PROCESS FOR MAKING 11-PIPERAZINO-DIAZEPINES, OXAZEPINES, THIAZEPINES AND AZEPINES

摘要

1418363 Preparation of piperidinylmorphanthridines and related tricyclic compounds WANDER Ltd 2 April 1973 [4 April 1972 (2)] 15667/73 Heading C2C The invention comprises a process for the preparation of compounds of Formula I wherein A represents a structure Z1 or Z2 R 1 is H, alkoxyalkyl having a total of 2 to 6 carbons, C 1-4 alkyl, C 1-4 hydroxyalkyl or acyloxyalkyl having a total of 3-22 carbons; R 4 is H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, halogen or CF 3 ; when A is Zl; X is OH 2 , O, S, NH or N-C 1-3 alkyl, R 2 is H, C 1-4 alkyl, di-C 1-4 alkylaminosulphonyl, C 1-4 alkylsulphonyl, C 1-4 alkoxy or alkylthio, halogen, NO 2 , CF 3 SO 2 , CF 3 O-, CF 3 S, CH 3 CO-, CN, or CF 3 and R 3 is H, halogen or C 1-4 alkyl; when A represents Z2, X is CH 2 or S or their acid addition salts in which a compound of Formula II is reacted with a metal-amine complex comprising Ti, Zr, Hf or V and a compound of Formula III the metal-amine moiety of the complex being obtainable by reacting Ti, Zr, Hf or V respectively in tetrahalide form with a compound of Formula III. The reaction may be effected in a solvent, in the presence of an acid binding agent. Substituents represented by R 1 may be converted by known means, into other groups also within the scope of the definition of R 1 , i.e. an acyloxyalkyl group may be saponified to produce a hydroxyalkyl group. 1-Benzyl-4-tert.-butylpiperazine is prepared by reaction of bis-(2-chloroethyl)-t.-butylamine and benzylamine in ethanol and is then hydrogenated to cleave off the benzyl group and obtain 4-t.-butylpiperazine. 2-(2-Aminobenzyl)-thiophene is prepared by reduction of the corresponding ketone with hydrazine hydrate and is then reacted with phosgene to obtain 2-(2-isocyanato benzyl)thiophene which is converted into 4,5-dihydro-10H- thieno[3,2 - c][1]benzazepin-4-one by heating with polyphosphoric acid. N - p - toluenesulphonyl - 4 - chloroanthranilic acid chloride and the corresponding 5-chloro compound are obtained by reacting the free acid with thionyl chloride. Reaction of the acid chloride with thiophene in the presence of SnCl 4 gives 2 - (2 - p - toluenesulphonylamido - 4(5 - )- chlorophenyl-thienone which is hydrolysed by treatment with cone. sulphuric acid to 2-(2- amino-5(4-)chlorophenyl)-thienone. This ketone is reduced with hydrazine hydrate to 2-(2- amino - 5 - chloro(4 - chloro) - benzyl)thiophene which gives 2-(2-isocyanato-5(4)-chlorobenzyl) thiophene on reaction with phosgene. The isocyanato compound undergoes ring closure on reaction with polyphosphoric acid to obtain 7a(8) - chloro - 4,5 - dihydro - 10H - thieno[3,2- c][1]benzazepin-4-one. The products of Formula I are described as having central nervous system activity.