Hydrochloric Acid → Ammonia

Participants

Reaction Steps

One of skill in the art will recognize that this general scheme may be modified and yet still produce the compounds of the present invention. As shown in Scheme 1, reaction of a suitably substituted 2,4-dichloropyrimidin-5-amine III with a proper amine IV under both acidic conditions (Chem. Pharm. Bull. 1987, 35 (12), 4972-4976) and basic conditions provides 2-chloropyrimidine-4,5-diamine V. 5-Chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine VI can be prepared by cyclizing an intermediate of 2-chloropyrimidine-4,5-diamine V in the presence of a nitrite salt, such as NaNO2, a suitable acid, e.g. hydrochloric acid, and/or acetic acid and the like, and alternatively in the presence of isoamyl nitrite in a suitable solvents under heating. Treatment of 5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine VI with NH3 in a suitable solvent, such as ethanol, affords 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine VII. The amino group at the 5-position on the 3H-[1,2,3]triazolo[4,5-d]pyrimidine VII can be converted into iodide or bromine by treatment with isoamyl nitrite in diiodomethane or tribromomethane (Chem. Pharm. Bull. 1991, 39 (11), 3037-3040) to provide 5-iodo or bromo-3H-[1,2,3]triazolo[4,5-d]pyrimidine VIII. A transition-metal catalyzed cross-coupling reaction of 5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine VI or 5-iodo or bromo-3H-[1,2,3]triazolo[4,5-d]pyrimidine VIII with an appropriately substituted boronic acid, boronate ester, zincate or stannane R1Y under Suzuki (Miyaura, N., Suzuki, A., Chem. Rev. 1995, 95, 2457), Negishi (J. Org. Chem. 1977, 42, 1821), or Stille conditions (Agnew. Chem., Int. Ed. Engl. 1986, 25, 508 and references therein) provides the coupling product, 5-substituted-3H-[1,2,3]triazolo[4,5-d]pyrimidine I and II.

Provenance & Evidence