Patent GB-806531-A (GB)
Title: New derivatives of thiophenylpyridylamine and their production
IPC: C07D513/04
Filed: 1955-09-16
Abstract: The invention comprises thiophenylpyridylamines, their N9-carbalkoxy-methyl derivatives, acid salts and quaternary ammonium salts which may be substituted in the benzene nucleus by a halogen atom, a hydroxyl group, an alkyl radical or an alkoxy radical and/or at the N9-nitrogen atom by an alkyl, aralkyl or acyl group or by an amino-alkyl radical of the general formula R1R2N-Alkin which "Alk" represents a straight or branched-chain alkylene radical and R1 and R2 represent alkyl residues which may be linked to form a ring which ring may also contain a further hetero-atom or R1 and/or R2 together with the nitrogen atom and the radical "Alk" may form a heterocyclic ring system.  The thiophenylpyridylamine has the formula <FORM:0806531/IV (b)/1> The N9-substituted thiophenylpyridylamines are obtained by reacting the corresponding secondary thiophenylpyridylamine at elevated temperature and in the presence of a hydrogen halide acceptor with a halide yielding the desired substituent for the N9-nitrogen atom.  The corresponding secondary thiophenylpyridylamine may be reacted with a halide of the general formula R1-Hal or R1-CO-Hal, where R1 is an alkyl or aralkyl radical or with a halide of the general formula R1R2N-Alk-Hal and the products may be converted to acid addition salts or, by reaction with an alkyl halide or alkyl sulphate, to mono or bi-quaternary salts. The invention also comprises a process for the production of thiophenylpyridylamine or of the substitution derivatives defined above, wherein phenylpyridylamine or the appropriately substituted phenylpyridylamine is reacted with sulphur or another substance which forms a sulphur bridge between the benzene and pyridine nuclei under the conditions of the reaction.  The reaction may be effected with sulphur, suitably in the presence of iodine, aluminium chloride or boron fluoride as catalyst, or with sulphur di- or monochloride, sodium thiosulphate, antimony or arsenic pentasulphide, thionyl chloride or an alkali metal polysulphide, at elevated temperature. The amine may be used in the form of its salt.  Best yields are obtained when only two thirds of the theoretical amount of sulphur is used in the reaction.  The thiophenylpyridylamine may be recovered by treating the reaction mixture with dilute hydrochloric acid.  The hydrochloride precipitates while the unreacted phenylpyridylamine hydrochloride remains in solution, detailed description of the method being given.  In example (1) thiophenylpyridylamine is heated in toluene with sodamide and then reacted with dimethylaminoethyl chloride to give N9-2-dimethyl-aminoethyl-thiophenylpyridylamine which is converted to its mono-and di-hydrochlorides.  In a generally similar manner are prepared analogous compounds substituted at the 9-position by (2) 2-dimethylaminoisopropyl; (3) diethylaminoethyl; (4) methyl; (5) acetyl; (6) 1-dimethylamino-2-methyl-propyl; (7) benzyl; (8) 1-methyl-piperidyl-4; (9) morpholinoethyl groups.  In further examples (10) dimethylaminoethylthiophenylpyridylamine is quaternated by reaction with methyl iodide; (11) to (15) thiophenylpyridylamine is prepared by heating phenylpyridylamine with (11) sulphur and iodine, (12) sulphur and aluminium chloride, (13) sodium thiosulphate, the hydrochloride of the amine being used, (14) sulphur dichloride and (15) disulphur dichloride.  In analogous manner are prepared (16) 6-chlorothiophenylpyridylamine; (17) 6-methyl-thiophenyl-pyridylamine; (18) 7-chlorothiophenylpyridylamine; (19) thiophenylpyridylamine-N9-acetic acid ethyl ester; (20) N9-diisopropylaminoethyl-thiophenylpyridylamine; (21) N9 - diethylaminoethyl - thiophenylpyridylamine; (22) N9 - diethylaminoisopropyl - thiophenyl - pyridylamine; (23) N9 - di - n - butylamino - ethyl - thiophenylpyridylamine; (24) N9 - dimethylamino - n-propyl - thiophenylpyridylamine; (25) N9 - diethylamino - n - propyl - thiophenylpyridylamine; (26) N9 - pyrrolidino - N - ethyl - thiophenylpyridylamine; (27) N9 - piperidino - N-ethyl - thiophenylpyridylamine; (28) N9-piperidino - n - propyl - thiophenylpyridylamine; (29) N9 - pyrrolidino - n - propyl - thiophenylpyridylamine; (30) N9 - (N - methylpiperidino-4) - methylene - thiophenylpyridylamine; (31) N - methyl - N - diethyl - N - (a  - methyl - b -N9 - thiophenyl - pyridylamino - ethyl) ammonium methyl sulphate; (32) N-trimethyl-N-(a -methyl - b  - N9 - thiophenylpyridyl aminoethyl ammonium - methyl sulphate; (33) N9 - dimethylaminoisopropyl - thiophenylpyridylamine 8-chlorotheophyllinate.