Patent GB-583220-A (GB)
Title: Improvements in the manufacture of mepacrine derivatives
IPC: C07D219/12
Filed: 1943-06-16
Abstract: Mepacrine Hydrochloride (i.e. the 2-methoxy-6 - chloro - 9 - (41-diethylamino - 11 - methylbutyl - amino)-acridine dihydrochloride hydrate) or mixtures of the mono- and dihydrochlorides of mepacrine base, i.e. 2-methoxy-6-chloro-9-(41-diethylamino - 11 - methyl - butylamino) - acridine ("monohydrochloride" denoting whatever compound or mixtures of compounds arises from the combination of mepacrine base with one molecular proportion of hydrogen chloride) are made by heating, in a phenol as a solvent, approximately equi-molecular proportions of 2-amino-5-diethylamino pentane and a 2-methoxy - 6 - chloro - 9 - aryloxyacridine, in the presence of 1.25 to 2.25 equivalents of hydrogen chloride, or, alternatively, in the case of the dehydrochloride of hydrogen bromide or sulphuric acid, per mole. of the amino pentane or of the acridine, and, in the alternative method, subsequently liberating the mepacrine base by treatment with alkali and then converting this to the dihydrochloride.  Advantageously, the 2-methoxy-6-chloro-9-aryloxyacridine may be generated in situ from 2-methoxy-6 : 9-dichloro aryloxyacridine and the appropriate phenol. Examples relate to the preparation of: (1) Mepacrine Hydrochloride (dihydrate) 2-amino-5-diethylaminopentane is converted into its dihydrochloride by treatment with the stoichiometric quantity of hydrogen chloride in warm phenolic solution.  2 - Methoxy - 6 : 9 - dichloracridine is added to the mixture which on being heated yields 2-methoxy-6-chloro-9-phenoxyacridine hydrochloride.  A further quantity of 2-amino-5-diethylaminopentane is added and the mixture is heated and then treated with a mixture of benzene and caustic soda solution when the phenol is dissolved by the alkali and the mepacrine base by the benzene.  The base is extracted as acetate from the benzene by treatment with aqueous acetic acid and precipitated as the hydrated form of the dihydrochloride by the addition of aqueous hydrochloric acid, preferably as described in Specification 583,221. (2) Mepacrine Hydrochloride (monohydrate) 2-amino-5-diethylaminopentane is converted into its dihydrochloride by treatment with the stoichiometric amount of aqueous hydrochloric acid in phenolic solution.  Xylene is added to the mixture which is refluxed so that of the two phase distillate the xylene layer is returned to the vessel while the aqueous layer is discarded, until all the water is removed.  To the xylene solution is added 2-methoxy-6 : 9-dichloroacridine and the mixture is heated. 2-Amino-5-diethylaminopentane is then added and the mixture is heated again to complete the formation of the Mepacrine Hydrochloride which is isolated as described in (1). Alternatively, the base can be isolated by extraction from the benzene solution with aqueous acetic acid, the acetate solution then being made alkaline to liberate the free base which may then be extracted with ether in the manner described in Specification 365,392.  The free base monohydrate may be obtained by dissolving the base in acetone and adding water; and the monohydrate may be converted into the dihydrochloride by treatment in ether solution, with an ether solution of hydrogen chloride.  The phenol may be replaced by acrylic acid and the xylene may be replaced by other inert, water-immiscible solvents such as chlorobenzene or toluene.  (3) Mepacrine Hydrochloride (dihydrate) 2-amino-5-diethylaminopentane is converted into its dihydrochloride by treating its phenolic solution with the stoichiometric amount of dry hydrogen chloride.  2-methoxy - 6 - chloro - 9 - phenoxy acridine base is then added and the mixture is heated, the Mepacrine Hydrochloride being isolated by either of the methods of (1) and (2). (4) Mepacrine Hydrochloride. 2-Amino-5-diethylaminopentane in phenolic solution is treated with the stoichiometric amount of aqueous hydrobromic acid, xylene is added and water is distilled out of the mixture as in (2).  The xylene is distilled off leaving a mixture of phenol and the dihydrobromide of 2-amino-5-diethylaminopentane to which are added after cooling to about 90 DEG  C.  2-methoxy-6 : 9-dichloroacridine and 2-amino-5-diethylaminopentane as in (2). When the reaction is complete, the mixture is added to approximately equal quantities of benzene and aqueous caustic soda solution and Mepacrine Hydrochloride is isolated by either of the methods of (1) and (2).  (5) Mepacrine Hydrochloride. 2-Amino-5-diethylaminopentane in phenolic solution is treated with xylene and dilute sulphuric acid until neutralization is complete.  Water and most of the xylene are distilled out as described in (2), and 2-methoxy-6-chloro-9-phenoxyacridine is added to the cooled mixture which on being heated yields Mepacrine Hydrochloride which is then isolated by the method of (4).