Patent GB-363392-A (GB)
Title: Process for the manufacture of n-substituted 2-alkoxy-6-halogen-9-aminoacridines
IPC: C07D219/12
Filed: 1930-06-18
Abstract: 9-Aminoacridines which contain a basic substituent in the amino group and a halogen or alkyl group in the 6-position, and which may also contain a halogen, alkyl or alkoxy group in the 2-position, are prepared by the methods described in Specifications 267,169,282,453, and 286,087, [all in Class 2 (iii), Dyes &c.].  The basic substituents present in the 9-amino group are residues containing at least one nitrogen atom, either as an amino group which may be substituted or in heterocyclic combination, the said nitrogen atom being linked by means of an aliphatic, carbocyclic or aliphatic-carbocyclic residue; the substituent may also contain ether or thio-ether linkages, as well as other groups such as hydroxy groups.  The products possess therapeutic properties.  The examples describe the preparation of (1) 9-(diethylamino-ethylamino) - 2 - ethoxy - 6 - chloroacridine from 2-ethoxy-6 : 9-dichloroacridine (see Specification 353,537) and 2 - diethylamino - 1 - aminoethane; (2) 9 - (diethylaminopentylamino) - 2 - methoxy-6 - chloroacridine from 2 - methoxy - 6 : 9 - dichloroacridine (see Specification 353,537) and 5-diethylamino-1-aminopentane; (3) 9-(a -diethylamino-d -pentylamino)-2-methoxy-6-chloroacridine from 2-methoxy-6 : 9-dichloroacridine and 5-diethylamino-2-aminopentane; 2-methoxy-6-bromo-9-(a -diethylamino-d -pentylamino)-acridine and the corresponding 6-iodo compound are similarly obtained from 2-methoxy-6-bromo or iodo-9-chloroacridine (see Specification 353,537) respectively; (4) 9-(1<1>:3<1>-tetraethyldiamino-2<1>-propylamino) -2-methoxy-6-chloroacridine from 2 - methoxy - 6 : 9 - dichloroacridine and 1 : 3-tetraethyldiamino-2-aminopropane; (5) 9-(3<1>-diethylamino-2<1>-hydroxy-1<1>-propylamino) -2-methoxy-6-chloroacridine from 2-methoxy-6 : 9-dichloroacridine and 3-diethylamino-2-hydroxy-1-aminopropane; from the same acridine starting material, 2-methoxy-6-chloro-9-(a -dimethylamino-g -propylamino)-acridine is obtained using a -dimethylamino-g -aminopropane, 2-methoxy-6-chloro - 9 - (a  - diethylamino-g -butylamino) - acridine using a -diethylamino-g -aminobutane, 2-methoxy-6 - chloro-9-(a -diallylamino-g -butylamino) - acridine using a -diallylamino-g -aminobutane, and 2-methoxy-6-chloro-9-(a -diallylamino-b -ethylamino) - acridine employing a  - diallylamino - b  - aminoethane; (6-8) products whose formul  are given by interaction of 2 - methoxy - 6 : 9 - dichloroacridine with 4 - amino - 1 - N - (ethyldiethylaminoethyl) - aminobenzene, 4-amino-1-diethylaminoethoxybenzene and 2 - piperidino - 1 - aminoethane; (9) 2 - methoxy - 6-chloro-9-phenoxyacridine by interaction of 2-methoxy-6 : 9-dichloroacridine with phenol and treatment of the product with a triamine of the formula H2N.CH2.CH2.N (C2H5). CH2.CH2.N (C2H5)2 to form the corresponding 9-substituted aminoacridine; (10) 2-methoxy-6-chloro-9-diethylaminoethylaminoacridine by treating 2-methoxy-6 : 9-dichloroacridine with aminoethyl alcohol, converting the 9-hydroxyethylamino compound into the 9-chloroethylamino body and finally combining with diethylamine; the same product is obtained by converting 4<1>-methoxy-3-chlorodiphenylamine-6-carboxylic acid (see Specification 353,537) into its acid chloride with phosphorus pentachloride, treating with 2-diethylamino-1-aminoethane and effecting ring closure of the product with the aid of phosphorus pentoxide; the same product is also obtained by interaction of 2-methoxy-6-nitro-9-chloroacridine (prepared by ring closure of 4<1>-methoxy-3-nitrodiphenylamine-6-carboxylic acid, itself obtained by condensation of 4-anisidine with 4-nitro-2-chlorobenzoic acid) and 2-diethylamino-1-aminoethane, reduction of the resulting 2-methoxy-6-nitro-9-diethylaminoethylaminoacridine to the 6-amino compound, followed by diazotization and treatment with cuprous chloride; (11) 6-chloro-9 - (a  - diethylamino - d  - pentylamino) - acridine and 6-chloro-9-(a -diethylamino-g -butylamino) - acridine by interaction of 6 : 9-dichloroacridine (obtained by ring closure of 3-chlorodiphenylamine-6-carboxylic acid and chlorination of the resulting acridone) with a -diethylamino-d -aminopentane and a -diethylamino-g -aminobutane respectively; in an analogous manner, 2-methyl-6-chloro-9-(a -diethylamino-d -pentylamino)-acridine is obtained from 2-methyl-6 : 9-dichloroacridine (prepared by p condensing 2 : 4-dichlorobenzoic acid with 4-toluidine, ring closing the resulting 4<1>-methyl-3-chlorodiphenylamine-6-carboxylic acid and chlorinating the acridone formed), 2 : 6-dichloro-9-(a -diethylamino-d -pentylamino)-acridine from 2 : 6 : 9-trichloroacridine (obtained by condensing 2 : 4-dichlorobenzoic acid with 4-chloroaniline, ring closing and chlorinating), 2-methoxy-6-methyl-9-(a -diethylamino-d -pentylamino)-acridine from 2-methoxy-6-methyl-9-chloroacridine (formed when the condensation product of 4-methyl-2-chlorobenzoic acid with 4-anisidine is subjected to ring closure and chlorination), 6-methyl-9-(a -diethylamino-d -pentylamino)-acridine from 6 - methyl - 9 - chloroacridine (produced by condensing 4-methyl-2-chlorobenzoic acid with aniline, ring closing and chlorinating), 2 : 6 - dimethyl - 9 - (a -diethylamino-d -pentylamino)-acridine from 2 : 6-dimethyl-9-chloroacridine (prepared by ring closing the condensation product of 4-methyl-2-chlorobenzoic acid with 4-toluidine and chlorinating the acridone), 6-methyl-2-chloro-9-(a -diethylamino-d -pentylamino)-acridine from 6-methyl-2 : 9-dichloroacridine (prepared by condensing 4-methyl-2-chlorobenzoic acid with 4-chloroaniline, ring closing the product and chlorinating), 2-ethyl-6-chloro-9-(a -diethylamino-d -pentylamino)-acridine from 2-ethyl-6 : 9-dichloroacridine (obtained from the condensation of 2 : 4-dichlorobenzoic acid with 4-ethylaniline, followed by ring closure and chlorination); (12) 2-methoxy-6-chloro-9-(4<1>-aminomethylphenylamino)-acridine by heating 2-methoxy-6-chloro-9-phenoxyacridine with N-(4-aminobenzyl)-acetamide and saponifying the product. 4-Amino-1-diethylaminoethoxybenzene is prepared by treating potassium 4-nitrophenolate with diethylaminoethyl chloride and reducing the product with iron and acetic acid.  N-(4-Aminobenzyl)-acetamide is prepared by reduction of the corresponding nitro compound with iron and acetic acid.  Amines.-- 5 - Diethylamino - 2 - aminopentane is prepared by the reduction of 5-diethylamino-2-pentanone with sodium amalgam.  1 : 3-Tetraethyldiamino-2-aminopropane is obtained by converting epichlorhydrin with excess diethylamine into 1 : 3-tetraethyldiamino-2-propanol, chlorinating with thionyl chloride, reacting the 1 : 3-tetraethyldiamino - 2 - chloropropane with potassium phthalimide and finally saponifying.  a -Dimethylamino-g -aminopropane results from the splitting off of phthalic acid from the reaction product of brompropylphthalimide with dimethylamine. g -Diethylamino-g -aminobutane is obtained by converting a -diethylamino-g -butanone (see Specification 14231/13, [Class 2 (iii), Dyes &c.]), with hydroxylamine into the oxime and reducing with sodium amalgam.  a -Diallylamino-g -aminobutane is prepared by treating diallylamine with formaldehyde and acetone, converting the resulting a -diallylamino-g -butanone into its oxime and reducing the latter with sodium amalgam. a -Diallylamino-b -aminoethane is obtained by converting diallylamine with ethylene oxide into diallylaminoethyl alcohol, chlorinating with thionyl chloride, treating the diallylaminoethyl chloride with potassium phthalimide and splitting off phthalic acid. 4-Amino-1-N-(ethyldiethylaminoethyl)-aminobenzene is prepared by introducing the nitroso group into N-(ethyl - diethylaminoethyl) - aminobenzene with subsequent reduction (see Specification 274,058, [Class 2 (iii), Dyes &c.]).  A triamine of the formula H2N.CH2.CH2.N(C2H5).CH2. CH2.N(C2H5)2 is formed when the reaction product of 2-diethylamino-1-ethylaminoethane with bromoethylphthalimide is saponified.