - chloro - 9 - [a  - methyl - o  - (substituted amino) polymethylene-amino] acridines of the general formula <FORM:0605870/IV(b)/1> wherein R and R1 are different saturated nontertiary hydrocarbon radicals, the sum of the carbon atoms in R and R1 does not exceed 10 and n is an integer between 1 and 4 inclusive, are prepared by condensing substituted diamines of the general formula <FORM:0605870/IV(b)/2> where R, R1 and n have the above significance, with 2 - methoxy - 6 : 9 - dichloroacridine.  The resulting substituted acridines may be converted into their corresponding salts by the addition of acids.  In examples, substituted acridines of the above general formula are prepared and converted into their hydrochloride, hydrobromide, sulphate, nitrate, phosphate, lactate or propionate salts.  In particular, 9-[11-methyl-41-(methyl-n-butylamino) butylamino]-, 9-[11-methyl-41-(n-propyl-isopropylamino) butyl - amino]-, 9 - [11 - methyl - 41 - (methylethylamino) butylamino]-, 9-[11-methyl-41-(methyl-n-propylamino) butylamino]-, 9-[11-methyl-41-(ethyl-n-propylamino) butylamino]-, 9 - [11 - methyl - 41-(ethylisopropylamino) butylamino]-, 9 - [11-methyl-41-(ethyl-n-butylamino) butylamino]-, 9-[11-methyl-41-(isopropylisobutylamino) butylamino]-, 9 - [11 - methyl - 31 - (methyl - n - propylamino) propylamino]-, 9 - [11 - methyl - 31 - (n - butylisobutylamino) propylamino]-, 9 - [11-methyl - 51 - (isobutyl - sec - butylamino) pentyl - amino]-, and 9-[11-methyl-21-(n-butylisobutylamino) ethylamino] - 2 - methoxy - 6 - chloro - acridines are prepared.  Diamines of the general formula <FORM:0605870/IV(b)/3> wherein R, R1 and n have the above significance, are prepared by reducing an oxime of the general formula <FORM:0605870/IV(b)/4> e.g. by treating an alcohol solution of the oxime with hydrogen under pressure and heat or with metallic sodium.  In examples (1) to (15), diamines of the above general formula are prepared and in particular 4-(methyl-n-butylamino)-, 4 - (n - propylisopropylamino)-, 4-(methylethylamino)-, 4 - (methyl - n - propyl - amino)-, 4-(ethyl-n-propylamino)-, 4-(ethylisopropylamino)-, 4 - (ethyl - n - butylamino)- and 4 - (isopropylisobutylamino) - 1 - methyl - butyl - amines, 3 - (methyl - n - propylamino)-, and 3-(n-butylisobutylamino) - 1 - methyl - propylamines, 1 - methyl - 5 - (isobutyl-sec-butylamino) pentylamine and 1-methyl-2-(n-butylisobutylamino) ethylamines.  Amino-oximes of the general formula <FORM:0605870/IV(b)/5> wherein R, R1 and n have the above significance, are prepared by heating a ketone of the general formula <FORM:0605870/IV(b)/6> with hydroxyl ammonium chloride.  In examples (1) to (15), amino-oximes of the above general formula are prepared and in particular 1-methyl-n-butylamino-, 1-n-propylisopropylamino-, 1 - methylethylamino-, 1 - methyl - n - propylamino-, 1-ethyl-n-propylamino-, 1-ethyl-isopropylamino-, 1 - ethyl - n - butylamino-, and 1 - isopropylisobutylamino - 4 - pentanonoximes, 1-methyl-n-propylamino-, and 1-n-butyl-isobutylamino-3-butanonoximes, 1-(isobutyl-secbutylamino)-5-hexanonoxime and 1-n-butylisobutylamino-2-propononoxime.  Aminoketones of the general formula <FORM:0605870/IV(b)/7> wherein R, R1 and n have the above significance, are prepared by condensing a o -chloroalkylketone with a secondary amine of the general formula <FORM:0605870/IV(b)/8> In examples (1) to (8), (12) and (13) aminoketones of the above general formula are prepared and in particular 1-methyl-n - butylamino-, 1 - n - propylisopropylamino-, 1-methylethylamino-, 1-methyl-n-propylamino-, 1 - ethyl - n - propylamino-, 1 - ethylisopropyl - amino-, 1 - ethyl - n - butylamino- and 1 - iso - propylisobutylamino - 4 - pentanones and 1-n-butylisobutylamino-2-propanone. 1-Methyl-n-propylamino-3-butanone is prepared by refluxing acetone, methyl-n-propylamine hydrochloride and formalin. 1-n-Butyl-isobutylamino-3-pentanone may be prepared by a similar method and other amino-ketones may be similarly prepared by employing other secondary amines of the above general formula. 1-(Isobutyl-sec-butylamino)-5-hexanone is prepared by refluxing sodium, ethylacetoacetate and 3-(isobutyl-sec-butylamino) propylchloride-1.  Other amino-ketones may be similarly prepared by employing other secondary amines of the above general formula. Secondary amines of the general formula <FORM:0605870/IV(b)/9> , wherein R and R1 have the above significance, are prepared by reacting a primary amine containing one desired R or R1 substituent with hydrogen and an aldehyde or ketone having the carbon skeleton of the other desired R or R1 substituent in the presence of a catalyst such as Raney nickel.  In examples (1), (2), (3), (7), (8), (10) and (11), the following secondary amines are prepared: methyl-n-butylamine, n - propylisopropylamine, methyl - ethylamine, ethyl-n-butylamine, isopropyl-isobutylamine, n-butylisobutylamine and isobutyl-sec-butylamine.  3 - (Isobutyl - sec - butylamino) - propanol-1 is prepared by heating isobutyl-sec-butylamine and 1-chloropropanol-3.  3-(Isobutyl-sec-butylamino) propyl chloride-1 is prepared by reacting 3-(isobutyl-sec-butylamino) propanol-1 with thionyl chloride.ALSO:2 - Methoxy - 6 - chloro - 9 - [a  - methyl-o -(substituted amino) polymethylene-amino] acridines of general formula <FORM:0605870/IV (c)/1> wherein R and R1 are different saturated non-tertiary hydrocarbon radicals, the sum of the carbon atoms in R and R1 does not exceed 10 and n is an integer between 1 and 4 inclusive, are prepared by condensing substituted diamines of the general formula <FORM:0605870/IV (c)/2> where R, R1 and n have the above significance, with 2-methoxy-6 : 9-dichloroacridine.  The resulting substituted acridines may be converted into their corresponding salts by the addition of acids.  In examples, substituted acridines of the above general formula are prepared and converted into their hydrochloride, hydrobromide, sulphate, nitrate, phosphate, lactate or propionate salts.  In particular, 9-[11-methyl-41-(methyl-n-butylamino) butylamino]-, 9-[11-methyl-41-(n-propyl-isopropylamino) butylamino]-, 9-[11-methyl-41-(methylethylamino) butylamino]-, 9 - [11 - methyl - 41 - (methyl - n - propylamino) butylamino]-, 9 - [11 - methyl-41-(ethyl-n-propylamino) butylamino]-, 9 - [11 - methyl - 41 - (ethylisopropylamino) butyl - amino]-, 9 - [1 - methyl - 4 - (ethyl - n - butylamino) butylamino]-, 9 - [11 - methyl - 41 - (isopropyliso - butylamino) butylamino]-, 9 - [11 - methyl - 31 - (methyl - n - propylamino) propylamino]-, 9 - [11 - methyl - 31 - (n - butylisobutylamino) propyl - amino]-, 9 - [11 - methyl - 51 - (isobutyl - sec - butyl - amino) pentylamino]-, and 9-[11-methyl-21-(n-butylisobutylamino) ethylamino]-2-methoxy-6-chloro-acridines are prepared.