Patent GB-789696-A (GB)
Title: Process for producing acridine compounds
Inventor: MORGAN EDWARD NORMAN
IPC: C07D219/02
Filed: 1955-08-26
Abstract: 5-Methyl acridines and their addition salts having in the free base form the general formula: <FORM:0789696/IV (b)/1> are obtained by reacting a 5-haloacridine of formula: <FORM:0789696/IV (b)/2> with a malonic acid derivative M-CH(Y)Z in the presence of an anhydrous organic solvent at a temperature above 50 DEG  C. to obtain an acridyl-5-malonic acid derivative of formula: <FORM:0789696/IV (b)/3> the latter derivative is then subjected to direct hydrolysis at a temperature of at least 75 DEG  C. in the presence of an aqueous mineral acid or to stepwise hydrolysis firstly in an aqueous basic medium at a temperature in the range 90-150 DEG  C. and then in the presence of aqueous mineral acid at a temperature above 750 DEG  C., M being an alkyl metal, R1 and R2 being the same or different and representing hydrogen, lower alkyl, lower alkoxy or halogen radicals, X being a chlorine or bromine radical and Y and Z being the same or different and representing nitrile or lower alkoxy-carbonyl groups. Lower alkyl and alkoxy groups are those containing not more than 4 carbon atoms.  Suitable solvents for the reaction between the 5-haloacridine and the malonic acid derivative are, for example, lower aliphatic alcohols, cyclic ethers such as dioxane, aromatic hydrocarbons such as benzene and toluene, and petroleum ether.  In the examples: (a) a solution of 5-chloroacridine in toluene is added to diethyl sodio-malonate and the mixture is heated; hydrochloric acid is added and 5-methyl acridine hydrochloride crystallizes out; the pure base is obtained by treating the hydrochloride with ammonia; (b) 5-chloracridine is added to a solution of diethyl sodio-malonate and the mixture is heated and treated with hydrochloric acid; the hydrochloride formed is treated with caustic soda to give diethyl acridyl-5-malonate, <FORM:0789696/IV (b)/4> which on treatment with hydrochloric acid gives 5-methyl acridine hydrochloride; (c) a mixture of 5-chloroacridine and benzene is added to a solution of sodium ethoxide and malononitrile in ethanol and the resulting mixture is heated; on acidification dicyano methyl acridine <FORM:0789696/IV (b)/5> is obtained; on treating with sulphuric acid 5-methylacridine sulphate is obtained and this gives the free base on treatment with ammonia; (d) 3,5-dichloroacridine is added to a solution of sodium and ethyl malonate in ethanol; toluene is added and the mixture is heated; the resulting mixture is heated with hydrochloric acid to give 3-chloro-5-methylacridine hydrochloride; (e) 2,5,8-trichloroacridine is added to a solution of sodium and ethyl malonate in ethanol and the mixture is heated, hydrochloric acid is added and the precipitate formed is treated with ammonia to give 2,8-dichloro-5-methylacridine; (f) 5-chloroacridine is treated with ethyl cyano acetate and sodium ethoxide in a mixture of benzene and ethanol to give ethyl acridyl-5-cyanoacetate; on treating with sodium carbonate solution 5-cyanomethyl acridine is obtained and this on treatment with hydrobromic acid followed by treatment with ammonia gives 5-methyl acridine; (g) 3-methoxy-5,8-dichloroacridine is dissolved in toluene and added to a mixture of sodium, ethyl malonate and ethanol to give diethyl-3-methoxy - 8 - chloroacridyl - 5 - malonate hydrochloride; on hydrolysis with hydrochloric acid and subsequent treatment with ammonia 3 - methoxy - 5 - methyl - 8 - chloroacridine is obtained; and (h) 2-methyl-5-chloroacridine is added to diethyl sodio-malonate, the mixture is heated and hydrochloric acid is added; 2,5-dimethylacridine hydrochloride is obtained and on treatment with ammonia it gives the free base.