ORGANIC
LETTERS
2003
Vol. 5, No. 21
3907-3909
Novel Synthetic Approach to
6,7-Dihydro-5H-imidazo[1,5-a]-pyrazin-8-ones
Ariamala Gopalsamy* and Mengxiao Shi
Chemical and Screening Sciences, Wyeth Research, Pearl RiVer, New York 10965
Received August 1, 2003
ABSTRACT
A novel route to highly substituted chiral 6,7-dihydro-5H-imidazo[1,5-a]pyrazine-8-ones starting from Meldrum’s acid is disclosed. The key
features of the methodology are the incorporation of amino esters as a chiral pool and facile mild intramolecular cyclization to form the
pyrazine ring. Incorporation of various substituents at different stages of the synthesis from various building block sets makes this methodology
readily amenable to parallel synthesis.
Imidazopyrazines 1 are structural units found in numerous
bioactive natural products, drugs, and drug candidates. They
are well represented in the area of medicinal chemistry, acting
on a number of targets including the CRF receptor,1 GABAA
receptor,2 melanocortin receptor,3 etc. Recently, 6,7-dihydro-
5H-imidazo[1,5-a]pyrazin-8-ones 2 were disclosed as Factor
Xa inhibitors4 (Figure 1).
The imidazo[1,5-a]pyrazine heterocyclic system is one of
the less known members of the azaindolizine family.
Reported synthetic methods involve either the formation of
Figure 1.
the imidazole ring5 or the much lesser known routes of
formation of the pyrazine ring6 by ring closure onto an
existing imidazole intermediate. A recent report by Trcek et
pyrazine system based on the cyclocondensation of 3-[(2-
al.7 describes a one-pot approach to the imidazo[1,5-a]-
amino-1,2-dicyanoethen-1-yl)amino]-2-(benzylamino)-pro-
penoates with ortho esters. However, these methods do not
(1) (a) Hibi, S.; Takahashi, Y.; Hoshino, Y.; Kikuchi, K.; Siejima, M.;
provide an easy entry to 6,7-dihydro-5H-imidazo[1,5-a]-
pyrazine-8-ones of interest. This partially saturated system
opens the avenue to build chirality into the molecule and
introduce much desired diversity points for generation of
Yoshiuchi, T.; Shin, K.; Ono, M.; Shibata, H.; Ino, M.; Hirakawa, T.
WO 0262800, 2002. (b) Hartz, R. A.; Gilligan, P. J.; Kausik, K. N.; Tebben,
A. J.; Fitzgerald, L. W.; Miller, K. Bioorg. Med. Chem. Lett. 2002, 12,
291.
(2) Goodacre, S. C.; Hallett, D. J.; Street, L. J. WO 0210170, 2002.
(3) Carpino, P. A.; Cole, B. M.; Morgan, B. P. WO 0200654, 2002.
(4) Pinto, D. J. P.; Li, R. US 20030118023, 2003.
(5) (a) Montgomery, J. A.; Secrist, J. A., III. In ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon
Press: Oxford, 1984; Vol. 5, Part 4A, p 607. (b) Sliskovic, D. R. In
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F., Eds.; Pergamon Press: Oxford, 1996; Vol. 9, p 345.
(6) (a) Chattopadhyay, G.; Ray, S. J. Chem. Res., Synop. 1992, 170. (b)
Sen, A. K.; Sengupta, D. K. Indian J. Chem., Sect. B 1983, 22B, 30. (c)
El-Bayouki, K. A. M.; Hammad, M.; Osman, S. A.; Basyouni, W. M. Egypt
J. Chem. 1986, 29, 581.
(7) Trcek, T.; Meden, A.; Vercek, B. Synlett 2000, 10, 1458.
10.1021/ol035455i CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/18/2003