CHAPTER 9
9 BICYCLIC FUSED HETEROCYCLES
1. COMPOUNDS WITH FIVE-MEMBERED RINGS
FUSED TO SIX-MEMBERED RINGS
A. Compounds with Two Heteroatoms
The platelet aggregation inhibitors ticlopidine and clopidogrel consist of
substitued thienopiperidines, as does the recent entry prasugrel ( 9 ).
Alkylation of the enolate from treatment ofN-(4-chlorobenzyl)piperidine,
( 1 ), with sodium hydride with ethyl chloroacetate affords the ketoester ( 2 ).
Reaction of 2 with hydrogen sulfide leads to formation the thiolactone ( 3 ).^1
This transform can be rationalized by assuming initial conversion of the
ketone to a thioenol; the thioenol attacks the ester to close the ring.
Reaction of the product would then form the corresponding enol acetate
( 4 ). In a convergent sequence, the Grignard reagent from the benzyl
bromide ( 5 ) is added to cyanocyclopropane ( 6 ). This afford ketone 7
after hydrolysis. Treatment of 7 with NBS leads to formation of the bromi-
nated derivative ( 8 ). Reaction of this last with the thienopiperidine ( 4 ) leads
to displacement of bromine and formation of the alkylation product. Thus 9
is obtained.^2
The Organic Chemistry of Drug Synthesis, Volume 7. By Daniel Lednicer
Copyright#2008 John Wiley & Sons, Inc.
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