Oxidation of 2-methoxy-4-nitrotoluene (I) with CrO3 in the presence of sulfuric acid and acetic anhydride produced acylal (II), which was further hydrolyzed to the benzaldehyde (III) under acidic conditions. The isoxazole derivative (IV) was obtained by treatment of aldehyde (III) with tosylmethyl isocyanide in the presence of K2CO3 in refluxing methanol. Then, catalytic hydrogenation of the nitro group of (IV) over Pd/C afforded aniline (V).
Addition of phenylmagnesium bromide (VII) to cyanuric chloride (VI) provided 2,4-dichloro-6-phenyltriazine (VIII). This was subsequently condensed with aniline (V) to afford the aminotriazine (IX). Finally, displacement of the remaining chlorine of (IX) with 2-(3-pyridyl)ethylamine (X) furnished the target diaminotriazine derivative.
Intermediate (VII) is prepared by the following route. Oxidation of 2-methoxy-4-nitrotoluene (I) by means of chromic acid in the presence of Ac2O affords acylal (II), which is further hydrolyzed to aldehyde (III) under acidic conditions. Treatment of benzaldehyde (III) with TOSMIC reagent in the presence of K2CO3 gives rise to the phenyl oxazole derivative (IV). Nitro group reduction in (IV) with H2 and Pd/C yields aniline (V). This is then converted into isothiocyanate (VII) employing 1,1'-thiocarbonyldi-2(2H)-pyridone (VI).
2-Bromoaniline (VIII) is acylated by bromoacetyl chloride (IX) in pyridine to produce the corresponding bromoacetanilide (X). Subsequent displacement of the aliphatic bromide of (X) with morpholine (XI) furnishes the morpholinoacetanilide (XII). Alkylation at the amide N of (XII) with iodomethane and NaH leads to the N-methyl amide (XIII). Stille coupling of aryl bromide (XIII) with tributyl (1-ethoxyvinyl)tin (XIV) yields the enol ether (XV). Bromination of enol ether (XV) with N-bromosuccinimide in moist THF produces the bromo acetophenone (XVI), which is further reacted with NaN3 to give the azido ketone (XVII). The target amino oxazole compound is finally obtained by condensation of azido ketone (XVII) with isothiocyanate (VII) in the presence of PPh3 in hot dioxane.