Patent GB-587936-A (GB)
Title: New quinazoline derivatives
Filed: 1944-09-05
Abstract: Quinazoline derivatives containing in the 2-position an arylamino group devoid of acidic substituents and in the 4-position a basic group of the formula NR11-A-NRR1, wherein R11 stands for hydrogen or an alkyl or substituted alkyl (e.g. alkoxyalkyl or dialkylaminoalkyl) group, A stands for a linking group which is aliphatic, alicyclic or aliphatic-carbocyclic and is devoid of acidic substituents, but may be substituted, for example, by hydrocarbon radicals, hydroxy, alkoxy or dialkylaminoalkyl groups and where A or part A is an aliphatic chain it may be interrupted by oxygen, nitrogen or sulphur atoms, and NRR1 is a strongly basic amino or substituted amino group such as alkylamino or dialkylamino or piperidino or other strongly basic nitrogen-containing heterocyclic group and which quinazoline derivatives may contain in other nuclear positions one or more non-acidic substituents, e.g. alkyl, alkoxy, halogen or nitro groups or fused-on carbocyclic rings, e.g. as in 6 : 7-benzoquinazoline, are obtained by the interaction of an appropriate arylamine devoid of acidic substituents with a quinazoline containing in the 4-position the basic group NR11-A-NRR1 and in the 2-position a labile group such as a halogen atom, e.g. chlorine or bromine, or a hydrocarbon radical which is attached by an ether or thioether linkage, e.g. an aryloxy group or alkyl mercapto group.  The reaction is effected by heating together the reagents, optionally in the presence of a solvent or diluent, or conveniently in an aqueous medium with one molecular proportion each of the arylamine and the quinazoline and one molecular proportion or a slight excess thereover of a mineral acid. The arylamines may bear one or more non-acidic substituents, such as halogen atoms, nitro groups, hydrocarbon radicals (which may be substituted and may be attached to the arylamino group directly or through an oxygen, nitrogen or sulphur atom or through a sulphonyl or carbonyl group), cyano groups or esterified carboxyl groups.  The products form salts with mineral and organic acids such as hydrogen halides, sulphuric and phosphoric acids, acetic, lactic, tartaric and lower alkane sulphonic acids.  Substituents in the arylamino group or in the quinazoline nucleus may be converted into another suitable substituent.  Examples describe the preparation, from the appropriate arylamines and the appropriate 2-chloro-4-substituted quinazolines, of: 2-p-methoxyanilino-, 2-anilino-, 2-p-toluidino-, 2-b -naphthylamino- and 2-p-chloroanilino-4-g -diethylaminopropylaminoquinazoline; 2-p-methylmercaptoanilino- and 2-(21-naphthylamino)-4-b -diethylaminoethylaminoquinazoline; 4 - b  - diethylaminoethylamino-, 4 - b  - dimethylaminoethylamino-, 4 - g  - dimethylaminopropylamino-, 4 - g  - n - butylaminopropylamino-, 4 - g - diethylaminobutylamino-and 4-g -piperidinopropylamino - 2 - p - chloroanilinoquinazoline; 2-(61-bromo-21-naphthylamino)- and 2-(41 : 81-dichloro-21-naphthylamino) -4-b -diethylaminoethylaminoquinazoline; 7 - chloro-, 6 - chloro-, 7-methyl-, 7-methoxy-, 6-methoxy-, 8-methoxy-, and 7 - nitro - 2 - p - chloroanilino - 4 - b  - diethyl aminoethylaminoquinazoline; 2-p-chloroanilino4 - b  - diethylaminoethylamino - 6 : 7 - benzoquin - azoline; 2 - p - chloroanilino - 4 - b  - diethylamino - ethylamino - 6 : 7 - dimethoxyquinazoline; 4 - b  - diethylaminoethylamino-, 4 - g  - piperidinopro - pylamino-, 4 - b  - dimethylaminoethylamino and 4 - b  - diethylaminoethylamino - 5 - methoxy - 2 - p - chloroanilino - quinazoline; 2 - p - nitroanilino - 4 - b -diethylaminoethylaminoquinazoline; 6-nitro-and 6 - amino - 2 - p - chloroanilino - 4 - b  - diethylaminoethylaminoquinazoline; 4-b -aminoethylamino - 2 - p - chloroanilinoquinazoline; 2 - p - chloroanilino - 4 - methyl - b  - diethylaminoethyl - aminoquinazoline; 2 - N - ethylanilino - 4 - b  - diethylaminoethylaminoquinazoline.  Quinazolines containing ether or thioether groups are obtained by the interaction of the 2-halogeno-derivatives with the appropriate hydroxy or mercapto compounds or with alkali metal derivatives od such compounds. 4-Basically substituted-2-halogeno-quinazolines which form starting materials for this invention, are made from the appropriate diamine and the requisite 2 : 4-dichloroquinazoline, e.g. by the action of b -diethylaminoethylamine on 2 : 4 : 6-trichloroquinazoline, 2 : 4-dichloro-7-methoxy, 7-methyl, 7-nitro, 6 : 7-benzo-, 6 : 7-dimethoxy-, 5-methoxy or 6-nitroquinazoline, themselves obtainable by the action of phosphorous halides on the corresponding 2 : 4-dihydroxy compounds which may be made by cyclisation of the products obtained by the action of an alkali cyanate on methyl-5-chloro-anthranilate, 2-amino-4-methoxy- or 4-methyl-benzamide, 4-nitroanthranilic acid, 6-aminoveratric acid (obtained by the reduction of 6-nitroveratric acid) and 2 - amino - 6 - methoxybenzonitrile respectively or of an excess of urea on 2-naphthylamine-3-carboxylic acid.  Specifications 287,179 and 309,102, [both in Class 2 (iii)], are referred to.