Recent Advances in Imidazo[5,1-f][1,2,4]triazin-4(3H)-ones Chemistry:
An Overview of the Synthetic Routes to Vardenaﬁl and Its Analogues
Vo l 5 5
Moustafa A. Gouda
Department of Chemistry, Faculty of Science and Arts, Taibah University, Ulla, Saudi Arabia
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
Received September 20, 2017
Published online 31 January 2018 in Wiley Online Library (wileyonlinelibrary.com).
The biological and medicinal properties of imidazo[5,1-f][1,2,4]triazin-4(3H)-ones and its analogues have
prompted enormous research aimed at developing synthetic routes to these heterocycles. This review focuses
on the chemical properties associated with these systems.
J. Heterocyclic Chem., 55, 564 (2018).
Vardenaﬁl hydrochloride 1 (Levitra, Bayer) (Fig. 1) is
marketed as an approved drug for the treatment of
erectile dysfunction in men  by an action of blocking
the PDE5 activity; cGMP accumulates in the corpus
cavernosum and eventually leads to penile erection.
PDE5 is a therapeutic target of considerable research
interest as can be seen by numerous publications
regarding the design, synthesis, and optimization of new
PDE5 inhibitors such as vardenaﬁl, tadalaﬁl, and other
compounds under clinical trials [2–4].
Furthermore, the imidazo[5,1-f][1,2,4]triazinone scaffold
2 has recently received attention as the core structure of
vardenaﬁl (Levitra) (1), a potent and effective PDE5
inhibitor for the treatment of erectile dysfunction [5–9]. So
this review presents a systematic and comprehensive
survey of the method of preparation and the chemical
reactivity of imidazo[5,1-f][1,2,4]triazinones and their
Synthesis. From carboximidohydrazide.
2-hydrozybenzonitrile 3 with ethyl bromide, followed by
addition of ammonia to the nitrile functionality using
, generated in situ by addition of
ammonium chloride with trimethylaluminum, gave the
amidine 5. In situ addition of hydrazine hydrate to
amidine 5 in ethanol, gave the carboximidohydrazide 6.
On the other hand,
-alanine was acylated with butyryl
chloride to provide 7, which underwent a Dakin–West
reaction with ethyl oxalyl chloride 8 to furnish the
Heating a solution of crude 9 in ethanol with the
carboximidohydrazide 6 at 70°C for 4 h to give the
product 10 gave the imidazotriazinone 11 after cyclization
with phosphorous oxychloride (Scheme 1) .
Reaction of 11 with chlorosulfonic acid provided the
sulfonyl chloride 12, which was treated with N-substituted
piperazine 13 in dichloromethane to obtain vardenaﬁl
derivatives 1, R = Et, and 14, R = Me. Treatment of 1,
R = Et, and 14, R = Me, with hydrochloric acid in ether
© 2018 Wiley Periodicals, Inc.