A. Dalby et al. / Tetrahedron Letters 54 (2013) 2737–2739
2739
Scheme 3. Synthesis of D159404 (16) and D159153 (17).
overall cleanliness of the HPLC trace versus those of alternative
conditions examined. The second Suzuki coupling (conversion of
compound 10 to 7) was conducted under the same stoichiometric
reaction conditions, altering only the temperature under which the
coupling was conducted and the duration of the reaction. Applica-
tion of these conditions allowed for generation of product 7
(D159687) to be conducted on gram scale.
Now armed with an efficient process for assembling this class of
compounds, the applicability of the sequential Suzuki couplings
was tested with the synthesis of the two other identified PDE4D
partial allosteric modulators, D159404 and D159153. The synthe-
ses of these two compounds required preparation of pivotal fluoro
substituted intermediate 14 (Scheme 3). The commercially avail-
able 2-bromo-3-fluoroanisole 11 was converted into aldehyde 12
then reduced to alcohol 13 with sodium borohydride.9 Alcohol
13 was converted into dibromide 14 using NBS. The initial Suzuki
coupling of dibromide 14 with boronic ester 9 proceeded as ex-
pected to provide urea 15. Urea 15 undergoes Suzuki coupling with
3-chlorophenylboronic acid to give D159404 (16) and 3-nitro-
phenyl boronic acid to give D159153 (17), albeit in modest isolated
yields of 40 and 41%.
from deCODE; Jasbir Singh, Wayne Zeller, Gary Schiltz, Adalie Mot-
ta, Munagala Rao and others for their work on the discovery of
biaryl PDE4 inhibitors.
Supplementary data
Supplementary data (experimental procedures and character-
ization data for compounds) associated with this article can be
References and notes
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Acknowledgments
NIU for the financial support through a Research and Artistry
Grant. T.J.H. would also like to acknowledge medicinal chemists
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WO20090136473, May 28, 2009.