Patent GB-808239-A (GB)
Title: Improvements in or relating to phenthiazine derivatives and processes for their production
IPC: C07D279/18
Filed: 1957-01-01
Abstract: The invention comprises phenothiazines of the general formula <FORM:0808239/IV (b)/1> and their acid addition salts and quaternary ammonium derivatives (wherein X is a sulphur atom or an SO2 group, R is an alkyl group containing not more than four carbon atoms, R1 and R2 are the same or different and either each represents an alkyl group containing not more than five carbon atoms or one of R1 and R2 is hydrogen and the other is an alkyl group containing not more than five carbon atoms, or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic ring such as pyrrolidino, piperidino, morpholino, piperazino or 4-alkylpiperazino, and B is a straight or branched chain aliphatic hydrocarbon group of from 2 to 5 carbon atoms, unsubstituted or substituted by a group <FORM:0808239/IV (b)/2> wherein A is a single bond or -CH2-) and their preparation by (1) reacting a phenothiazine of the general formula <FORM:0808239/IV (b)/3> with a halogenoamine of the formula <FORM:0808239/IV (b)/4> (wherein Hal is a halogen atom), (2) decomposing a phenothiazine-10-carboxylate of an aminoalcohol of the general formula <FORM:0808239/IV (b)/5> by heating above 100 DEG  C.; and (3) when X is an SO2 group, oxidizing the corresponding compound in which X is a sulphur atom.  When B is an asymmetric branched chain, reactions (1) and (2) may cause isomerization.  Reaction (1) is carried out in the presence or absence of a condensing agent, with or without a solvent; advantageously the reaction is carried out in an aromatic hydrocarbon solvent in the presence of a condensing agent, preferably an alkali metal or a derivative thereof.  Reaction (2) may be carried out without a diluent, or in an inert medium, or in the classical decarboxylation diluents.  Examples describe the preparation of 3 - methoxycarbonyl - 10 - (3 - dimethylaminopropyl) - phenothiazine maleate, 3 - methoxycarbonyl - 10 - (2 - methyl - 3 - dimethylaminopropyl) - phenothiazine hydrochloride, 3-methoxycarbonyl - 10 - (3 - pyrrolidinopropyl) - phenothiazine acid oxalate, 3-methoxycarbonyl - 10 - (2 - methyl - 3 - pyrrolidinopropyl) - phenothiazine, 3 - ethoxycarbonyl - 10 - (3 - dimethylaminopropyl) - phenothiazine acid maleate and 3-butoxycarbonyl-10-(3-dimethylaminopropyl)-phenothiazine acid oxalate by condensing 3 - alkoxycarbonyl - phenothiazines with the appropriate haloalkylamines in xylene in the presence of sodamide and, if required, preparing acid addition salts of the bases so formed; 3-methoxycarbonyl - 10 - (2 - diethylaminoethyl)-phenothiazine hydrochloride, 3 - methoxycarbonyl - 10 - (2 - diethylaminopropyl) - phenothiazine and its hydrochloride, 3-methoxycarbonyl - 10 - (3 - 41 - methylpiperazinopropyl)-phenthiazine dihydrochloride and 3-methoxycarbonyl - 10 - (2 : 3 - bis - dimethylaminopropyl)-phenothiazine monomaleate by thermal decarboxylation of the corresponding aminoalcohol 3-methoxycarbonylphenothiazine-10-carboxylates and, if necessary, salt formation; 3-methoxycarbonyl - 9 : 9 - dioxy - 10 - (3 - dimethylaminopropyl) - phenothiazine by the action of hydrogen peroxide in a mixture of acetic and sulphuric acid on 3-methoxycarbonyl10 - (3 - dimethylaminopropyl) - phenothiazine, and 3 - methoxycarbonyl - 9 : 9 - dioxy - 10 - (2-methyl - 3 - dimethylaminopropyl) - phenothiazine hydrochloride by similarly treating 3-methoxycarbonyl - 10 - (2 - methyl - 3 - dimethylaminopropyl) - phenothiazine, and forming the hydrochloride. 3 - Ethoxycarbonyl - and 3 - butoxycarbonylphenothiazine are prepared by esterifying phenothiazine-3-carboxylic acid with ethanol and n-butanol, respectively, in the presence of sulphuric acid.  3 - Methoxycarbonylphenothiazine - 10 - carbonyl chloride is prepared by the action of phosgene on 3-methoxycarbonylphenothiazine, and converted into 2-diethylaminoethyl-3-methoxycarbonylphenothiazine - 10 - carboxylate, 3 - diethylamino - 2 - propyl 3 - methoxycarbonylphenothiazine-10-carboxylate (and its hydrochloride), 3 - (4 - methylpiperazino) - propyl 3 - methoxycarbonyl - phenothiazine - 10 - carboxylate (and its dihydrochloride) and 1 : 3 - bis - dimethylamino - 2 - propyl 3 - methoxycarbonylphenothiazine - 10 - carboxylate (and its ditartrate).