incontinence, as well as depression and schizophrenia.^9 The quinoline
portion of this compound is prepared by base-catalyzed Pfitzinger conden-
sation of isatin ( 46 ) with the methoxy acetophenone ( 47 ). The methoxy
ether in the product ( 48 ) is next cleaved by means of hydrogen bromide.
Amide formation of ( 49 ) with the chiral a-phenylpropylamine ( 50 )
affords the antagonist ( 51 ).^10
NHOO46+OCH 3O47NKOH OCH^3CO 2 HHBrNOHCO 2 H49NH 2
NOHO NH514850Cholesterol is not absorbed from the intestine as such, it first needs to be
esterified. Another enzyme, cholesteryl ester transfer protein (CETP), then
completes absorption of cholesterol. Drugs that interfere with the action of
these peptides would aid in lowering cholesterol levels by complementing
the action of the statins that inhibit endogenous production of cholesterol.
The CEPT inhibitortorcetrapib( 60 ), proved very effective in lowering
cholesterol levels in humans; the drug not only lowered low-density lipo-
proteins (LDL and VLDL) but also raised levels of high density, “good”
lipoproteins (HDL). The drug was, however, withdrawn from the market
not long after its introduction as a result of serious concerns as to its
safety. The synthesis of this compound involves an unusual method for
preparing the tetrahydroquinoline moiety. The sequence starts with the
reaction of the trifluormethylaniline ( 52 ) with propanal in the presence
of benzotriazole ( 53 ) to produce the aminal 54. Condensation of 54 with
the vinyl carbamate ( 55 ) adds three carbon atoms in what may be
viewed formally as a 3þ3 cycloaddition sequence. This yields the tetra-
hydroquinoline ring ( 56 ) with expulsion of the benzotriazole fragment.
The ring nitrogen is then protected as its ethyl carbamate by acylation
- COMPOUNDS WITH ONE HETEROATOM 169