Patent GB-802725-A (GB)
Title: Improvements in or relating to phenthiazine derivatives and processes for their production
IPC: C07D279/18
Filed: 1956-11-19
Abstract: The invention comprises phenthiazines of the general formula <FORM:0802725/IV (b)/1> and their salts and quaternary derivatives (wherein R1 and R2 are each a lower alkyl group containing up to five carbon atoms or one represents hydrogen and the other lower alkyl, or together with the nitrogen atom they constitute a heterocyclic ring, e.g. pyrrolidine, piperidine, morpholine, piperazine or 4-alkylpiperazine; B represents a straight or branched aliphatic hydrocarbon chain containing from two to five carbon atoms, and which may be substituted by a group A-NR1R2 in which A represents a single bond or -CH2-), together with processes for their preparation (a) by the reaction of 3-methylthiophenthiazine with a halogeno-amine Hal-B-NR1R2 (to prepare compounds in which R1 is hydrogen the reaction is preferably effected with an N-acyl derivative of the halo amine followed by hydrolysis) preferably in an aromatic hydrocarbon solvent and using the hydride, amide, hydroxide, alcoholate, alkyl or aryl derivative of an alkali metal as a condensing agent; (b) by condensation of an amine HNR1R2 with a 3-methylthiophenthiazine substituted in position 10 by the group -B1Y, Y being the residue of a reactive ester, e.g. a halogen atom or a sulphuric or sulphonic ester residue, and B1 representing a straight or branched aliphatic hydrocarbon chain containing from two to five carbons which may be substituted by a group -AY1, A being defined above and Y1 being the residue of a reactive ester or -NR1R2; (c) by decarboxylation of a 3-methylthiophenthiazine-10-carboxylate of an amino alcohol HO-B-NR1R2 by heating it above 100 DEG  C., preferably between 150 DEG  and 220 DEG  C., and in an inert medium, e.g. liquid paraffin, diphenyl, diphenyl oxide, quinoline or o-dichlorobenzene: (d) in the case of the secondary and tertiary alkyl amines by alkylation, e.g. methylation with HCHO and hydrogen in the presence of a catalyst. Specified acid addition salts are those derived from hydrohalic, phosphoric, nitric, sulphuric, maleic, fumaric, citric, tartaric, oxalic, methane sulphonic, ethane disulphonic acids and quaternary derivatives may be formed, e.g. with methyl or ethyl iodide, chloride or bromide, or allyl or benzyl chloride or bromide.  In examples, 3-methylthiophenthiazine is heated with sodamide in xylene and condensed with 3-dimethylamino-1-chloropropane, giving 3-methylthio-10-(3-dimethylaminopropyl)-phenthiazine, and subsequently its hydrochloride and picrate; (2) and (3), similarly there are prepared the following 3-methylthio-phenthiazines:-10 - (3 - dimethylamino - 2 - methylpropyl)-, 10 - (3 - 41 - methylpiperzinylpropyl)-, 10 - (2 - dimethylaminopropyl)- and 10-(3-pyrrolidinopropyl)-; (4) 3-41-methylpiperazinyl - 2 - methylpropyl 3 - methylthiophenthiazine - 10 - carboxylate is heated in o-dichlorobenzene until no more CO2 is evolved and the resulting base treated with ethanolic maleic acid giving 3-methylthio-10-(3-41-methylpiperazinyl - 2 - methylpropyl) - phenthiazine acid dimaleate; (5) 1,3-bis-dimethylamino-2-propyl - 3 - methylthiophenthiazine - 10 - carboxylate similarly gives 3-methylthio-10-(2,3-bis - dimethylaminopropyl) - phenthiazine as its neutral fumarate; (6) 3-methylthio-10-(3-toluene - p - sulphonyloxypropyl) - phenthiazine is autoclaved with diethylamine in toluene and extracted with dilute HCl giving 3-methylthio-10 - (3 - diethylaminopropyl) - phenthiazine hydrochloride, and when using methylamine, 3 - methylthio - 10 - (3 - monomethylaminopropyl)-phenthiazine as its oxalate; (7) 3-methylthio - 10 - (3 - aminopropyl) - phenthiazine and 30 per cent formaldehyde is treated with hydrogen and platinum oxide giving 3-methylthio - 10 - (3 - dimethylaminopropyl) - phenthiazine.  Starting materials. 3-41-Methylpiperazinyl-2 - methylpropyl 3 - methylthiophenthiazine - 10 - carboxylate is prepared by heating in toluene 3 - 41 - methylpiperazinyl - 2 - methylpropanol with 3 - methylthiophenthiazinyl - 10 - carbonyl chloride, itself prepared from 3-methylphenthiazine and phosgene in the presence of pyridine; 1,3 - bis - dimethylamino - 2 - propyl 3 - methylthiophenthiazine - 10 - carboxylate is likewise prepared; 3-methylthio-10-(3-toluene-p-sulphonyloxypropyl) - phenthiazine is obtained by condensing in pyridine toluene-p-sulphonyl chloride with 3-methylthio-10-(3-hydroxypropyl)-phenthiazine, itself obtained by hydrolysis of 3 - methylthio - 10 - (3 - tetrahydropyramyloxypropyl)-phenthiazine prepared by condensation of 3 - tetrahydropyranyloxy - 1 - chloropropane with 3-methylthiophenthiazine; 3-methylthio-(3 - aminopropyl) - phenthiazine is prepared by heating in toluene 3-methylthio-10-(3-toluene-p-sulphonyloxypropyl)-phenthiazine with excess ammonia.  Specification 802,726 is referred to.