D. Gala et al. / Tetrahedron Letters 44 (2003) 2721–2723
2723
nines can hydrolyze the pyrimidine portion of guanine to
generate substituted imidazoles. With this in view, expo-
sure of compound 9 and subsequent intermediates to the
aqueous basic conditions was minimized. The reduction
of 9 to diamine 12 progresses well under standard
hydrogenation conditions (60 psi H2, 50% water wet 5%
Pd/C, rt, overnight). Compound 12 without isolation,
was reacted with appropriate acid chlorides in the
presence of Hunigh base as an acid scavenger to form
stable, isolable, solids 13a and 13b in unoptimized 65 and
80% yields, respectively.9 Cyclization of 13 to the corre-
sponding PDE inhibitors proved difficult under a variety
of conditions (toluene, pTSA, reflux, solvent/SOCl2 or
oxalyl chloride) especially in view of the fact that it is an
intramolecular reaction and it forms a five membered
ring. This may be due to conformational rigidity
imparted by the preexisting three rings in 13. However,
when 13 was refluxed in neat POCl3, it was transformed
to the target compounds in good (80% for both 1a, and
1b) isolated yield.10
3. Gala, D.; DiBenedetto, D. J.; Kugelman, M.; Puar, M. S.
Tetrahedron Lett. 2003, 44, 2717–2720.
4. Gala, D.; DiBenedetto, D.; Gunter, F.; Kugelman, M.;
Maloney, D.; Cordero, M.; Mergelsberg, I. Org. Process
Res. Development 1996, 1, 163.
5. (a) Pfleiderer, W. Ber. 1957, 2272; (b) Roehrkasten, R.;
Raatz, P.; Kerher, R. P.; Blaszkewicz, M. Zeitschrift fuer
Naturforschung B: Chemical 1997, 52, 1526–1532; (c)
Low, J. N.; Scrimgeour, S. N.; Egglishaw, C.; Howie, R.
A.; Moreno-Carretero, M. N.; Hueso-Urena, F. Commu-
nications 1994, 50, 1329.
6. For the preparation of Cyclopentylamino alcohol, see: (a)
Barnard, H. Can. J. Chem. 1958, 36, 1252; (b) Overman,
L. E.; Sugai, S. J. Org. Chem. 1985, 50, 4154; (c) Barr,
A.; Frencel, I.; Robinson, J. B. Can. J. Chem. 1977, 55,
4180.
7. Nitrosation as well as nitration of 2a were both poor
yielding reactions leading to a mixture of products. After
partial purification, when these compounds were reacted
with 6, they led to a complex mixture of products. For
these reasons the methoxy group was deemed less desir-
able than the thiomethyl group, and hence it is not
described in this manuscript.
8. Gala, D.; Puar, M. S.; Czarniecki, M.; Das, P. R.;
Kugelman, M.; Kaminiski, J. Tetrahedron Lett. 2000, 41,
5025.
9. Preliminary work suggests that p-CF3-Ph-CH2COCl is
more susceptible to hydrolysis leading to a lower yield
compared to CH3(CH2)5COCl. 50% Water Wet 5% Pd/C
used for hydrogenation reaction was the source of water
in reaction medium.
In summary, a new synthetic strategy for the preparation
of the tetracyclic guanine PDE inhibitors from an
advanced tricyclic pyrimidine intermediate has been
developed. This strategy bypasses recently reported regio
chemistry issues with the common intermediate
approach.
References
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10. Here, prior to isolation of the products, a carefully
temperature (0–20°C) and pH (0–10) controlled neutral-
ization of residual POCl3 was preformed to prevent
hydrolysis of the products (Ref. 7).
2. Vemulapalli, S.; Watkins, R. W.; Chintala, M.; Davis,
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