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

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).^13,14Hence, CETP acts to decrease

HDL-C levels and increase LDL-C levels and so could be con-

sidered to be a pro-atherogenic factor.¹⁵On the other hand

CETP also enhances the rate of RCT, suggesting a possible

antiatherogenic role.¹⁶Studies 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.^15,16A population of CETP deﬁcient humans has

been identiﬁed in Japan.^17,18These individuals displayed high

levels of HDL-C and low levels of LDL-C and apoB.¹⁸Although

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).¹Elevated

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%.^2,3Therefore, 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.^4ꢀ7Some cholesterol lowering drugs, including

niacin, the ﬁbrates, and the statins, have a modest eﬀect on

increasing HDL-C levels.^8ꢀ11Niacin 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.^19ꢀ26These clinical studies established

that pharmacological inhibition of CETP leads to signiﬁcant

increases in plasma HDL-C concentrations.²⁷Despite 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.^31,32Consistent 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.^37ꢀ41Given 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 1^a

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.⁴²Anacetrapib 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.^43ꢀ48It was also found that HDL

isolated from humans treated with anacetrapib had increased

potential to promote cholesterol eﬄux and retained anti-inﬂam-

matory eﬀects.⁴⁹Preclinical 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 1.⁵²This 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

^aReagents: (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 2^a

Scheme 3^a

^aReagents: (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 4^a

^aReagents: (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).

^aReagents: (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 2.⁵³This 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 5^a

Scheme 7^a

^aReagents: (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 8^a

^aReagents: (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 6^a

^aReagents: (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%.

^aReagents: (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

^aAverage of one or more 10-point titrations. ^bTransgenic mouse

pharmacodynamic assay: C57BL/6 male mice 12ꢀ16 weeks of age

expressing cynomolgus monkey CETP were used.⁵⁸Predose 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). ^dn.m.: not measured. ^en.d.:

not determined; indicates <50% inhibition of CETP at a concentration

of 100 μM. ^fMean increase in HDL cholesterol in B6-Tg(CETP) mice

(mean of 9 mice per dose). ^gThis compound was synthesized using the

same procedure as for compound (ꢀ)-2⁵³by 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 26.⁵⁴Diastereoselec-

tive reduction of ketone 26 with triethylsilane in TFA aﬀorded

syn-alcohol 27.⁵⁵Treatment 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

^aTransgenic 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.⁵⁶The 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 IC₅₀of 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 Mouse^a

Cl_b^b(mL/min/kg)

V_d^b(L/kg)

T_1/2^b(h)

AUCN_IV^b(μM h kg/mg)

AUCN_PO^b(μM h kg/mg)

C_max^b(μM)

T_max^b(h)

F_oral^b(%)

3

3 3

11

2.0

3.6

2.40

0.356

0.28

1.0

15

^aThe 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. ^bCl_b, blood clearance; V_d, volume of distribution; T_1/2, terminal

half-life; AUCN_IV, IV normalized area under curve; AUCN_PO, PO normalized area under curve; C_max, observed maximal plasma concentration following

oral dosing; T_max, time to reach the C_max; F_oral, 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 IC₅₀of 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 IC₅₀to 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 MgSO₄on 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 (ꢀ)-2⁵³was 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% CH₂Cl₂in hexanes) to afford

2-iodo-5-(trifluoromethyl)benzonitrile (9) (3.11 g, 64%), as a colorless

solid. R_f= 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 F₂₅₄plates. 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. R_f=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%

CH₂Cl₂in 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.

R_f= 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. R_f= 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 (ES^þ) calcd for

C₂₈H₂₉F₃NO₃(M þ H)^þm/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. R_f= 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. R_f= 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

(ES^þ) calcd for C₂₈H₂₉F₃NO₃(M þ H)^þm/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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dx.doi.org/10.1021/jm200484c |J. Med. Chem. 2011, 54, 4880–4895

Journal of Medicinal Chemistry

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. R_f= 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 (ES^þ) calcd for C₃₀H₂₇F₉NO₃

(M þ H)^þm/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 (ES^þ) calcd for C₃₀H₂₇F₉NO₃(M þ H)^þm/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:

R_f= 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: R_f= 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. R_f= 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 (ES^þ) calcd for C₃₀H₂₇F₉NO₃

(M þ H)^þm/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 (ES^þ) calcd for C₃₀H₂₇F₉NO₃(M þ H)^þm/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: R_f= 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. R_f= 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 (ES^þ) calcd for

C₃₁H₂₉F₉NO₃(M þ H)^þm/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. R_f= 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: R_f= 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 (ES^þ) calcd for

C₃₁H₂₉F₉NO₃(M þ H)^þm/e, 634.1998; found, 634.1995.

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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. R_f= 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. R_f=

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 N₂and 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 N₂and 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. R_f= 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 N₂for 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 N₂was 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 N₂for 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 (ES^þ) calcd for C₃₀H₂₆F₁₀NO₃(M þ H)^þm/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%). R_f= 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%). R_f= 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. R_f= 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 (ES^þ) calcd

for C₃₁H₂₈F₁₀NO₃(M þ H)^þm/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 (ES^þ) calcd for C₃₁H₂₈F₁₀NO₃

(M þ H)^þm/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 CH₂Cl₂at 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%). R_f= 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%). R_f= 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 N₂was 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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Journal of Medicinal Chemistry

ARTICLE

(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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Eﬃcacy and safety of cholesterol-lowering treatment: prospective meta-

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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 (ES^þ) calcd for C₃₁H₂₈F₁₀NO₃(M þ H)^þ

m/e, 652.1904; found, 652.1887).

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Density Lipoprotein and High-Density Lipoprotein Particle Subclasses

Predict Coronary Events and Are Favorably Changed by Gemﬁbrozil

Therapy in the Veterans Aﬀairs High-Density Lipoprotein Intervention

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Wedel, H.; Berg, K.; Wilhelmsen, L.; Haghfelt, T.; Thorgeirsson, G.;

Pyorala, K.; Miettinen, T.; Christophersen, B.; Tobert, J. A.; Musliner,

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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.

(16) Barter, P. J.; Brewer, H. B., Jr; Chapman, M. J.; Hennekens,

C. H.; Rader, D. J.; Tall, A. R. Cholesteryl ester transfer protein: a novel

target for raising HDL and inhibiting atherosclerosis. Arterioscler.

Thromb. Vasc. Biol. 2003, 23, 160–167.

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Whitlock, M. E.; Marcel, Y. L.; Milne, R. W.; Koizumi, J.; Mabuchi, H.;

Takeda, R.; Tall, A. R. Molecular basis of lipid transfer protein deﬁciency

in a family with increase high-density lipoproteins. Nature 1989,

342, 448–451.

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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dx.doi.org/10.1021/jm200484c |J. Med. Chem. 2011, 54, 4880–4895

Article Doi

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

DOI: 10.1021/jm200484c

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Full text of DOI:10.1021/jm200484c

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