Patent GB-821100-A (GB)
Title: Basically substituted 4-halogen-2-amino-1:3:5-trimethyl-benzenes and process for their manufacture
IPC: C07D295/073
Filed: 1955-12-28
Abstract: The invention comprises compounds of the general formula <FORM:0821100/IV (a)/1> wherein Hal represents a halogen atom, R1 represents a hydrogen atom or an alkyl group containing 1/3 carbon atoms, and X represents an aminoalkyl group of the general formula <FORM:0821100/IV (a)/2> wherein R2 represents a straight or branched alkylene chain containing 2/5 carbon atoms, and R3 and R4 each represent a hydrogen atom or an alkyl, alkenyl or cycloalkyl radical containing 1 to 3 carbon atoms, that may contain a hydroxy or alkoxy group containing 1 to 3 carbon atoms, and in which the nitrogen atom together with R3 or R4 or with R2 and R4 may form a saturated heterocyclic ring system, and acid addition salts of these compounds, and the preparation thereof by reacting, if desired in several stages, a compound of the general formula <FORM:0821100/IV (a)/3> wherein Hal and R1 have the above significance, with a compound containing an aminoalkyl radical of the general formula <FORM:0821100/IV (a)/4> wherein R2, R3 and R4 have the above signi ficance.  Thus the 4-halogeno-2-amino-1,3,5-trimethylbenzene may be reacted with the required alkanolamine or a reactive ester thereof such as an ester of hydrohalic or sulphonic acid, if desired in the presence of a condensing agent, e.g. a hydrohalic acid, and when the desired product is obtained in the form of an acid addition salt, the desired free base is liberated therefrom; or the 4-halogeno-2-amino-1,3,5-trimethylbenzene may be reacted with the required alkylene halogenhydrin, the hydroxy group of the resulting condensation product converted into a reactive ester group such as an ester of hydrohalic acid by reacting with a hydrohalic acid, thionyl chloride or a phosphoric acid halide, the reactive ester group is reacted with ammonia or the required primary or secondary amine, and when ammonia or a primary amine is used, if desired, the amino group is alkylated such as by reacting with formaldehyde followed by hydrogenating in the presence of nickel, and when the desired product is obtained in the form of an acid addition salt, the desired free base is liberated therefrom. Suitable alkanolamines and reactive esters thereof that may be used as reactants are ethanolamine, b -dimethylaminoethyl chloride, b -diethylaminoethyl chloride, b -di-n-propylaminoethyl chloride, b -di-isopropylaminoethyl chloride, b -(di-b -methoxyethylamino) ethyl chloride, g -dimethylamino-n-propyl chloride, b -diethylamino-isopropyl chloride, d -dimethylamino - n - butyl chloride, 2 - chloro - 3 - di - ethylamino - butane, 1 - chloro - 3 - diethyl - amino - butane, 3 - chloro - 4 - diethylamino - pentane, b  - piperidino - ethyl chloride, b -morpholino - ethyl chloride, 2 - chloro - 3 - piperidino - butane, b  - pyrrolidino - ethyl chloride and N-ethyl-3-chloro-piperidine.  Suitable alkylene - halogenhydrins that may be used as reactants are 1-chloro-propanol-(3), 1 - chloro - propanol - (2), 1 - chlorobutanol-(4), 1 - chlorobutanol - (3) and 2 - chloro - butanol-(3).  Acids which may be used for salt formation are hydrobromic, hydriodic, sulphuric, phosphoric, amido-sulphonic, formic, acetic, oxalic, succinic, malic, lactic, tartaric, maleic, citric, hydroxyethanesulphonic, aceturic, ethylenediamine-tetra-acetic, palmitic and stearic acids.  A large number of examples are given in which compounds of the above general formula are prepared wherein Hal represents chlorine, bromine and fluorine, and the group <FORM:0821100/IV (a)/5> represents the b -diethylaminoethylamino, b -allylamino-ethylamino, b -N-butylamino-ethylamino, b -cyclohexylamino-ethylamino, b -aminoethylamino, b -diethylaminoethyl-ethyl-amino, b  - diethylaminoethyl - methylamino, b  - morpholino-ethylamino, b -piperidino-ethylamino, b -pyrrolidino - ethylamino, b  - (b  - hydroxy - ethylamino) - ethylamino, b  - (b  - methoxy - ethyl - amino) - ethylamino, b  - [di - (b  - methoxyethyl) - amino] - ethylamino, b  - [di - (b -ethoxyethyl)-amino]-ethylamino, g -dimethylamino-n-propylamino, b -diethylamino-n-propylamino, b -diethylamino-n-propylamino, b -diethylamino-isopropylamino, and 11-ethyl-31-piperidylamino groups.  The examples also describe the preparation of intermediate compounds as follows: (a) 4-chloro-2-(b -hydroxyethylamino) - 1:3:5 - trimethyl - benzene by reacting 4 - chloro - 2 - amino - mesitylene with ethylene chlorhydrin and treating the product with sodium hydroxide; (b) 4-chloro-2-(b -bromethylamino) - 1:3:5 - trimethyl - benzene hydrobromide by treating the product of (a) with hydrobromic acid; (c) 4-chloro-2-ethylamino - 1:3:5 - trimethyl - benzene by treating 4 - chloro - 2 - amino - 1:3:5 - trimethyl-benzene with benzaldehyde to form a benzal, and treating the benzal with diethyl sulphate; (d) 4-chloro-2 - (b  - hydroxy - n - propylamino) - 1:3:5 - trimethyl-benzene is prepared by reacting 4-chloro - 2 - amino - 1:3:5 - trimethyl - benzene with 1-chloro-propanol-(2), and is converted into 4-chloro-2-(b -bromo-n-propylamino)-1:3:5-trimethyl-benzene hydrobromide by reacting with hydrobromic acid.