2 research outputs found
Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852A
HCV NS5B polymerase inhibitor GSK852A
(<b>1</b>) was synthesized
in only five steps from ethyl 4-fluorobenzoylacetate (<b>3</b>) in 46% overall yield. Key to the efficient route was the synthesis
of the highly functionalized benzofuran core <b>15</b> from
the β-keto ester in one pot and the efficient conversion of
ester <b>6</b> to amide <b>19</b> via enamine lactone <b>22</b>. Serendipitous events led to identification of the isolable
enamine lactone intermediate <b>22</b>. Single crystal X-ray
diffraction and NMR studies supported the intramolecular hydrogen
bond shown in enamine lactone <b>22</b>. The hydrogen bond was
considered an enabler in the proposed pathway from ester <b>6</b> to enamine lactone <b>22</b> and its rearrangement to amide <b>19</b>. GSK852A (<b>1</b>) was obtained after reductive
amination and mesylation with conditions amenable to the presence
of the boronic acid moiety which was considered important for the
desirable pharmacokinetics of <b>1</b>. The overall yield of
46% in five steps was a significant improvement to the previous synthesis
from the same β-keto ester in 5% yield over 13 steps
Development of Large-Scale Routes to Potent GPR119 Receptor Agonists
Practical and scalable syntheses
were developed that were used
to prepare multikilogram batches of GSK1292263A (<b>1</b>) and
GSK2041706A (<b>15</b>), two potent G protein-coupled receptor
119 (GPR119) agonists. Both syntheses employed relatively cheap and
readily available starting materials, and both took advantage of an
S<sub>N</sub>Ar synthetic strategy