Biphenyl-substituted oxazolidinones as cholesteryl ester transfer protein inhibitors: Modifications of the oxazolidinone ring leading to the discovery of anacetrapib

Article abstract of DOI:10.1021/jm200484c

The development of the structure-activity studies leading to the discovery of anacetrapib is described. These studies focused on varying the substitution of the oxazolidinone ring of the 5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl group with the cis-stereochemistry relative to the 5-aryl group afforded compounds with increased cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing HDL-C levels in transgenic mice expressing cynomolgus monkey CETP.

Full text of DOI:10.1021/jm200484c

ARTICLE
pubs.acs.org/jmc
Biphenyl-Substituted Oxazolidinones as Cholesteryl Ester Transfer
Protein Inhibitors: Modifications of the Oxazolidinone Ring Leading to
the Discovery of Anacetrapib
Cameron J. Smith,*,† Amjad Ali,† Milton L. Hammond,† Hong Li,† Zhijian Lu,† Joann Napolitano,†
Gayle E. Taylor,† Christopher F. Thompson,† Matt S. Anderson,‡ Ying Chen,‡ Suzanne S. Eveland,‡
Qiu Guo,‡ Sheryl A. Hyland,‡ Denise P. Milot,‡ Carl P. Sparrow,‡ Samuel D. Wright,‡
Anne-Marie Cumiskey,§ Melanie Latham,§ Laurence B. Peterson,§ Ray Rosa,§ James V. Pivnichny,||
Xinchun Tong,|| Suoyu S. Xu,|| and Peter J. Sinclair†
†Departments of Medicinal Chemistry, ‡Cardiovascular Diseases, §Pharmacology, and Drug Metabolism, Merck Research Laboratories,
Rahway, New Jersey 07065, United States
ABSTRACT: The development of the structureꢀactivity studies leading to the discovery of anacetrapib
is described. These studies focused on varying the substitution of the oxazolidinone ring of the
5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl
group with the cis-stereochemistry relative to the 5-aryl group afforded compounds with increased
cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing
HDL-C levels in transgenic mice expressing cynomolgus monkey CETP.
’ INTRODUCTION
mechanism of the protective effect of HDL is more complex.12
The beneficial antiatherogenic effects of HDL are thought to
arise primarily from its participation in reverse cholesterol
transport (RCT), although anti-inflammatory and antioxidant
properties have also been ascribed to this lipoprotein class.
Reverse cholesterol transport is the process by which excess
cholesterol is moved from lipid laden macrophages (foam cells)
and HDL to the liver for catabolism or excretion into the bile.
Cholesteryl ester transfer protein (CETP) is a 476-residue
hydrophobic glycoprotein that mediates the exchange of choles-
teryl ester (CE) from HDL with triglycerides from the apolipo-
protein B (apoB)-containing lipoproteins, primarily very low
density lipoprotein (VLDL).13,14 Hence, CETP acts to decrease
HDL-C levels and increase LDL-C levels and so could be con-
sidered to be a pro-atherogenic factor.15 On the other hand
CETP also enhances the rate of RCT, suggesting a possible
antiatherogenic role.16 Studies to investigate the therapeutic
potential of CETP inhibition in animal models have been
inconclusive. In mice, a species that lacks natural CETP expres-
sion, results have been mixed and in rabbits, a species where
CETP is expressed in high levels, inhibition appears to reduce
atherogenesis.15,16 A population of CETP deficient humans has
been identified in Japan.17,18 These individuals displayed high
levels of HDL-C and low levels of LDL-C and apoB.18 Although
the effect of CETP deficiency on atherosclerosis was not clear,
Cardiovascular disease (CVD) is now the leading cause of
death worldwide. In 2005, approximately 17.5 million deaths
were attributed to CVD, with approximately 7.6 million of those
mortalities resulting from coronary heart disease (CHD).1 Elevated
levels of low density lipoprotein-cholesterol (LDL-C) are consid-
ered to be a major risk factor for CHD. The development of the
statins (3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase inhibitors, e.g. simvastatin and atorvastatin) has sig-
nificantly helped to reduce LDL-C levels in patients at risk for
CHD and to reduce cardiovascular events but only by approxi-
mately 30%.2,3 Therefore, patients on statin therapy can still be at
significant risk of CVD. There is now a growing body of
epidemiological evidence linking increased levels of high density
lipoprotein-cholesterol (HDL-C) with decreased risk of devel-
opment of CHD.4ꢀ7 Some cholesterol lowering drugs, including
niacin, the fibrates, and the statins, have a modest effect on
increasing HDL-C levels.8ꢀ11 Niacin is the only therapy cur-
rently approved for raising HDL-C levels, despite its modest
efficacy (∼20% increase). Consequently, the identification of
improved approaches to raising HDL-C remains to be addressed.
Low density lipoproteins (LDL) and high density lipoproteins
(HDL) are macromolecular lipoprotein structures that are
comprised of a hydrophobic core of cholesteryl esters and
triglycerides encased by a hydrophilic layer of phospholipids,
free cholesterol, and apolipoproteins. Both LDL and HDL are
responsible for the transport of lipids in the plasma. LDL has a
well established role in the promotion of atherogenesis, but the
Received: April 21, 2011
Published: June 17, 2011
r
2011 American Chemical Society
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the observed lipid profiles for these individuals highlights the
potential of CETP as a therapeutic target for raising HDL.16
Torcetrapib and dalcetrapib were the first CETP inhibitors to
be developed and tested in humans with phase III data only
available for torcetrapib.19ꢀ26 These clinical studies established
that pharmacological inhibition of CETP leads to significant
increases in plasma HDL-C concentrations.27 Despite this ob-
servation, the RADIANCE 1 and 2 imaging studies showed
torcetrapib had no effect on the progression of atherosclerosis.28ꢀ30
The ILLUSTRATE imaging study was consistent with the
RADIANCE studies, but a small group of patients that presented
the highest increases in HDL-C levels did show some regression
in atheroma plaque volume.31,32 Consistent with earlier clinical
studies, the ILLUMINATE phase III outcomes trial showed
significant increases in HDL-C levels, but the study was halted
prematurely due to increased mortality in patients receiving
torcetrapib relative to the atorvastatin-only arm. There was also
an increase in mean systolic blood pressure as well as changes in
blood electrolytes levels in the torcetrapib-treated arm. Post hoc
analysis indicated increased aldosterone levels in these patients,
which was consistent with the observed changes in electroytes.
Studies in preclinical species have recapitulated both the blood
pressure and aldosterone-releasing effects of torcetrapib and have
shown that they occur independently of CETP inhibition.33ꢀ36
Thus, it has been established that torcetrapib possesses off-target
activities affecting blood pressure and aldosterone levels,
although the underlying causative mechanism has not yet been
elucidated. There is currently a significant debate regarding the
off-target activities of torcetrapib, and whether they can account
for the increased mortality observed in the ILLUMINATE trial
and/or whether they were a contributing factor to the lack of
efficacy observed in the imaging studies.37ꢀ41 Given the potential
cardiovascular benefits that may be realized by pharmacologic
increase in HDL-C, however, there remains continued interest in
the development of CETP inhibitors. To determine whether
CETP inhibition will be beneficial, large scale clinical studies on a
compound or compounds lacking both the blood pressure and
aldosterone effects will be required.
Figure 1
Scheme 1a
A chemistry program was initiated at Merck in order to
identify a suitable CETP inhibitor for development as a treat-
ment for atherosclerosis, and this program led to the discovery of
anacetrapib. The ability of anacetrapib to inhibit CETP-mediated
transfer of both cholesteryl ester and triglycerides and its
mechanism of action has been characterized.42 Anacetrapib has
been extensively profiled in phase I and II clinical trials and was
shown to elicit a dose-dependent increase in HDL-C levels and
decrease in LDL-C levels.43ꢀ48 It was also found that HDL
isolated from humans treated with anacetrapib had increased
potential to promote cholesterol efflux and retained anti-inflam-
matory effects.49 Preclinical and clinical studies with anacetrapib,
including recent results from the phase III safety study DEFINE,
have thus far given no evidence of blood pressure or aldosterone
increases and so development of the compound continues.33,50,51
Herein we describe the medicinal chemistry that led to the
discovery of anacetrapib.
Early development of CETP inhibitors at Merck led to the
discovery of the first benchmark compound 1.52 This compound
was a moderately potent inhibitor of CETP-mediated CE
transfer and only elicited an modest increase in HDL-C levels
in the B6-Tg(CETP) mouse in vivo model. The SAR was
subsequently advanced by introduction of a conformational
constraint that restricted the conformation of the methyl
a Reagents: (a) CuCN, DMF, Δ, 1 h, 90%; (b) t-BuONO, CH2I2, 60 °C,
30 min, 83%; (c) 10, Pd(PPh3)4, 2 M Na2CO3, DME, EtOH, H2O, μλ,
150 °C, 10 min, 98%; (d) KOH, i-PrOH, H2O, μλ, 130 °C, 4 h, 43%;
(e) borane, THF, reflux, 3 h, 61%; (f) Br4C, Ph3P, CH2Cl2, 0ꢀ25 °C,
1 h, quant; (g) (ꢀ)-4 or (þ)-4, NaHMDS, THF, 25 °C, 15 h, 63%
and 55%.
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Scheme 2a
Scheme 3a
a Reagents: (a) (i) N-methylmorpholine, t-BuOCOCl, CH2Cl2; (ii)
Me(MeO)NH2Cl, 99%; (b) (i) i-PrMgCl, THF, ꢀ15 °C, 15 min; (ii)
[3,5-bis(trifluoromethyl)phenyl]magnesium bromide (25), THF, ꢀ15
to 25 °C, 2 h, 83%; (c) PhMe2SiH, TFA, 0 °C, 15 h; (d) KOH, MeOH,
THF, 25 °C, 3 h, 68% over 2 steps.
Scheme 4a
a Reagents: (a) MeMgBr, THF, 0 °C, 4 h, 80%; (b) MsCl, Et3N,
CH2Cl2, 0ꢀ25 °C, 2 h, 56%; (c) NaHMDS, MePh3PBr, THF, ꢀ78 °C,
1.5 h, 63%; (d) (i) H2, 10% Pd/C, MeOH, 25 °C, 1 h; (ii) Ag2SO4, I2,
MeOH, 25 °C, 4 h, 75%; (e) n-BuLi, (MeO)3B, ꢀ78 °C, 3 h, 60%.
further substitution of oxazolidinone ring system of compound 2,
ultimately leading to identification of the clinical candidate
anacetrapib 3 (Figure 1).
a Reagents: (a) (i) EtNO2,or n-PrNO2, 10% aq NaOH, EtOH, 0 °C, 1 h;
(ii) 2% aq AcOH, 25 °C, 1 h, 97ꢀ99%; (b) H2, RaNi, 30% aq HCO2H,
MeOH, 25 °C, 15 h, 86ꢀ94%; (c) i-Pr2NEt, (Cl3CO)2CO, CH2Cl2, 0
°C, 1 h, 75ꢀ78%; (d) separation of diastereoisomers by flash chroma-
tography; (e) 5, NaHMDS, THF, 25 °C, 15 h, 51ꢀ96%.
’ CHEMISTRY
The first two 4-substituted oxazolidinone derivatives investi-
gated, (þ)-6 and (ꢀ)-6, were synthesized by coupling benzyl
bromide 5 with commercially available norephedrine derived
oxazolidinones (ꢀ)-4 and (þ)-4, respectively, as in Scheme 1.
Benzyl bromide 5 was derived from aryl iodide 7. Cyanation to
give aryl cyanide 8 was followed by Sandmeyer reaction to afford
aryl iodide 9. Palladium catalyzed coupling of 9 with boronic acid
10 afforded nitrile 11. Nitrile hydrolysis to afford carboxylic acid
12 was followed by reduction with borane to give benzyl alcohol
13. This was efficiently transformed into benzyl bromide 5 with
triphenylphosphine and carbon tetrabromide. Deprotonation of
oxazolidinones (ꢀ)-4 and (þ)-4 with NaHMDS followed by
carbamate to afford oxazolidinone 2.53 This compound, though
slightly more potent in CE transfer inhibition, did not have any
effect on HDL-C levels in vivo at 10 mpk, possibly due to the
poor pharmacokinetic profile observed. We therefore investi-
gated further modifications of the lead series in an effort to afford
compounds with potent CETP inhibition and improved phar-
macokinetic profiles that would be effective in increasing HDL-C
levels in our in vivo model. Herein we detail the investigation of
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Scheme 5a
Scheme 7a
a Reagents: (a) (i) N-methylmorpholine, t-BuOCOCl, CH2Cl2, 0 °C,
1.5 h; (ii) Me(MeO)NH2Cl, 3 h, 41%; (iii) DIBALH, THF, ꢀ78 °C, 4 h,
98%; (b) [3,5-bis(trifluoromethyl)phenyl]magnesium bromide (25),
THF, ꢀ20 to 25 °C, 4 h, 49%; (c) 38, NaH, DMF, 25 °C, 15 h, 40%.
Scheme 8a
a Reagents: (a) KOH, H2O, i-PrOH, Δ, 14 h, 66%; (b) borane, THF, Δ,
1.5 h, 88%; (c) Br4C, Ph3P, CH2Cl2, 0ꢀ25 °C, 48 h, 96%; (d) (ꢀ)-cis-
18, NaH, THF, 25 °C, 14 h, 83%; (e) 28, (Ph3P)4Pd, Na2CO3, C6H6,
EtOH, H2O, Δ, 14 h, 76%.
Scheme 6a
a Reagents: (a) MeMgBr, Et2O, 25 °C, 2 h, 94%; (b) KOH, MeOH,
THF, 25 °C, 3 h, 92%; (c) 38, NaH, DMF, 25 °C, 2 h, 65%.
a Reagents: (a) 28, (Ph3P)4Pd, Na2CO3, EtOH, H2O, Δ, 24 h, 97%; (b)
Br4C, Ph3P, CH2Cl2, 0ꢀ25 °C, 2 h, 93%.
trans-diastereoisomers cis-18 and trans-18. Coupling of cis-18
and trans-18 with benzyl bromide 5 afforded racemic biphenyl
oxazolidinones (()-cis-14 and (()-trans-14, which were each
separated into the corresponding pure enantiomers (þ)-cis-14,
(ꢀ)-cis-14, (þ)-trans-14, and (ꢀ)-trans-14 by chiral HPLC.
The synthesis of racemic cis- and trans-ethyl derivatives 19 was
achieved by a method analogous to that for 14 starting with
nitropropane (Scheme 2).
coupling with benzyl bromide 5 gave biphenyl oxazolidinones
(þ)-6 and (ꢀ)-6.
Initially, the synthesis of oxazolidinone 14 was conducted in
racemic fashion as shown in Scheme 2. Nitro-aldol reaction of
benzaldehyde 15 with nitroethanol gave alcohol 16. Reduction
with Raney nickel afforded amine 17. Reaction with triphosgene
gave oxazolidinone 18, which was separated into racemic cis- and
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Table 1. Continued
Table 1. SAR of Biphenyl-Substituted Oxazolidinones
a Average of one or more 10-point titrations. b Transgenic mouse
pharmacodynamic assay: C57BL/6 male mice 12ꢀ16 weeks of age
expressing cynomolgus monkey CETP were used.58 Predose blood
samples were collected by retro-orbital bleed. Compounds were for-
mulated in DMSO/cremophor/saline at a 4:4:92 ratio and screened at
10 mg/kg PO BID. Twenty-four hours after the first dose, the mice were
euthanized and blood was collected by cardiac puncture. HDL-C was
measured on the pre- and postbleed samples using a HDL-E biochemical
assay kit from Wako Chemicals USA (catalogue no. 431-52501),
following manufacturer’s instructions. The ΔHDL-C reported is relative
to the baseline. A change in HDL-C of 5 mg/dL or less was generally
c
considered not significant. Mean increase in HDL cholesterol in B6-
Tg(CETP) mice (mean of 5 mice per dose). d n.m.: not measured. e n.d.:
not determined; indicates <50% inhibition of CETP at a concentration
of 100 μM. f Mean increase in HDL cholesterol in B6-Tg(CETP) mice
(mean of 9 mice per dose). g This compound was synthesized using the
same procedure as for compound (ꢀ)-253 by substituting boronic acid
10 for boronic acid 28.
A more efficient synthesis of the required oxazolidinone
enantiomer (ꢀ)-cis-18 was developed as shown in Scheme 3.
Amide 23, conveniently accessed from carboxylic acid 24, was
initially deprotonated with an equivalent of isopropylmagnesium
chloride and then treated with Grignard reagent 25 (generated
by treatment of 1-iodo-3,5-bis(trifluoromethyl)benzene with
ethylmagnesium bromide) to give ketone 26.54 Diastereoselec-
tive reduction of ketone 26 with triethylsilane in TFA afforded
syn-alcohol 27.55 Treatment of this alcohol with aqueous sodium
hydroxide gave oxazolidinone (ꢀ)-cis-18 in enantiopure form.
Parallel SAR studies had shown that incorporation of fluorine
into the anisole ring was beneficial for improving potency and
pharmacokinetics. The requisite fluorine atom was incorporated
at the 4-position of the biphenyl moiety as shown in Schemes 4,
5, and 6. The required boronic acid 28 was synthesized as shown
in Scheme 4. Acetophenone 29 was treated with methylmagne-
sium bromide to afford alcohol 30. Elimination of 30 to afford
the styrene derivative 31 was effected by treatment with mesyl
chloride. Alternatively, acetophenone 29 was reacted with
methyltriphenylphosphonium bromide to directly afford 31.
Reduction of alkene 31 was facilitated by hydrogenation with
palladium on carbon, and then iodination of the resulting
product with iodine and silver sulfate afforded aryl iodide 32.
Iodide 32 was converted to boronic acid 28 by treatment with
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butyllithium and trimethyl borate. Boronic acid 28 was subse-
quently incorporated into derivatives by one of two methods.
As shown in Scheme 5, nitrile 9 was hydrolyzed to carboxylic
acid 33 with KOH. This was then reduced to benzyl alcohol 34
with borane. 34 was converted to benzyl bromide 35 with
triphenylphosphine and carbon tetrabromide. Benzyl bromide
35 was then coupled with oxazolidinone (ꢀ)-cis-18 to afford
36. Finally, aryl iodide 36 was coupled with boronic acid 28 to
afford derivative (þ)-cis-3. Alternatively, as in Scheme 6, palla-
dium catalyzed coupling of boronic acid 28 with 34 afforded
alcohol 37, which was further converted to benzyl bromide 38
using triphenylphosphine and carbon tetrabromide. Benzyl
bromide 38 was incorporated into final derivatives in a manner
analogous to Scheme 1 and in the following description.
Multiple substitution of the oxazolidinone 4-position was
investigated by synthesizing gem-dimethyl derivative 39. This
compound was synthesized by a route analogous to that shown in
Scheme 3 starting with 40, followed by separation of enantiomers
by chiral HPLC (Scheme 7). Carboxylic acid 40 was first
converted to aldehyde 41 via reduction of the corresponding
Weinreb amide 42 with DIBAL-H. Treatment of aldehyde 41
with [3,5-bis(trifluoromethyl)phenyl]magnesium bromide (25)
afforded racemic alcohol 43. In situ cyclization and coupling of
43 with benzyl bromide 38 using two equivalents of NaH
afforded derivatives (þ)-39 and (ꢀ)-39.
Table 2. Dose Titration of Anacetrapib ((þ)-cis-3) in B6-
Tg(CETP) Mice
oral dose BID (mg/kg)
ΔHDL-C (mg/dL)a
10
3
35.3 ( 1.17
21.7 ( 1.26
16.4 ( 1.56
14.0 ( 1.06
1
0.3
a Transgenic mouse pharmacodynamic assay: C57BL/6 male mice
12ꢀ16 weeks of age expressing cynomolgus monkey CETP were used.58
Predose blood samples were collected by retro-orbital bleed. Com-
pounds were formulated in DMSO/cremophor/saline at a 4:4:92 ratio
and screened at 10 mg/kg PO BID. Twenty-four hours after the first
dose, the mice were euthanized and blood was collected by cardiac
puncture. HDL-C was measured on the pre- and postbleed samples
using a HDL-E biochemical assay kit from Wako Chemicals USA
(catalogue no. 431-52501), following manufacturer’s instructions. The
ΔHDL-C reported is relative to the baseline. A change in HDL-C of 5
mg/dL or less was generally considered not significant. Mean increase in
HDL cholesterol ( SEM in B6-Tg(CETP) mice (mean of 9 mice per
dose).
Compound (þ)-44 was synthesized as shown in Scheme 8.
Ketone 26 was treated with methylmagnesium bromide to afford
alcohol 45 with a diastereoselectivity of >98:2. Treatment of 45
with potassium hydroxide afforded oxazolidinone 46, which was
coupled with benzyl bromide 38 to afford compound (þ)-44.
’ RESULTS AND DISCUSSION
The inhibition of CETP mediated CE transfer for compounds
synthesized was characterized in vitro using a fluorescence
transfer assay with human recombinant CETP.56 The assay uses
synthetic HDL donor particles that contain self-quenching
BODIPY labeled CE along with an additional fluorescence
quencher. As the BODIPY labeled CE is transferred from the
donor particle to an acceptor lipoprotein by CETP, fluorescence
is observed and quantified. Inhibition of CETP mediated CE
transfer is characterized by a decrease in levels of fluorescence
observed relative to control.
Test compounds were characterized in an in vivo pharmaco-
dynamic assay using C57BL/6 mice that were transgenic for
Cynomolgus monkey CETP (B6-Tg(CETP)UCTP20Pnu mice).
Mice were prebled and HDL-C levels were measured for each
mouse prior to compound dosing. Compounds were dosed at 10
mg/kg po BID at t = 0 and 7 h, and a terminal bleed was
performed at t = 24 h. HDL-C levels were again measured, and a
change in HDL-C levels was characterized for each animal. Five
mice were dosed with each compound and a mean change in
HDL-C was calculated.
The reason for the lack of efficacy of oxazolidinone 2 in vivo
was not known positively, but it was postulated to be because of a
poor pharmacokinetic profile. It was hypothesized that potency
and pharmacokinetics could be enhanced by further conforma-
tional restriction of the compound. Substitution of the oxazoli-
dinone core with small alkyl groups was one such idea to test this
hypothesis. The first such derivatives investigated were the two
methyl substituted cis-oxazolidinone enantiomers, (þ)-cis-6 and
(ꢀ)-cis-6. Gratifyingly, the CE transfer inhibition potency for
Figure 2
isomer (þ)-cis-6 was found to be 39 nM (isomer (ꢀ)-cis-6 was
inactive), and it elicited a modest increase in HDL-C levels
in vivo of 6.3 mg/dL (Table 1).
Incorporation of the bis-3,5-trifluoromethyl substitution
pattern into the oxazolidinone phenyl ring as found in lead
compound 2 was investigated next. All four possible cis- and
trans-diastereoisomers 14 were synthesized, and the biological
properties of these compounds are shown in Table 1. Consistent
with previous compounds, the majority of the biological activity
was found with cis-enantiomer (þ)-cis-14, which had a CE
transfer inhibition IC50 of 15 nM and increased HDL-C levels
in vivo by 22 mg/dL. The active trans-enantiomer (ꢀ)-trans-14
had the same stereoconfiguration at the oxazolidinone aryl
stereocenter as that found in (þ)-cis-14 and was found to be
approximately 10-fold less active (Table 1). Thus, it was shown
that the (S)- and (R)-stereochemistries at the 4-and 5-positions
respectively were very important for potent CETP inhibition.
The substitution of the oxazolidinone at the 4-position was
further investigated by the synthesis of racemic ethyl derivatives
19. This compound was found to be 10-fold less potent,
indicating a low tolerance for steric bulk in this portion of the
structure (Table 1).
Incorporation of a fluorine atom at the 4-position of the
biphenyl moiety seemed to enhance both potency (compare
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Table 3. Mean Pharmacokinetic Parameters of Anacetrapib ((þ)-cis-3) in Mousea
Clbb (mL/min/kg)
Vdb (L/kg)
T1/2b (h)
AUCNIVb (μM h kg/mg)
AUCNPOb (μM h kg/mg)
Cmaxb (μM)
Tmaxb (h)
Foralb (%)
3
3
3 3
11
2.0
3.6
2.40
0.356
0.28
1.0
15
a The IV doses were formulated in DMSO:PEG400:water (10:55:35. v/v/v) and injected at 0.6 mg/kg to male C57BL/6 mice. The oral doses were
formulated in DMSO:cremophor:saline (2:4:94, v/v/v) and given at 2 mg/kg to mice. b Clb, blood clearance; Vd, volume of distribution; T1/2, terminal
half-life; AUCNIV, IV normalized area under curve; AUCNPO, PO normalized area under curve; Cmax, observed maximal plasma concentration following
oral dosing; Tmax, time to reach the Cmax; Foral, oral bioavailability.
compounds 1 to 51 and (ꢀ)-2 to (ꢀ)-52) and pharmacokinetic
profile (data not shown). Incorporation of this feature into (þ)-
cis-14 gave compound (þ)-cis-3. This compound was found to
inhibit CE transfer with an IC50 of 17 nM and elicit an increase
in HDL-C levels of 28 mg/dL in the B6-Tg(CETP) mouse
in vivo model.
The SAR of the 4-position of the oxazolidinone was further
investigated by the synthesis of gem-dimethyl derivative (þ)-39.
This compound was found to have an identical IC50 to that of
(þ)-cis-3 but did not elicit as great an increase in HDL-C in vivo.
Further substitution of the oxazolidinone 5-position with a
methyl group, affording compound (þ)-44, completely sup-
pressed activity.
After further investigation of the substitution of the oxazoli-
dinone failed to yield any further enhancements in biological
properties, compound (þ)-cis-3 was further characterized by
a dose-titration in the B6-Tg(CETP) mouse in vivo model
(Table 2 and Figure 2). The compound consistently increased
HDL-C levels in a dose dependent manner at doses of 0.3, 1, 3,
and 10 mg/kg, respectively. The pharmacokinetics of (þ)-cis-3
was characterized in mice (Table 3), rats and rhesus monkeys.57
Across species, the compound was found to have a pharmaco-
kinetic profile with moderate oral bioavailabilities, and clearances
and half-lives appropriate for QD dosing. On the basis of its
favorable in vitro and in vivo properties, compound (þ)-cis-3 was
selected as a candidate for further development.
and/or cerium ammonium molybdate stain. Low resolution mass
spectra were obtained using a liquid chromatography mass spectrometer
(LCMS) that consisted of an Agilent 1100 series LC coupled to a Waters
Micromass ZQ mass spectrometer (electrospray positive ionization).
The LC used an Xterra C18 3.5 μM column, and compounds were
analyzed using a gradient of 10% MeCN/90% water to 98% MeCN/2%
water over 3.75 min and then 98% MeCN/2% water for 1 min; LC
solvents contained 0.05% TFA. High-resolution mass spectra were
obtained using a LTQ-Orbitrap (Thermo Fisher Scientific) with a
electrospray ionization coupled with Waters Acquity UPLC. Approxi-
mately 3 μL of 10 μM samples were introduced to the mass spectro-
meter by an external loop using 50% MeCN/0.1% HCO2H in water at a
flow rate of 400 μL/min. Preparative chiral HPLC was performed using
20 mm ꢁ 250 mm Chiralpak columns manufactured by Daicel Chemical
Industries, Ltd. Optical purity was characterized by analytical chiral
HPLC with 4.6 mm ꢁ 250 mm Chiralpak or Chiralcel columns
manufactured by Daicel Chemical Industries, Ltd. using a Shimadzu
analytical HPLC system equipped with a Jasco CD-1595 detector. The
sign of rotation was characterized as the sign observed in the CD
spectrum at 235 nm. Reagents were purchased commercially and used
without further purification unless otherwise stated. Final compounds
were judged to be g95% analytically pure based on their LCMS and 1H
NMR spectra. Compounds gave a single LCMS peak with desired MW,
and the only signals detected in the NMR corresponded to the final
compound.
2-Amino-5-(trifluoromethyl)benzonitrile (8). A 2 L flask was
charged with 4-amino-3-iodobenzotrifluoride (7) (100 g, 0.348 mol),
CuCN (40 g, 0.447 mol), and DMF (750 mL). The mixture was heated
at reflux for 1 h. The reaction was cooled and poured into water (3 L)
containing concentrated ammonium hydroxide (300 mL). To the
mixture was added CH2Cl2 (1 L). The mixture was then filtered through
Celite. The layers were separated, and the aqueous layer was back
extracted with CH2Cl2. The organic extracts were combined and the
solvent removed under reduced pressure. The residue was dissolved in
Et2O (1.5 L), and the resulting solution was washed with 1 N
ammonium hydroxide, aq sodium bisulfite, 1 N aq HCl, and brine.
The solution was dried (MgSO4) and filtered through a silica gel plug
containing a layer of MgSO4 on top. The plug was washed with Et2O
(5 L). The Et2O solutions were combined and concentrated to 750 mL
and let stand at room temperature. After 2 days, the resulting solids were
collected, washed with hexanes, and dried under reduced pressure to
’ CONCLUSIONS
Further substitution of the phenyl oxazolidinone moiety of the
CETP inhibitor scaffold (ꢀ)-253 was investigated. Substitution
of the oxazolidinone 4-position in particular provided com-
pounds that were potent orally active inhibitors of CETP. These
compounds inhibited CETP with excellent potency and good
in vivo efficacy in the B6-Tg(CETP) mouse in vivo model. Small
alkyl groups were preferred as substituents at the oxazolidinone
4-position. 4-Methyl and 5-[3,5-bis(trifluoromethyl)phenyl]
were the best substitutions on the oxazolidinone moiety. It was
also shown that the (S)- and (R)-stereochemistries at the 4-and
5-positions respectively were very important for potent CETP
inhibition. Compound (þ)-cis-3 was identified as the compound
with the best overall profile. This compound had excellent CETP
inhibition potency and good preclinical pharmacokinetic para-
meters and in vivo efficacy. Compound (þ)-cis-3 was selected
for clinical study in man and was ultimately designated as
anacetrapib.
1
afford 2-amino-5-(trifluoromethyl)benzonitrile (8) (64.8 g, 76%). H
NMR (500 MHz, CDCl3) δ 7.68 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 6.81
(d, J = 8.5 Hz, 1H), 4.80 (br s, 2H).
2-Iodo-5-(trifluoromethyl)benzonitrile (9). 2-Amino-
5-(trifluoromethyl)benzonitrile (8) (3.06 g, 16.45 mmol) was sus-
pended in CH2I2 (36 mL), and t-butyl nitrite (3.9 mL, 32.9 mmol)
was added dropwise by syringe. The reaction was heated slowly to
100 °C and was maintained at this temperature for 30 min. The reaction
mixture was cooled to room temperature, diluted with hexanes
(200 mL), loaded on a silica gel column, and eluted with 100% hexanes
to 15% EtOAc in hexanes gradient. The resulting product was further
purified by flash chromatography (Si, 5% CH2Cl2 in hexanes) to afford
2-iodo-5-(trifluoromethyl)benzonitrile (9) (3.11 g, 64%), as a colorless
solid. Rf = 0.44 (15% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz)
’ EXPERIMENTAL SECTION
1
General Methods. H NMR spectra were recorded on a Varian
InNova 600 or 500 MHz instrument. Analytical thin-layer chromatog-
raphy (TLC) was carried out using Merck silica gel 60 F254 plates. All
compounds were visualized as single spots using short wave UV light
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Journal of Medicinal Chemistry
ARTICLE
δ 8.10 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.52 (dd, J = 8.5, 1.8
Hz, 1H).
was stirred at room temperature for 1 h, and the reaction mixture was
concentrated in vacuo to afford the crude product. This was purified
by flash chromatography (Si, 12 mm ꢁ 160 mm, 0ꢀ20% EtOAc in
hexanes gradient) to give 2-(bromomethyl)-20-methoxy-50-(propan-2-yl)-4-
(trifluoromethyl)biphenyl (5) (68.6 mg, quantitative yield) as a colorless
oil. Rf =0.95(20%EtOAc/hexanes). LCMScalcd=387.05; found= 387.0
(M þ H)þ. 1H NMR (500 MHz, CDCl3) δ 7.83 (br s, 1H), 7.60 (dd, J =
8.0, 1.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 8.5, 2.3 Hz, 1H),
7.14 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 8.5, 1H), 4.45 (d, J = 10.6 Hz, 1H),
4.33 (d, J = 10.6 Hz, 1H), 3.76 (s, 3H), 2.94 (septet, J = 6.9 Hz, 1H), 1.29
(d, J = 6.9 Hz, 6H).
20-Methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-
2-carbonitrile (11). To a solution of 2-iodo-5-(trifluoromethyl)-
benzonitrile (9) (2.0 g, 6.7 mmol) and (5-isopropyl-2-methoxyphenyl)-
boronic acid (10) (1.6 g, 8.4 mmol) in dimethyl ethylene glycol
(30.4 mL) was added 2 M aq Na2CO3 (6.8 mL), ethanol (9.6 mL),
and water (10 mL). The solution was degassed with nitrogen for 2 min.
(PPh3)4Pd (774 mg, 0.67 mmol) was added, and the solution was
degassed with nitrogen again for 2 min. The solution was divided equally
into two 40 mL microwave tubes. Each tube was degassed with nitrogen
for 1 min, sealed, and placed in a microwave reactor. The wattage was set
for 200 W until the temperature reached 150 °C, and then the
temperature was held at 150 °C for 10 min. The tubes were then cooled
to room temperature, combined, poured into water (50 mL), and
extracted with EtOAc (100 mL). The organic layer was washed with
brine (50 mL), dried (Na2SO4), and concentrated in vacuo to give the
crude product. This was purified by flash chromatography (Si, 15%
CH2Cl2 in hexanes) to afford 20-methoxy-50-(propan-2-yl)-4-(trifluoro-
methyl)biphenyl-2-carbonitrile (11) (2.14 g, 98%), as a light-yellow oil.
Rf = 0.65 (25% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3) δ 7.97
(s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.31 (dd, J =
8.5, 2.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 3.82
(s, 3H), 2.93 (m, 1H), 1.27 (d, J = 7.0 Hz, 6H).
(þ)-(4S,5R)-3-{[20-Methoxy-50-(propan-2-yl)-4-(trifluorome-
thyl)biphenyl-2-yl]methyl}-4-methyl-5-phenyl-1,3-oxazoli-
din-2-one ((þ)-6). Sodium bis(trimethylsilyl)amide (115 μL of a 1 M
solution in THF, 0.115 mmol) was added to a stirred solution of
(4S,5R)-4-methyl-5-phenyl-1,3-oxazolidin-2-one ((ꢀ)-4) (18.5 mg,
0.104 mmol) in dry THF (1 mL) at room temperature under N2. The
reaction was stirred for 15 min and a solution of 2-(bromomethyl)-50-
isopropyl-20-methoxy-4-(trifluoromethyl)biphenyl (5) (20.2 mg,
0.0522 mmol) in dry THF (2 mL) was added via cannula. The reaction
was stirred at room temperature for 3 days. The reaction was quenched
with saturated aq NH4Cl (10 mL) and extracted with EtOAc (3 ꢁ
20 mL). The combined organic extracts were washed with brine
(10 mL), dried (Na2SO4), and concentrated in vacuo to give the crude
product. This was purified by flash chromatography (Si, 12 mm ꢁ 160
mm, 0ꢀ40% EtOAc in hexanes gradient) to afford (þ)-(4S,5R)-3-{[20-
methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-
methyl-5-phenyl-1,3-oxazolidin-2-one ((þ)-6) (16.1 mg, 63%) as a
colorless oil. Rf = 0.45 (20% EtOAc/hexanes). LCMS calcd = 484.21;
found = 484.2 (M þ H)þ. 1H NMR (500 MHz, benzene-d6, 1:1 mixture
of atropisomers) δ 7.99 (s, 0.5H), 7.77 (s, 0.5H), 7.35 (d, J = 7.7 Hz,
1H), 7.12ꢀ6.95 (m, 5H), 6.94ꢀ6.86 (m, 3H), 6.64 (d, J = 8.5 Hz, 0.5H),
6.55 (d, J = 8.5 Hz, 0.5H), 4.97ꢀ4.75 (m, 2H), 4.06 (d, J = 15.8 Hz,
0.5H), 3.95 (d, J = 15.9 Hz, 0.5H), 3.36 (s, 1.5H), 3.23ꢀ3.16 (m, 2H),
3.15ꢀ3.06 (m, 0.5H), 2.79ꢀ2.68 (m, 1H), 1.20ꢀ1.14 (m, 6H), 0.09 (d,
J = 6.5 Hz, 1.5H), 0.03 (d, J = 6.5 Hz, 1.5H). HRMS (ESþ) calcd for
C28H29F3NO3 (M þ H)þ m/e, 484.2094; found, 484.2081.
20-Methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-
2-carboxylic acid (12). A solution of 20-methoxy-50-(propan-2-yl)-
4-(trifluoromethyl)biphenyl-2-carbonitrile (11) (727 mg, 2.28 mmol)
and KOH (767 mg, 13.7 mmol) in water (7.70 mL) and i-PrOH
(11.55 mL) was subjected to microwave irradiation (300 W, 130 °C, 4 h)
in a sealed tube. The reaction mixture was concentrated in vacuo to
remove the i-PrOH. The aqueous slurry obtained was diluted with
water (50 mL) and extracted with EtOAc (50 mL). The organic extract
was dried (Na2SO4) and concentrated in vacuo to afford byproduct
50-isopropyl-20-methoxy-4-(trifluoromethyl)biphenyl-2-carboxamide.
The aqueous layer was acidified with concentrated HCl and extracted
with EtOAc (3 ꢁ 50 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo to give 20-methoxy-50-(propan-2-
yl)-4-(trifluoromethyl)biphenyl-2-carboxylic acid (12) (335.2 mg, 43%)
as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 8.01 (s, 1H), 7.71
(d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.04
(s, 1H), 6.77 (d, J = 8.1 Hz, 1H), 3.68 (s, 3H), 2.84 (septet, J = 6.7 Hz,
1H), 1.19 (d, J = 6.7 Hz, 6H).
[20-Methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-
2-yl]methanol (13). A solution of borane in THF (1 M, 2.98 mL,
2.98 mmol) was added dropwise to a stirred solution of 20-methoxy-
50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-carboxylic acid (12)
(335.2 mg, 0.992 mmol) in dry THF (10.5 mL) at room temperature
under N2. The reaction was stirred overnight at room temperature and
carefully quenched with water (10 mL). The mixture was extracted with
EtOAc (3 ꢁ 20 mL), and the combined extracts were washed with brine,
dried (Na2SO4), and concentrated in vacuo to give the crude product.
This was purified by flash chromatography (Si, 25 mm ꢁ 160 mm,
0ꢀ30% EtOAc in hexanes gradient) to afford [20-methoxy-50-(propan-
2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methanol (13) (268.5 mg, 83%), as
a colorless oil. Rf = 0.27 (10% EtOAc/hexanes). 1H NMR (500 MHz,
CDCl3) δ 7.89 (br s, 1H), 7.62 (dd, J = 8.0, 1.3 Hz, 1H), 7.36 (d, J = 8.0
Hz, 1H), 7.29 (dd, J = 8.5, 2.3 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H), 6.96 (d,
J = 8.5, 1H), 4.51 (m, 2H), 3.74 (s, 3H), 2.93 (septet, J = 7.0 Hz, 1H),
2.51 (s, 1H), 1.29 (d, J = 7.0 Hz, 6H).
(ꢀ)-(4R,5S)-3-{[20-Methoxy-50-(propan-2-yl)-4-(trifluoro-
methyl)biphenyl-2-yl]methyl}-4-methyl-5-phenyl-1,3-oxazo-
lidin-2-one ((ꢀ)-6). Sodium bis(trimethylsilyl)amide (105 μL of a
1 M solution in THF, 0.105 mmol) was added to a stirred solution
of (4R,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one ((þ)-4) (16.8 mg,
0.0950 mmol) in dry THF (1 mL) at room temperature under N2. The
reaction was stirred for 15 min, and a solution of 2-(bromomethyl)-50-
isopropyl-20-methoxy-4-(trifluoromethyl)biphenyl (5) (18.4 mg, 0.0475
mmol) in dry THF (2 mL) was added via cannula. The reaction was
stirred at room temperature for 3 days. The reaction was quenched with
saturated aq NH4Cl (10 mL) and extracted with EtOAc (3 ꢁ 20 mL).
The combined organic extracts were washed with brine (10 mL), dried
(Na2SO4), and concentrated in vacuo to give the crude product. This
was purified by flash chromatography (Si, 12 mm ꢁ 160 mm, 0ꢀ40%
EtOAc in hexanes gradient) to afford (ꢀ)-(4R,5S)-3-{[20-methoxy-
50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-meth-
yl-5-phenyl-1,3-oxazolidin-2-one ((ꢀ)-6) (12.7 mg, 55%) as a color-
less oil. Rf = 0.45 (20% EtOAc/hexanes). LCMS calcd = 484.21;
1
found = 484.2 (M þ H)þ. H NMR (500 MHz, benzene-d6, 1:1
mixture of atropisomers) δ 7.99 (s, 0.5H), 7.77 (s, 0.5H), 7.35 (d, J =
7.6 Hz, 1H), 7.12ꢀ6.95 (m, 5H), 6.94ꢀ6.86 (m, 3H), 6.64 (d, J = 8.5
Hz, 0.5H), 6.55 (d, J = 8.5 Hz, 0.5H), 4.96ꢀ4.75 (m, 2H), 4.06 (d, J =
15.8 Hz, 0.5H), 3.95 (d, J = 15.9 Hz, 0.5H), 3.36 (s, 1.5H), 3.34ꢀ3.03
(m, 2H), 3.16ꢀ3.07 (m, 0.5H), 2.79ꢀ2.68 (m, 1H), 1.20ꢀ1.14 (m,
6H), 0.09 (d, J = 6.5 Hz, 1.5H), 0.03 (d, J = 6.5 Hz, 1.5H). HRMS
(ESþ) calcd for C28H29F3NO3 (M þ H)þ m/e, 484.2094; found,
484.2083.
2-(Bromomethyl)-20-methoxy-50-(propan-2-yl)-4-(trifluoro-
methyl)biphenyl (5). CBr4 (112 mg, 0.211 mmol) and Ph3P (55 mg,
0.211 mmol) were added successively to a stirred solution of [20-methoxy-
50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methanol (13) (57.1
mg, 0.176 mmol) in dry CH2Cl2 (1 mL) at 0 °C under N2. The solution
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ARTICLE
1-[3,5-Bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol (16).
A stirred solution of 3,5-bis(trifluoromethyl)benzaldehyde (15) (1.00 g,
4.13 mmol) and nitroethane (1.13 g, 1.08 mL, 15.1 mmol) in absolute
EtOH (20 mL) at 0 °C was treated with 10% (m/v) aq NaOH (1.73 mL,
4.34 mmol), stirred for 1 h, and treated with 2% (m/v) aq acetic acid
(13.0 mL, 4.34 mmol). The reaction was stirred for 1 h at room
temperature and then partitioned between water (50 mL) and EtOAc
(50 mL). The aqueous layer was extracted with EtOAc (2 ꢁ 50 mL), and
the combined organic extracts were washed with saturated aq NaHCO3
(50 mL) and brine (50 mL), dried (Na2SO4), and concentrated in vacuo
to afford a 1.5:1 mixture of trans- and cis-1-[3,5-bis(trifluoromethyl)-
phenyl]-2-nitropropan-1-ol (16) (1.30 g, 99%) as a colorless oil. 1H NMR
(500 MHz, CDCl3) trans-diastereoisomer: δ 7.88 (br s, 1H), 7.86 (br s,
2H), 5.22 (d, J = 8.4 Hz, 1H), 4.77 (dq, J = 8.4, 6.9 Hz, 1H), 3.03 (br s
1H), 1.42 (d, J = 6.9 Hz, 3H); cis-diastereoisomer: δ 7.90 (br s, 1H), 7.86
(br s, 2H), 5.59 (d, J = 3.2 Hz, 1H), 4.72 (dq, J = 3.2, 6.9 Hz, 1H), 3.03 (br
s 1H), 1.50 (d, J = 6.9 Hz, 3H).
2-Amino-1-[3,5-bis(trifluoromethyl)phenyl]propan-1-ol
(17). A suspension of Raney nickel (50 mg) in a solution of a 1.5:1
mixture of trans- and cis-1-[3,5-bis(trifluoromethyl)phenyl]-2-nitropro-
pan-1-ol (16) (50 mg, 0.158 mmol) in 30% (v/v) aq HCO2H (0.75 mL)
and MeOH (10 mL) was stirred overnight at room temperature under
H2 (15 psi). The reaction mixture was filtered through a pad of Celite,
and the filtrate was concentrated in vacuo to remove the MeOH. The
aqueous slurry was adjusted to pH 9ꢀ10 with 28% aq NH4OH, diluted
with water (20 mL), and extracted with EtOAc (3 ꢁ 20 mL). The
combined extracts were washed with brine (10 mL), dried (Na2SO4),
and concentrated in vacuo to afford a 1.5:1 mixture of trans- and cis-2-
amino-1-[3,5-bis(trifluoromethyl)phenyl]propan-1-ol (17) (39.1 mg,
86%) as a colorless solid. LCMS calcd = 288.08; found = 288.1 (M þ
H)þ. 1H NMR (500 MHz, CDCl3) trans-diastereoisomer: δ 7.79 (br s,
3H), 4.35 (br s, 1H), 3.25 (br s, 1H), 2.59 (br s, 3H), 0.86 (d, J = 6.1 Hz,
3H); cis-diastereoisomer: δ 7.79 (br s, 3H), 4.71 (br s, 1H), 3.00 (br s,
1H), 2.59 (br s, 3H), 1.06 (d, J = 5.0 Hz, 3H).
5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[20-methoxy-50-(propan-
2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-
oxazolidin-2-one ((þ)-cis-14). Sodium bis(trimethylsilyl)amide
(172 μL of a 1 M solution in THF, 0.172 mmol) was added to a stirred
solution of cis-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazoli-
din-2-one ((()-cis-18) (50 mg, 0.129 mmol) in dry THF (1 mL) at
room temperature under N2. The reaction was stirred for 15 min, and a
solution of 2-(bromomethyl)-50-isopropyl-20-methoxy-4-(trifluoromethyl)-
biphenyl (5) (27.0 mg, 0.0861 mmol) in dry THF (2 mL) was added
via cannula. The reaction was stirred at room temperature for 3 days.
The reaction was quenched with saturated aq NH4Cl (10 mL) and
extracted with EtOAc (3 ꢁ 20 mL). The combined organic extracts were
washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo
to give the crude product. This was purified by flash chromatography (Si,
12 mm ꢁ 160 mm, 0ꢀ40% EtOAc in hexanes gradient) to afford cis-
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[20-methoxy-50-(propan-2-yl)-4-
(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
((()-cis-14) (40.8 mg, 76%) as a colorless oil. Rf = 0.64 (20% EtOAc/
hexanes). LCMS calcd = 620.18; found = 620.2 (M þ H)þ. 1H NMR
(600 MHz, benzene-d6, 1:1 mixture of atropisomers) δ 7.94 (s, 0.5H),
7.72 (s, 0.5H), 7.64 (s, 0.5H), 7.63 (s, 0.5H), 7.39ꢀ7.34 (m, 3H),
7.12ꢀ7.04 (m, 2H), 6.95 (d, J = 2.1 Hz, 0.5H), 6.86 (d, J = 1.7 Hz, 0.5H),
6.64 (d, J = 8.5 Hz, 0.5H), 6.56 (d, J = 8.5 Hz, 0.5H), 4.99 (d, J = 15.9 Hz,
0.5H), 4.93 (d, J = 15.9 Hz, 0.5H), 4.73 (d, J = 7.9 Hz, 0.5H), 4.61 (d, J =
7.9 Hz, 0.5H), 3.88 (d, J = 15.9 Hz, 0.5H), 3.82 (d, J = 15.9 Hz, 0.5H),
3.35 (s, 1.5H), 3.24 (s, 1.5H), 3.05 (septet, J = 6.9 Hz, 0.5H), 3.01
(septet, J = 6.9 Hz, 0.5H), 2.75 (m, 1H), 1.19 (dd, J = 6.9, 2.7 Hz, 3H),
1.17 (dd, J = 10.9, 6.9 Hz, 3H), ꢀ0.18 (d, J = 6.4 Hz, 1.5H), ꢀ0.33 (t, J =
6.4 Hz, 1.5H). This compound was separated into its enantiomers
(ꢀ)-(4R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[20-methoxy-50-
(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-
oxazolidin-2-one ((ꢀ)-cis-14) (HRMS (ESþ) calcd for C30H27F9NO3
(M þ H)þ m/e, 620.1842; found, 620.1823) and (þ)-(4S,5R)-5-[3,5-
bis(trifluoromethyl)phenyl]-3-{[20-methoxy-50-(propan-2-yl)-4-(triflu-
oromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one ((þ)-
cis-14) (HRMS (ESþ) calcd for C30H27F9NO3 (M þ H)þ m/e,
620.1842; found, 620.1826) using chiral HPLC (AD column, 20 mm
ꢁ 250 mm, 3% i-PrOH in heptane).
5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazo-
lidin-2-one (18). Diisopropylethylamine (106 mg, 142 μL, 0.817
mmol) and triphosgene (20.2 mg, 0.068 mmol) were added successively
to a stirred solution of a 1.5:1 mixture of trans- and cis-2-amino-1-[3,5-
bis(trifluoromethyl)phenyl]propan-1-ol (17) (39.1 mg, 0.136 mmol) in
dry CH2Cl2 (10 mL) at 0 °C under N2. The reaction was stirred at 0 °C
for 1 h and then concentrated in vacuo to a volume of about 5 mL. The
mixture was diluted with water (50 mL) and extracted with EtOAc (3 ꢁ
50 mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to give the crude product. This was purified by
flash chromatography (Si, 12 mm ꢁ 160 mm, 0ꢀ70% EtOAc in hexanes
gradient) to afford trans-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-
1,3-oxazolidin-2-one ((()-trans-18) (17.5 mg) and cis-5-[3,5-bis-
(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one ((()-cis-18)
(14.4 mg) (overall yield 75%), as colorless solids. trans-Diastereoisomer:
Rf = 0.63 (50% EtOAc/hexanes). LCMS calcd = 314.06; found = 314.1
(M þ H)þ. 1H NMR (600 MHz, CDCl3) δ 7.90 (br s, 1H), 7.83 (br s,
2H), 6.71 (br s, 1H), 5.17 (d, J = 7.0 Hz, 1H), 3.86 (br pentet, J = 6.2 Hz,
1H), 1.48 (d, J = 6.2 Hz, 1H). cis-diastereoisomer: Rf = 0.38 (50%
EtOAc/hexanes). LCMS calcd = 314.06; found =314.1 (M þ H)þ. 1H
NMR (600 MHz, CDCl3) δ 7.90 (br s, 1H), 7.79 (br s, 2H), 5.83 (d, J =
8.0 Hz, 1H), 5.34 (br s, 1H), 4.31 (br pentet, J = 7.0 Hz, 1H), 0.84 (d, J =
6.6 Hz, 1H). This compound was separated into its enantiomers
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-
one ((ꢀ)-cis-18) and (4R,5S)-5-[3,5-bistrifluoromethyl)phenyl]-4-
methyl-1,3-oxazolidin-2-one ((þ)-cis-18) using chiral HPLC (AS col-
umn, 20 mm ꢁ 250 mm, 15% i-PrOH in heptane).
(þ)-(4S,5S)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[20-meth-
oxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-
4-methyl-1,3-oxazolidin-2-one ((þ)-trans-14) and (ꢀ)-(4R,5R)-
5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[20-methoxy-50-(propan-
2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-
oxazolidin-2-one ((ꢀ)-trans-14). Sodium bis(trimethylsilyl)amide
(112 μL of a 1 M solution in THF, 0.112 mmol) was added to a stirred
solution of trans-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazo-
lidin-2-one ((()-trans-18) (17.5 mg, 0.0559 mmol) in dry THF (1 mL)
at room temperature under N2. The reaction was stirred for 15 min, and
a solution of 2-(bromomethyl)-50-isopropyl-20-methoxy-4-(trifluorome-
thyl)biphenyl (5) (32.0 mg, 0.0838 mmol) in dry THF (2 mL) was added
via cannula. The reaction was stirred at room temperature for 3 days. The
reaction was quenched with saturated aq NH4Cl (10 mL) and extracted
with EtOAc (3 ꢁ 20 mL). The combined organic extracts were washed
with brine (10 mL), dried (Na2SO4), and concentrated in vacuo to give
the crude product. This was purified by flash chromatography (Si, 12 mm
ꢁ 160 mm, 0ꢀ50% EtOAc in hexanes gradient) to afford trans-5-[3,5-
bis(trifluoromethyl)phenyl]-3-{[20-methoxy-50-(propan-2-yl)-4-(trifluo-
romethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one ((()-
trans-14) (30.2 mg, 87%) as a colorless oil. Rf = 0.46 (20% EtOAc/
hexanes). LCMS calcd = 620.18; found = 620.2 (M þ H)þ. 1H NMR
(600 MHz, benzene-d6, 1:1 mixture of atropisomers) δ 7.83 (s, 0.5H),
7.80 (s, 0.5H), 7.70 (s, 1H), 7.52 (s, 1H), 7.49 (s, 1H), 7.31ꢀ7.24 (m,
1H), 7.12ꢀ7.07 (m, 1H), 7.04 (d, J = 8.0 Hz, 0.5H), 7.00 (d, J = 7.9 Hz,
0.5H), 6.88ꢀ6.87 (m, 1H), 6.61 (d, J = 8.5 Hz, 0.5H), 6.58 (d, J = 8.5 Hz,
(ꢀ)-(4R,5S)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[20-meth-
oxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-
4-methyl-1,3-oxazolidin-2-one ((ꢀ)-cis-14) and (þ)-(4S,5R)-
4888
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Journal of Medicinal Chemistry
ARTICLE
0.5H), 4.72 (d, J = 16.3 Hz, 0.5H), 4.44 (d, J = 16.3 Hz, 0.5H), 4.30ꢀ4.22
(m, 1.5H), 4.05 (d, J = 16.3 Hz, 0.5H), 3.23 (s, 1.5H), 3.20 (s, 1.5H),
2.79ꢀ2.72 (m, 1.5H), 2.74ꢀ2.67 (m, 0.5H), 1.20ꢀ1.17 (m, 6H),
0.42ꢀ0.37 (m, 3H). This compound was separated into its enantiomers
(þ)-(4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[20-methoxy-50-
(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-
1,3-oxazolidin-2-one ((þ)-trans-14) (HRMS (ESþ) calcd for C30H27F9NO3
(M þ H)þ m/e, 620.1842; found, 620.1824) and (ꢀ)-(4R,5R)-5-[3,5-
bis(trifluoromethyl)phenyl]-3-{[20-methoxy-50-(propan-2-yl)-4-(trifluoro-
methyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one ((ꢀ)-trans-
14) (HRMS (ESþ) calcd for C30H27F9NO3 (M þ H)þ m/e, 620.1842;
found, 620.1825) using chiral HPLC (AD column, 20 mm ꢁ 250 mm, 3% i-
PrOH in heptane).
NMR (500 MHz, CDCl3) δ 7.89 (s, 1H), 7.81 (s, 2H), 7.16 (s, 1H), 5.25
(d, J = 6.1 Hz, 1H), 3.69 (q, J = 6.2 Hz, 1H), 1.90ꢀ1.70 (m, 2H),
1.09ꢀ1.02 (m, 3H). cis-diastereoisomer: Rf = 0.49 (50% EtOAc/
hexanes). LCMS calcd = 328.08; found = 328.1 (M þ H)þ. 1H NMR
(500 MHz, CDCl3) δ 7.88 (s, 1H), 7.78 (s, 2H), 7.14 (s, 1H), 5.84 (d, J =
8.3 Hz, 1H), 4.11ꢀ4.05 (m, 1H), 1.08ꢀ0.94 (m, 2H), 0.86 (t, J = 7.3 Hz,
3H).
(()-cis-5-[3,5-Bis(trifluoromethyl)phenyl]-4-ethyl-3-{[20-
methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]-
methyl}-1,3-oxazolidin-2-one (19). Sodium bis(trimethylsilyl)amide
(138 μL of a 1 M solution in THF, 0.138 mmol) was added to a stirred
solution of (()-cis-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethyl-1,3-oxazoli-
din-2-one ((()-cis-22) (23.0 mg, 0.0689 mmol) in dry THF (1 mL) at
room temperature under N2. The reaction was stirred for 15 min, and a
solution of 2-(bromomethyl)-20-methoxy-50-(propan-2-yl)-4-(trifluoro-
methyl)biphenyl (5) (40.0 mg, 0.0838 mmol) in dry THF (2 mL) was
added via cannula. The reaction was stirred at room temperature for 3 days.
The reaction was quenched with saturated aq NH4Cl (10 mL) and
extracted with EtOAc (3 ꢁ 20 mL). The combined organic extracts were
washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo to
give the crude product. This was purified by flash chromatography (Si, 12
mm ꢁ 160 mm, 0ꢀ40% EtOAc in hexanes gradient) to afford (()-cis-
5-[3,5-bis(trifluoromethyl)phenyl]-4-ethyl-3-{[20-methoxy-50-(propan-2-yl)-
4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one ((()-cis-
19) (22.6 mg, 51%) as a colorless oil. Rf = 0.53 (20% EtOAc/hexanes).
LCMS calcd = 634.20; found = 634.2 (M þ H)þ. 1H NMR (500 MHz,
benzene-d6, 1:1 mixture of atropisomers) δ 7.95 (s, 0.5H), 7.69 (s, 0.5H),
7.61 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.38 (s, 0.5H), 7.36 (s, 0.5H),
7.13ꢀ7.05 (m, 1H), 7.04 (d, J=8.5Hz, 1H), 6.95(d,J= 2.4 Hz, 0.5H), 6.87
(d, J = 2.3 Hz, 0.5H), 6.62 (d, J = 8.5 Hz, 0.5H), 6.52 (d, J = 8.5 Hz, 0.5H),
5.00 (d, J = 8.3 Hz, 0.5H), 4.97 (d, J = 8.1 Hz, 0.5H), 4.70 (d, J = 7.9 Hz,
0.5H), 4.57 (d, J = 7.8 Hz, 0.5H), 3.94 (d, J = 15.8 Hz, 0.5H), 3.90 (d, J =
15.7 Hz, 0.5H), 3.38 (s, 1.5H), 3.18 (s, 1.5H), 2.99ꢀ2.88 (m, 1H),
2.78ꢀ2.68 (m, 1H), 1.19ꢀ1.14 (m, 6H), 0.62ꢀ0.30 (m, 2H), ꢀ0.04 (t, J =
7.4 Hz, 1.5H), ꢀ0.12 (t, J = 7.4 Hz, 1.5H). HRMS (ESþ) calcd for
C31H29F9NO3 (M þ H)þ m/e, 634.1998; found, 634.1974.
1-[3,5-Bis(trifluoromethyl)phenyl]-2-nitrobutan-1-ol (20).
A stirred solution of 3,5-bis(trifluoromethyl)benzaldehyde (15) (1.00 g,
4.13 mmol) and nitropropane (1.34 g, 1.08 mL, 15.1 mmol) in absolute
EtOH (20 mL) at 0 °C was treated with 10% aq NaOH (m/v) (1.73 mL,
4.34 mmol), stirred for 1 h, and treated with 2% (m/v) aq acetic acid
(13.0 mL, 4.34 mmol). The reaction was stirred for 1 h at room
temperature and then partitioned between water (50 mL) and EtOAc
(50 mL). The aqueous layer was extracted with EtOAc (2 ꢁ 50 mL), and
the combined organic extracts were washed with saturated aq NaHCO3
(50 mL) and brine (50 mL), dried (Na2SO4), and concentrated in vacuo
to afford a 2:1 mixture of trans- and cis-1-[3,5-bis(trifluoromethyl)-
1
phenyl]-2-nitrobutan-1-ol (20) (1.33 g, 97%), as a colorless oil. H
NMR (600 MHz, CDCl3) trans-diastereoisomer: δ 7.89 (br s, 1H), 7.86
(br s, 2H), 5.20 (d, J = 8.5 Hz, 1H), 4.63ꢀ4.56 (m, 1H), 3.14 (br s 1H),
1.98ꢀ1.87 (m, 1 H), 1.51ꢀ1.43 (m, 1 H), 0.92 (t, J = 7.3 Hz, 3H); cis-
diastereoisomer: δ 7.89 (br s, 1H), 7.86 (br s, 2H), 5.36 (d, J = 4.3 Hz,
1H), 4.63ꢀ4.56 (m, 1H), 3.14 (br s 1H), 2.22ꢀ2.13 (m, 1 H), 1.83ꢀ
1.75 (m, 1 H), 0.94 (t, J = 7.3 Hz, 3H).
2-Amino-1-[3,5-bis(trifluoromethyl)phenyl]butan-1-ol (21).
A suspension of Raney nickel (500 mg) in a solution of a 2:1 mixture of
trans- and cis-1-[3,5-bis(trifluoromethyl)phenyl]-2-nitrobutan-1-ol (20)
(1,22 g, 3.68 mmol) in 30% (v/v) aq HCO2H (3.75 mL) and MeOH
(50 mL) was stirred overnight at room temperature under H2 (15 psi). The
reaction mixture was filtered through a pad of Celite, and the filtrate was
concentrated in vacuo to remove the MeOH. The aqueous slurry was
adjusted to pH 9ꢀ10 with 28% aq NH4OH, diluted with water (50 mL),
and extracted with EtOAc (3 ꢁ 50 mL). The combined extracts were
washed with brine (50 mL), dried (Na2SO4), and concentrated in vacuo to
afford a 2:1 mixture of trans- and cis-2-amino-1-[3,5-bis(trifluoromethyl)-
phenyl]butan-1-ol (21) (1.04 g, 94%) as a colorless solid. LCMS calcd =
302.10; found = 302.1 (M þ H)þ. 1H NMR (600 MHz, CDCl3) trans-
diastereoisomer: δ 7.80 (br s, 3H), 4.43 (d, J = 5.8 Hz, 1H), 2.75ꢀ2.71 (m,
1H), 1.57ꢀ1.49 (m, 1 H), 1.37ꢀ1.24 (m, 1H), 0.98 (t, J = 7.4 Hz, 3H); cis-
diastereoisomer: δ 7.80 (br s, 3H), 4.74 (d, J = 4.3 Hz, 1H), 3.02ꢀ2.98 (m,
1H), 1.37ꢀ1.24 (m, 1H), 1.07 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H).
(()-trans-5-[3,5-Bis(trifluoromethyl)phenyl]-4-ethyl-3-{[20-
methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]-
methyl}-1,3-oxazolidin-2-one (19). Sodium bis(trimethylsilyl)-
amide (138 μL of a 1 M solution in THF, 0.138 mmol) was added to
a stirred solution of (()-trans-5-[3,5-bis(trifluoromethyl)phenyl]-4-eth-
yl-1,3-oxazolidin-2-one ((()-trans-19) (23.0 mg, 0.0689 mmol) in dry
THF (1 mL) at room temperature under N2. The reaction was stirred for
15 min, and a solution of 2-(bromomethyl)-20-methoxy-50-(propan-2-yl)-
4-(trifluoromethyl)biphenyl (5) (40.0 mg, 0.0838 mmol) in dry THF
(2 mL) was added via cannula. The reaction was stirred at room
temperature for 3 days. The reaction was quenched with saturated aq
NH4Cl (10 mL) and extracted with EtOAc (3 ꢁ 20 mL). The combined
organic extracts were washed with brine (10 mL), dried (Na2SO4), and
concentrated in vacuo to give the crude product. This was purified by
flash chromatography (Si, 12 mm ꢁ 160 mm, 0ꢀ40% EtOAc in hexanes
gradient) to afford (()-trans-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethyl-
3-{[20-methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]-
methyl}-1,3-oxazolidin-2-one ((()-trans-19) (41.4 mg, 93%) as a color-
less oil. Rf = 0.41 (20% EtOAc/hexanes). LCMS calcd = 634.20; found =
5-[3,5-Bis(trifluoromethyl)phenyl]-4-ethyl-1,3-oxazolidin-
2-one (22). Diisopropylethylamine (2.68 g, 3.61 mL, 20.7 mmol) and
triphosgene (513 mg, 1.73 mmol) were added successively to a stirred
solution of 2:1 mixture of trans- and cis-2ꢀ2-amino-1-[3,5-bis(trifluoro-
methyl)phenyl]butan-1-ol (21) (1.04 g, 3.46 mmol) in dry CH2Cl2
(220 mL) at 0 °C under N2. The reaction was stirred at 0 °C for 2 h then
concentrated in vacuo to a volume of about 5 mL. The mixture was
diluted with water (50 mL) and extracted with EtOAc (3 ꢁ 50 mL). The
combined organic extracts were dried (Na2SO4) and concentrated in
vacuo to give the crude product. This was purified by flash chromatog-
raphy (Si, 40 mm ꢁ 160 mm, 0ꢀ70% EtOAc in hexanes gradient) to
afford trans-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethyl-1,3-oxazolidin-
2-one ((()-trans-22) (561 mg) and cis-5-[3,5-bis(trifluoromethyl)-
phenyl]-4-ethyl-1,3-oxazolidin-2-one ((()-cis-22) (315.7 mg) (overall
yield 78%) as colorless solids. trans-diastereoisomer: Rf = 0.80 (50%
EtOAc/hexanes). LCMS calcd = 328.08; found = 328.1 (M þ H)þ. 1H
1
634.2 (M þ H)þ. H NMR (500 MHz, benzene-d6, 1:1 mixture of
atropisomers) δ 7.75 (s, 0.5H), 7.70 (s, 1.5H), 7.55ꢀ7.51 (m, 2H),
7.27ꢀ7.20 (m, 1H), 7.09ꢀ7.05 (m, 1H), 7.00 (d, J = 8.0 Hz, 0.5H), 6.97
(d, J = 8.0 Hz, 0.5H), 6.90ꢀ6.78 (m, 1H), 6.56 (d, J = 8.5 Hz, 0.5H), 6.53
(d, J = 8.5 Hz, 0.5H), 4.97 (d, J = 16.2 Hz, 0.5H), 4.54ꢀ4.44 (m, 1.5H),
4.24 (d, J =16.2Hz, 0.5H), 3.94(d, J= 16.2 Hz, 0.5H), 3.18 (s, 1.5H), 3.15
(s, 1.5H), 2.92ꢀ2.81 (m, 1H), 2.77ꢀ2.69 (m, 1H), 1.19ꢀ1.15 (m, 6 H),
0.92ꢀ0.78 (m, 2H), 0.29ꢀ0.24 (m, 3H). HRMS (ESþ) calcd for
C31H29F9NO3 (M þ H)þ m/e, 634.1998; found, 634.1995.
4889
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Journal of Medicinal Chemistry
ARTICLE
Benzyl {(2S)-1-[Methoxy(methyl)amino]-1-oxopropan-2-
yl}carbamate (23). N-Methylmorpholine (5.66 g, 6.16 mL, 56.0
mmol) and isobutyl chloroformate (3.82 g, 3.66 mL, 28.0 mmol) were
added successively to a stirred solution of N-[(benzyloxy)carbonyl]-L-
alanine (24) (5.00 g, 22.4 mmol) in dry CH2Cl2 (50 mL) at 0 °C under
N2. The resulting cloudy mixture was stirred for 15 min at 0 °C. N,O-
Dimethylhydroxylamine hydrochloride (2.62 g, 26.9 mmol) was added
portionwise, and the reaction was warmed to room temperature and
stirred for 3 h. The reaction was poured into 1 N aq HCl (50 mL) and ex-
tracted with CH2Cl2 (3 ꢁ 50 mL). The combined extracts were dried
(Na2SO4) and concentrated in vacuo to give the crude product. This was
purified by flash chromatography (Si, 40 mm ꢁ 160 mm, 0ꢀ70% EtOAc
in hexanes gradient) to afford benzyl {(2S)-1-[methoxy(methyl)-
amino]-1-oxopropan-2-yl}carbamate (23) (5.80 g, 99%) as a colorless
solid. Rf = 0.53 (50% EtOAc/hexanes). LCMS calcd = 267.13; found =
267.3 (M þ H)þ. 1H NMR (500 MHz, CDCl3) δ 7.36ꢀ7.28 (m, 5H),
5.59 (d, J = 8.5 Hz, 1H), 5.12 (d, J = 12.2 Hz, 1H), 5.07 (d, J = 12.3 Hz,
1H), 4.74 (t, J = 7.8 Hz, 1H), 3.77 (s, 3H), 3.20 (s, 3H), 1.34 (d, J = 6.9
Hz, 3H).
vacuo to give the crude product. This was purified by flash chroma-
tography (Si, 40 mm ꢁ 160 mm, 0ꢀ100% EtOAc in hexanes gradient)
to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-ox-
azolidin-2-one ((ꢀ)-cis-18) (660 mg, 68%) as a colorless solid. Rf =
0.33 (50% EtOAc/hexanes). LCMS calcd = 314.06; found = 314.2
(M þ H)þ. 1H NMR (500 MHz, CDCl3) δ 7.89 (s, 1H), 7.78 (s, 2H),
6.33 (s, 1H), 5.82 (d, J = 8.0 Hz, 1H), 4.36ꢀ4.27 (m, 1H), 0.83 (d, J =
6.6 Hz, 3H).
2-(2-Fluoro-4-methoxyphenyl)propan-2-ol (30). A solution
of MeMgBr (2.4 M in THF, 11.6 mmol, 27.8 mmol) was added to a
solution of 20-fluoro-40-methoxyacetophenone (29) (4.45 g, 26.5 mmol)
in dry THF (50 mL) at 0 °C under N2. The mixture was stirred at 0 °C
and then at room temperature for 4 h. The reaction was quenched with
saturated aq NH4Cl. The resulting mixture was extracted with EtOAc
(3 ꢁ 50 mL). The combined extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo to give the crude product. This
was purified by flash chromatography (Si, 20% EtOAc in hexanes) to
afford 2-(2-fluoro-4-methoxyphenyl)propan-2-ol (30) (3.89 g, 80%), as
an oil.
Benzyl {(2S)-1-[3,5-Bis(trifluoromethyl)phenyl]-1-oxo-
propan-2-yl}carbamate (26). A solution of isopropyl magnesium
chloride (1.84 mL of a 2 M solution in THF, 3.68 mmol) was added
dropwise to a stirred solution of benzyl {(2S)-1-[methoxy(methyl)-
amino]-1-oxopropan-2-yl}carbamate (23) (1.00 g, 3.76 mmol) in dry
THF (4.8 mL) at ꢀ15 °C under N2. The reaction was stirred at ꢀ15 °C
for 15 min, and then a solution of 3,5-bis(trifluoromethyl)phenyl
magnesium bromide (25) (prepared by added ethyl magnesium bro-
mide (5.63 mL of a 1 M soln in THF, 5.63 mmol) to a stirred solution of
1-iodo-3,5-bis(trifluoromethyl)benzene (2.11 g, 1.10 mL, 6.20 mmol) in
dry THF (3 mL) at room temperature under N2 and stirring for 25 min)
in dry THF was added dropwise via cannula. The reaction was allowed to
warm to room temperature and was stirred for 45 min. After this time,
additional 3,5-bis(trifluoromethyl)phenyl magnesium bromide (25)
(prepared by added ethyl magnesium bromide (2.82 mL of a 1 M
solution in THF, 2.82 mmol) to a stirred solution of 1-iodo-3,5-
bis(trifluoromethyl)benzene (1.05 g, 0.55 mL, 3.10 mmol) in dry
THF (1.5 mL) at room temperature under N2 and stirring for 25 min)
in THF was generated and added at 0 °C. After stirring for 2 h at room
temperature, the reaction was quenched with 1 N aq HCl (20 mL) and
extracted with EtOAc (3 ꢁ 50 mL). The combined extracts were washed
with brine, dried (Na2SO4), and concentrated in vacuo to give the crude
product. This was purified by flash chromatography (Si, 40 mm ꢁ 160
mm, 0ꢀ20% EtOAc in hexanes gradient) to afford benzyl {(2S)-1-[3,5-
bis(trifluoromethyl)phenyl]-1-oxopropan-2-yl}carbamate (26) (1.30 g,
83%) as a colorless solid. Rf = 0.27 (10% EtOAc/hexanes). LCMS calcd =
420.10; found = 420.2 (M þ H)þ. 1H NMR (500 MHz, CDCl3) δ 8.44
(s, 2H), 8.12 (s, 1H), 7.38ꢀ7.30 (m, 5H), 5.79 (d, J = 7.6 Hz, 1H),
5.42ꢀ5.33 (m, 1H), 5.15 (s, 2H), 1.48 (d, J = 7.2 Hz, 3H).
2-Fluoro-1-isopropenyl-4-methoxybenzene (31). MsCl
(1.95 mL, 25.4 mmol) and Et3N (6.52 mL, 46.5 mmol) were added
successively to a solution of 2-(2-fluoro-4-methoxyphenyl)propan-2-ol
(30) (3.89 g, 21.14 mmol) in dry CH2Cl2 (50 mL) at 0 °C under N2.
The resulting solution was stirred at 0 °C and then at room temperature
for 2 h. The solution was diluted with CH2Cl2 (100 mL), washed with
water, dried (Na2SO4), and concentrated in vacuo to give the crude
product. This was purified by flash chromatography (Si, 10% EtOAc in
hexanes) to afford 2-fluoro-1-isopropenyl-4-methoxybenzene (31)
1
(1.96 g, 56%) as an oil. H NMR (500 MHz, CDCl3) δ 7.25 (t, J =
9.0 Hz, 1H), 6.68 (dd, J = 8.5, 2.5 Hz, 1H), 6.63 (dd, J = 13, 2.5 Hz,1H),
5.20 (d, J = 17.0 Hz, 2H), 3.82 (s, 3H), 2.18 (s, 3H). Alternate method: A
solution of sodium bis(trimethylsilyl)-amide (1.0 M in THF, 714 mL,
0.714 mmol) was added to a suspension of methyltriphenylphospho-
nium bromide (255 g, 0.714 mmol) in dry THF (2.50 L) cooled with an
ice bath. The resultant yellow-colored suspension was stirred for 30 min
at ice bath temperature and then cooled to ꢀ78 °C. A solution of
2-fluoro-4-methoxyacetophenone (29) (100 g, 0.595 mmol) in THF
(200 mL) was added dropwise, and the resulting mixture was stirred at
ꢀ78 °C for 1.5 h. The reaction mixture was allowed to warm to room
temperature over 1 h and then quenched with AcOH (∼80 mL, pH ∼7).
The mixture was stirred for 30 min, concentrated to a slush, diluted with
hexane/EtOAc (7:2), and allowed to stand overnight. Solids were
removed by filtration, and the filtrate was concentrated in vacuo to give
yellow oil. This was purified by flash chromatography (Si, 10% EtOAc in
hexanes) to afford 2-fluoro-1-isopropenyl-4-methoxybenzene (31)
(62.30 g, 63%) as an oil.
1-Fluoro-4-iodo-2-isopropyl-5-methoxybenzene (32). A
solution of 2-fluoro-1-isopropenyl-4-methoxybenzene (31) (1.96 g,
11.81 mmol) in MeOH (30 mL) was charged with hydrogen at 1 atm
with catalytic amount of 10% Pd/C. The mixture was stirred at room
temperature for 1 h. The mixture was filtered through a plug of Celite.
The filtrate obtained was added to a mixture of Ag2SO4 (3.68 g, 11.81
mmol) and I2 (3.00 g, 11.81 mmol) in MeOH (10 mL), and the resulting
mixture was stirred at room temperature for 3 h until the color of the
solution became light yellow. The mixture was filtered, and the filtrate
was concentrated in vacuo to give the crude product. This was purified
by flash chromatography (Si, 5% EtOAc in hexanes) to afford 1-fluoro-4-
iodo-2-isopropyl-5-methoxybenzene (32) (2.60 g, 75%). 1H NMR (500
MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 12.5 Hz, 1H), 3.90
(s, 3H), 3.18 (m, 1H), 1.28 (m, 6H).
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-
oxazolidin-2-one ((ꢀ)-cis-18). A solution of benzyl {(2S)-1-[3,5-
bis(trifluoromethyl)phenyl]-1-oxopropan-2-yl}carbamate (26) (1.30 g,
3.10 mmol) and dimethylphenylsilane (507 mg, 570 μL, 3.72 mmol)
in trifluororoacetic acid (5 mL) was stirred at 0 °C under N2 for 5 h.
The reaction was quenched with saturated aq NaHCO3 (∼50 mL) and
extracted with EtOAc (3 ꢁ 50 mL). The combined extracts were dried
(Na2SO4) and concentrated in vacuo to afford benzyl {(1R,2S)-1-[3,5-
bis(trifluoromethyl)phenyl]-1-hydroxypropan-2-yl}carbamate (27) as
a colorless oil. LCMS calcd = 422.12; found = 422.1 (M þ H)þ. A
solution of this compound in 7.5 N aq KOH (22 mL), MeOH (45 mL),
and THF (89 mL) was stirred at room temperature overnight. The
reaction mixture was concentrated in vacuo to remove the majority of
organic solvents, and the resulting aqueous slurry was acidified with 1
N aq HCl and extracted with EtOAc (3 ꢁ 50 mL). The combined
extracts were washed with brine, dried (Na2SO4), and concentrated in
(4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic Acid
(28). n-BuLi (4.26 mL of a 2.5 M solution in hexanes, 10.65 mmol)
was added dropwise to a solution of 1-fluoro-4-iodo-2-isopropyl-5-
methoxybenzene (32) (2.61 g, 8.88 mmol) in dry THF at ꢀ78 °C
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under N2. The resulting solution was stirred at ꢀ78 °C for 30 min.
(MeO)3B (2.98 mL, 26.6 mmol) was added, and the solution was stirred
at ꢀ78 °C for 3 h. The reaction was quenched at ꢀ78 °C with saturated
aq NH4Cl, and the mixture was warmed to room temperature. The
mixture was extracted with EtOAc (3 ꢁ 50 mL). The combined extracts
were washed with brine, dried (Na2SO4), and concentrated in vacuo to
afford (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (28) (1.13 g,
60%) as a colorless solid pure. 1H NMR (500 MHz, CDCl3) δ 7.74 (d,
J = 10.0 Hz, 1H), 6.62 (d, J = 12.5 Hz, 1H), 5.65 (br s, 2H), 3.92 (s, 3H),
3.20 (m, 1H), 1.22 (m, 6H).
2-Iodo-5-(trifluoromethyl)benzoic Acid (33). Potassium hy-
droxide (3.78 g, 0.0673 mol) was added to a stirred solution of 2-iodo-
5-(trifluoromethyl)benzonitrile (9) (4 g, 0.0135 mol) in a 1:1 2-propa-
nol:water solution (60 mL). The reaction was heated at reflux for 14 h
and then partitioned between water (50 mL) and EtOAc (50 mL). The
aqueous layer was extracted with EtOAc (50 mL) and acidified to pH 5
with 6 N HCl. The aqueous layer was further extracted with EtOAc (4 ꢁ
50 mL), and the combined extracts were washed with brine (50 mL),
dried (MgSO4), filtered, and concentrated in vacuo to afford 2-iodo-
5-(trifluoromethyl)benzoic acid (33) (2.81 g, 66%), as a yellow solid.
LCMS calcd = 316.93; found = 317.0 (M þ H)þ. 1H NMR (500 MHz,
CDCl3) δ 8.27 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.47 (dd, J =
8.2, 1.8 Hz, 1H).
[2-Iodo-5-(trifluoromethyl)phenyl]methanol (34). Boraneꢀ
THF (1.0 M solution in THF, 94 mL, 94 mmol) was added to a stirred
solution of 2-iodo-5-(trifluoromethyl)benzoic acid (33) (2.97 g, 9.4
mmol) in THF (300 mL) at 0 °C under N2. The reaction was heated
at reflux for 90 min and then carefully quenched with 6 N HCl until no
further gas evolution. The reaction was diluted with water (250 mL) and
extracted with EtOAc (3 ꢁ 250 mL). The combined extracts were washed
with brine (300 mL), dried (MgSO4), filtered, and concentrated in vacuo.
The crude material was purified by flash chromatography (Si, 0ꢀ25%
EtOAc in hexanes gradient) to afford [2-iodo-5-(trifluoromethyl)-
phenyl]methanol (34) (2.29 g, 88%) as a white solid. LCMS calcd =
284.94; found = 285.0 (M-17)þ. 1H NMR (500 MHz, CDCl3) δ 7.97 (d,
J = 8.3 Hz, 1H), 7.79 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.75 (s, 2H).
2-(Bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (35).
Carbon tetrabromide (1.86 g, 5.6 mmol) and triphenylphosphine (1.47 g,
5.6 mmol) were added successively to a stirred solution of [2-iodo-
5-(trifluoromethyl)phenyl]methanol (34) (1.13 g, 3.74 mmol) in dry
CH2Cl2 (25 mL) at 0 °C under N2. The reaction was stirred at room
temperature for 48 h. A second equivalent of carbon tetrabromide (1.2 g,
3.74 mmol) and triphenylphosphine (0.98 g, 3.74 mmol) was added, and
the reaction was stirred an additional 14 h. The solvent was removed in
vacuo, and the residue was purified by flash chromatography (Si, 0ꢀ25%
EtOAc in hexanes gradient) to afford 2-(bromoethyl)-1-iodo-4-(triflu-
oromethyl)benzene (35) (1.30 g, 96%) asa clear oil. 1H NMR (500 MHz,
CDCl3) δ 8.02 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.26 (dd, J =
8.3, 1.8 Hz, 1H), 4.64 (s, 2H).
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(tri
fluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (36). To
a stirred suspension of NaH (60% dispersion in mineral oil; 1.30 g, 0.0325
mol) in THF (60 mL) at 0 °C under N2 was added dropwise a solution
of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-
2-one ((ꢀ)-cis-18)) (4.077 g, 0.013 mol) in THF (50 mL). Gas evolution
was observed. The resultant mixture stirred at 0 °C for 30 min prior to
addition of a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)-
benzene (35) (4.754 g, 0.013 mol) in THF (20 mL). The reaction was
allowed to warm to room temperature and stirred for 14 h. The reaction
was carefully quenched with water (15 mL) and partitioned between
EtOAc (250 mL) and water (75 mL). The aqueous layer was extracted with
EtOAc (3 ꢁ 100 mL). The combined organic layers were washed with brine
(100 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (Si, 0ꢀ20% EtOAc/hexanes gradient)
to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoro-
methyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (36) (6.4 g, 83%) as a
white solid. LCMS calcd = 597.99; found = 598.1 (M þ H)þ. 1H NMR
(500 MHz, CDCl3) δ 8.03 (d, J = 8.2 Hz, 1H), 7.90 (s, 1H), 7.79 (s, 2H),
7.58 (s, 1H), 7.30 (dd, J = 8.2 Hz, J = 2.0 Hz, 1H), 5.76 (d, J = 8 Hz, 1H),
4.88 (d, J = 15.8 Hz, 1H), 4.37 (d, J = 15.8 Hz, 1H), 4.09ꢀ4.02 (m, 1H),
0.80 (d, J = 6.6 Hz, 3H).
(þ)-(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[40-fluoro-
20-methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]-
methyl}-4-methyl-1,3-oxazolidin-2-one ((þ)-cis-3). A stirred
mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(tri-
fluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (36) (4.29 g, 7.19
mmol), [4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]boronic acid (28)
(4.57 g, 21.57 mmol), (Ph3P)4Pd (1.0 g, 0.86 mmol), and sodium
carbonate (6.35 g) in C6H6/EtOH/water (120 mL/17 mL/51 mL) was
heated at reflux (100 °C) under N2 for 14 h. The reaction was
partitioned between EtOAc (200 mL) and water (100 mL). The
aqueous phase was extracted with EtOAc (3 ꢁ 200 mL). The combined
organic phases were washed with brine (100 mL), dried (MgSO4),
filtered, and concentrated in vacuo. The residue was purified by silica-gel
flash chromatography (Si, 0ꢀ25% EtOAc/hexanes gradient) to afford
(þ)-(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[40-fluoro-20-methoxy-
50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-
1,3-oxazolidin-2-one ((þ)-cis-3), (3.50 g, 76%), as a colorless solid.
LCMS calcd = 638.18; found = 638.3 (M þ H)þ. 1H NMR (500 MHz,
benzene-d6, 1:1 mixture of atropisomers) δ 7.82 (s, 0.5H), 7.60 (s,
0.5H), 7.57 (s, 1H), 7.33 (d, J = 8 Hz, 1H), 7.27 (d, J = 9.9 Hz, 2H),
7.02ꢀ6.98 (m, 1H), 6.89 (d, J = 8.5 Hz, 0.5H), 6.82 (d, J = 8.5 Hz,
0.5H), 6.45 (d, J = 12.1 Hz, 0.5H), 6.35 (d, J = 11.9 Hz, 0.5H), 4.94 (d, J =
16.0 Hz, 0.5H), 4.87 (d, J = 15.8 Hz, 0.5H), 4.54 (d, J = 8.0 Hz, 0.5H),
4.50 (d, J = 7.8 Hz, 0.5H), 3.74ꢀ3.66 (m, 1H), 3.23ꢀ3.15 (m, 1H), 3.12
(s, 1.5H), 2.99 (s, 1.5H), 2.97ꢀ2.92 (m, 0.5H), 2.89ꢀ2.84 (m, 0.5H),
1.21ꢀ1.09 (m, 6H), ꢀ0.27 (d, J = 6.7 Hz, 1.5H), ꢀ0.40 (d, J = 6.7 Hz,
1.5H). HRMS (ESþ) calcd for C30H26F10NO3 (M þ H)þ m/e,
638.1748; found, 638.1731.
Alternate Procedure for Synthesizing (4S,5R)-5-[3,5-Bis-
(trifluoromethyl)phenyl]-3-{[40-fluoro-20-methoxy-50-(pro-
pan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-meth-
yl-1,3-oxazolidin-2-one ((þ)-cis-3). A mixture of (4S,5R)-5-[3,
5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-
4-methyl-1,3-oxazolidin-2-one (36) (50 mg, 0.084 mmol), [4-fluoro-2-
methoxy-5-(propan-2-yl)phenyl]boronic acid (28) (22 mg, 0.105
mmol), palladium acetate (6 mg, 0.0103 mmol), and potassium carbo-
nate (29 mg, 0.257 mmol) in 5:1 acetone/water (6 mL) was heated at
reflux for 1 h. The acetone was removed in vacuo, and the residue was
diluted with water (10 mL) and extracted with CH2Cl2 (3 ꢁ 10 mL).
The combined extracts were washed with brine (10 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was purified
by flash chromatography (Si, 0ꢀ25% EtOAc/hexanes gradient) to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[40-fluoro-20-methoxy-
50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-meth-
yl-1,3-oxazolidin-2-one ((þ)-cis-3) (23 mg, 44%) as a clear glass.
[40-Fluoro-20-methoxy-50-(propan-2-yl)-4-(trifluoromethyl)-
biphenyl-2-yl]methanol (37). A mixture of [2-iodo-5-(trifluoro-
methyl)phenyl]methanol (34) (3.09 g, 10.2 mmol), (4-fluoro-5-iso-
propyl-2-methoxyphenyl)boronic acid (28) (4.34 g, 20.5 mmol),
(Ph3P)4Pd (1.42 g, 1.23 mmol), and Na2CO3 (9.11 g, 85.9 mmol) in
benzene/EtOH/water (7:1:3, 250 mL) was heated at reflux for 24 h
under N2. After cooling to room temperature, the aqueous phase was
separated and extracted with CH2Cl2 (3 ꢁ 50 mL). The combined
organic layers were dried (Na2SO4) and concentrated in vacuo to give
the crude product. This was purified by flash chromatography (Si, 65 ꢁ
200 mm, 0ꢀ20% EtOAc in hexanes gradient) to afford [40-fluoro-20-
methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methanol
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(37) (3.38 g, 97%). Rf = 0.50 (20% EtOAc in hexanes). 1H NMR (500
MHz, CDCl3) δ 7.86 (s, 1 H), 7.59 (d, J = 6.7 Hz, 1H), 7.30 (d, J = 7.9
Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 12.0 Hz, 1H), 4.52 (br s,
1H), 4.46 (br s, 1H), 3.73 (s, 3H), 3.25ꢀ3.17 (m, 1H), 1.82 (br s, 1H),
1.24 (d, J = 6.8 Hz, 6H).
purified by flash chromatography (Si, 25 mm ꢁ 160 mm, 0ꢀ40% EtOAc
in hexanes gradient) to afford benzyl {2-[3,5-bis(trifluoromethyl)-
phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate ((()-43) (158.7 mg,
49%). Rf = 0.40 (20% EtOAc in hexanes). LCMS calcd = 436.13; found =
436.0 (M þ H)þ. 1H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.77 (s,
2H), 7.39ꢀ7.33 (m, 5H), 5.13 (br s, 1H), 5.12ꢀ5.08 (m, 2H), 4.90 (d,
J = 4.4 Hz, 1H), 4.81 (s, 1H), 1.36 (s, 3H), 1.23 (s, 3H).
20-(Bromomethyl)-4-fluoro-2-methoxy-5-(propan-2-yl)-40-
(trifluoromethyl)biphenyl (38). A solution of triphenylphosphine
(3.11 g, 11.8 mmol) in dry CH2Cl2 (7 mL) was added via cannula to a
stirred solution of carbon tetrabromide (3.93 g, 11.8 mmol) and [40-
fluoro-20-methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]-
methanol (37) (3.38 g, 9.87 mmol) in dry CH2Cl2 (56 mL) at 0 °C under
N2. The reaction was allowed to warm to room temperature. After 2 h, the
reaction mixture was concentrated in vacuo to give the crude product.
This was purified by flash chromatography (Si, 65 mm ꢁ 200 mm,
0ꢀ20% EtOAc in hexanes gradient) to afford 20-(bromomethyl)-4-fluoro-
2-methoxy-5-(propan-2-yl)-40-(trifluoromethyl)biphenyl (38) (3.71 g,
93%). 1H NMR (500 MHz, CDCl3) δ 7.83 (s, 1H), 7.61 (d, J = 8.0 Hz,
1H), 7.35 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.72 (d, J =
12.0 Hz, 1H), 4.43 (br d, J = 10.0 Hz, 1H), 4.30 (br d, J = 10.2 Hz, 1 H),
3.76 (s, 3H), 3.30ꢀ3.22 (m, 1H), 1.29 (d, J = 6.9 Hz, 6H).
(ꢀ)-(5S)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[40-fluoro-
20-methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-
yl]methyl}-4,4-dimethyl-1,3-oxazolidin-2-one ((ꢀ)-39) and
(þ)-(5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[40-fluoro-20-
methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]-
methyl}-4,4-dimethyl-1,3-oxazolidin-2-one ((þ)-39). NaH
(60% dispersion in mineral oil, 20.6 mg, 0.515 mmol) was added to a
stirred solution of benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydro-
xy-1,1-dimethylethyl}carbamate ((()-43) (89.7 mg, 0.206 mmol) in
dry DMF (1 mL) at room temperature under N2. The reaction was
stirred for 15 min, and a solution of 20-(bromomethyl)-4-fluoro-2-
methoxy-5-(propan-2-yl)-40-(trifluoromethyl)biphenyl (38) (100 mg,
0.247 mmol) in dry DMF (2 mL) was added via cannula. The reaction
was stirred at room temperature overnight. The reaction was quenched
with saturated aq NH4Cl (10 mL) and water (10 mL) and extracted with
EtOAc (3 ꢁ 20 mL). The combined organic extracts were washed with
brine (10 mL), dried (Na2SO4), and concentrated in vacuo to give the
crude product. This was purified by flash chromatography (Si, 12 mm ꢁ
160 mm, 0ꢀ40% EtOAc in hexanes gradient) to afford (()-5-[3,5-
bis(trifluoromethyl)phenyl]-3-{[40-fluoro-20-methoxy-50-(propan-2-yl)-
4-(trifluoromethyl)biphenyl-2-yl]methyl}-4,4-dimethyl-1,3-oxazolidin-
2-one ((()-39) (54.2 mg, 40%) as a colorless oil. Rf = 0.44 (20%
EtOAc/hexanes). LCMS calcd = 652.19; found = 652.2 (M þ H)þ. 1H
NMR (600 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.89 (s, 1H),
7.80ꢀ7.72 (m, 3H), 7.57 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 6.99
(dd, J = 10.3, 8.2 Hz, 1H), 6.70 (dd, J = 11.9, 3.0 Hz, 1H), 5.29 (s, 0.5H),
5.25 (s, 0.5H), 4.67 (d, J = 16.5 Hz, 0.5H), 4.36 (d, J = 16.7 Hz, 0.5H),
4.31 (d, J = 16.7 Hz, 0.5H), 3.96 (d, J = 16.5 Hz, 0.5H), 3.75 (s, 3H),
3.27ꢀ3.17 (m, 1H), 1.26ꢀ1.18 (m, 7.5H), 1.07 (s, 1.5H), 0.54 (s,
1.5H), 0.51 (s, 1.5H). This compound was separated into its enantio-
mers (ꢀ)-(5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[40-fluoro-20-
methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-
4,4-dimethyl-1,3-oxazolidin-2-one ((ꢀ)-39) (HRMS (ESþ) calcd
for C31H28F10NO3 (M þ H)þ m/e, 652.1904; found, 652.1885) and
(þ)-(5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[40-fluoro-20-methoxy-
50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4,4-dimethyl-
1,3-oxazolidin-2-one ((þ)-39) (HRMS (ESþ) calcd for C31H28F10NO3
(M þ H)þ m/e, 652.1904; found, 652.1889) using chiral HPLC (IA
column, 20 mm ꢁ 250 mm, 2% i-PrOH in heptane).
Benzyl {2-[Methoxy(methyl)amino]-1,1-dimethyl-2-oxo-
ethyl}carbamate (42). N-Methyl morpholine (682 mg, 741 μL,
6.74 mmol) and iso-butyl chloroformate (460 mg, 441 μL, 3.37 mmol)
were added successively to a stirred solution of N-carbobenzyloxy-2-
methylalanine (40) (0.64 g, 2.69 mmol) in dry CH2Cl2 at 0 °C under N2.
The resulting cloudy mixture was stirred at 0 °C for 90 min. N,O-
Dimethylhydroxylamine hydrochloride (316 mg, 3.24 mmol) was added
portionwise, and the mixture was warmed to room temperature and
stirred for 3 h. The mixture was poured into 1 N HCl (30 mL) and
extracted with CH2Cl2 (3 ꢁ 40 mL). The combined extracts were
washed with 1 N HCl (30 mL), dried (Na2SO4), and concentrated in
vacuo to give the crude product. This was purified by flash chromatog-
raphy (Si, 40 mm ꢁ 160 mm, 0ꢀ80% EtOAc in hexanes gradient)
to afford benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-ox-
oethyl}carbamate (42) (308.8 mg, 41%). Rf = 0.47 (50% EtOAc in
hexanes). LCMS calcd = 303.13; found = 303.2 (M þ Na)þ. 1H NMR
(500 MHz, CDCl3) δ 7.37ꢀ7.29 (m, 5H), 5.82 (s, 1H), 5.09 (s, 2H),
3.60 (s, 3H), 3.18 (s, 3H), 1.60 (s, 6H).
Benzyl (1,1-Dimethyl-2-oxoethyl)carbamate (41). Diisobu-
tylaluminum hydride (1.77 mL, 1 M solution in toluene, 0.708 mmol)
was added to a stirred solution of benzyl {2-[methoxy(methyl)amino]-
1,1-dimethyl-2-oxoethyl}carbamate (42) (198.5 mg, 0.708 mmol) in
dry THF (7.1 mL) at ꢀ78 °C under N2. The reaction was stirred at
ꢀ78 °C for 4 h. MeOH (100 μL) and 1 N HCl (250 μL) were added,
and the reaction was allowed to warm to room temperature. The mixture
was diluted with Et2O (50 mL) and washed with 1 N HCl (2 ꢁ 50 mL),
50% saturated aq NaHCO3 (50 mL), and water (50 mL) and then dried
(MgSO4) and concentrated in vacuo to give benzyl (1,1-dimethyl-2-
oxoethyl)carbamate (41) (153.5 mg, 98%). Rf = 0.40 (20% EtOAc in
hexanes). LCMS calcd = 244.09; found = 244.1 (M þ Na)þ. 1H NMR
(500 MHz, CDCl3) δ 9.43 (s, 1H), 7.38ꢀ7.30 (m, 5H), 5.34 (s, 1H),
5.09 (s, 2H), 1.37 (s, 6H).
Benzyl{(2S)-3-[3,5-bis(trifluoromethyl)phenyl]-3-hydro-
xybutan-2-yl}carbamate (45). To a vigorously stirred solution of
benzyl{(2S)-1-[3,5-bis(trifluoromethyl)phenyl]-1-oxopropan-2-yl}carbamate
(26) (150 mg, 0.358 mmol) in dry Et2O (15 mL) under N2 was added
methylmagnesium bromide (3 M in Et2O, 418 μL, 1.25 mmol). The
resulting mixture was stirred at room temperature for 2 h. Saturated aq
NH4Cl was added to the reaction solution. The mixture was diluted
with water, and the aqueous phase was extracted with EtOAc (3 ꢁ
20 mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. Flash chromatography of the residue yielded
benzyl{(2S)-3-[3,5-bis(trifluoromethyl)phenyl]-3-hydroxybutan-2-yl}-
carbamate (45) (146 mg, 94%). LCMS calcd = 436.13; found = 436.1
(M þ H)þ. 1H NMR (500 MHz, CDCl3) δ 7.95 (2H, s), 7.83 (s, 1H),
7.46ꢀ7.34 (m, 5H), 5.27ꢀ5.11 (m, 2H), 4.99 (d, J = 8.8 Hz, 1H),
4.13ꢀ4.02 (m, 1H), 2.82 (s, 1H), 1.67 (s, 3H), 0.96 (d, J = 6.6 Hz, 3H).
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4,5-dimethyl-
1,3-oxazolidin-2-one (46). To a solution of benzyl{(2S)-3-
[3,5-bis(trifluoromethyl)phenyl]-3-hydroxybutan-2-yl}carbamate (45)
Benzyl {2-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-1,
1-dimethylethyl}carbamate ((()-43). Ethyl magnesium bromide
(1.63 mL, 1 M in THF, 1.63 mmol) was added dropwise to a stirred
solution of 1-iodo-3,5-bis(trifluoromethyl)benzene (608 mg, 317 μL,
1.79 mmol) in dry THF (1 mL) at room temperature under N2, and the
reaction was stirred for 30 min. The resulting solution was added to a
stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate (41)
(163.5 mg, 0.739 mmol) in dry THF (1 mL) at ꢀ20 °C, and the
reaction was allowed to warm to room temperature over 3 h. Saturated
aq NH4Cl (10 mL) and water (10 mL) were added, and the mixture was
extracted with EtOAc (3 ꢁ 20 mL). The combined extracts were dried
(Na2SO4) and concentrated in vacuo to give the crude product. This was
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(116 mg, 0.266 mmol) inMeOH(8 mL) and THF (16mL) was added aq
KOH (7.5 N, 4 mL). The mixture was stirred at room temperature
overnight. The mixture was neutralized with 1 N HCl to pH 7. The
mixture was extracted with EtOAc (3 ꢁ 30 mL). The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo. Flash chroma-
tography of the residue yielded (4S,5R)-5-[3,5-bis(trifluoromethyl)
phenyl]-4,5-dimethyl-1,3-oxazolidin-2-one (46) (80.3 mg, 92%). LCMS
calcd = 328.08; found= 328.1(M þ H)þ. 1H NMR (500 MHz, CDCl3) δ
7.90 (s, 1H), 7.83 (s, 2H), 6.27 (s, 1H), 4.02ꢀ3.95 (m, 1H), 1.91 (s, 3H),
0.82 (d, J = 6.5 Hz, 3H).
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(þ)-(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[40-fluoro-
20-methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-
2-yl]methyl}-4,5-dimethyl-1,3-oxazolidin-2-one ((þ)-44). Toa
solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4,5-dimethyl-1,
3-oxazolidin-2-one (46) (27.9 mg, 0.085 mmol) in DMF (0.5 mL) was
added NaH (60% dispersion in mineral oil) (5.1 mg, 0.128 mmol). The
mixture was stirred at room temperature for 15 min. To the above mixture
was added
a
solution of 20-(bromomethyl)-4-fluoro-2-methoxy-
5-(propan-2-yl)-40-(trifluoromethyl)biphenyl (38) (34.4 mg, 0.085
mmol) in DMF (0.5 mL). The mixture was stirred at room temperature
for 2 h. Saturated aq NH4Cl was added to the reaction solution. The
mixture was diluted with water, and the aqueous phase was extracted with
EtOAc (3 ꢁ 15 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. Flash chromatography of the
residue yielded (þ)-(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[40-
fluoro-20-methoxy-50-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-
yl]methyl}-4,5-dimethyl-1,3-oxazolidin-2-one ((þ)-44) (36.2 mg, 65%).
LCMS calcd = 652.19; found = 652.2 (M þ H)þ. 1H NMR (500 MHz,
CDCl3, 1:1mixture ofatropisomers)δ 7.85 (s, 0.5H), 7.84 (s, 0.5H), 7.76
(s, 1H), 7.75 (s, 1H), 7.70 (s, 0.5H), 7.68 (s, 0.5H), 7.66ꢀ7.58 (m, 1H),
7.41ꢀ7.32 (m, 1H), 7.02 (d, J = 8.39 Hz, 0.5H), 6.97 (d, J = 8.4Hz, 0.5H),
6.74ꢀ6.64 (m, 1H), 4.90 (d, J = 15.9 Hz, 0.5H), 4.75 (d, J = 16.0 Hz, 0.5
H), 4.13 (d, J = 16.0 Hz, 0.5H), 3.87 (d, J = 15.9 Hz, 0.5H), 3.76 (s, 1.5H),
3.75 (s, 1.5H), 3.63ꢀ3.56 (m, 0.5H), 3.43ꢀ3.36 (m, 0.5H), 3.26ꢀ3.18
(m, 1H), 1.77 (s, 3H), 1.30ꢀ1.13 (m, 6H), 0.51 (d, J = 6.5 Hz, 1.5H), 0.33
(d, J = 6.5 Hz, 1.5H). (HRMS (ESþ) calcd for C31H28F10NO3 (M þ H)þ
m/e, 652.1904; found, 652.1887).
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’ AUTHOR INFORMATION
Corresponding Author
*Phone: þ1 732 594 2529. Fax: þ1 732 594 9545. E-mail:
cameron_smith@merck.com.
’ ACKNOWLEDGMENT
(13) Tall, A. R.; Yvan-Charvet, L.; Terasaka, N.; Pagler, T.; Wang, N.
HDL, ABC Transporters, and Cholesterol Efflux: Implications for the
Treatment of Atherosclerosis. Cell Metab. 2008, 7, 365–375.
(14) Barkowski, R. S.; Frishman, W. H. HDL metabolism and CETP
inhibition. Cardiol. Rev. 2008, 16, 154–162.
We acknowledge Kithsiri Herath for performing the high
resolution mass spectra measurements.
’ ABBREVIATIONS USED
(15) Masson, D.; Jiang, X. C.; Lagrost, L.; Tall, A. R. The role of
plasma lipid transfer proteins in lipoprotein metabolism and atherogen-
esis. J. Lipid Res. 2009, 50 (Suppl S), S201–S206.
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CVD, cardiovascular disease; CHD, coronary heart disease;
LDL-C, low density lipoprotein-cholesterol; HMG-CoA, 3-hy-
droxy-3-methylglutaryl-coenzyme A; HDL-C, high density lipo-
protein-cholesterol; LDL, low density lipoprotein; HDL, high
density lipoproteins; CETP, cholesteryl ester transfer protein;
RCT, reverse cholesterol transport; apoB, apolipoprotein B; VLDL,
very low-density lipoprotein; CE, cholesteryl ester; BODIPY, bor-
on-dipyrromethene; μλ, microwave
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