I. R. Baxendale, S. V. Ley / Bioorg. Med. Chem. Lett. 10 (2000) 1983±1986
1985
solution of 13 containing a catalytic amount of sodium
ethoxide (10 mol%). Simple removal of the water
formed during the cyclisation step (magnesium sulfate)
and evaporation of the solvent gave a quantitative yield
of sildena®l 1 as a white analytically pure powder.
Conclusions
Scheme 3. Synthesis of the acid coupling component 2.
Our synthesis of this commercially important molecule
demonstrates the principles of using supported reagents
in both a sequential and convergent fashion. We believe
this route also indicates how these reagents could be easily
adapted to the synthesis of other drug-like molecules
either as target directed syntheses, or in a multi-parallel
mode. Clearly these methods would also allow for the
preparation of analogues of 1.5c
Acknowledgements
We would like to thank P®zer Process Research and
Development for providing a preprint of the commercial
synthesis. We are also grateful to P®zer Central
Research for a Postdoctoral Fellowship (to IRB), the
BP endowment and the Novartis Research Fellowship
(to SVL) for their ®nancial support.
References and Notes
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worth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997, 1217.
(e) Hinez, B.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1997,
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Scheme 4. Coupling strategy and dehydration step involved in the
formation of sildena®l 1.
loading of the resin 12 was not determined but was
assumed to be 100% based on the original HOBt resin
(a two-fold excess of the DMF solution of acid 2 was
used in its preparation). Immersion of the resin 12 in a
THF solution of the amino-pyrazole 3 gave, after removal
of the unreacted pyrazole 3 with an isocyanate resin, the
coupled material in a reasonable yield and as a clean
product. The ®nal cyclisation and dehydration step was
achieved by microwave irradiation (MW)18 of an ethanolic