Patent GB-466505-A (GB)
Title: Process for the manufacture of acridine derivatives
IPC: C07D219/08
Filed: 1935-11-28
Abstract: Acridine compounds containing both a basically-substituted 9-amino group and at least one sulphonamide group are prepared by (1) reacting upon acridines, containing a sulphonamide substituent and in the 9-position a halogen, aryloxy, alkoxy, mercapto, substituted mercapto or sulphonic group, with bases or their salts which contain at least two basic nitrogen atoms, at least one of which is in a primary or secondary amino group; (2) reacting upon the acridines specified in (1) with a base or salt thereof containing at least two amino groups, one of which is substituted by an acyl group, and subsequently splitting off the latter by saponification; (3) reacting upon the acridines specified in (1) with an amino-alcohol or an amino-substituted halogen alkyl compound and further reacting the product with ammonia or a primary or secondary amine, if desired after replacement of the hydroxyl group by halogen; (4) treating an acridine compound containing not only a basically-substituted 9-amino group but also a sulphonic ester or halide group with ammonia or an amine; (5) subjecting a diphenylamine-6-carboxylic acid amide basically-substituted in the amide group and containing a sulphonamide substituent to ring closure to form the acridine compound.  The basic radicle substituting the amino group may contain more than one nitrogen atom and may be further substituted by, for example, hydroxyl groups; it may also contain ether or thioether groups and aliphatic, isocyclic or heterocyclic constituents.  In examples: (1) 2 - methoxy - 7 - sulphondimethylamido - 9-chloroacridine, prepared by condensing 5-sulphondimethylamido-2-chlorobenzoic acid with 4-anisidine and ring closing the product in the presence of phosphorus oxychloride, is condensed with a -diethylamino-d -aminopentane, a  - diethylamino - b - hydroxy - g -propylamine or the triamine of the formula H2N.CH2.CH2.NH.CH2.CHOH.CH2.N (C2H5)2; similarly 2 - methoxy - 7 - sulphondiethylamido - 9 - chloroacridine, prepared by condensing 5 - sulphondiethylamido - 2-chlorobenzoic acid with 4-anisidine and heating the product with phosphorus oxychloride, is condensed with a -diethylamino-b -hydroxy-g  - propylamine; (2) 2 - sulphondimethylamido - 7 - methyl - 9 chloroacridine, prepared by ring closing the reaction product of 5 - sulphondimethylamido - 2 - chlorobenzoic acid and 4-toluidine with phosphorus oxychloride, is condensed with a -diethylamino-b -hydroxy - g  - aminopropane; its salt with methylene - bis - (2 - hydroxy - 3 - naphthoic acid) is described; the acridine starting material may be replaced by the corresponding 9 - methoxy, 9 - (p - methylphenylmercapto) or 9-sulphonic acid sodium salt compounds which are obtained by treating the 9-chloro compound with sodium methylate, p-thiocresol or sodium sulphite respectively; as starting material may also be employed 2-sulphondimethylamide - 6 - methyl - 9 - chloroacridine, which is prepared by condensing 5-sulphondimethylamido - 2 - chlorobenzoic acid with 3-toluidine and heating with phosphorus oxychloride; (3) 2-methoxy - 6 - sulphondimethylamido - 9 - chloroacridine is first prepared by reacting 2-chlorotoluene-4-sulphochloride with dimethylamine, oxidizing the product to 4 - sulphondimethylamido - 2 - chlorobenzoic acid, condensing with 4-anisidine and finally heating with phosphorus oxychloride, and is then condensed with a -diethylamino-d -aminopentane and with the triamine referred to in (1); (4) 4<1>-methoxy-4 - sulphondiethylamidodiphenylamine - 2 - carboxylic acid is converted into its chloride using phosphorus pentachloride, condensed with a -diethylamino-b -aminoethane, and the resulting amide heated with phosphorus oxychloride to give 2-methoxy-7-sulphondiethylamido - 9 - (a  - diethylamino-b  - ethylamino) - acridine; (5) 2 - sulphondimethylamido - 7 - methyl - 9 - phenoxy - acridine, obtained by treating the 9-chloro compound with phenol, is condensed with 4-aminophenyl - b  - hydroxyethylether and the reaction product treated first with thionyl chloride and then with diethylamine to give 2 - sulphondimethylamido - 7 - methyl-9-(p - diethylaminoethoxy - phenylamino)-acridine; (6) 2 - sulphondimethylamido-7-methyl - 9 - phenoxy - acridine is condensed with N - (4 - aminobenzyl) - acetamide and the product saponified with hydrochloric acid to the 9-(p-aminomethylphenylamino) compound; (7) 2-sulphondimethylamido-7-methyl-9-bromoacridine, prepared by treating the corresponding acridone with phosphorus pentabromide, is condensed with the diamine NH2.(CH2)3.S.(CH2)2.N (C2H5)2 and with a -piperido - b  - aminoethane; (8) 9 - (a -diethylamino - b  - ethylamino) acridine, obtained by heating 9-chloroacridine with a -diethylamino-b -ethylamine in phenol, is sulphonated with chlorsulphonic acid and the product treated with ammonia or methylamine; several sulphonamide groups can be introduced in this way using increased temperatures for the sulphonation. Specifications 267,169, 282,453, 283,510, 286,087, 304,280, 363,392, [all in Class 2 (iii)], 437,953, 441,007, and 441,132, are referred to.  The triamine of (1) above is obtained by reacting a  - diethylamino - b  - hydroxy - g -propylamine with bromethylphthalimide and then splitting off phthalic acid.  4 - Aminophenyl - b  - hydroxyethylether is prepared by reacting potassium 4-nitrophenolate with chlorethyl alcohol and reducing with iron and acetic acid.