Process for producing 3-substituted 1,2,4-triazines

#Various substituted 1,4,5,6-tetrahydro-1,2,4-triazines are described as having antidepressant properties in U.S. Pat. No. 3,471,486. In general the compounds are prepared by reacting an imino ester hydrohalide dissolved in glacial acetic acid, methanol or ethanol with a 2-aminoalkylhydrazine. This method of preparing the compounds is tedious and gives poor yields making the overall procedure uneconomical for commercial production. The present invention is directed to a new synthetic route which can be used to prepare triazines of the type described above.

#In related art substituted 2-imidazolines have been synthesized by the cyclization of a diamine with a nitrile in the presence of elemental sulfur. Nippon Kagaku Zasshi 1968, 89 (8), 780 (Chem. Abs. 70:19983q.)

#The present invention is directed to a process of preparing a 3-substituted 1,2,4-triazine which comprises reacting a nitrile with a 2-aminoethylhydrazine or substituted 2-aminoethylhydrazine in the presence of a catalytic amount of a transition metal salt or elemental sulfur. The process is particularly useful in preparing a triazine having the general formula ##STR1## wherein R is hydrogen or methyl and A and B independently represent hydrogen, alkyl of from 1 to 5 carbon atoms, phenyl, substituted phenyl, benzyl, or substituted benzyl. Substitutions on the phenyl and benzyl rings described above may include almost any group which will not react with hydrazine under the conditions of the reaction process. Such substitutions include halo, lower alkyl, lower alkoxy, nitro, napthyl and pyridyl. As used herein lower alkyl and alkoxy refers to a group having from 1 to 3 carbon atoms.

#The following examples will serve to further clarify the present invention and will serve to illustrate certain preferred embodiments thereof; however, they are not to be construed as a limitation upon the scope of the invention.

#Step one: A reaction vessel consisting of a 2 liter round bottom flask fitted with a mechanical stirrer, thermometer, nitrogen inlet and reflux condenser was charged with 585 g (574 ml; 5.0 moles) of benzyl cyanide, 250 ml of 50% sodium hydroxide and 12.5 g (0.055 mole; 4.4 mole %) of benzyltriethylammonium chloride. While maintaining the temperature at about 50.degree. C in a cool water bath, 224.4 g (1.77 mole) of benzyl chloride was slowly added dropwise over a period of about 1 hour. The reaction mass was stirred for an additional 1 hour after which 400 ml of deionized water was added to dissolve the sodium chloride and caused a separation of the aqueous and organic layers. In this step if an emulsion formed, methylene chloride was added. The organic layer was distilled to separate the 2,3-diphenylpropionitrile from the other reactants and impurities. The identity of the compound was confirmed by elemental analysis, NMR, IR, and mass spectrophotometry data.

#Step two: The nitrile intermediate prepared in step one (35.0 g, 0.169 mole) was heated under nitrogen with 0.379 gram (0.012 gram-atom, 7 mole %) of sulfur to about 70.degree. C in a 100 ml round bottom flask until the sulfur dissolved (about 2 hours). The reaction vessel was charged with 25.4 grams (0.338 moles; 2 equiv.) of 2-aminoethylhydrazine. The temperature was increased to about 100.degree. C and held for about 5 hours. The reaction mass was cooled to about 50.degree. C after which 75 ml of toluene was added followed by extraction with 75 ml of water. Absolute alcohol (35 ml) was added and the mixture refluxed while hydrogen chloride was bubbled into the flask. The 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride crystallized out and was filtered off then washed with a 90/10 toluene/ethanol mixture. The product was dried in vacuo. Elemental analysis, X-ray crystallography, NMR, and mass spectrophotometry were used to confirm the structure.