Discovery of a simple picomolar inhibitor of cholesteryl ester transfer protein

Article abstract of DOI:10.1021/jm020528+

A novel series of substituted N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-trifluoro-3- amino-2-propanols is described which potently and reversibly inhibit cholesteryl ester transfer protein (CETP). Starting from the initial lead 1, various substituents were introduced into the 3-phenoxyaniline group to optimize the relative activity for inhibition of the CETP-mediated transfer of [³H]-cholesteryl ester from HDL donor particles to LDL acceptor particles either in buffer or in human serum. The better inhibitors in the buffer assay clustered among compounds in which the phenoxy group was substituted at the 3, 4, or 5 positions. In general, small lipophilic alkyl, haloalkyl, haloalkoxy, and halogen moieties increased potency relative to 1, while analogues containing electron-donating or hydrogen bond accepting groups exhibited lower potency. Compounds with polar or strong electron-withdrawing groups also displayed lower potency. Replacement of the phenoxy ring in 1 with either simple aliphatic or cycloalkyl ethers as well as basic heteroaryloxy groups led to reduced potency. From the better compounds, a representative series 4a-i was prepared as the chirally pure R(+) enantiomers, and from these, the 4-chloro-3-ethylphenoxy analogue was identified as a potent inhibitor of CETP activity in buffer (4a, IC₅₀ 0.77 nM, 59 nM in human serum). The simple R(+) enantiomer 4a represents the most potent acyclic CETP inhibitor reported. The chiral synthesis and biochemical characterization of 4a are reported along with its preliminary pharmacological assessment in animals.

Full text of DOI:10.1021/jm020528+

2152
J . Med. Chem. 2003, 46, 2152-2168
Discover y of a Sim p le P icom ola r In h ibitor of Ch olester yl Ester Tr a n sfer
P r otein
Emily J . Reinhard,† J ane L. Wang, Richard C. Durley,* Yvette M. Fobian, Margaret L. Grapperhaus,
Brian S. Hickory, Mark A. Massa, Monica B. Norton, Michele A. Promo, Michael B. Tollefson,
William F. Vernier, Daniel T. Connolly, Bryan J . Witherbee, Michele A. Melton, Karen J . Regina,
Mark E. Smith, and J ames A. Sikorski‡
Pharmacia Discovery Research (currently Pfizer Global Research and Development), 700 Chesterfield Parkway West,
Chesterfield, Missouri 63017-1732
Received November 21, 2002
A novel series of substituted N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-
trifluoro-3-amino-2-propanols is described which potently and reversibly inhibit cholesteryl
ester transfer protein (CETP). Starting from the initial lead 1, various substituents were
introduced into the 3-phenoxyaniline group to optimize the relative activity for inhibition of
the CETP-mediated transfer of [3H]-cholesteryl ester from HDL donor particles to LDL acceptor
particles either in buffer or in human serum. The better inhibitors in the buffer assay clustered
among compounds in which the phenoxy group was substituted at the 3, 4, or 5 positions. In
general, small lipophilic alkyl, haloalkyl, haloalkoxy, and halogen moieties increased potency
relative to 1, while analogues containing electron-donating or hydrogen bond accepting groups
exhibited lower potency. Compounds with polar or strong electron-withdrawing groups also
displayed lower potency. Replacement of the phenoxy ring in 1 with either simple aliphatic or
cycloalkyl ethers as well as basic heteroaryloxy groups led to reduced potency. From the better
compounds, a representative series 4a -i was prepared as the chirally pure R(+) enantiomers,
and from these, the 4-chloro-3-ethylphenoxy analogue was identified as a potent inhibitor of
CETP activity in buffer (4a , IC50 0.77 nM, 59 nM in human serum). The simple R(+) enantiomer
4a represents the most potent acyclic CETP inhibitor reported. The chiral synthesis and
biochemical characterization of 4a are reported along with its preliminary pharmacological
assessment in animals.
In tr od u ction
pathway. CETP is also expressed in macrophages within
atherosclerotic lesions and may initiate the early RCT
process.10 Alternatively, the CETP-mediated transfer of
CE from HDL to LDL increases LDL-cholesterol (LDLc)
and lowers HDLc. Epidemiological studies have dem-
onstrated an inverse relationship between serum HDLc
levels and the incidence of coronary heart disease
(CHD).11 Low levels of HDLc represent a significant
independent risk factor in CHD irrespective of whether
patients have elevated LDLc.12 Thus, inhibiting CETP
activity should elevate HDLc and provide a potential
therapeutic benefit for patients with CHD.
Numerous animal studies support the hypothesis that
modulation of CETP activity has a beneficial effect on
HDLc levels and attenuates atherosclerosis. For ex-
ample, administration of TP-2, a CETP-neutralizing
monoclonal antibody, to hamsters produced a dramatic
reduction in CETP activity with a concomitant elevation
of HDLc,13 and cholesterol fed-rabbits treated with
antisense oligodeoxynucleotides designed against CETP
had elevated HDLc and displayed significantly reduced
aortic lesion areas.14 Rabbits treated with a covalent
modifier of CETP had elevated HDLc, lowered LDLc,
and attenuated atherosclerosis.15,16
CETP is a plasma glycoprotein that mediates the
transfer of neutral lipids among various plasma lipo-
proteins.1,2 CETP facilitates the transfer of cholesteryl
ester (CE) from high-density lipoprotein (HDL) to apo-
lipoprotein B-containing lipoproteins such as very low-
density lipoprotein (VLDL) and low-density lipoprotein
(LDL) with a balanced exchange of triglyceride (TG).
CETP plays a potential pro-atherogenic role by moving
CE from HDL into pro-atherogenic VLDL and LDL
particles, thereby lowering atheroprotective HDL-
cholesterol (HDLc). Assigning a definitive role for CETP
in atheroclerosis has been the subject of considerable
debate.2-5 There is an ongoing need to identify potent,
selective, and specific CETP inhibitors that could be
used to more clearly define the role of CETP in pre-
clinical models of atherosclerosis and to better under-
stand the overall pharmacology of this system.2
CETP also plays a potential antiatherogenic role in
reverse cholesterol transport (RCT), a process that helps
remove CE from peripheral tissues to the liver.6-9 By
regulating HDLc plasma levels and the size of HDL
particles, CETP is an important protein in this RCT
In humans, the effects of inhibiting CETP activity is
less clear. In some studies, CETP lowering has been
shown to raise HDLc and be atheroprotective. For
example, human CETP deficiency results in hyperal-
phalipoproteinemia, i.e., elevated HDLc, and protection
* To whom correspondence should be addressed. Tel: (636) 247-
6792. Fax: (636) 247-5234. E-mail: richard.c.durley@pfizer.com.
† Current address: Alteon Inc., 170 Williams Dr., Ramsey, NJ
07446.
‡ Current address: AtheroGenics, Inc., 8995 Westside Parkway,
Alpharetta, GA 30004.
10.1021/jm020528+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/26/2003

Inhibitor of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2153
from atherosclerosis.17 Also, analysis for CETP poly-
morphism in the Framingham Offspring Study identi-
fied a B2B2 allele in men associated with significantly
reduced CETP activity, elevated HDLc, and a reduced
risk for CHD.18 Finally, a CETP inhibitor, J TT-705,
when given to human subjects with mild hyperlipidemia
for 4 weeks, decreased CETP activity by 37% and
increased HDLc by 34%.19 On the other hand, in a
recent prospective clinical study of healthy middle-aged
US males, carriers of the B2 allele of the Taq1B
polymorphism in the CETP gene had higher HDLc, but
did not have a lower risk of myocardial infarction.20
Likewise, those populations exhibiting hyperalphalipo-
proteinemia were only protected against atherosclerosis
below a certain HDLc level,21 and analysis of a Danish
population group associated different CETP mutations
with decreased HDLc in both men and women with a
possible paradoxical decreased risk of ischemic heart
disease in women.22
Despite these controversies, there is intense interest
in identifying potent and selective CETP inhibitors to
determine whether they could represent a new thera-
peutic approach to improve the HDLc/LDLc ratio and
provide an important therapeutic benefit to CHD pa-
tients with low HDLc levels.2,23 While potentially re-
versible CETP inhibitors from a variety of structural
classes are known,2 they typically exhibit only modest
micromolar IC50 values for inhibiting CETP-mediated
transfer of 3H-CE from HDL to LDL under buffered
assay conditions in vitro.2 Identifying CETP inhibitors
that exhibit submicromolar activity when this CETP-
mediated transfer process is assayed in the presence of
human serum has been especially difficult.2 However,
synthetic studies for a series of tetrahydronaphthalene
derivatives with low nanomolar potency in vitro have
been described,24 and related tetrahydoquinoline de-
rivatives have also been reported (activities not given).25
We recently reported the discovery of several trifluoro-
3-(tert-amino)-2-propanols, including 1 and its chiral
R-enantiomer 1a as representative of a simple new class
of potent CETP inhibitors.26,27 Here we describe our
efforts to optimize the activity of this series through
modification and replacement of the aniline 3-phenoxy
group in 1. These efforts produced the substituted
phenoxy analogues 2a -ll and the replacement series
3a -j that incorporated various heterocyclic, benzylic,
and cyclic aliphatic ethers in place of the phenoxy group
in 1. Previous studies had demonstrated that an unex-
pected 10-fold increase in potency was achieved when
analogues of 1a were prepared as their pure chiral
R-enantiomers.26,27 Since the substituted phenoxy series
displayed the better in vitro potency compared to 1, a
series of related chiral R-enantiomers 4a -i were pre-
pared as analogues of 1a . As a result, 4a was identified
as a simple picomolar CETP inhibitor in buffer with
significant nanomolar activity in the presence of human
serum.
highly versatile and easily synthesized intermediate
that in one final step could be converted in parallel to
many desired compounds. Ideally, each library con-
tained no more than 20 distinct members, and the
structure-activity relationship (SAR) developed from
these smaller libraries was then used to design subse-
quent iterations. The recent improvements in new
synthetic methods to prepare diaryl ethers developed
by Buchwald and Hartwig led us to explore their
approaches for library generation.28 Their versatile
cross-coupling methods accommodated both activated
and inactivated aryl bromides with a wide range of
phenols to give the corresponding diaryl ethers in good
yield with a high level of functional group tolerance.29,30
Initially, our strategy involved exploring functionality
changes to optimize potency in analogues of 1 where
the enantiomeric purity was less than optimal, and then
those substituents that improved activity were incor-
porated into the chirally pure R-enantiomers 4a -i as
analogues of 1a .
Many of the desired N,N-disubstituted trifluoro-3-
amino-2-propanols 2a -ii were conveniently prepared in
modest to reasonable yield from the cross-coupling
reaction of commercially available phenols with pro-
tected aryl bromide 9 (Scheme 1). The required N-ben-
zyl-3-bromoaniline 7 was conveniently prepared in good
yield by standard reductive amination sequences de-
scribed previously26 from the reaction of 3-(1,1,2,2-
tetrafluoroethoxy)benzaldehyde 5 and 3-bromoaniline 6
with sodium triacetoxyborohydride. The ring-opening
reaction of N-benzyl-3-bromoaniline 7 with commer-
cially available 1,1,1-trifluoro-2,3-epoxypropane of un-
specified enantiomeric composition26 gave the desired
trifluoro-3-(tert-amino)-2-propanol 8 as the penultimate
intermediate. The ring opening of this epoxide under
these conditions proceeded with complete regioselectiv-
ity, since none of the isomeric 2-amino-3-propanol
product was detected. This reaction proceeded smoothly
in the presence of catalytic quantities of ytterbium(III)
triflate in warm acetonitrile. The ytterbium(III) triflate
facilitates the reaction at lower temperature and mini-
mizes the need for large excess quantities of this volatile
Ch em istr y
Since the 3-phenoxyaniline moiety provided an im-
portant contribution to the potency of 1,26 we became
interested in chemical approaches that could quickly
explore modifications to this key substituent. We chose
to explore small focused libraries generated from a

2154 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11
Reinhard et al.
Sch em e 1a
a
Reagents: (a) NaBH(OAc)3, AcOH, DCE, rt; (b) 1,1,1-trifluoroepoxypropane, Y(SO3CF3)3, CH3CN, 50 °C, 2 h; (c) TBDMS(SO3CF3),
TEA, DCM, rt, 4 h; (d) appropriate phenol, Cs2CO3, Cu(SO3CF3)2, naphthoic acid, toluene/DMA, 100 °C, 24-72 h.29,30
Sch em e 2a
a
Reagents: (a) NaBH(OAc)3, AcOH, DCE, rt; (b) 1,1,1-trifluoroepoxypropane, Yb(SO3CF3)3, CH3CN, 50 °C, 2 h; (c) appropriate aryl
halide, Cs2CO3, Cu(SO3CF3)2, naphthoic acid, toluene/EtOAc, 100 °C, 24-72 h; (d) alkyl/benzyl halide, Cs2CO3, acetone, 60 °C, 18 h or
CH3CN, 50 °C, 48 h.29,30
epoxide due to thermal loss. The carbinol group in 8 was
protected as the tert-butyldimethylsilyl (TBDMS) ether
to ensure that no interfering reaction occurred at the
propanol center during the subsequent aryl ether cross-
coupling reactions. The best yields of 9 were obtained
by stirring 8 with tert-butyldimethylsilyl triflate in
dichloromethane in the presence of triethylamine.
The diaryl ether cross-coupling reactions were carried
out in parallel using glass 2-dram vials equipped with
mini stir bars. Reaction vials containing a mixture of 9
with the desired phenol, cesium carbonate, copper
triflate-benzene complex, and naphthoic acid in a
solution of toluene and N,N-dimethylacetamide were
capped and heated with stirring in a Pierce Reacti-
Therm system for 24-48 h to give varying yields of 2a -
ii. Reactions of 9 with various phenols usually required
48-72 h to go to completion. The best isolated yields
were obtained with phenols bearing 3-alkyl substitu-
ents. Reactions of 9 with phenols containing electron-
withdrawing groups required either longer reaction
times (96 h), or in some cases (e.g., 4-nitro 2ll) an
alternative synthesis. All final products were purified
via reverse phase chromatography to greater than 98%
purity using a Gilson combichem purification system.
Later it was found to be unnecessary to do a separate
TBDMS protection/deprotection. The TBDMS protecting
group in 9 is lost during the cross-coupling reaction and
as a result is not required for efficient cross coupling to
occur. Once the cleavage of the TBDMS group was
discovered, we utilized 8 to provide analogues of 2 with
no loss in yield.
Phenols containing strongly electron withdrawing
groups (2jj-ll) or heteroaryl moieties (3a ,b) failed to
give the desired diaryl ethers under these conditions.
Consequently, the phenolic trifluoro-3-(tert-amino)-2-
propanol intermediate 12 (Scheme 2) was utilized with
either aryl or heteroaryl bromides to prepare the aryl
and heteroaryl ether analogues (2jj-ll; 3a ,b) that could
not be synthesized via the original copper-catalyzed
cross-coupling reaction sequence (Scheme 1). This func-
tional group switch (Scheme 2) allowed us to further
expand our libraries using commercial available starting
materials, i.e., substituted aryl bromides. The required
N-benzyl-3-hydroxy-aniline 11 was conveniently pre-

Inhibitor of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2155
Sch em e 3a
Ta ble 1. In Vitro Inhibition of Phenoxy-Substituted
N-[3-(1,1,2,2-Tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-
trifluoro-3-amino-2-propanols Using Recombinant Human
CETP in Buffer or in Human Seruma
IC50 (µM)
IC50 (µM)
compound
R1
in bufferb in human serumb,c
1
2a
2b
2c
2d
2e
H
0.14
0.02
0.03
0.03
0.03
0.03
0.06
0.07
0.08
0.08
0.08
0.08
0.08
0.09
0.09
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.2
6.0
2.3
3.8
4.1
0.6
0.9
1.0
1.1
3.8
6.5
3.1
7.8
3.4
13.3
5.2
ND
6.9
11.4
ND
10.3
21.3
11.5
ND
27.2
9.7
ND
10.0
34.2
31.3
30.1
9.0
15.6
ND
ND
ND
ND
5.6
3-isopropyl
3-trifluoromethoxy
4-fluoro
2,3-dichloro
4-chloro-3-ethyl
3-ethyl
3,5-dimethyl
3-tert-butyl
3,4-dimethyl
4-fluoro-3-methyl
3,4-dichloro
3-ethyl-5-methyl
3-methyl
3,4-(CH2)4-
2,3-difluoro
4-trifluoromethyl
4-methyl
4-chloro-3-methyl
3-trifluoromethyl
4-n-propyl
3,5-difluoro
3-n,n-dimethylamino
3-methyl-4-isopropyl
3-fluoro
2-chloro
4-chloro
4-propoxy
4-isopropyl
4-trifluoromethoxy
4-amino
3-methoxy
4-benzyl
4-phenyl
4-hydroxy
4-thiol
3-fluoro-2-nitro
2-nitro
a
Reagents: (a) (R)-(+)-1,1,1-trifluoroepoxypropane, Yb(OSO2-
2f
CF3)3, CH3CN, 50 °C, 2 h; (b) Cs2CO3, DMSO, 100 °C, 18 h; (c)
zinc, AcOH, rt, 1 h; (d) appropriate R3-C6H4CHO, NaBH(OAc)3,
AcOH, DCE, rt, 2 h; (e) appropriate R3-C6H4CH2Br, cyclohexane,
reflux, 24 h.26
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
pared in good yield using a standard reductive amina-
tion sequence26 from the reaction of 3-aminophenol 10
and 5 with sodium triacetoxyborohydride. Intermediate
12 was subsequently prepared from the standard ring-
opening reaction of 11 with commercially available
1,1,1-trifluoroepoxypropane of unspecified enantiomeric
composition.26 In a few cases, there were some desired
analogues that could not be synthesized using either
approach. We were limited particularly in the number
of 2- and 3-substitutuents that could be incorporated
successfully. To further expand the SAR, we also
explored a limited series of simple alkyl, cycloalkyl, and
benzylic ether analogues 3c-j (Scheme 2). The alkyla-
tion of phenol 11 with the desired alkyl, benzylic, or
cycloalkyl halide using cesium carbonate in acetone with
heating overnight gave the desired compounds 3c-j in
good yield.
2s
2t
2u
2v
2w
2x
2y
2z
2a a
2bb
2cc
2d d
2ee
2ff
2gg
2h h
2ii
2jj
2k k
2ll
0.3
0.3
0.3
0.4
0.4
0.4
0.7
1.0
2.4
2.5
3.5
The desired chiral R-enantiomers 4a -i were prepared
in quantities amenable for in vitro testing using previ-
ously described procedures26 from the ring-opening
reaction of the appropriately substituted N-benzyl-3-
phenoxyanilines 13 with the known (R)-(+)-1,1,1,-tri-
fluoro-2,3-epoxypropane31 and catalytic amounts of yt-
terbium(III) triflate in warm acetonitrile (Scheme 3).
Within the limits of detection by chiral HPLC, no
racemization of the amino alcohol center was observed
under these conditions. When larger quantities of mate-
rial were desired to support animal testing, an alterna-
tive approach to the required substituted N-benzyl-3-
phenoxyanilines 13 was developed. The substituted (3-
nitrophenoxy)benzene 15 was synthesized by heating
together 1,3-dinitrobenzene with the appropriately sub-
stituted phenol 14 in the presence of cesium carbonate.
The nitro group in 15 was reduced using zinc in acetic
acid to give the desired substituted 3-phenoxyanilines
16 in good yield. Standard reductive amination proce-
dures26 were then used to incorporate the necessary
benzylic substituents into the N-benzyl-3-phenoxy-
anilines 13 from the reaction of anilines 16 with the
appropriately substituted benzaldehyde. The potency of
4a led us to prepare a limited set of closely related
analogues 4f-i varying the benzylic substituent while
>50
0.1
0.4
0.5
ND
29.3
4-nitro
a
b
Reference 27. Data represents average of duplicate values.
c ND, not determined.
maintaining the 3-(4-chloro-3-ethylphenoxy)aniline moi-
ety constant. For one of these, the secondary amine
precursor,26 1-(bromomethyl)-3-pentafluoroethylben-
zene, was prepared by treatment of 3-iodotoluene with
sodium pentafluoroethyl propionate at high temperature
in the presence of catalytic CuI, followed by bromination
with N-bromosuccinimide.
Biologica l Resu lts a n d Discu ssion
In Vitr o Activity a n d Str u ctu r e-Activity Rela -
tion sh ip s. Modifications of the 3-phenoxy substituents
in 2 were explored to optimize inhibition of CETP-
mediated CE transfer in both a buffered in vitro assay
using reconstituted reagents as well as in human serum
(Table 1).27,32 The IC50 values in human serum are
indicative of the inhibitory activity in the target tissue,
human blood, when other plasma lipoproteins are also

2156 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11
Reinhard et al.
Ta ble 2. In Vitro Inhibition of Phenoxy-Replacement Groups
in N-[3-(1,1,2,2-Tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-
trifluoro-3-amino-2-propanols Using Recombinant Human
CETP in Buffer or in Human Seruma
present. We suspect that the shift to weaker potency in
human serum than that observed in buffer is due to
nonspecific binding of the inhibitors to nontarget plasma
proteins. Results for 2a -ll and 3a -j were compared to
the IC50 values observed previously26,27 for compound 1
in buffer (IC50 0.14 µM) and in serum (IC50 6.0 µM).
Notably, inhibitors 2a -e exhibited 6-10-fold higher
potency than 1 in the buffer assay, and in particular,
inhibitors 2d and 2e were about 7-10-fold more potent
than 1 in the serum assay.
IC50 (µM) in
IC50 (µM)
human
compound
R2
in bufferb
serumb,c
As summarized below, several key structural changes
provided insights into the general SAR of this series
(Table 1). The better inhibitors in the buffer assay
appeared to cluster with phenoxy having substituents
in the 3, 4, and 5 positions. In general, small, lipophilic
alkyl, haloalkyl, and haloalkoxy moieties appeared to
increase potency at the 3 and 5 positions while better
activity was usually observed with halogen substituents
in the 2, 3, or 4 positions. The best single substituent
changes incorporated branched alkyl groups at the
3-position and appeared to be optimal with a 3-isopropyl
moiety as in 2a (IC50 0.02 µM). The related analogues
incorporating either a 3-methyl group as in 2m (IC50
0.09 µM), a 3-ethyl group as in 2f (IC50 0.06 µM), or a
3-tert-butyl group as in 2h (IC50 0.08 µM) were all more
potent than 1, but not as potent as 2a . Surprisingly,
moving the bulky isopropyl group in 2a to the 4-position
as in 2bb (IC50 0.4 µM) dramatically reduced potency
by more than 20-fold, whereas the activity of the
3-methyl analogue 2m (IC50 0.09 µM) was comparable
to that of the 4-methyl isomer 2q (IC50 0.1 µM). The
addition of more extended groups at the 4-position such
as the 4-n-propyl analogue 2t (IC50 0.2 µM), the 4-benzyl
analogue 2ff (IC50 2.4 µM), or the 4-phenyl 2gg (IC50
2.5 µM) all led to lower potencies relative to 1 and
suggested that a spatial constraint on the CETP protein
was present limiting activity at this position. A similar
trend was observed with the nonplanar26,33 trifluo-
romethoxy substituent where the 3-isomer 2b (IC50 0.03
µM) had 10-fold higher potency than the corresponding
4-isomer 2cc (IC50 0.4 µM). In contrast, the analogue
2s (IC50 0.2 µM), with an in-plane 3-trifluoromethyl
substituent, displayed potency comparable to the 4-
isomer 2p (IC50 0.1 µM). However, while both the
3-methyl analogue 2m (IC50 0.09 µM) and 4-methyl
analogue 2q (IC50 0.1 µM) displayed potencies similar
to 1, the cyclic tetrahydronaphthyl analogue 2n (IC50
0.09 µM) had only similar, but not dramatically in-
creased potency (Table 1).
3a
3b
3c
3d
3e
3f
3g
3h
3i
2-pyridyl
3-pyridyl
3-trifluoromethoxybenzyl
3-trifluoromethylbenzyl
cyclohexylmethyl
benzyl
4-trifluoromethoxybenzyl
isopropyl
cyclopentyl
>100
1.3
0.06
0.09
0.2
0.2
0.3
0.3
0.4
ND
ND
5.7
7.7
ND
12.1
39.4
ND
ND
ND
3j
cyclohexyl
2.6
a
b
Reference 27. Data represents average of duplicate values.
c ND, not determined.
0.06 µM) or the single 4-chloro moiety as in 2z (IC50 0.3
µM). In contrast, the combination of 4-chloro and
3-methyl substituents as in 2r (IC50 0.2 µM) did not
improve the potency of the single 3-methyl group as in
2m (IC50 0.09 µM).
In general, the presence of electron-donating or
hydrogen-bond accepting groups led to lower potency.
For example, the 3-N(CH3)2 analogue 2v (IC50 0.2 µM),
4-propoxy analogue 2a a (IC50 0.4 µM), and 3-methoxy
analogue 2ee (IC50 1.0 µM) had lower potency than 1.
Similarly, hydrogen-bond donating groups at the 4-posi-
tion such as 4-amino 2d d (IC50 0.7 µM), 4-hydroxy 2h h
(IC50 3.5 µM), or 4-thiol 2ii (IC50 >50 µM) all dramati-
cally reduced potency relative to 1. In this series,
potency decreased significantly as the acidity of the
substituent increased (Table 1).
Analogues containing polar and strongly electron-
withdrawing groups, such as 2-nitro as in 2k k (IC50 0.4
µM) or 4-nitro as in 2ll (IC50 0.5 µM), also had dramati-
cally reduced potency relative to 1 (Table 1). However,
the negative effect of a 2-nitro substituent could be
partially overcome by adding a 3-fluoro group as in 2jj
(IC50 0.1 µM). This contribution by the 3-fluoro group
in combination with a 2-nitro moiety is unexpected given
the relative lack of potency displayed by the 3-fluoro
substituent alone as in 2x (IC50 0.3 µM). Replacing the
3-phenoxy group with basic heteroaryl moieties such as
the 3-pyridyl analogue 3b (IC50 1.3 µM) reduced potency
relative to 1 by nearly 10-fold, but an even more
dramatic effect was observed for the 2-pyridyl isomer
3a (IC50 >100 µM) which displayed a >500-fold potency
reduction relative to 1 (Table 2). The contrast in activity
between 1 and 3a is particularly striking and confirms
the sensitivity within the CETP binding site for basic
groups. These results are not surprising given the highly
hydrophobic environment expected within the CETP
CE-binding site. Since CETP recognizes only natural
substrates containing weak hydrogen bond acceptors
such as present in the TG or CE substrates, the paucity
of hydrogen bond interactions likely present at that site
should disfavor substituents containing strong hydrogen
bond acceptors or donors.
Whereas the addition of single halogen substituents
such as 2-chloro 2y (IC50 0.3 µM), 4-chloro 2z (IC50 0.3
µM), or 3-fluoro 2x (IC50 0.3 µM) generally reduced
potency relative to 1, the smaller 4-fluoro analogue 2c
(IC50 0.03 µM) had nearly 5-fold better potency than 1.
Interestingly, a dihalogenated analogue incorporating
2,3-dichloro groups 2d (IC50 0.03 µM) actually exhibited
nearly 5-fold higher potency than 1 (Table 1). Compound
2d exhibited improved activity than either the corre-
sponding 3,4-dichloro analogue 2k (IC50 0.08 µM) or the
2,3-difluoro analogue 2o (IC50 0.1 µM). Even more
surprising was the observation that the combination of
a 4-chloro and 3-ethyl substituent as in 2e (IC50 0.03
µM) displayed greater potency than 1 as well as higher
potency than the single 3-ethyl group alone as in 2f (IC50

Inhibitor of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2157
Ta ble 3. In Vitro Inhibition of Chiral R-Enantiomers of Phenoxy-Substituted
N-[3-(1,1,2,2-Tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-trifluoro-3-amino-2-propanols Using Recombinant Human CETP in
Buffer or in Human Seruma
compound
R1
R3
IC50 (nM) in bufferb
IC50 (nM) in human serumb
1a
4a
H
3-(1,1,2,2-tetrafluoroethoxy)
3-(1,1,2,2-tetrafluoroethoxy)
16 ( 4
3.0 ( 1.3c
0.77 ( 0.08d
1.2 ( 0.2
4.0 ( 1.2
8.1 ( 2.7
12 ( 4
640 ( 140
59 ( 5
4-chloro-3-ethyl
4b
4c
4d
4e
4f
4g
4h
4i
3-ethyl
3-trifluoromethoxy
4-methyl
3-(1,1,2,2-tetrafluoroethoxy
3-(1,1,2,2-tetrafluoroethoxy)
3-(1,1,2,2-tetrafluoroethoxy)
3-(1,1,2,2-tetrafluoroethoxy)
3-trifluoromethoxy
3-pentafluoroethyl
2-fluoro-5-trifluoromethyl
2-fluoro-4-trifluoromethyl
72 ( 16
190 ( 20
620 ( 60
110 ( 30
790 ( 130
440 ( 120
770 ( 270
590 ( 140
3-isopropyl
4-chloro-3-ethyl
4-chloro-3-ethyl
4-chloro-3-ethyl
4-chloro-3-ethyl
35 ( 14
45 ( 15
49 ( 17
40 ( 11
a
b
d
Reference 27. Data represents the mean ( SEM (n ) 3-5). c Standard buffer conditions. Assayed with lower [CETP] (<1 nM) and
18 h assay time.
Replacement of the 3-phenoxy group in 1 with either
a simple aliphatic isopropyl ether as in 3h (IC50 0.3 µM),
and cycloalkyl ether moieties such as cyclopentyl 3i (IC50
0.4 µM) or cyclohexyl 3j (IC50 2.6 µM) all reduced
potency relative to 1, while the cyclohexylmethyl ether
3e (IC50 0.2 µM) and benzyl ether 3f (IC50 0.2 µM) had
activity comparable to 1 (Table 2). The substituted
benzyl ethers such as 3c (IC50 0.06 µM) and 3d (IC50
0.09 µM) showed somewhat greater potency than 1 in
the buffer assay, but this increased activity failed to
translate to the serum assay (Table 2). Interestingly,
the same spatial preference for 3-trifluoromethoxy-
substituted ring systems was observed for the benzylic
ethers as that described earlier for the corresponding
meta-substituted aryl ethers. A 5-fold preferential in-
teraction was observed for the 3-trifluoromethoxybenzyl
ether 3c (IC50 0.06 µM) versus its 4-trifluoromethoxy
isomer 3g (IC50 0.3 µM).
For the most part, compounds that showed signifi-
cantly better potency than 1 in the buffer assay also
tended to exhibit qualitatively better potency in the
presence of human serum (Tables 1 and 2), but the
quantitative effects were difficult to predict. In some
cases the correlation in improved activity between buffer
and serum was nearly quantitative. For example, the
4-chloro-3-ethylphenoxy analogue 2e exhibited 5-fold
better potency than 1 in buffer and 7-fold better potency
than 1 serum. On the other hand, the 3-ethylphenoxy
analogue 2f displayed 2-fold better potency than 1 in
buffer, but 6-fold greater potency than 1 in serum.
Similarly, the 2,3-dichlorophenoxy analogue 2d exhib-
ited 5-fold better potency than 1 in buffer and 10-fold
better potency than 1 in serum. In contrast, the 3-iso-
propylphenoxy compound 2a was 7-fold more potent
than 1 in buffer, but only 3-fold more potent in serum.
Similar reduced relative activity in serum versus buffer
was also observed for the 3-trifluoromethoxy analogue
2c, the 4-fluorophenoxy analogue 2b and the 4-meth-
ylphenoxy analogue 2q.
trations in serum. Previous studies26 have shown that
the chirally pure R-enantiomers in this series produced
an unexpected potency improvement of nearly 10-fold.
This led us to prepare and evaluate the chiral R-
enantiomers of a limited subset of the better compounds
in Table 1 and compare their efficacy versus R-enanti-
omer 1a (IC50 buffer 16 nM, serum IC50 650 nM). The
resulting chiral compounds 4a -e all exhibited better
potency than 1a (IC50 1-12 nM) in the buffer assay
(Table 3). These compounds displayed IC50 values in the
low nM range, under conditions where the CETP protein
concentration typically was about 8 nM, effectively
titrating the protein under these assay conditions.27
Modification of the buffered assay conditions by extend-
ing the assay time to 18 h permitted the use of lower
protein concentrations, below 1 nM. Under these ex-
tended conditions, the potency of the 4-chloro-3-eth-
ylphenoxy compound 4a was improved from an IC50 of
3.0 nM to 0.77 nM (Table 3, Figure 1A). The chiral
compounds 4a -e thus represent some of the most
potent inhibitors of CETP reported to date.
In the presence of serum, the quantitative improve-
ment of activity observed in buffer for 4a -e over 1a was
again variable (Table 3). For example, the 4-methylphe-
noxy analogue 4d was more potent than 1a in buffer,
but the activity of 4d in serum did not improve relative
to 1a . In contrast, the 3-ethylphenoxy analogue 4b was
16-fold more active than 1a in buffer and about 9-fold
more active than 1a in serum. The most potent com-
pound in serum, 4a (Table 3, Figure 1C) (although
statistically the same potency as 4b), contained the
4-chloro-3-ethylphenoxy substituent. Compound 4a (IC50
buffer 0.77 nM, IC50 serum 59 nM) was 20-fold more
potent than 1a in buffer and 10-fold more potent than
1a in serum. Similar excellent potency was also ob-
served for 4a in serum from both hamster (hamster
serum IC50 73 nM) and rabbit (rabbit serum IC50 80
nM). The total CE concentration in the buffer assay
estimated from the total CE present in LDL plus HDL
was approximately 100 µM. Consequently, the concen-
tration of 4a needed to inhibit CE transfer by 50% (0.77
nM) was about 125 000-fold lower than the concentra-
tion of CE, or 0.0008 mol % inhibitor relative to CE.
The desire to identify compounds for evaluation in
pharmacological models led us to focus on those ana-
logues 2a -f that had the potential to inhibit CETP
activity preferentially at low or sub-micromolar concen-

2158 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11
Reinhard et al.
F igu r e 2. Time dependence of inhibition by 4a . Purified
CETP was incubated in the presence of the indicated concen-
trations of compound 4a for 15 h prior to the measurement of
[3H]CE transferred in the reconstituted HDL/LDL assay
described in Figure 1A. The amount of CE transferred during
the HDL/LDL assay was compared with similar samples that
did not undergo the 15 h incubation. The amount of CE
transferred during the incubations was compared with control
samples without added inhibitor.
cantly reduced the potency relative to 4a , particularly
in serum. The amplitude of this reduction in activity
was similar to that observed previously when the
3-trifluoromethoxy group was introduced into analogues
of 1.26 Likewise, removing the ether linkage at the
benzylic 3-substituent as in the 3-pentafluoroethyl
analogue 4g also reduced activity by approximately 10-
fold relative to 4a . The introduction of m- and p-
trifluoromethyl substituents in combination with an
o-fluorine as in respectively 4h and 4i also significantly
reduced the activity in both buffer and serum relative
to 4a . Thus, as observed previously in the SAR of the
series developed from 1,26,33 the 3-(1,1,2,2-tetrafluoro-
ethoxy)benzyl moiety also appears to be the optimum
benzylic substituent in this chiral 4a series.
Bioch em ica l Ch a r a cter iza tion of 4a . On the basis
of its excellent activity in serum, compound 4a was
selected as a prototype of this series for further bio-
chemical and pharmacological characterization using
methods previously reported for 1 and 1a .27 The results
of these efforts demonstrate that like 1a , compound 4a
is a potent reversible inhibitor of CETP-mediated CE
and TG transfer (Figures 1A, 1B, and 1C), and there is
no additional time-dependent effect on the inhibitory
activity (Figure 2). The plots of activity versus inhibitor
4a concentrations are virtually superimposable in the
presence or absence of preincubation. These results for
1a and 4a are consistent with a reversible mode of
action and stand in sharp contrast to the recently
reported covalent modifiers of CETP.15,34 Like 1a , the
CETP inhibitory activity of 4a is not only specific, but
is also highly selective since 4a does not block phos-
pholipid transfer protein (PLTP, IC50 > 100 µM) or
lecithin cholesterol acyl transferase (LCAT, IC50 > 100
µM) at concentrations more than 100 000-fold higher
than its IC50 for CETP.
F igu r e 1. Inhibition of CETP-mediated neutral lipid transfer
by compound 4a in buffer. (A) Inhibition of [3H]CE transfer
in the reconstituted HDL/LDL assay, when [CETP] ) 8 nM
(9) and < 1 nM (b). The amount of CE transferred during the
incubation was compared with control samples without added
inhibitor. The assay in which [CETP] ) 8 nM was incubated
for 2 h, while the assay in which [CETP] < 1 nM required an
incubation of 16 h. All samples contained donor HDL particles
labeled with [3H]CE, acceptor LDL particles, and CETP. (B)
Inhibition of [3H]TG transfer in the reconstituted HDL/LDL
assay with purified CETP. The experiment was performed as
in panel A, except that [3H]TG-HDL was used. (C) Inhibition
of CETP-mediated transfer of [3H]CE from HDL to LDL in
human serum. [3H]CE-HDL was added to plasma at a final
concentration of 25 µg/mL cholesterol. The indicated concen-
trations of inhibitor were added to plasma containing [3H]CE-
HDL and incubated for 4 h at 37 °C. The CETP plasma
transfer assay was used to measure the CETP-mediated
transfer of [3H]CE from HDL to LDL.
Thus, CETP has a highly specific ability to recognize
and interact with 4a in the presence of relatively high
CE concentrations.
Having identified the 4-chloro-3-ethylphenoxy moiety
as an optimized aniline substituent in 4a , we briefly
investigated the modification of the 3-(1,1,2,2-tetrafluo-
roethoxy)benzyl group to give analogues 4f-i to broaden
the SAR of this series. Shortening the benzylic sub-
stituent to a 3-trifluoromethoxy group as in 4f signifi-
Like 1a , 4a associates with both LDL and HDL, but
does not effect the overall structural integrity of these
lipoprotein particles (Figure 3). At concentrations up to
1000-fold higher than its CETP serum IC50, 4a had no
effect on the overall integrity of either LDL or HDL.
Competition experiments using size-exclusion chroma-

Inhibitor of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2159
F igu r e 3. Effects of 4a on lipoprotein integrity. Compound 4a was incubated with purified lipoproteins at concentrations up to
1000× its IC50 (as determined by in vitro assay) for 2 h at 37 °C prior to subjecting the mixture to buffered agarose gel
electrophoresis. Cholesteryl sulfate (Ch. Sulf.), a compound previously shown to alter LDL and HDL structures, was included as
a positive control.27 The gel was fixed to film and stained to visualize the migration of lipoproteins. Lane 1, HDL + DMSO (control);
lane 2, HDL + cholesteryl sulfate (100 µM); lane 3, HDL + 4a (800 nM); lane 4, HDL + 4a (80 nM); lane 5, HDL + 4a (8 nM);
lane 6, LDL + DMSO (control); lane 7, LDL + cholesteryl sulfate (100 µM); lane 8, LDL + 4a (800 nM); lane 9, LDL + 4a (80 nM);
lane 10, LDL + 4a (8 nM).
a 30 mg/kg dose where the average Cmax was >3 µM or
60-fold above the human serum IC50, and at the 24 h
level, the average Cmax was twice the human serum IC50.
In these two species there was an apparent increase in
terminal plasma t1/2 after oral dosing, as compared to
the â phase plasma t1/2 determined from iv dosing. This
suggests that 4a is absorbed sufficiently slowly over the
24 h of the experiment to yield a plasma concentration
greater than would be predicted from the iv dosing
kinetics. This slow absorption process would support
maintenance of plasma levels in excess of the efficacy
target IC50 with only qd dosing.
P h a r m a cology of 4a . Using a single oral dose of 30
F igu r e 4. Inhibition of cholesteryl ester binding to CETP by
4a . [3H]CE HDL was incubated alone, with 60 µg of CETP, or
with 60 µg of CETP and 100 µM of 4a for 2 h at 37 °C. The
samples were applied to a Superose 12 size-exclusion column
and the radioactivity in each fraction measured by liquid
scintillation spectrometry. The elution of CETP, determined
by ELISA, was in fractions 18-22. The presence of radiolabel
in the CETP fractions indicates the association of [3H]CE with
CETP.
mg/kg, 4a inhibited 38% of the CETP-mediated transfer
3
of H-CE-HDL to LDL after 30 min in human-CETP
transgenic B57/Bl mice (h-CETP mice) (n ) 6). Similarly
after a single oral dose of 30 mg/kg, 4a inhibited the
CETP-mediated transfer of 3H-CE-HDL to LDL after 4
h in hamsters (n ) 6) by about the same amount (Figure
5). Thus, 4a modulates CETP activity ex vivo to about
the same extent as observed previously for 1 and 1a ,26
and the 10-fold improvement in potency of 4a over 1a
in the human serum assay does not translate into
improved activity ex vivo for either hCETP mice or
hamsters.
tography27 (Figure 4) demonstrated that 4a , like 1a ,
completely blocked the binding of [3H]CE to purified
recombinant human CETP. These results are again
consistent with a reversible and competitive biochemical
mode of action for 4a .
Multiple oral dosingof 4a at 30 mg/kg qd for 5 days
in hCETP mice (n ) 6) produced a statistically signifi-
cant 12% elevation of HDL, a 12% reduction in LDL,
and a 22% reduction in VLDL. Plasma levels taken 4 h
after the final oral dose were about 100-fold above the
human serum IC50. Multiple oral qd dosing of 4a at 3
and 30 mg/kg for 5 days in hamsters (n ) 6) produced
a small elevation of HDL (6.2% and 5.4%, respectively),
along with no significant change in LDL or VLDL. Thus,
the efficacy of 4a for raising HDLc and lowering LDLc
P h a r m a cok in etic Ch a r a cter iza tion of 4a . Phar-
macokinetic studies of 4a were conducted in the C57/
Bl mouse and Syrian golden hamster (Table 4). A single
oral dose in the hamster (n ) 6) at 30 mg/kg gave an
average Cmax at 60 min of >1 µM or 15-fold above the
in vitro hamster serum IC50 for CETP inhibition.
Plasma levels at 24 h in hamster approximated the IC50.
In the mouse (n ) 6), similar results were obtained with
Ta ble 4. Pharmacokinetics Data for 4a in Mouse and Hamstera
species
% BA
t1/2 (R) iv h
t1/2 (â) iv h
t1/2 obsd hours
AUC/dose iv µg‚h/mL‚kg
Cl mL/h/kg
Vss mL/kg
mouse (n ) 6)
hamster (n ) 6)
22.0b
10.0b
0.042
0.18
0.51
4.4
16.0
5.1
0.382
19.7
7842
210
1957
480
a
After iv or oral dose of 30 mg/kg in both species. Area under the curve (AUC) calculations were performed using the linear trapezoidal
rule. Bioavailability (BA) was calculated as the ratio of dose-normalized oral to iv AUC’s for the same time frame. The half-life (t1/2) is the
amount of time to eliminate half the concentration of compound from the plasma and is given for the initial (R) and final (â) elimination
phases from the iv dose and also from the elimination phase determined for the oral dose. Clearance (Cl) is the rate at which a given
amount of plasma is totally cleared of unbound compound. Volume of distribution (Vss) is an approximation of the volume that the compound
b
would occupy at steady state. Oral dosing vehicle EtOH/0.5% methylcellulose.

2160 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11
Reinhard et al.
mined with HPLC using a Chiralpak AD 10 µ analytical
column. Typically, a mobile phase of 10%/90% 2-propanol/
heptane, a flow rate of 1.0 mL/min, and detection at 250 nm
provided the optimum chromatography conditions for separa-
tion of the individual enantiomers. For each chirally pure
product, the achiral mixture was used as a standard to ensure
complete separation and detection of each enantiomer. Optical
rotations of individual enantiomers were obtained on a Perkin-
Elmer 241 polarimeter using a 1.0 mL microcell and CH3OH
as solvent.
3-Br om o-N-[3-(1,1,2,2-t et r a flu or oet h oxy)b en zyl]a n i-
lin e (7). To a solution of 3-(1,1,2,2-tetrafluoroethoxy)benzal-
dehyde (2.00 g, 9.0 mmol) in 1,2-dichloroethane (30 mL) were
added 3-bromoaniline (0.98 mL, 9.0 mmol), NaB(OAc)3H (2.48
g, 11.7 mmol), and acetic acid (0.57 mL, 10 mmol). The cloudy
mixture was stirred at room temperature for 1 h. The reaction
mixture was poured into water and extracted with dichlo-
romethane. The organic layer was washed with saturated
NaHCO3 and brine, dried over anhyd MgSO4, and evaporated
to yield 7 (3.27 g, 96%) as a brown oil which was used without
further purification. 1H NMR (300 MHz, CDCl3) δ 7.49 (t, 1H),
7.25 (m, 2H), 7.11 (m, 2H), 6.45 (t 1H), 6.56 (m, 2H), 5.90 (tt,
1H), 4.34 (s, 2H). MS m/z 377 [M+].
F igu r e 5. Single dose modulation of CETP activity by 4a in
hamsters and transgenic human-CETP mice as measured ex
vivo. [3H]CE-HDL was added to hamster or transgenic human-
CETP plasma at a final concentration of 25 µg/mL cholesterol
and incubated for 4 h at 37 °C. The ex vivo CETP plasma
transfer assay was used to measure the CETP-mediated
transfer of [3H]CE from HDL to LDL.
3-{(3-Br om op h en yl)[3-(1,1,2,2-tetr a flu or oeth oxy)ben -
zyl]a m in o}-1,1,1-t r iflu or op r op a n -2-ol (8). To a dichlo-
romethane (9 mL) solution of 7 (3.27 g, 8.65 mmol) were added
1,1,1-trifluoro-2,3-epoxypropane (0.968 mL, 11.3 mmol) and
Yb(OTf)3 (0.536 g, 0.86 mmol). The cloudy mixture was stirred
at room temperature for 24 h, then diluted with diethyl ether.
The organic layer was washed with water and brine, dried over
anhyd MgSO4, and evaporated to yield 4.20 g (99%) of the title
compound as a pale brown oil which can be used without
further purification. The formation of the desired product was
confirmed by the presence of the alcohol peak (δ 1.5, d) in the
1H NMR spectrum (C6D6). An analytical sample was purified
by silica gel chromatography eluting with 20% ethyl acetate
in hexane to give 8 as a yellow oil. 1H NMR (300 MHz, CDCl3)
δ 7.36 (t, 1H), 7.09 (m, 3H), 7.06 (s, 1H), 6.92 (m, 2H), 6.66
(dd, 1H), 5.92 (tt, 1H), 4.69 (s, 2H), 4.36 (m, 1H), 3.88 (dd,
1H), 3.55-3.63 (m, 1H). FABMS m/z 490 [M + H]+.
N-(3-Br om op h en yl)-N-[2-[[(1,1-d im eth yleth yl)d im eth -
ylsilyl]oxy]-3,3,3-tr iflu or op r op yl]-3-(1,1,2,2-tetr a flu or o-
et h oxy)b en zen em et h a n a m in e (9). To a dichloromethane
(10 mL) solution of 8 (4.20 g, 8.57 mmol) were added tert-
butyldimethylsilyl trifluoromethanesulfonate (3.0 mL, 13.1
mmol) and triethylamine (2.40 mL, 17.3 mmol). The resulting
solution was stirred at room temperature for 4 h. The reaction
mixture was diluted with dichloromethane and washed se-
quentially with saturated NaHCO3 and brine. The organic
layer was dried over anhyd MgSO4 and evaporated to an oil.
Purification by flash chromatography on silica eluting with
2.5% ethyl acetate in hexane gave 9 (3.0 g, 58%) as a colorless
oil. 1H NMR (300 MHz, CDCl3) δ 6.97 (t, 1H), 6.89 (m, 2H),
6.81 (m, 2H), 6.68 (t, 1H), 6.61 (d, 1H), 6.33 (dd, 1H), 5.10 (tt,
1H), 4.12 (q, 1H), 4.11 (s, 2H), 3.38 (m, 2H), 0.88 (s, 9H), -0.06
(s, 3H), -0.19 (s, 3H). 19F NMR (CDCl3) δ -78.5 (d, 3F), -88.2
(m, 2F), -137.2 (dt, 2F). HRMS calcd for C24H30BrF7NO2Si
604.1112 [M + H]+, found 604.1128.
occurs at similar levels to that observed previously for
1,26 and the 100-fold improvement in potency of 4a over
1 in the human serum assay does not translate into
significantly improved activity in vivo for either hCETP
mice or hamsters. This may be partially due to the
known tight affinity that members of this series have
exhibited for other plasma proteins, particularly serum
albumin,26 or due to other factors present in the animal
serum. The strong association of 4a with human serum
albumin (Kd e 0.01 µM) was confirmed independently
using 19F NMR methods (data not shown). Thus, the
unfavorable interaction of 4a with other plasma proteins
may limit their overall in vivo efficacy.
In conclusion, we have discovered additional examples
of chiral N,N-disubstituted trifluoro-3-amino-2-pro-
panols as a new simple class of potent acyclic CETP
inhibitors. Several analogues in this series exhibited low
nanomolar potency and represent the most potent
acyclic CETP inhibitors reported to date. However,
further optimization is needed to improve the relatively
poor oral exposure and in vivo efficacy of this series.
Exp er im en ta l Section
Gen er a l Meth od s. All reagents were purchased from
commercially available sources and used without further
purification. Column chromatography was carried out on flash
silica gel (Merck 230-400 mesh). Reverse phase chromatog-
raphy was carried out on a Gilson automated chromatography
system (254 nM) using a YMC ODS-A column (50 × 20 mm,
5um, 120A, 50-90% acetonitrile in water (spiked with 0.05%
trifluoroacetic acid)). All isolated final purified products were
routinely analyzed for purity by reverse-phase HPLC and met
a minimum of 90% purity as determined by reverse-phase
HPLC monitoring with UV detection (220, 254, and 285 nM).
1H NMR, 13C NMR, and 19F NMR spectra were collected on a
Varian VXR-400 or VXR-300 spectrometer. The samples were
dissolved in CDCl3, C6D6, or DMSO-d6 100 atom % (MSD
Isotopes, St. Louis, MO) at a concentration of 0.3-0.7 wt %
and placed in 5 mm NMR tubes (Wilmad Glass, Buena, NJ ).
Mass spectrometry was performed using a SCIEX (Thornhill,
Ontario, Canada) API-III mass spectrometer utilizing an
electrospray interface. High-resolution mass spectra were
obtained by electron impact on a MAT 90 instrument using
Electro Calibration with PEG and samples dissolved in H2O/
CH3CN (50:50). UV absorption spectra were taken on a
Hewlett-Packard 8451A diode array spectrophotometer. The
chiral purity of individual enantiomeric products was deter-
Gen er a l P r oced u r e for Ar yl Eth er Cou p lin gs w ith 9.
3-{[3-(4-Ch lor o-3-et h yl-p h en oxy)p h en yl][3-(1,1,2,2-t et -
r a flu or oet h oxy)ben zyl]a m in o}-1,1,1-t r iflu or op r op a n -2-
ol (2e). A solution of 9 (75 mg, 0.124 mmol), cesium carbonate
(81 mg, 0.248 mmol), 4-chloro-3-ethylphenol (44 mg, 0.358
mmol), copper triflate benzene complex (6.24 mg, 10 mol %),
1-naphthoic acid (43 mg, 0.248 mmol) in 2:1 toluene, and
dimethylacetamide (3.0 mL) was heated at 105 °C for 48 h.
The reaction mixture was filtered through Celite, and the
solvent was evaporated. The residue was purified by reverse
phase chromatography eluting with 50-90% acetonitrile in
1
water to afford 2e (16.2 mg, 23%) as an orange oil. H NMR
(300 MHz, CDCl3) δ 7.0-7.34 (m, 5H), 6.87 (d, 1H), 6.69 (dd,
1H), 6.48 (dd, 1H), 6.32-6.40 (m, 2H), 5.84 (tt, 1H), 4.63 (s,
2H), 3.87 (dd, 1H), 4.28-4.39 (m, 1H), 3.50-3.61 (m, 1H), 2.69
(q, 2H), 1.18 (t, 3H). 19F NMR (CDCl3) δ -79.2 (d, 3F), -88.6

Inhibitor of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2161
(m, 2F), -137.2 (dt, 2F). HRMS calcd for C26H24ClF7NO3
566.1332 [M + H]+, found 566.1332.
3-{[3-(4-Flu or o-3-m eth ylph en oxy)ph en yl][3-(1,1,2,2-tet-
r a flu or oet h oxy)ben zyl]a m in o}-1,1,1-t r iflu or op r op a n -2-
ol (2j). Tan oil, yield 10.1 mg (15%). 1H NMR (300 MHz,
CDCl3) δ 7.31 (t, 1H), 7.17-7.09 (m, 2H), 7.00 (bs, 1H), 6.91
(t, 1H), 6.81-6.68 (m, 2H), 6.49 (dd, 1H), 6.39-6.34 (m, 2H),
5.88 (tt, 1H), 4.63 (s, 2H), 4.34 (m, 1H), 3.84 (dd, 1H), 3.61-
3.52 (m, 1H), 2.22 (s, 3H). 19F NMR (CDCl3) δ -79.2 (d, 3F),
-88.5 (m, 2F), -120.4 (m, 1F), -137.2 (dt, 2F). HRMS calcd
for C25H22F8NO3 536.1471 [M + H]+, found 536.1480.
3-{[3-(3-Isop r op ylp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu o-
r oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2a ).
Tan oil, yield 7.0 mg (10%). 1H NMR (300 MHz, CDCl3) δ 7.32
(t, 1H), 7.20-7.08 (m, 4H), 7.02 (bs, 1H), 6.97 (d, 1H), 6.88 (t,
1H), 6.74 (dd, 1H), 6.53 (dd, 1H), 6.46-6.44 (m, 2H), 5.88 (tt,
1H), 4.64 (s, 2H), 4.34 (m, 1H), 3.84 (dd, 1H), 3.61-3.53 (m, 1
H), 2.86 (m, 1H), 1.21 (d, 6H). 19F NMR (CDCl3) δ -79.2 (d,
3F), -88.4 (m, 2F), -137.2 (dt, 2F). HRMS calcd for C27H27F7-
NO3 546.1879 [M + H]+, found 546.1878.
3-{[3-(3-Tr iflu or om eth oxyp h en oxy)p h en yl][3-(1,1,2,2-
tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (2b). Tan oil, yield 9.2 mg (12%). 1H NMR (300 MHz,
CDCl3) δ 7.32 (t, 1H), 7.27 (t, 1H), 7.20 (t, 1H), 7.11 (d, 2H),
7.01 (bs, 1H), 6.92 (dd, 1H), 6.86-6.81 (m, 2H), 6.56 (dd, 1H),
6.45 (dd, 1H), 6.39 (t, 1H), 5.87 (tt, 1H), 4.65 (s, 2H), 4.33 (m,
1H), 3.86 (dd, 1H), 3.62-3.54 (m, 1H).19F NMR (CDCl3) δ
-58.3 (s, 3F), -79.2 (d, 3F), -88.6 (m, 2F), -137.2 (dt, 2F).
HRMS calcd for C25H20F10NO4 588.1232 [M + H]+, found
588.1236.
3-{[3-(4-F lu or op h en oxy)p h en yl][3-(1,1,2,2-tetr a flu or o-
eth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2c). Tan
oil, yield 1.19 g (64%).1H NMR (300 MHz, CDCl3) δ 7.35 (t,
1H), 7.21-7.10 (m 3H), 7.15-6.89 (m, 5H), 6.49 (dd, 1H), 6.38
(dd, 1H), 6.33 (m, 1H), 5.92 (tt, 1H), 4.67 (ABq, 2H), 4.37 (m,
1H), 3.91 (dd, 1H), 3.59 (dd, 1H), 2.48 (d, 1H). 19F NMR (300
MHz, CDCl3) δ -79.2 (d, 3F), -88.5 (m, 2F), -120.3 (m, 1F),
-137.2 (dt, 2F). HRMS calcd for C24H20F8NO3 522.1315 [M +
H]+, found 522.1297.
3-{[3-(3,4-Dich lor op h en oxy)p h en yl][3-(1,1,2,2-tetr a flu -
or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2k ).
1
Tan oil, yield 6.0 mg (8%). H NMR (300 MHz, CDCl3) δ 7.32
(t, 2H), 7.19 (t, 1H), 7.08 (t, 2H), 7.04-7.01 (m, 3H), 6.76 (dd,
2H), 6.52 (dd, 1H), 5.88 (tt, 1 H), 4.65 (s, 2H), 4.33 (m, 1H),
3.88 (dd, 1H), 3.62-3.54 (m, 1H). 19F NMR (CDCl3) δ -79.4
(d, 3F), -88.7 (m, 2F), -137.2 (dt, 2F). HRMS calcd for C24H19
-
Cl2F7NO3 572.0630 [M + H]+, found 572.0630.
3-{[3-(3-Eth yl-5-m eth ylp h en oxy)p h en yl][3-(1,1,2,2-tet-
r a flu or oet h oxy)ben zyl]a m in o}-1,1,1-t r iflu or op r op a n -2-
ol (2l). Tan oil, yield 2.5 mg (4%). 1H NMR (300 MHz, CDCl3)
δ 7.10 (m, 1H), 7.02-6.99 (m, 2H), 6.85 (m, 3H), 6.81 (m, 3H),
6.67 (s, 1H), 5.90 (s, 1H), 5.88 (tt, 1H), 4.64 (s, 2H), 4.32 (m,
1H), 3.78 (bs, 1H), 3.55-3.48 (m, 1H), 3.08 (m, 1H), 2.73 (q,
2H), 2.27 (s, 3H), 1.23 (t, 3H). HRMS calcd for C27H27F7NO3
546.1879 [M + H]+, found 546.1899.
3-{[3-(3-Meth ylp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu or o-
eth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2m ). Tan
1
oil, yield 39.8 mg (19%). H NMR (300 MHz, CDCl3) δ 7.44 (t,
1H), 7.42-7.22 (m, 5H), 7.09 (t, J ) 2 Hz, 2H), 6.98 (bs, 1H),
6.61 (dd, 1H), 6.38 (dd, 1H), 6.29 (t, 1H), 5.85 (tt, 1H), 4.66 (q,
2H), 4.33 (m, 1H), 3.83 (dd, 1H), 3.70-3.58 (m, 1H), 2.70 (s, 3
H). HRMS calcd for C25H23F7NO3 517.1488 [M + H]+, found
517.1493.
3-{[3-(2,3-Dich lor op h en oxy)p h en yl][3-(1,1,2,2-tetr a flu -
or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2d ).
1
Tan oil, yield 3.1 mg (4%). H NMR (300 MHz, CDCl3) δ 7.24
(t, 1H), 7.18-7.14 (m, 2H), 7.10-7.01 (m, 2H), 6.85 (bs, 1H),
6.77 (t, 1H), 6.70-6.65 (m, 2 H), 6.34 (d, 1H), 5.98 (d, 1H),
5.88 (tt, 1H), 4.64 (s, 2H), 4.35 (m, 1H), 3.88 (dd, 1H), 3.59-
3.50 (m, 1H). 19F NMR (CDCl3) d -79.4 (d, 3F), -88.7 (m, 2F),
-137.2 (dt, 2F). HRMS calcd for C24H19Cl2F7NO3 572.0630 [M
+ H]+, found 572.0653.
3-{[3-(5,6,7,8-Tetr a h yd r on a p h th a len -2-yloxy)p h en yl]-
[3-(1,1,2,2-tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu o-
r op r op a n -2-ol (2n ). Tan oil, yield 13.8 mg (20%). 1H NMR
(300 MHz, CDCl3) δ 7.31 (t, 1H), 7.18-7.06 (t, 1H), 7.02 (bs,
1H), 6.98-6.95 (m, 1H), 6.72-6.68 (m, 2 H), 6.44 (dd, 1H),
6.38-6.36 (m, 2H), 5.88 (tt, 1H), 4.63 (s, 2H), 4.35 (m, 1H),
3.85 (dd, 1H), 3.56-3.49 (m, 1H), 2.72-2.69 (m, 4H), 1.78-
1.76 (m, 4H). HRMS calcd for C28H27F7NO3 558.1879 [M + H]+,
found 558.1881.
3-{[3-(3-E t h ylp h en oxy)p h en yl][3-(1,1,2,2-t et r a flu or o-
eth oxy)ben zyl]am in o}-1,1,1-tr i-flu or opr opan -2-ol (2f). Tan
1
oil, yield 7.7 mg (12%). H NMR (300 MHz, CDCl3) δ 7.31 (t,
1 H), 7.22-7.07 (m, 4H), 7.022 (bs, 1H), 6.96-6.87 (m, 1H),
6.84 (bs, 1H), 6.76 (dd, 1H), 6.47 (dd, 1H), 6.41-6.39 (m, 2H),
5.88 (tt, 1H), 4.64 (s, 2H), 4.33 (m, 1H), 3.83 (dd, 1H), 3.60-
3.49 (m, 1 H), 2.61 (q, 2H), 1.204 (t, 3H).19F NMR (CDCl3) δ
-79.3 (d, 3F), -88.6 (m, 2F), -137.2 (dt, 2F). HRMS calcd for
3-{[3-(2,3-Diflu or op h en oxy)p h en yl][3-(1,1,2,2-tetr a flu -
or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2o).
Tan oil, yield 1.7 mg (2%). H NMR (300 MHz, CDCl3) δ 7.24
1
(t, 1H), 7.18-7.14 (m, 2H), 7.10-7.01 (m, 2H), 6.85 (bs, 1H),
6.77 (t, 1H), 6.70-6.65 (m, 2 H), 6.34 (d, 1H), 5.98 (d, 1H),
5.88 (tt, 1H), 4.64 (s, 2H), 4.35 (m, 1H), 3.88 (dd, 1H), 3.59-
3.50 (m, 1H). HRMS calcd for C24H19F9NO3 540.1221 [M + H]+,
found 540.1182.
3-{[3-[4-(Tr iflu or om eth yl)p h en oxy]p h en yl][3-(1,1,2,2-
tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (2p ). Tan oil, yield 259 mg (43%).1H NMR (300 MHz,
CDCl3) δ 7.49 (d, 2H), 7.30 (t 1H), 7.20 (t, 1H), 7.07 (m, 2H),
7.00 (s, 1H), 6.96-6.90 (d, 2H), 6.55 (dd, 1H), 6.43 (dd, 1H),
6.34 (t, 1H), 5.87 (tt, 1H), 4.64 (ABq, 2H), 4.33 (m, 1H), 3.88
(dd, 1H), 3.58 (dd, 1H), 2.43 (d, 1H). 19F NMR (300 MHz,
CDCl3) δ -62.2 (s, 3F), -79.2 (d, 3F), -88.6 (m, 2F), -137.2
(dt, 2F). HRMS calcd for C25H20F10NO3 572.1282 [M + H]+,
found 572.1268.
3-{[3-(4-Meth ylp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu or o-
eth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2q). Tan
oil, yield 43.2 mg (20%). 1H NMR (300 MHz, CDCl3) δ 7.34
(m, 2H), 7.19-7.08 (m, 4H), 7.00 (s, 1H), 6.84 (d, 2H), 6.537-
6.40 (m, 3H), 5.87 (tt, 1H), 4.62 (q, 2H), 4.34-4.24 (m, 4H),
3.83 (dd, 1H), 3.59 (m, 1H), 2.32 (s, 3H).19F NMR (CDCl3) δ
-79.3 (d, 3F), -88.6 (m, 2F), -137.2 (dt, 2F). HRMS Calcd
for C25H23F7NO3 518.1566 [M + H]+, found 518.1561.
3-{[3-(4-Ch lor o-3-m et h ylp h en oxy)p h en yl][3-(1,1,2,2-
tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (2r ). Tan oil, yield 29.3 mg (13%). 1H NMR (300 MHz,
CDCl3) δ 7.32 (t, 1H), 7.24-7.06 (m, 4H), 7.01 (bs, 1H), 6.84
(d, 1H), 6.72 (dd, 1H), 6.55 (dd, 1 H), 6.49 (dd, 1H), 6.45 (t,
1H), 5.88 (tt, 1H), 4.64 (s, 2H), 3.85 (dd, 1H), 3.82 (dd, 1H),
C
26H25F7NO3 532.1722 [M + H]+, found 532.1705.
3-{[3-(3,5-Dim eth ylp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu -
or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2g).
Tan oil, yield 6.6 mg (10%). 1H NMR (300 MHz, CDCl3) δ 7.10
(m, 1H), 7.02-6.99 (m, 2H), 6.85 (m, 3H), 6.81 (m, 3H), 6.67
(s, 1H), 5.90 (s, 1H), 5.88 (tt, 1H), 4.64 (s, 2H), 4.32 (m, 1H),
3.78 (bs, 1H), 3.55-3.48 (m, 1H), 3.08 (m, 1H), 2.25 (s, 6H).
19F NMR (CDCl3) δ -79.1 (d, 3F), -88.4 (m, 2F), -137.2 (dt,
2F). HRMS calcd for C26H25F7NO3 532.1722 [M + H]+, found
532.1705.
3-{[3-(3-ter t-Bu tylp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu o-
r oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2h ).
Tan oil, yield 6.8 mg (10%). 1H NMR (300 MHz, CDCl3) δ 7.31
(t, 1 H), 7.24-7.16 (m, 1H), 7.15-7.07 (m, 5), 7.02 (bs, 1H),
6.74 (d, 1H), 6.48-6.37 (m, 3H), 5.88 (tt, 1H), 4.64 (d, 2H),
4.32 (m, 1H), 3.85 (dd, 1H), 3.56-3.48 (m, 1H), 1.28 (s, 9H).
19F NMR (CDCl3) δ -79.2 (d, 3F), -88.5 (m, 2F), -137.2 (dt,
2F). HRMS calcd for C28H28F7NO3 560.2035 [M + H]+, found
560.2055.
3-{[3-(3,4-Dim eth ylp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu -
or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2i).
Tan oil, yield 38.9 mg (18%). 1H NMR (300 MHz, CDCl3) δ
7.32 (t, 1H), 7.19-7.04 (m, 4 H), 7.00 (bs, 1 H), 6.77 (d, 1 H),
6.69 (dd, 1H), 6.55 (dd, 1H), 6.49 (dd, 1H), 6.45 (t, 1H), 5.88
(t, 1H), 4.64 (q, 2H), 4.34 (m, 1H), 3.82 (dd, 1H), 3.64-3.55
(m, 1H), 2.23 (s, 3H), 2.21 (s, 3H). HRMS calcd for C26H25F7-
NO3 531.1644 [M + H]+, found 531.1649.

2162 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11
3.64-3.55 (m, 1H), 2.23 (s, 3H). 19F NMR (CDCl3) δ -79.3 (d,
Reinhard et al.
3-{[3-(4-iso-P r op ylp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu -
or oeth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2bb).
Tan oil, yield 9.2 mg (14%). 1H NMR (300 MHz, CDCl3) δ 7.31
(t, 1H), 7.14 (q, 4H), 7.11 (s, 1H), 7.01 (bs, 1H), 6.88 (d, 2H),
6.48 (dd, 1H), 6.43-6.37 (m, 2H), 5.88 (tt, 1H), 4.63 (s, 2H),
4.33 (m, 1H), 3.84 (dd, 1H), 3.58-3.50 (m, 1H), 2.88 (m, 1H),
1.23 (d, 6H). HRMS calcd for C27H27F7NO3 546.1879 [M + H]+,
found 546.1899.
3-{[3-(4-Tr iflu or om eth oxyp h en oxy)p h en yl][3-(1,1,2,2-
tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (2cc). Tan oil, yield 238 mg (62%).1H NMR (300 MHz,
CDCl3) δ 7.32 (t 1H), 7.32 (t, 1H), 7.20-7.09 (m, 4H), 7.03 (s,
1H), 6.94 (d, 2H), 6.54 (dd, 1H), 6.42 (dd, 1H), 6.36 (t, 1H),
5.90 (tt, 1H), 4.67 (ABq, 2H), 4.36 (m, 1H), 3.90 (dd, 1H), 3.61
(dd, 1H), 2.52 (bs, 1H). 19F NMR (300 MHz, CDCl3) δ -58.7
(s, 3F), -79.2 (d, 3F), -88.6 (m, 2F), -137.3 (dt, 2F). HRMS
calcd for C25H20F10NO4 588.1233 [M + H]+, found 588.1241.
3-{[3-(4-Am in op h en oxy)p h en yl][3-(1,1,2,2-tetr a flu or o-
eth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2d d ).
Tan oil, yield 13.4 mg (40%). 1H NMR (300 MHz, CDCl3) δ
7.42 (t, 1H), 7.36-7.14 (m, 2H), 7.08 (t, 1H), 6.90 (d, 1H), 6.74-
6.64 (m, 2H), 6.57-6.39 (m, 2H), 6.36-6.32 (m, 1H), 6.2 (d,
1H), 5.75 (t, 1H), 4.79 (s, 2H), 4.55-4.43 (m, 1H), 3.97 (dd,
1H), 3.64 (dd, 1H). HRMS calcd for C24H22F7N2O3 519.1519
[M + H]+, found 519.1529.
3F), -88.6 (m, 2F), -137.2 (dt, 2F). HRMS calcd for C25H22
-
ClF7NO3 551.1098 [M + H]+, found 551.1101.
3-({3-[3-(Tr iflu or om eth yl)p h en oxy]p h en yl}[3-(1,1,2,2-
tetr a flu or oeth oxy)ben zyl]a m in o)-1,1,1-tr iflu or op r op a n -
2-ol (2s). Tan oil, yield 4.6 mg (7%). 1H NMR (300 MHz,
CDCl3) δ 7.39 (t, 2H), 7.32 (m, 2H), 7.21 (s, 1H), 7.12-7.09
(m, 4H), 7.01 (bs, 1H), 6.58 (dd, 1 H), 6.48-6.38 (m, 2H), 5.88
(tt, 1H), 4.66 (s, 2H), 4.34 (m, 1H), 3.86 (dd, 1H), 3.63-3.55
(m, 1H). HRMS calcd for C25H20F10NO3 572.1283 [M + H]+,
found 572.1265.
3-{[3-(4-n -P r op ylp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu o-
r oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2t).
1
Tan oil, yield 32.9 mg (36%). H NMR (CDCl3, 400 MHz) 7.32
(t, 1H), 7.19-7.03 (m, 5H), 7.00 (s, 1H), 6.87 (d, 2H), 6.48 (dd,
1H), 6.43-6.33 (m, 2H), 5,87 (tt, 1H), 4.64 (s, 2H), 4.37-4.28
(m, 1H), 3.85 (dd, 1H), 3.60-3.48 (m, 1H), 2.53 (t, 2H), 1.68-
1.54 (m, 2H), 0.92 (t, 3H). HRMS calcd for C27H27F7NO3
545.1801 [M + H]+, found 545.1782.
3-{[3-(3,5-Diflu or op h en oxy)p h en yl][3-(1,1,2,2-tetr a flu -
or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2u ).
1
Tan oil, yield 4.1 mg (6%). H NMR (300 MHz, CDCl3) δ 7.32
(t, 2H), 7.22 (t, 1H), 7.14-7.09 (m, 2H), 7.02 (bs, 1H), 6.61 (dd,
1H), 6.53-6.38 (m, 4H), 5.88 (tt, 1H), 4.66 (s, 2H), 4.32 (m,
1H), 3.86 (dd, 1H), 3.64-3.56 (m, 1H). HRMS calcd for
C
24H19F9NO3 540.1221 [M + H]+, found 540.1217.
3-{[3-(3-Meth oxyp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu o-
r oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2ee).
Tan oil, yield 2.9 mg (5%). H NMR (300 MHz, CDCl3) δ 7.32
(t, 1H), 7.20-7.08 (m, 4H), 7.02 (bs, 1H), 6.97 (d, 1H), 6.88 (t,
1H), 6.74 (dd, 1H), 6.53 (dd, 1H), 6.46-6.44 (m, 2H), 5.88 (tt,
1H), 4.64 (s, 2H), 4.34 (m, 1H), 3.84 (dd, 1H), 3.65 (s, 3H),
3.61-3.53 (m, 1H). HRMS calcd for C25H23F7NO4 533.1437 [M
+ H]+, found 533.1450.
3-{[3-(4-N,N-Dim eth ylam in oph en oxy)ph en yl][3-(1,1,2,2)-
1
tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (2v) Tan oil, yield 1.9 mg, (5%). 1H NMR (300 MHz,
CDCl3) δ 7.32 (t, 1H), 7.03 (t, 3H), 6.85 (m, 4H), 6.66 (d, 1H),
6.35-5.93 (m, 4H), 5.44 (tt, 1H), 4.42 (s, 2H), 4.20 (m, 1H),
3.08 (dd, 1H), 3.00 (s, 6H), 2.90 (m, 1H). HRMS calcd for
C
26H26F7N2O3 547.1831 [M + H]+, found 547.1844.
3-{[3-(4-Ben zylp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu or o-
eth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2ff). Tan
oil, yield 9.3 mg (12%). 1H NMR (300 MHz, CDCl3) δ 7.32-
7.01 (m, 12H), 6.87 (d, 2H), 6.44 (dd, 1H), 6.38 (dd, 1H), 6.34
(t, 1H), 5.87 (tt, 1H), 4.62 (s, 2H), 4.32 (m, 1H), 3.94 (s, 2H),
3.85 (dd, 1H), 3.57-3.48 (m, 1H). 19F NMR (CDCl3) δ -79.1
(d, 3F), -88.3 (m, 2F), -137.2 (dt, 2F)HRMS calcd for C31H27F7-
NO3 594.1879 [M + H]+, found 594.1906.
3-{[3-(1,1′-Bip h en yl-4-yloxy)p h en yl][3-(1,1,2,2-tetr a flu -
or oeth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2gg).
Tan oil, yield 7.2 mg (10%). 1H NMR (300 MHz, CDCl3) δ 7.58-
7.48 (m, 4H), 7.43 (t, 2H), 7.36-7.26 (m, 2H), 7.184 (t, 1H),
7.09 (m, 2H), 7.024-6.99 (m, 3H), 6.55-6.39 (m, 3H), 5.842
(tt, 1H), 4.65 (s, 2H), 4.37-4.33 (m, 1H), 3.88 (dd, 1H), 3.60-
3.52 (m, 1H). HRMS calcd for C30H25F7NO3 580.1722 [M + H]+,
found 580.1741.
3-{[3-(4-iso-P r op yl-3-m eth ylph en oxy)p h en yl][3-(1,1,2,2-
tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (2w ). Tan oil, yield 9.7 mg (14%). 1H NMR (300 MHz,
CDCl3) δ 7.31 (t, 1H), 7.16-7.06 (m, 4H), 7.02 (bs, 1H), 6.77-
6.75 (m, 2H), 6.46-6.35 (m, 3H), 5.88 (tt, 1H), 4.64 (s, 2H),
4.32 (m, 1H), 3.84 (dd, 1H), 3.55-3.48 (m, 1H), 3.08 (m, 1H),
2.27 (s, 3H), 1.20 (d, 6H). 19F NMR (CDCl3) δ -79.1 (d, 3F),
-88.5 (m, 2F), -137.2 (dt, 2F). HRMS calcd for C28H29F7NO3
560.2035 [M + H]+, found 560.2055.
3-{[3-(3-F lu or op h en oxy)p h en yl][3-(1,1,2,2-tetr a flu or o-
eth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2x). Tan
1
oil, yield 3.0 mg (5%). H NMR (300 MHz, CDCl3) δ 7.32 (t, 1
H), 7.21-7.18 (m, 2H), 7.13 (m, 4H), 7.01 (bs, 1H), 6.80-6.56
(m, 3H), 6.49-6.43 (m, 1H), 5.88 (tt, 1H), 4.65 (s, 2H), 4.34
(m, 1H), 3.85 (dd, 1H), 3.64-3.55 (m, 1H). 19F NMR (CDCl3) δ
-79.2 (d, 3F), -88.6 (m, 2F), -120.0 (m 1H) -137.2 (dt, 2F).
HRMS calcd for C24H20F8NO3 522.1315 [M + H]+, found
522.1337.
4-{3-[[3-(1,1,2,2-Tetr a flu or oeth oxy)ben zyl](3,3,3-tr iflu -
or o-2-h yd r oxyp r op yl)-a m in o]p h en oxy}p h en ol (2h h ). Tan
1
oil, yield 82 mg (26%). H NMR (C6D6, 400 MHz) δ 6.92-6.79
3-{[3-(2-Ch lor op h en oxy)p h en yl][3-(1,1,2,2-tetr a flu or o-
eth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2y). Tan
oil, yield 3.7 mg (7%). 1H NMR (300 MHz, CDCl3) δ 7.41 (d,
1H), 7.27 (m, 1H), 7.20-7.03 (m, 4H), 6.88-6.64 (m, 4H), 6.35
(d, 1H), 6.03 (d, 1H), 5.48 (tt, 1H), 4.42 (s, 2H), 4.18 (m, 1H),
3.09 (dd, 1H), 2.94 (m, 1H). HRMS calcd for C24H20ClF7NO4
538.1019 [M + H]+, found 538.1021.
3-{[3-(4-Ch lor op h en oxy)p h en yl][3-(1,1,2,2-tetr a flu or o-
eth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2z). Tan
oil, yield 3.1 mg (6%). 1H NMR (300 MHz, CDCl3) δ 7.32 (t,
1H), 7.22 (d, 2H), 7.19-7.08 (m, 3H), 7.00 (bs, 1H), 6.85 (d,
2H), 6.58 (dd, 1H), 6.44 (dd, 1H), 6.40 (t, J ) 1 Hz, 1H), 5.88
(tt, 1H), 4.64 (s, 2H), 4.35 (m, 1H), 3.86 (dd, 1H), 3.64-3.59
(m, 1H). HRMS calcd for C24H20ClF7NO3 537.0942 [M + H]+,
found 537.0944.
(m, 6H), 6.67 (d, 1H), 6.42-6.38 (m, 4H), 6.17 (d, 1H), 5.10
(tt, 1H), 4.52 (bs, 2H), 4.10 (bs, 1H), 3.44 (d, 1H), 3.18 (q, 1H),
3.09, 3.05 (dd, 1H), 1.96 (d, 1H). HRMS calcd for C24H21F7-
NO4 520.1359 [M + H]+, found 520.1325.
3-{[3-(4-Mer ca p top h en oxy)p h en yl][3-(1,1,2,2-tetr a flu o-
r oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (2ii).
Tan oil, yield 3.6 mg (4%). 1H NMR (300 MHz, CDCl3) δ 7.37-
7.17 (m, 9H), 7.04-6.99 (m, 1H), 6.96-6.82 (m, 2H), 5.88 (tt,
1H), 4.76 (d, 1H), 4.40 (d, 1H), 4.39-4.27 (m, 1H), 3.82-3.65
(m, 2H). 19F NMR (CDCl3) δ -79.4 (d, 3F), -88.7 (m, 2F),
-137.2 (dt, 2F). HRMS calcd for C24H21F7NO3S 536.1130 [M
+ H]+, found 536.1163.
3-{[3-(1,1,2,2-T e t r a flu o r o e t h o x y )b e n z y l]a m i n o }-
p h en ol (11). To a solution of 3-aminophenol (4.91 g, 45.0
mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g,
45.0 mmol) dissolved in 100 mL of 1,2-dichloroethane were
added sodium triacetoxyborohydride (14.28 g 67.5 mmol) and
glacial acetic acid (2.7 mL, 47.3 mmol). The reaction mixture
was stirred for 6 h, water was added, and the mixture was
extracted with dichloromethane. The organics were washed
with saturated aqueous sodium bicarbonate then dried over
anhyd MgSO4. The dried organic layer was evaporated to give
3-{[3-(4-n -P r op oxyp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu -
or oeth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2aa).
1
Tan oil, yield 4.9 mg (7%). H NMR (300 MHz, CDCl3) δ 7.31
(t, 1H), 7.16-7.10 (m, 3H), 7.00 (bs, 1H), 6.86 (q, 4H), 6.48
(dd, 1H), 6.40-6.37 (m, 2H), 5.88 (tt, 1H), 4.62 (s, 2H), 4.33
(m, 1H), 3.89 (t, 2H), 3.84 (dd, 1H), 3.60-3.51 (m, 1H), 1.79
(m, 2H), 1.04 (t, 3H). HRMS calcd for C27H27F7NO4 562.1828
[M + H]+, found 562.1803.

Inhibitor of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2163
11 (11.00 g, 78%) as a dark orange oil, that was used below
without further purification. 1H NMR (300 MHz, CDCl3) δ 7.33
(t, 1H), 7.24-7.27 (m, 2H), 7.11 (dd, 1H), 7.00 (t, 1H), 6.17-
6.22 (m, 2H), 6.08 (t, 1H), 5.88 (tt, 1H), 4.32 (s, 2H). HRMS
calcd for C15H14F4NO2 316.0960 [M + H]+, found 316.0989.
and 3-trifluoromethoxybenzyl bromide (70.0 mg, 0.27 mmol)
in 2.5 mL of acetone was added solid cesium carbonate (100
mg, 0.31 mmol). The reaction mixture was heated to 60 °C for
18 h, then cooled. The reaction mixture was filtered through
Celite, and the solvent was evaporated from the filtrate. The
residue was purified by C18 reverse phase HPLC with mobile
phase acetonitrile/water (1:1 to 9:1) to afford 3c (63.3 mg, 45%)
3-{[3-(1,1,2,2-Tetr a flu or oeth oxy)ben zyl](3,3,3-tr iflu or o-
2-h yd r oxyp r op yl)a m in o}p h en ol (12). A solution of 11 (11.0
g, 34.9 mmol), 3,3,3-trifluoro-1,2-epoxypropane (4.5 mL, 52.4
mmol), and ytterbium trifluoromethanesulfonate (2.2 g, 10 mol
%) in 20 mL of acetonitrile was heated at 50 °C in a sealed
glass tube for 16 h. The reaction mixture was cooled, water
was added, and the reaction mixture was extracted with ether.
The ether layer was washed with saturated aqueous sodium
bicarbonate and brine, then dried over anhyd MgSO4. The
dried organic layer was evaporated to give 12 (8.07 g, 89%) as
1
as an orange oil. H NMR (300 MHz, CDCl3) δ 7.04-7.42 (m,
9H), 6.43-6.55 (m, 3H), 5.84 (tt, 1H), 4.98 (s, 2H), 4.62 (s, 2H),
4.32-4.39 (m, 1H), 3.83 (dd, 1H), 3.61 (dd, 1H). 19F NMR
(CDCl3) δ -58.1 (s, 3F) -79.3 (d, 3F), -88.4 (m, 2F), -137.2
(dt, 2F). HRMS calcd for C26H23F10NO4 602.1389 [M + H]+,
found 602.1380.
3-{(3-[[3-(Tr iflu or om eth yl)ben zyloxy]ph en yl][3-(1,1,2,2-
tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (3d ). Tan oil, yield 68.1 mg (48%). 1H NMR (300 MHz,
CDCl3) δ 7.64-7.44 (m, 4 H), 7.37-7.12 (m, 6H), 6.60-6.52
(m, 2H), 5.86 (tt, 1H), 5.01 (s, 2H), 4.62 (s, 2H), 4.40-4.32 (m,
1H), 3.82 (dd, 1H), 3.63 (dd, 1H). 19F NMR (CDCl3) d -62.1 (s,
3F) -79.3 (d, 3F), -88.5 (m, 2F), -137.2 (dt, 2F). HRMS calcd
for C26H22F10NO3 586.1440 [M + H]+, found 586.1419.
3-{[3-(Ben zyloxy)p h en yl][3-(1,1,2,2-tetr a flu or oeth oxy)-
ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (3f). Tan oil,
1
a yellow oil. H NMR (300 MHz, CDCl3) δ 7.35 (t, 1H), 7.07-
7.14 (m, 4H), 6.25-6.37 (m, 3H), 5.91 (tt, 1H), 4.68 (s, 2H),
4.39 (m, 1H), 3.88 (dd, 1H), 3.58 (dd, 1H). 19F NMR (CDCl3) δ
-79.0 (d, 3F), -88.0 (m, 2F), -137.2 (dt, 2F). HRMS calcd for
C
18H17F7NO3 428.1097 [M + H]+, found 428.1104.
Gen er a l P r oced u r e for Ar yl Eth er Cou p lin gs w ith 12.
3-{[3-(2-Nit r op h en oxy)-p h en yl][[3-(1,1,2,2-t et r a flu or o-
eth oxy)p h en yl]m eth yl]a m in o}-1,1,1-tr iflu or o-2-p r op a n ol
(2k k ). A solution of 12 (100 mg, 0.23 mmol), 1-bromo-2-
nitrobenzene (52.4 mg, 0.26 mmol), copper(I) trifluoromethane-
sulfonate benzene complex (3 mg, 2.5 mol %), and cesium
carbonate (100 mg, 0.31 mmol) in toluene (1 mL) and ethyl
acetate (1 µL) was heated at 95 °C in a sealed vial for 4 days.
The reaction mixture was filtered through Celite, and the
solvent was evaporated from the filtrate. The residue was
purified by reverse phase HPLC eluting with acetonitrile/water
1
yield 69.5 mg (52%). H NMR (300 MHz, CDCl3) δ 7.42-7.28
(m, 6H), 7.20-7.12 (m, 3H), 7.07 (s, 1H), 6.47 (d, 1H), 6.41-
6.39 (m, 2H), 5.91 (tt, 1H), 5.03 (s, 2H), 4.67 (s, 2H), 4.37-
4.31 (m, 1H), 3.86 (dd, 1H), 3.56 (dd, 1H). 19F NMR (CDCl3) d
-79.1 (d, 3F), -88.5 (m, 2F), -137.2 (dt, 2F). HRMS calcd for
C
25H22F7NO3 518.1566 [M + H]+, found 518.1578.
3-{[3-(Cycloh exylm eth oxy)p h en yl][3-(1,1,2,2-tetr a flu o-
r oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (3e).
Bromomethylcyclohexane (42 µL, 0.30 mmol) and 12 (100 mg,
0.23 mmol) were dissolved in 2 mL of acetonitrile. Cesium
carbonate (144 mg, 0.44 mmol) was added, and the stirred
solution was warmed to 50 °C for 48 h, at which time HPLC
analysis indicated that no phenolic starting material remained.
The reaction was quenched with water and filtered through
prewetted Celite eluting with ethyl acetate. The solvent was
evaporated, and the residue was purified by reverse phase
HPLC eluting with 10% to 90% acetonitrile in water to afford
3e (55 mg, 35%) as a brown oil, which was greater than 99%
pure by reverse phase HPLC analysis. 1H NMR (300 MHz,
CDCl3) δ 0.9-1.4 (m, 5H), 1.7-1.9 (m, 6H), 3.6 (m, 3H), 3.9
(dd, 1H), 4.3 (m, 1H), 4.7 (m, 2H), 5.1 (s, 1H), 5.9 (tt, 1H), 6.5
(m, 3H), 7.0-7.4 (m, 5H). 19F NMR (CDCl3) d -79.2 (d, 3F),
-88.4 (m, 2F), -137.2 (dt, 2F). HRMS calcd for C25H30F7NO3
524.2036 [M + H]+, found 524.2028.
1
(1:1 to 9:1) to afford 2k k (14.1 mg, 11%) as an orange oil. H
NMR (CDCl3) δ 7.97 (d, 1H), 6.98-7.50 (m, 8H), 6.47-6.67
(m, 3H), 5.90 (tt, 1H), 4.64 (s, 2H), 4.35-4.42 (m, 1H), 3.84
(dd, 1H), 3.63 (dd, 1H). 19F NMR (CDCl3) δ -79.4 (d, 3F), -88.6
(m, 2F), -137.2 (dt, 2F). HRMS calcd for
C24H20F7N2O5
549.1260 [M + H]+, found 549.1235.
3-{[3-(3-F lu or o-2-n it r op h en oxy)p h en yl][3-(1,1,2,2-t et -
r a flu or oet h oxy)ben zyl]a m in o}-1,1,1-t r iflu or op r op a n -2-
ol (2jj). Tan oil, yield 14.0 mg (10%). 1H NMR (300 MHz,
CDCl3) δ 7.78-7.69 (m, 1H), 7.41-6.98 (m, 7H), 6.75-6.70 (m,
1H), 6.50-7.42 (m, 2H), 5.91 (tt, 1H), 4.63 (s, 2H), 4.42-4.33
(m, 1H), 3.85 (dd, 1H), 3.64 (dd, 1H). 19F NMR (CDCl3) δ -79.8
(d, 3F), -88.7 (m, 2F), -120.1 (m, 1H), -137.2 (dt, 2F). HRMS
calcd for C24H19F8N2O5 567.1166 [M + H]+, found 567.1135.
3-{[3-(4-Nit r op h en oxy)p h en yl][3-(1,1,2,2-t et r a flu or o-
eth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (2ll). Tan
3-{3-[[4-(Tr iflu or om eth oxy)ben zyloxy]ph en yl][3-(1,1,2,2-
tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (3g). Tan oil, yield 69.2 mg (47%). 1H NMR (300 MHz,
CDCl3) δ 7.42-7.20 (m, 8H), 7.02 (s, 1H), 6.55-6.42 (m, 3H),
5.88 (tt, 1H), 4.99 (s, 1H), 4.63 (s, 1H), 4.39-4.31 (m, 1H), 3.82
(dd, 1H), 3.59 (dd, 1H). 19F NMR (CDCl3) δ -61.6 (s, 3F). -79.3
(d, 3F), -88.6 (m, 2F), -137.2 (dt, 2F). HRMS calcd for
1
oil, yield 14.9 mg (11%). H NMR (300 MHz, CDCl3) δ 8.16-
8.11 (m, 1H), 7.38-7.24 (m, 5H), 7.10 (t, 2H), 7.01 (s, 1H), 6.96
(d, 1H), 6.63 (d, 1H), 6.47 (d, 1H), 6.39 (s, 1H), 5.85 (tt, 1H),
4.66 (s, 2H), 4.42-4.32 (m, 1H), 3.90 (dd, 1H), 3.61 (dd, 1H).
HRMS calcd for C24H20F7NO5 549.1260 [M + H]+, found
549.1306.
C
26H22F10NO4 602.1389 [M + H]+, found 602.1383.
3-{[3-(P yr id in -2-yloxy)p h en yl][3-(1,1,2,2-t et r a flu or o-
eth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (3a). Tan
3-{(3-Isop r op oxyp h en yl)[3-(1,1,2,2-tetr a flu or oeth oxy)-
1
oil, yield 0.5 mg (1%). H NMR (CDCl3, 300 MHz)) δ 8.24 (d,
ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (3h ). Tan oil,
1
1H), 7.67(t, 1H), 7.18-7.14 (m, 2H), 7.05 (t, 1H), 6.85 (d, 1H),
6.81 (t, 1H), 6.68 (dd, 1H), 6.72-6.59 (m, 1H), 6.47 (d, 1H),
6.12 (dd, 1H), 5.85(bs, 1H), 5.44 (tt, 1H), 4.68 (s, 2H), 4.36 (bs,
1H), 3.79 (d, 1H), 3.59-3.69 (m, 1H).19F NMR (CDCl3) δ -79.5
(d, 3F), -88.7 (m, 2F), -137.2 (dt, 2F). HRMS calcd for
yield 77 mg (59%). H NMR (CDCl3, 300 MHz) δ 7.35 (t, 1H),
7.20-7.05 (m, 4H), 6.35 (t, 1H), 6.25 (bs, 1H), 5.90 (tt, 1H),
4.65 (s, 2H), 4.45 (q, 1H), 4.35 (m, 1H), 3.85 (dd, 1H), 3.55 (dd,
1H), 2.55 (bs, 1H), 1.25 (t, 6H). 19F NMR (CDCl3) δ -79.3 (d,
3F), -88.6 (m, 2F), -137.2 (dt, 2F). HRMS calcd for C21H23F7-
NO3 470.1488 [M + H]+, found 470.1565.
C
23H20F7N2O3 505.1362 [M + H]+, found 505.1378.
3-{[3-(P yr id in -3-yloxy)p h en yl][3-(1,1,2,2-t et r a flu or o-
3-{[3-(Cyclop en t yloxy)p h en yl][3-(1,1,2,2-t et r a flu or o-
eth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (3i). Tan
eth oxy)ben zyl]am in o}-1,1,1-tr iflu or opr opan -2-ol (3b). Tan
1
1
oil, yield 12.2 mg (14.6%). H NMR (CDCl3, 300 MHz) δ 8.35
oil, yield 15 mg (13%). H NMR (CDCl3, 300 MHz) δ 7.35 (t,
(d, 2H), 7.79 (d, 1H), 7.63 (s, 1H), 7.32 (t, 1H), 7.20-7.29 (m,
1H), 7.11 (t, 2H), 7.02 (s, 1H), 6.62 (d, 1H), 6.55 (s, 1H), 6.47
(d, 1H), 5.89 (tt, 1H), 4.68 (q, 2H), 4.36 (bs, 1H), 3.79 (d, 1H),
3.59-3.69 (m, 1H). HRMS calcd for C23H20F7N2O3 505.1362
[M + H]+, found 505.1369.
3-{(3-[[3-(T r iflu o r om e t h ox y)b e n zy lo x y ]p h e n yl][3-
(1,1,2,2-tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or o-
p r op a n -2-ol (3c). To a solution of 12 (100 mg, 0.23 mmol)
1H), 7.20-7.05 (m, 4H), 6.55-6.3 (m, 3H), 5.90 (tt, 1H), 4.65
(s, 3H), 4.35 (m, 1H), 3.85 (dd, 1H), 3.55 (dd, 1H), 3.05 (bs,
1H), 1.9-1.5 (m, 8H). HRMS calcd for C23H25F7NO3 496.1723
[M + H]+, found 496.1719.
3-{[3-(Cycloh exyloxy)p h en yl][3-(1,1,2,2-t et r a flu or o-
eth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (3j). Tan
oil, yield 1.8 mg (1.5%). HRMS calcd for C24H27F7NO3 510.1880
[M + H]+, found 510.1910.

2164 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11
Reinhard et al.
1-Ch lor o-2-eth yl-4-(3-n itr op h en oxy)ben zen e (15a ). To
a solution of 1,3-dinitrobenzene (16.8 g, 0.1 mol) and 4-chloro-
3-ethylphenol (15.6 g, 0.1 mol) in 200 mL of dimethyl sulfoxide
was added cesium carbonate (65 g, 0.2 mol). The reaction
mixture was heated at 100 °C under nitrogen overnight, then
cooled to room temperature. The reaction mixture was filtered
through Celite, then rinsed with diethyl ether and a small
amount of water. The filtrate was extracted several times with
diethyl ether. The organic layers were combined, washed with
water and brine, dried over anhyd MgSO4, and concentrated
in vacuo to give 15a (21.8 g, 78%) as a dark orange oil, which
was greater than 90% pure by reverse phase HPLC analysis.
1H NMR (CDCl3) δ 7.89 (dd, 1H), 7.72 (t, 1H), 7.46 (t, 1H),
7.27 (dd 1H), 7.30 (dd, 1H), 6.99 (m, 2H), 2.85 (q, 2H), 1.27 (t,
3H). HRMS calcd for C14H13ClNO3.NH4 295.0849 [M + NH4]+,
found 295.0862.
(dd, 1H), 6.40 (dd, 1H), 6.38 (t, 1H), 5.85 (tt, 1H), 4.62 (s, 2H),
4.33 (m, 1H), 3.82 (dd, 1H), 3.55 (dd, 1H), 2.47 (q, 2H), 2.35
(bs, 1H), 1.12 (t, 3H). 19F NMR (CDCl3) δ -79.3 (d, 3F), -88.6
(m, 2F), -137.2 (dt, 2F). HRMS calcd for C26H25F7NO3 532.1723
[M + H]+, found 532.1713.
1-Nitr o-3-[3-(tr iflu or om eth oxy)ph en oxy]ben zen e (15c).
To a solution of 1,3-dinitrobenzene (4.5 g, 0.03 mol) and
3-trifluoromethoxyphenol (4.8 g, 0.03 mol) in 54 mL of di-
methyl sulfoxide was added cesium carbonate (21.8 g, 0.07
mol). The reaction mixture was heated at 100 °C under
nitrogen overnight, then cooled to room temperature. The
reaction mixture was diluted with water and extracted with
diethyl ether several times. The organic layers were combined,
washed with 1 N HCl and water, dried over anhyd MgSO4,
and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel eluting with 1:9 ethyl
acetate in hexane to afford 15c (3.0 g, 38%) as a yellow-orange
liquid, which was 85% pure by reverse phase HPLC analysis.
HRMS calcd for C13H8NO3 300.0484 [M + H]+, found 300.0463.
This material was carried on below without further purifica-
tion.
3-(4-Ch lor o-3-eth ylp h en oxy)a n ilin e (16a ). To a solution
of 15a (10 g, 0.036 mol) in 400 mL of glacial acetic acid and 1
mL of water was added zinc metal (20 g, 0.305 mol) at room
temperature, and the resultant mixture was stirred for 1 h.
The filtrate was neutralized with ammonium hydroxide and
extracted with ethyl acetate. The organic layer was washed
with water and brine, dried over anhyd MgSO4, and concen-
trated in vacuo to give 16a (10 g, 100%) as a dark orange oil,
which was greater than 90% pure by reverse phase HPLC
3-[3-(Tr iflu or om eth oxy)p h en oxy]a n ilin e (16c). To a
solution of 15c (3.0 g, 0.01 mol) in 100 mL of glacial acetic
acid was added zinc metal (6.6 g, 0.1 mol) at room temperature,
and the resulting mixture was stirred for 1 h. The reaction
mixture was filtered through Celite. The filtrate was neutral-
ized with ammonium hydroxide and extracted with diethyl
ether then ethyl acetate. The combined organic layers were
dried over anhyd MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
eluting with 1:9 ethyl acetate in hexane to afford 16c (1.2 g,
44%) as a yellow oil, which was 98% pure by C18 reverse phase
HPLC analysis. HRMS calc for C13H11F3NO2 270.0742 [M +
H]+, found 270.0767. Anal. Calcd for C13H10F3NO2 C, 58.00;
H, 3.74; N, 5.20, found C, 57.68; H, 3.57; N, 5.14.
1
analysis. H NMR (CDCl3) δ 7.27 (d, 1H), 7.11 (t 1H), 6.91 (d,
1H), 6.80 (dd, 79), 6.44 (d, 1H), 6.40 (d, 1H), 6.31 (s, 1H), 2.72
(q, 2H), 1.21 (t, 3H). HRMS calcd for C14H15ClNO 248.0842
[M + H]+, found 248.0833.
3-(4-Ch lor o-3-eth ylp h en oxy)-N-[3-(1,1,2,2-tetr a flu or o-
eth oxy)ben zyl]a n ilin e (13a ). To a solution of 16a (2.0 g, 8.1
mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.6 g, 7.3
mmol) in 30 mL of dichloroethane were added sodium triace-
toxyborohydride (2.0 g, 9.7 mmol) and glacial acetic acid (0.51
mL, 8.9 mmol). The reaction mixture was stirred at room
temperature for 1 h, then quenched with water and extracted
with diethyl ether. The organic layer was washed with water
and brine, dried over anhyd MgSO4, and concentrated in vacuo
to give 13a (3.5 g, 95%) as a brown oil, which was greater than
N-[3-(1,1,2,2-Tet r a flu or oet h oxy)b en zyl]-3-[(3-t r iflu o-
r om eth oxy)p h en oxy]a n ilin e (13c). To a solution of 16c (1.0
g, 3.7 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde
(0.83 g, 3.7 mmol) in 18.5 mL of dichloroethane were added
sodium triacetoxyborohydride (1.0 g, 4.7 mmol) and glacial
acetic acid (0.25 mL, 4.3 mmol). The reaction mixture was
stirred at room-temperature overnight, then quenched with
saturated aqueous sodium bicarbonate and extracted with
methylene chloride. The organic layer was dried over anhyd
MgSO4 and concentrated in vacuo to give 13c (1.8 g, 100%) as
a yellow oil, which was greater than 92% pure by reverse phase
HPLC analysis. 1H NMR (CDCl3) δ 7.33-7.21 (m, 3H), 7.18
(m, 3H), 6.93 (m, 2H), 6.88 (d, 1H), 6.42 (dd, 1H), 6.39 (dd,
1H), 6.28 (s, 1H), 5.89 (t, 1H), 4.34 (s, 2H). 19F NMR (CDCl3)
δ -58.2 (s, 3F), -88.4 (m, 2F), -137.1 (dt, 2F). HRMS calcd
for C22H17F7NO3 476.1097 [M + H]+, found 476.1069.
1
90% pure by reverse phase HPLC analysis. H NMR (CDCl3)
δ 7.25 (m 4H), 7.10 (m, 3H), 6.88 (d, 1H), 6.42 (d, 1H), 6.38 (d,
1H), 6.29 (s, 1H), 5.92 (t, 1H), 4.32 (s, 2H), 2.73 (q, 2H), 1.21
(t, 3H). 19F NMR (CDCl3) δ -88.3 (m, 2F), -137.2 (dt, 2F).
HRMS calcd for C23H21ClF4NO2 454.1197 [M + H]+, found
454.1220.
(2R)-3-{[3-(4-Ch lor o-3-eth ylp h en oxy)p h en yl][3-(1,1,2,2-
tetr a flu or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (4a ). A solution of 13a (1.8 g, 4.0 mmol), R-(+)-
1,1,1-trifluoro-2,3-epoxypropane29 (0.64 g, 5.7 mmol), and
ytterbium(III) trifluoromethanesulfonate (0.25 g, 0.4 mmol) in
1.5 mL of CH3CN was heated at 40 °C in a sealed glass tube
for 1 h. The reaction mixture was cooled to room temperature,
then diluted with water and diethyl ether and extracted. The
ether layer was washed with water and brine, dried over anhyd
MgSO4, and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel eluting with
1:7:0.01 of EtOAc:hexane:concentrated NH4OH to afford 4a
(1.5 g, 66%) as a yellow oil (97% ee by chiral HPLC analysis).
[R]25589 ) +36.9 (c 1.044 g%, CHCl3), [R]25365 ) +189.7 (c 1.044
(2R )-3-{[3-(3-Tr iflu or om e t h oxyp h e n oxy)p h e n yl][3-
(1,1,2,2-tetr a flu or oeth oxy)-ben zyl]a m in o}-1,1,1-tr iflu or o-
2-p r op a n ol (4c). A solution of 13c (1.8 g, 3.7 mmol), R-(+)-
1,1,1-trifluoro-2,3-epoxypropane29 (0.57 g, 5.2 mmol), and
ytterbium(III) trifluoromethanesulfonate (0.24 g, 0.38 mmol)
in 2.0 mL of acetonitrile was heated at 40 °C in a sealed glass
tube overnight. At this time reverse phase HPLC analysis
indicated that the reaction was only 50% complete. Additional
ytterbium(III) trifluoromethanesulfonate and R-(+)-1,1,1-tri-
fluoro-2,3-epoxypropane (0.26 g, 2.3 mmol) were added to the
reaction mixture and again heated at 40 °C in a sealed glass
tube for 48 h. The reaction mixture was cooled to room
temperature, then diluted with water and methylene chloride
and extracted. The organic layer was washed with brine, dried
over anhyd MgSO4, and concentrated in vacuo. The crude
product was purified by reverse phase HPLC eluting with 30%
to 90% acetonitrile in water to afford 4c (1.25 g, 23%) as
1
g%, CHCl3). The refractive index @ 25 °C is 1.5275. H NMR
(CDCl3) δ 7.30 (t, 1H), 7.20 (d, 1H), 7.15 (t, 1H), 7.08 (t, 2H),
7.00 (s, 1H), 6.86 (d, 1H), 6.68 (dd, 1H), 6.48 (dd, 1H), 6.36
(dd, 1H), 6.34 (t, 1H), 5.81 (tt, 1H), 4.62 (s, 2H), 4.32 (m, 1H),
3.84 (dd, 1H), 3.55 (dd, 1H), 2.67 (q, 2H), 2.45 (bs, 1H), 1.17
(t, 3H). 19F NMR (CDCl3) δ -79.2 (d, 3F), -88.6 (m, 2F), -137.2
(dt, 2F). HRMS calcd for C26H24ClF7NO3 566.1330 [M + H]+,
found 566.1323. Anal. Calcd for C26H23ClF7NO3: C, 55.18; H,
4.10; N, 2.48, found C, 54.92; H, 4.05; N, 2.33.
(2R)-3-{[3-(3-Eth ylp h en oxy)p h en yl][3-(1,1,2,2-tetr a flu -
or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (4b).
Prepared in a manner similar to 4a using 3-ethylphenol
instead of 4-chloro-3-ethylphenol. Product was a light brown
1
yellow-brown oil (92% ee by chiral HPLC analysis). H NMR
(CDCl3) δ 7.35-7.18 (m, 3H), 7.12 (t, 2H), 7.01 (s, 1H), 6.93
(d, 1H), 6.85 (d, 1H), 6.82 (s, 1H), 6.56 (dd, 1H), 6.47 (dd, 1H),
6.41 (s, 1H), 5.88 (t, 1H), 4.66 (s, 2H), 4.35 (m, 1H), 3.86 (d,
1H), 3.59 (dd, 1H), 2.02 (s, 1H). 19F NMR (CDCl3) δ -58.31 (s,
1
oil (final step 68%). H NMR (CDCl3) δ 7.28 (t, 1H), 7.16 (m,
2H), 7.10 (t, 2H), 6.98 (s, 1H), 6.84 (m, 2H), 6.78 (dd, 1H), 6.52

Inhibitor of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2165
3F), -79.2 (d, 3F), -88.6 (m, 2F), -137.2 (dt, 2F). HRMS calcd
for C25H20F10NO4 588.1233 [M + H]+, found 588.1225.
temperature, and the resultant mixture was stirred for 0.5 h.
The filtrate was neutralized with ammonium hydroxide and
extracted with diethyl ether. The organic layer was washed
with water and brine, dried over anhyd MgSO4, and concen-
trated in vacuo to give 16e (2.7 g, 94%) as a yellow oil, which
was used without further purification. 1H NMR (CDCl3) δ 7.2d
(m, 1H), 7.14 (t 1H), 7.00 (d, 1H), 6.95 (m, 1H), 6.85 (dd, 1H),
6.50 (m, 2H), 6.42 (m, 1H), 2.92 (m, 1H), 1.24 (d, 6H). HRMS
calcd for C15H18NO 228.1388 [M + H]+, found 228.1384.
3-(3-Isopr opylph en oxy)-N-[3-(1,1,2,2-tetr aflu or oeth oxy)-
ben zyl]a n ilin e (13e). To a solution of 16e (1.0 g, 4.4 mmol)
and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.9 g, 4 mmol)
in 20 mL of dichloroethane were added sodium triacetoxy-
borohydride (1.1 g, 5.2 mmol) and glacial acetic acid (0.3 mL,
4.8 mmol). The reaction mixture was stirred at room temper-
ature for 1.5 h, then quenched with saturated aqueous
NaHCO3 and extracted with diethyl ether. The organic layer
was washed with water and brine, dried over Na2SO4, and
concentrated in vacuo to give 13e (1.73 g, 100%) as a brown
oil, which was used without further purification. 1H NMR
(CDCl3) δ 7.38 (t, 1H), 7.28 (t, 1H), 7.24 (d, 1H), 7.14 (t, 1H),
7.00 (d, 1H), 6.94 (m, 1H), 6.8 (dd, 2H), 6.42 (d, 1H), 6.34 (s,
1H), 6.10 (t, 1H), 5.92 (t, 1H), 5.74 (t, 1H), 4.38 (s, 2H), 3.78
(s, 1H), 2.90 (m, 1H), 1.22 (d, 6H). 19F NMR (CDCl3) -88.7
(m, 2F), -137.3 (dt, 2F). HRMS calcd for C24H23F4NO2 434.1743
[M + H]+, found 434.1736.
(2R)-3-{[3-(3-Isop r op ylp h en oxy)p h en yl][3-(1,1,2,2-tet-
r a flu or oet h oxy)ben zyl]a m in o}-1,1,1-t r iflu or op r op a n -2-
ol (4e). A solution of 13e (1.0 g, 2.3 mmol), R-(+)-1,1,1-
trifluoro-2,3-epoxypropane29 (0.4 g, 3.5 mmol), and ytterbium(III)
trifluoromethanesulfonate (0.14 g, 0.23 mmol) in 0.8 mL of
CH3CN was heated at 40 °C in a sealed glass tube for 18 h.
The reaction mixture was cooled to room temperature, then
diluted with water and diethyl ether and extracted. The ether
layer was washed with water and brine, dried over Na2SO4,
and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel eluting with 9:1 hexanes:
ethyl acetate to afford 4e 0.68 g (54%). Tan oil, 683 mg (54%).
1H NMR (CDCl3, 300 MHz) δ 7.4-7.2 (m, 4H), 7.1 (m, 1H),
7.0, (d, 1H), 6.9 (s, 1H), 6.8 (d, 1H), 6.5 (m, 4H), 5.9 (tt, 1H),
4.7 (s, 2H), 4.4 (br s, 1H), 3.9 (dd, 1H), 3.6 (br m, 1H), 2.9 (m,
1H), 2.5 (br s, 1H), 1.2 (t, 6H). 19F NMR (CDCl3) δ -79.2 (d,
3F), -88.4 (m, 2F), -137.1 (dt, 2F). HRMS calcd for C27H27F7-
NO3 546.1879 [M + H]+, found 546.1900.
3-(4-Ch lor o-3-eth ylp h en oxy)-N-[3-(tr iflu or om eth oxy)-
ben zyl]a n ilin e (13f). To a solution of 16a (2.0 g, 8.1 mmol)
and 3-(trifluoromethoxy)benzaldehyde (1.4 g, 7.3 mmol) in 30
mL of dichloroethane and acetic acid (0.5 mL, 8.9 mmol) was
added solid sodium triacetoxyborohydride (2.0 g, 9.7 mmol).
The mixture was stirred at room temperature for 1 h, then
quenched with water and extracted with diethyl ether. The
ether layer was washed with water and brine, then dried over
anhyd MgSO4, and evaporated to give 3.0 g (88%) of 13f as a
brown oil, which was greater than 94% pure by reverse phase
HPLC analysis. 1H NMR δ (CDCl3) 7.34(t, 1H), 7.26(d, 1H),
7.21(m, 1H), 7.17 (m, 1H), 7.09 (m, 2H), 6.87(m, 1H), 6.72(dd,
1H), 6.46(dd, 1H), 6.43 (m, 1H), 6.32 (m, 1H), 4.32 (s, 1H), 2.69
(q, 2H), 1.19(t, 3H). 19F NMR (CDCl3) δ -58.4 (s, 3F). HRMS
calcd for C22H20NO2ClF3 422.1134 [M + H]+, found 422.1135.
3-(4-Meth ylp h en oxy)n itr oben zen e (15d ). To a solution
of p-cresol (5.76 g, 0.053 mol) and 1,3-dinitrophenol (8.97 g,
0.053 mol) in 100 mL of dimethyl sulfoxide was added cesium
carbonate (43.4 g, 0.133 mol). The reaction mixture was heated
at 100 °C for 18 h. The reaction mixture was cooled to room
temperature, quenched with water, and extracted with diethyl
ether. The organic layer was combined, washed with 0.1 N
HCl and water, dried over anhyd MgSO4, and concentrated in
vacuo. The crude product was purified by column chromatog-
raphy on silica eluting with 1:4 ethyl acetate:hexane to afford
1
15d (8.0 g, (66%) as a yellow oil. H NMR (CDCl3) d 7.83 (s,
1H), 7.64 (t, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 7.09 (d, 2H), 6.8
(d, 2H), 2.20 (s, 3H). ESMS m/z 230 [M + H]+.
3-(4-Meth ylp h en oxy)a n ilin e (16d ). A solution of 3-(4-
methylphenoxy)nitrobenzene (8.0 g, 0.035 mol) 15d in 25 mL
of ethanol under nitrogen was charged with 10% palladium
on carbon (0.80 g). The resulting mixture was hydrogenated
for 4 h at room temperature and 45 psi. The reaction mixture
was filtered through Celite and concentrated in vacuo to give
6.7 g (96%) of a yellow oil. ESMS m/z 200 [M + H]+.
3-(4-Meth ylp h en oxy)-N-[3-(1,1,2,2-tetr a flu or oeth oxy)-
ben zyl]a n ilin e (13d ). To a solution of 16d (2.5 g, 12.5 mmol)
and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (2.8 g, 12.7
mmol) in 40 mL of dichloroethane were added sodium triace-
toxyborohydride (3.1 g, 15.0 mmol) and glacial acetic acid (0.85
mL, 15.0 mmol). The reaction mixture was stirred at room
temperature for 1 h, then quenched with water and extracted
with diethyl ether. The organic layer was washed with water
and brine, dried over anhyd MgSO4, and concentrated in vacuo
to give 13d (3.5 g, 75%) as a tan oil, which was greater than
1
94% pure by reverse phase HPLC analysis. H NMR (CDCl3)
δ 7.20 (m 2H), 7.10 (m 3H), 6.88 (m, 3H), 6.80 (d, 1H), 6.49
(dd, 1H), 6.46 (dd, 1H), 6.19 (d, 1H), 5.82 (t, 1H), 4.30 (s, 2H),
2.33 (s, 3H). 19F NMR (CDCl3) δ -88.2 (m, 2F), -137.2 (dt,
2F). HRMS calcd for C22H20F4NO2 406.1430 [M + H]+, found
406.1420.
(2R)-3-{[3-(4-Meth ylph en oxy)ph en yl][3-(1,1,2,2-tetr aflu -
or oeth oxy)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -2-ol (4d ).
A solution of 13d (1.6 g, 4.0 mmol), R-(+)-1,1,1-trifluoro-2,3-
epoxypropane29 (0.64 g, 5.7 mmol), and ytterbium(III) ytter-
bium(III)trifluoromethanesulfonate (0.25 g, 0.4 mmol) in 1.5
mL of CH3CN was heated at 40 °C in a sealed glass tube for
1 h. The reaction mixture was cooled to room temperature,
then diluted with water and diethyl ether and extracted. The
ether layer was washed with water and brine, dried over anhyd
MgSO4, and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel eluting with
1:8:0.01 of EtOAc:hexane:concentrated NH4OH to afford 4d
(2.46 g, 48%) as a tan oil (96% ee by chiral HPLC analysis).
1H NMR (CDCl3) δ 7.17-7.01 (m, 5H), 6.92 (d, 2H), 6.82 (d,
2H), 6.65 (d, 1H), 6.34 (d, 1H), 5.92 (m, 1H), 4.48 (tt, 1H), 4.43
(s, 2H), 4.27-4.12 (m, 1H), 3.67 (bs, 1H), 3.11 (dd, 1H), 2.90
(m, 1H), 2.33 (s, 3H). 19F NMR (CDCl3) δ -79.3 (d, 3F), -88.6
(m, 2F), -137.2 (dt, 2F). HRMS calcd for C25H23F7NO3 518.1566
[M + H]+, found 518.1587.
1-Isop r op yl-3-(3-n itr op h en oxy)ben zen e (15e). To a so-
lution of 1,3-dinitrobenzene (5 g, 30 mmol) and 3-isopropyl
phenol (4.1 g, 30 mmol) in 72 mL of dimethyl sulfoxide was
added cesium carbonate (24 g, 74 mmol). The reaction mixture
was heated at 100 °C under nitrogen overnight, cooled to room
temperature, and poured into water, and the resulting solution
was extracted with diethyl ether. The ether layer was washed
with 0.1 N HCl and water. The organic layer was dried over
anhyd MgSO4 and concentrated in vacuo. The oil was chro-
matographed on silica (98:2 hexanes:ethyl acetate) give 15e
(3.7 g, 45%) as light brown oil. 1H NMR (CDCl3) δ 7.95 (dd,
1H), 7.82 (m, 2H), 7.51 (t, 1H), 7.35 (m, 1H), 7.12 (d, 1H), 6.99
(m, 1H), 6.89 (m, 1H) 2.95 (m, 1H), 1.35 (d, 6H). HRMS calcd
for C15H15NO3.NH4 275.1396 [M + NH4]+, found 275.1400.
(2R)-3-{[3-(4-Ch lor o-3-eth ylp h en oxy)p h en yl][3-(tr iflu -
or om eth oxy)ben zyl]am in o}-1,1,1-tr iflu or o-2-pr opan ol (4f).
To a solution of 13f (1.7 g, 4.0 mmol) and R-(+)-1,1,1-trifluoro-
2,3-epoxypropane29 (0.67 g, 6.0 mmol) in 1.5 mL of acetonitrile,
ytterbium(III) trifluoromethanesulfonate (0.25 g, 0.4 mmol)
was added, and the stirred solution was warmed to 40 °C for
1 h, at which time HPLC analysis indicated that no amine
starting material remained. The reaction was quenched with
water and extracted with diethyl ether. The ether layer was
washed with water and brine, then dried over anhyd MgSO4.
The crude product was purified by flash column chromatog-
raphy on silica gel eluting with ethyl acetate/hexane/am-
monium hydroxide (1:7:0.01) to give 4f (1.2 g, 56%) as a yellow
oil, (97% ee by chiral HPLC analysis). 1H NMR δ (CDCl3) 7.30
(t, 1H), 7.21 (d, 1H), 7.14 (t, 1H), 7.08 (t, 2H), 7.01 (s, 1H),
3-(3-Isop r op ylp h en oxy)a n ilin e (16e). To a solution of 15e
(3.5 g, 12.7 mmol) in 145 mL of glacial acetic acid and 1 mL of
water was added zinc metal (7.1 g, 108 mmol) at room

2166 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11
Reinhard et al.
6.86 (d, 1H), 6.68 (dd, 1H), 6.46 (dd, 1H), 6.36 (dd, 1H), 6.32
(t, 1H), 4.63 (d, 2H), 4.33 (m, 1H), 3.86 (dd, 1H), 3.84 (dd, 1H),
2.96 (bs, 1H), 2.67 (q, 2H), 1.17 (t, 3H). 19F NMR (CDCl3) δ
-58.22 (s, 3F), -79.23 (d, 3F). Anal. Calcd for C25H22NO3ClF6
C, 56.24; H, 4.15; N, 2.62, found C, 56.50; H, 4.33; N, 2.44.
HRMS calcd for C25H23NO3ClF6 534.1271 [M + H]+, found
534.1309.
ee by chiral HPLC analysis). 1H NMR (300 MHz, CDCl3) δ
7.47 (m, 4H), 7.23 (m, 3H), 6.90 (d, 1H), 6.72 (dd, 1H), 6.52 (d,
1H), 6.42 (m, 2H), 4.73 (s, 2H), 4.39 (m, 1H), 3.91 (dd, 1H),
3.58 (m, 2H), 2.73 (q, 2H), 2.57 (s, 1H), 1.22 (t, 3H). 19F NMR
(300 MHz, CDCl3) δ -79.2 (s, 3F), -84.9 (s, 3F), -115.2 (s,
2F). HRMS calcd for C26H23ClF8NO2 568.1290 [M + H]+, found
568.1296.
3-(4-Ch lor o-3-et h ylp h en oxy)-N-[2-flu or o-5-(t r iflu or o-
m eth yl)ben zyl]a n ilin e (13h ). 2-Fluoro-5-trifluoromethyl-
benzaldehyde (0.5 g, 2.6 mmol) and 16a (0.71 g, 2.96 mmol)
were dissolved in dichloroethane (15 mL). NaBH(OAc)3 (0.92
g, 4.3 mmol) and glacial acetic acid (0.18 mL, 3.12 mmol) were
added, and the reaction mixture was stirred at 25 °C for 12 h.
The reaction mixture was diluted with saturated aqueous
NaHCO3 and extracted with Et2O. The organic layers were
combined, washed with brine, dried over anhydrous anhyd
MgSO4, and concentrated in vacuo to give 0.844 g (77%) of 13h
1-Met h yl-3-(p en t a flu or oet h yl)b en zen e . Sodium pen-
tafluoroethylpropionate (8.4 g, 50 mmol) and 3-iodotoluene (5.5
g, 25 mmol) were dissolved in anhydrous DMF (300 mL) under
nitrogen. CuI (9.5 g, 50 mmol) was added, and the mixture
was heated to 160 °C under nitrogen for 4 h, at which time a
15 mL fraction of a mixture of DMF and 3-pentafluoroethyl-
toluene was collected by distillation. The distillate was diluted
with Et2O and washed with brine. The ether layer was dried
over anhyd MgSO4, filtered, and concentrated in vacuo to give
5.25 g (55%) of the title product as a colorless oil. 1H NMR
(300 MHz, CDCl3) δ 7.36 (m, 4H), 2.40 (s, 3H). 19F NMR (300
MHz, CDCl3) δ -85.2 (s, 3F), -115.2 (s, 2F). HRMS calcd for
1
as a yellow oil. H NMR (400 MHz, CDCl3) δ 7.7 (d, 1H), 7.6
(m, 1H), 7.2 (d, 1H), 7.1 (m, 2H), 6.8 (s, 1H), 6.7 (dd, 1H), 6.44
(d, 1H), 6.40 (d, 1H), 6.25 (s, 1H), 4.41 (s, 2H), 2.76 (q, 2H),
1.23 (t, 3H). 19F NMR (400 MHz, CDCl3) δ -62.4 (s, 3F), -114.6
(m, 1F). HRMS Calcd for C22H19ClF4NO 424.1091 [M + H]+,
found 424.1065.
C
13H10F3NO2 211.0532 [M + H]+, found 211.0546.
1-(Br om om eth yl)-3-(p en ta flu or oeth yl)ben zen e. N-Bro-
mosuccinimide (2.5 g, 13.8 mmol) and 1-methyl-3-pentafluo-
roethylbenzene (2.9 g, 13.8 mmol) were dissolved in CCl4 (25
mL). AIBN (50 mg, 0.3 mmol) was added, and the mixture was
refluxed for 3.5 h under N2. The reaction mixture was cooled
to room temperature and diluted with water. The layers were
separated, and the organic layer was washed with brine, dried
with anhyd MgSO4, filtered, and concentrated in vacuo to give
(2R)-3-{[3-(4-Ch lor o-3-eth ylp h en oxy)p h en yl][2-flu or o-
5-(tr iflu or om eth yl)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (4h ). To a solution of 13h (0.7 g, 1.65 mmol) in anhydrous
acetonitrile (1.0 mL) were added R-(+)-1,1,1-trifluoro-2,3-
epoxypropane29 (0.41 g, 3.63 mmol) and Yb(OTf)3 (100 mg, 0.16
mmol), and the reaction mixture was stirred under N2 at 45
°C in a sealed glass tube for 12 h. The reaction mixture was
then cooled to room temperature and diluted with Et2O and
saturated aqueous NaHCO3. The layers were separated, and
the aqueous layer was extracted with Et2O. The ether layers
were combined, washed with brine, dried with anhydrous Na2-
SO4, filtered, and concentrated in vacuo. The resulting viscous
oil was adsorbed onto silica gel and purified by column
chromatography eluting with hexane/ethyl acetate (95:5) yield-
ing 4h (0.679 g, 77%) as a viscous, colorless oil (99% ee by
1
3.4 g (87%) of the title crude product as a colorless oil. The H
NMR spectrum indicated that this crude product contained
the desired 1-bromomethyl-3-pentafluoroethylbenzene product
(70%), along with the corresponding 3-pentafluoroethylbenzyl-
dibromide (10%) and unreacted 1-methyl-3-pentafluoroethyl-
benzene (20%). 1H NMR (300 MHz, CDCl3) δ 7.60 (m, 2H),
7.50 (m, 2H), 4.50 (s, 2H). 19F NMR (300 MHz, CDCl3) δ -85.1
(s, 3F), -115.4 (s, 2F). This crude product was carried forward
in the next step without further purification.
3-(4-Ch lor o-3-eth ylp h en oxy)-N-[3-(p en ta flu or oeth yl)-
ben zyl]a n ilin e (13g). A solution of 3-(4-chloro-3-ethylphe-
noxy)aniline (16a ) (1.7 g, 6.9 mmol) was prepared in cyclo-
hexane (13 mL), and a solution of crude 1-bromomethyl-3-
pentafluoroethylbenzene (1 g, 3.5 mmol) in cyclohexane (10
mL) was added dropwise under nitrogen over 3 min. The
reaction mixture was refluxed under N2 for 24 h and then was
cooled to room temperature. The mixture was diluted with
diethyl ether and saturated aqueous NaHCO3. The layers were
separated, and the aqueous layer was extracted with diethyl
ether. The organic layer was washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The
residue was purified by chromatography on silica gel eluting
with hexanes in ethyl acetate (95:5) to give 13g (0.56 g, 35%)
as a brown oil. 1H NMR (300 MHz, CDCl3) δ 7.53 (m, 4H),
7.27 (d, 1H), 7.15 (t, 1H), 6.93 (d, 1H), 6.77 (dd, 1H), 6.41 (tt,
2H), 6.30 (t, 1H), 4.41 (s, 2H), 2.73 (q, 2H), 1.23 (t, 3H). 13C
NMR (300 MHz, CDCl3) δ 158.6, 156.1, 143.4, 141.3, 140.2,
131.3, 130.7, 130.4, 129.4, 128.1, 120.4, 117.8, 108.8, 103.9,
48.5, 27.5, 14.1. 19F NMR (300 MHz, CDCl3) δ -85.1 (s, 3F),
-115.2 (s, 2F). HRMS calcd for C23H20ClF5NO 456.1154 [M +
H]+, found 456.1164.
(2R)-3-{[3-(4-Ch lor o-3-et h ylp h en oxy)p h en yl][3-(p en -
t a flu or oet h yl)b en zyl]a m in o}-1,1,1-t r iflu or op r op a n -2-ol
(4g). A solution of 13g (0.4 g, 0.88 mmol) dissolved in
anhydrous acetonitrile (1.5 mL) was combined with R-(+)-
1,1,1-trifluoro-2,3-epoxypropane29 (0.22 g, 1.94 mmol), Yb(OTf)3
(22 mg, 0.035 mmol) was added, and the reaction mixture was
stirred under N2 at 45 °C in a sealed glass tube for 15 h. The
reaction mixture was then cooled to room temperature and
diluted with Et2O and saturated aqueous NaHCO3. The layers
were separated, and the aqueous layer was extracted with
Et2O. The ether layers were combined, washed with brine,
dried with anhydrous Na2SO4, filtered, and concentrated in
vacuo. The viscous oil was adsorbed onto silica gel and purified
by column chromatography eluting with hexane/ethyl acetate
(95:5) yielding 4g (0.32 g, 64%) as a viscous, colorless oil (98%
1
chiral HPLC analysis). H NMR (300 MHz, CDCl3) δ 7.7 (m,
1H), 7.4 (d, 1H), 7.3-7.1 (m, 4H), 6.9 (d, 1H), 6.7 (dd, 1H),
6.48 (dd, 1H), 6.43 (d, 1H), 6.28 (m, 1H), 4.69 (s, 2H), 4.38 (br
m, 1H), 3.89 (dd, 1H), 3.62 (dd, 1H), 2.79 (q, 2H), 2.6 (d, 1H),
1.22 (t, 3H). 19F NMR (400 MHz) δ -62.0 (s, 3F), -79.2 (s,
3F), -114.5 (m, 1F),. HRMS Calcd for C25H22ClF7NO2 536.1227
[M + H]+, found 536.1252.
3-(4-Ch lor o-3-et h ylp h en oxy)-N-[2-flu or o-4-(t r iflu or o-
m eth yl)ben zyl]an ilin e (13i). 2-Fluoro-4-trifluoromethylbenz-
aldehyde (0.5 g, 2.6 mmol) and 16a (0.71 g, 2.86 mmol) were
dissolved in dichloroethane (15 mL). NaBH(OAc)3 (0.72 g, 3.4
mmol) and glacial acetic acid (0.18 mL, 3.12 mmol) were added,
and the reaction mixture was stirred at 25 °C for 2 h. The
reaction mixture was diluted with saturated aqueous NaHCO3
and was extracted with Et2O. The organic layers were com-
bined, washed with brine, dried over anhydrous anhyd MgSO4
and concentrated in vacuo. The resulting oil was adsorbed onto
silica gel and purified by column chromatography eluting with
hexane/ethyl acetate (95:5) yielding 0.71 g (65%) of 13i as a
1
light brown oil. H NMR (300 MHz, CDCl3) δ 7.6 (m, 1H), 7.4
(m, 2H), 7.2 (t, 1H), 6.9 (d, 1H), 6.8 (dd, 1H), 6.4 (m, 2H), 6.3
(t, 2H), 4.4 (s, 2H), 2.7 (q, 2H), 1.2 (t, 3H). 19F NMR (300 MHz)
δ -63.1 (s, 3F), -116.3 (s, 1F). HRMS Calcd for C22H19ClF4-
NO 424.1091 [M + H]+, found 424.1084.
(2R)-3-{[3-(4-Ch lor o-3-eth ylp h en oxy)p h en yl][2-flu or o-
4-(tr iflu or om eth yl)ben zyl]a m in o}-1,1,1-tr iflu or op r op a n -
2-ol (4i). To a solution of 13i (0.6 g, 1.42 mmol) in anhydrous
acetonitrile (1.5 mL) were added R-(+)-1,1,1-trifluoro-2,3-
epoxypropane29 (0.55 g, 4.9 mmol) and Yb(OTf)3 (75 mg, 0.12
mmol), and the reaction mixture was stirred under N2 at 45
°C in a sealed glass tube for 15 h. The reaction mixture was
then cooled to room temperature and diluted with Et2O and
saturated aqueous NaHCO3. The layers were separated, and
the aqueous layer was extracted with Et2O. The ether layers
were combined, washed with brine, dried over anhydrous Na2-
SO4, filtered, and concentrated in vacuo. The resulting viscous
oil was adsorbed onto silica gel and purified by column

Inhibitor of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2167
chromatography eluting hexanes/ethyl acetate (95:5) to give
cholesterol and fat-supplemented chow for a minimum of two
weeks.26 Test compound 4a (30 mg/kg qd) was administered
for 5 d in selected aqueous- or oil-based vehicles. Similarly,
male golden Syrian hamsters, maintained on high cholesterol
diet for at least 2 weeks, were given 4a (3 or 30 mg/kg qd) for
5 d in selected aqueous- or oil-based vehicles. The animals were
sacrificed, and the serum was analyzed by size exclusion
chromatography using two Superose 6 columns and TSE buffer
as eluant for the relative abundance of VLDLc, LDLc, and
HDLc. The elution positions of VLDLc, LDLc, HDLc, and
albumin were determined by chromatographing standards26
under the same conditions.
0.25 g (32%) of 4i as a viscous, colorless oil (99% ee by chiral
1
HPLC analysis). H NMR (CDCl3) δ 7.4 (d, 2H), 7.3-7.2 (m,
3H), 6.9 (d, 1H), 6.7 (dd, 1H), 6.5 (dd, 2H), 6.4 (s, 1H), 4.8 (s,
2H), 4.4 (br m, 1H), 3.9 (dd, 1H), 3.6 (dd, 1H), 2.8 (q, 2H), 2.6
(br s, 1H), 1.2 (t, 3H). 19F NMR (400 MHz, CDCl3) δ -116.5
(m, 1F), -79.3 (s, 3F), -63.2 (s, 3F). HRMS Calcd for C25H22
-
ClF7NO2 536.1228 [M + H]+, found 536.1241.
CETP In h ibition . The buffer, the human plasma, and the
time-dependent CETP inactivation assays were carried out as
previously described.27
Deter m in a tion of Lip op r otein In tegr ity by Aga r ose
Electr op h or esis.27 A paragon Lipoprotein Electrophoresis Kit
(Beckman, Fullerton, CA) was used for the electophoretic
separation of lipoproteins, according to the manufacturer’s
instructions. Inhibitors were incubated with LDL or HDL at
concentration 1000-fold above the buffer assay IC50 value for
2 h at 37 °C. Cholesteryl sulfate was the positive control. After
electrophorisis, the lipoproteins in the gel were immobilized
in fixative. The gel was dried and the film stained to visualize
lipoproteins.
Ack n ow led gm en t . We thank Shengtian Yang,
Claude R. J ones, and J ohn Likos for NMR assistance;
J ames Doom and Gary Mappes for mass spectral
analysis. We also thank Anne Daiss for elemental
analysis. We are grateful to Brad McKinnis for analyses
by chiral chromatography.
In h ibition of Ch olester yl Ester Bin d in g to CETP .27
Samples containing [3H]-CE-HDL alone, [3H]-CE-HDL plus
CETP, and [3H]-CE-HDL plus CETP and inhibitor were
incubated for 2 h at 37 °C and then fractionated by Superose
12 size exclusion chromatography to separate CETP from
HDL. The fractions were assayed for [3H]-CE bound to CETP
by liquid scintillation counting.
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