Patent GB-863217-A (GB)
Title: Manufacture of new piperazo-[c]-pyridazines
IPC: C07D487/04
Filed: 1957-11-18
Abstract: The invention comprises piperazo-[c]-pyridazines containing the nucleus of the formula:  <FORM:0863217/IV (b)/1> which contain in the 5- and 8-positions unsubstituted or substituted alkyl or aralkyl groups, the substituents being free or alkylated amino groups, alkoxy or alkylmercapto groups or halogen atoms, in the 3-position hydrogen or halogen atoms or hydroxy, mercapto, alkoxy, alkylmercapto or free or alkylated amino groups, and in the 6- and/or 7-position hydrogen atoms or hydrocarbon radicals; and acid-addition salts thereof; and their preparation by reacting a 3:4:6- trihalogeno pyridazine with an appropriate ethylenediamine monosubstituted on one nitrogen atom by a suitable alkyl or aralkyl group and di-substituted on the other nitrogen atom by similar groups and then, when required, reductively splitting off the halogen in position-3 of the resulting piperazo-[c]-pyridazine or converting it into a hydroxy, mercapto, alkoxy, alkyl mercapto, amino or alkyl substituted amino group by reaction with metal derivatives of the corresponding hydroxy- or thio-compounds or with ammonia or amines.  In a multi-stage modification of this process the trihalogen pyridazine is first reacted with an appropriate ethylamine mono-substituted at the nitrogen atom by a suitable alkyl or aralkyl group and substituted in the b -position by a free or reactively esterified hydroxyl group and then the free hydroxyl group is reactively esterified, for example with a hydrohalic acid, and/or the esterified hydroxyl group is reacted with a secondary amine, the substituents of which are suitable alkyl or aralkyl groups, whereby ring closure is brought about.  In both the above processes it is the halogen atom in the 4-position of the pyridazine starting material which condenses with the mono-substituted nitrogen atom.  In Examples (1) and (13) 3:4:6-trichloropyridazine and N:N-dimethyl-N1-benzyl- or N:N1-dibenzyl-N-methyl-ethylenediamine give 3-chloro-5-benzyl-8-methyl-piperazo-[c]-pyridazine; (2), (3), (6), (7), (8), (9), (10), (11) and (12) the corresponding 5-benzyl-8-ethyl, 5:8-dimethyl, 5-(p-dimethylamino-benzyl)-8-ethyl, 5-(m-methoxy benzyl)-8-ethyl, 5-(p - chlorobenzyl) - 8 -ethyl, 5-benzyl-6-ethyl-8-methyl, 5:8-diethyl and 5-ethyl-8-methyl compounds are similarly prepared; (4) 3:4:6-trichloro pyridazine and N-benzylamino-ethanol give N-[3:6-dichloropyridazinyl-(4)]-N-(2-hydroxyethyl)-benzylamine, this with thionyl chloride gives the corresponding 2-chloroethyl compound and this with alcoholic dimethylamine at 120 DEG 130 DEG C. gives 3-dimethylamino-5-benzyl-8-methyl-piperazo-[c]-pyridazine; (5) 3:4:6-trichloropyridazine and bis-(2-hydroxyethyl)-amine give 4-[bis-(2-hydroxyethyl)-amino]-3;6-dichloropyridazine, this with thionyl chloride gives the corresponding bis-(2-chloroethyl) compound, and this with alcoholic dimethylamine at 120-130 DEG C. gives 3-chloro-5-(2-dimethylamino-ethyl)-8-methyl - piperazo - [c]-pyridazine; (14) the product of (1) is hydrogenated in presence of palladium-charcoal to give the 3-unsubstituted compound; (15) the product of (1) and dimethylamine give the product of (4); and (16) the product of (1) with sodium in methanol gives the 3-methoxy compound.  Hydrochlorides of some of the products are described and a list of further saltforming organic and inorganic acids is provided. N:N-diethyl-N -(p-dimethylamino benzyl)-ethylenediamine is prepared by reacting p-dimethylamino-benzaldehyde with N:N-diethylethylenediamine to give N:N-diethy-N1-(p-dimethylamino-benzal)-ethylenediamine and hydrogenating this in presence of Rupe nickel. N:N-diethyl-N1-(meta-methoxy-benzyl)-ethylenediamine is similarly prepared from m-methoxy-benzaldehyde and N:N-diethyl-ethylenediamine. N:N-diethyl-N1-(para-chloro-benzyl)-ethylenediamine is similarly prepared from p-chlorobenzaldehyde and N:N-diethyl-ethylenediamine. 1-Dimethylamino-2-benzylamino-butane is prepared by reacting 2-amino-1-butanol hydrochloride with thioryl chloride to form 1-chloro2-amino-butane hydrochloride, reacting this with dimethylamine to give 1-dimethylamino-2-amino-butane, reacting this with benzaldehyde to give 1-dimethylamino-2-benzalamino-butane and hydrogenating this in presence of Raney nickel. N:N1-dibenzyl-N-methyl-ethylenediamine is prepared by reacting chloroethylamine hydrochloride with benzyl methylamine to give N-benzyl-N-methyl-ethylenediamine, reacting this with benzaldehyde to give N-benzyl-N-methyl-N1-benzalethylenediamine, and hydrogenating this in presence of Raney nickel.