proper ( 22 ) and butyllithium is treated with ethylene oxide. The hydroxyl
group on the end of the ethyl group in 23 is next converted to its mesylate
( 24 ). Displacement of this newly introduced leaving group by the phenoxide
from 21 and potassium carbonate leads to the alkylated derivative 25.
Saponification of the terminal ester then yieldsragaglitazar( 26 ).^3
NHO
BuLiO
NOOHCH 3 SO 3 Cl
NOCH 3 O 2 SOCH=OO
C 6 H 5 CH 2O(C 2 H 5 O) 2 PCO 2 C 2 H (^5) O
C 6 H 5 CH 2
CO 2 C 2 H 5
O 1. H 2 HO
CO 2 C 2 H 5
O
Enzyme
HO
CO 2 H
O
HO
CO 2 CH(CH 3 ) 2
O
N
O
CO 2 CH(CH 3 ) 2
O
N
O
CO 2 H
O
NaOH K^2 CO^3
16 18 19
20
21
22
(^2324)
26 25
17 O
iPrOH
tBuOK
O O
Irritable bowel syndrome (IBS) is said to rank among the largest causes
for physician office visits. There are, in spite of this, very few means for
treating this very prevalent condition. The newly approved indication for
the recently introduced 5-HT serotonin antagonist tegoserod (see Chapter
7) comprises one of the first specific treatments for IBS. Acylation of the
indole ( 27 ) with trichloroacetyl chloride affords the ketone ( 28 ).
Treatment of that intermediate with methanolic base leads to loss of the tri-
chloromethyl group via the haloform reaction with concomitant esterifica-
tion of the carbonyl group 29. The benzyl protecting group is then
replaced by acetyl with successive hydrogenation and reaction of the result-
ing phenol with acetic anhydride ( 30 ). Reaction of 30 with NCS leads to
introduction of chlorine at the 2-position on the indole ring ( 31 ). This last
intermediate is then treated with 3-chloropropan-1-ol in the presence of
methylsulfonic acid, which forms the oxazine ring ( 32 ). Though the exact
sequence is unstated, this reaction involves replacement of chlorine on the
indole by oxygen and subsequent displacement of side-chain chlorine by
indole nitrogen. The acetyl function on the phenol, having served its
220 POLYCYCLIC FUSED HETEROCYCLES