Discovery of novel, potent benzamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) exhibiting oral activity in an enzyme inhibition ex vivo model

Article abstract of DOI:10.1021/jm800310g

We report the discovery of potent benzamide inhibitors of 11β-hydroxysteroid dehydrogenase (11β-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11β-HSD1 activity in a monkey ex vivo pharmacodynamic model.

Full text of DOI:10.1021/jm800310g

J. Med. Chem. 2008, 51, 3953–3960
3953
Discovery of Novel, Potent Benzamide Inhibitors of 11ꢀ-Hydroxysteroid Dehydrogenase Type 1
(11ꢀ-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model3
Lisa D. Julian,*,§ Zhulun Wang,§ Tracy Bostick,# Seb Caille, Rebekah Choi,§ Michael DeGraffenreid,§ Yongmei Di,§
Xiao He,§ Randall W. Hungate,§ Juan C. Jaen,| Jinsong Liu,§ Mario Monshouwer,‡ Dustin McMinn,§ Yosup Rew,§
Athena Sudom,§ Daqing Sun,§ Hua Tu,§ Stefania Ursu,§ Nigel Walker,§ Xuelei Yan,§ Qiuping Ye,§ and Jay P. Powers|
Amgen, Inc., 1120 Veterans BouleVard, South San Francisco, California 94080
ReceiVed March 19, 2008
We report the discovery of potent benzamide inhibitors of 11ꢀ-hydroxysteroid dehydrogenase (11ꢀ-HSD1).
The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through
modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable
pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11ꢀ-HSD1
activity in a monkey ex vivo pharmacodynamic model.
Introduction
Glucocorticoids regulate glucose and lipid homeostasis, acting
through intracellular glucocorticoid receptors in the liver,
adipose, and brain tissues.1 Elevated levels of glucocorticoids
can result in insulin resistance by impairment of insulin
dependent glucose uptake, enhanced hepatic gluconeogenesis,
increased lipolysis, and the inhibition of insulin secretion from
pancreatic ꢀ-cells.2 As a result of sustained glucocorticoid
Figure 1. Interconversion of cortisone and cortisol catalyzed by 11ꢀ-
excess, like that observed in Cushing’s syndrome, patients can
HSD.
develop dyslipidemia, visceral obesity, and other symptoms of
metabolic syndrome.3
from the pharmaceutical industry toward the development of
The 11ꢀ-hydroxysteroid dehydrogenase type I (11ꢀ-HSD1a)
enzyme catalyzes the conversion of cortisone to the active
glucocorticoid hormone cortisol, thus regulating the local
activation of glucocorticosteroid receptors (Figure 1).1 Its
counterpart, 11ꢀ-HSD2, catalyzes the reverse reaction of cortisol
to cortisone. Evidence supporting the therapeutic potential of
selectively inhibiting 11ꢀ-HSD1 for the treatment of type II
diabetes and obesity has been obtained from mouse genetic
models. Fat-specific 11ꢀ-HSD1 transgenic mice developed
symptoms of metabolic syndrome (i.e., increased levels of
glucose, insulin, triglycerides, and visceral fat accumulation).4
Conversely, 11ꢀ-HSD1 knockout mice showed impaired induc-
tion of gluconeogenetic enzymes, improved glucose tolerance
and insulin sensitivity, and resistance to obesity when fed a high
fat diet.5 These data, coupled with the increasing incidence of
obesity and diabetes today, have generated significant interest
an 11ꢀ-HSD1 inhibitor.6
As part of our drug discovery effort to develop small molecule
inhibitors of 11ꢀ-HSD1, we aimed to identify a novel chemical
series based in part on the structure-activity relationships
(SARs) derived from our previously reported sulfonamide
analogues (e.g., 1, Figure 2).6c Specifically, we envisioned that
an amide moiety could serve as a suitable isosteric replacement
of the sulfonamide core present in compound 1. Indeed, we
discovered that benzamide compound 2 demonstrated potent
activity toward full length recombinant human 11ꢀ-HSD1 (IC50
) 1.3 nM).7 While the potency of compound 2 was satisfactory
at this stage, the molecule demonstrated poor in vitro metabolic
stability, which translated into poor in vivo rodent pharmaco-
kinetics. Improvement of the unfavorable metabolic profile was
our initial objective in progressing this new series. In addition
to the necessary improvements in the pharmacokinetics of these
benzamide 11ꢀ-HSD1 inhibitors, our paradigm for compound
advancement required the demonstration of 11ꢀ-HSD1 activity
in an ex vivo model. This report describes the evolution of
benzamide compound 2 toward 11ꢀ-HSD1 inhibitors that exhibit
improved pharmacokinetics and significant primate ex vivo
activity.
3
Coordinates of the new structures have been deposited with the RCSB
Protein Data Bank (http://www.rcsb.org/pdb) with codes 3D3E (13-HSD1
complex) and 3D4N (20-HSD1 complex).
* To whom correspondence should be addressed. Phone: (650) 244-2581.
Fax: (650)837-9369. E-mail: ljulian@amgen.com.
§
Amgen, Inc., South San Francisco, CA.
Current address: Genentech, Inc., 1 DNA Way, South San Francisco,
#
CA 94080.
Chemistry
Current address: Amgen, Inc., 1 Amgen Center Drive, Thousand Oaks,
CA 91320.
Generally, benzamide inhibitors were prepared in two steps
from the corresponding cyclohexanone intermediate as shown
in Scheme 1. The incorporation of ethyl, cyclopropylmethyl,
and cyclopropyl substituents on nitrogen was accomplished by
reductive amination of cyclohexanone 3 (R1 ) H) with the
appropriate amine. The cyclohexylamines 4 were then coupled
to optically pure (S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-
benzoic acid 17, prepared from 4-acetylbenzonitrile 16, using
|
Current address: ChemoCentryx, Inc., 850 Maude Avenue, Mountain
View, CA 94043.
‡
Current address: Roche, 3431 Hillview Avenue, Palo Alto, CA 94034.
a Abbreviations: 11ꢀ-HSD1, 11ꢀ-hydroxysteroid dehydrogenase type 1;
11ꢀ-HSD2, 11ꢀ-hydroxysteroid dehydrogenase type 2; SPA, scintillation
proximity assay; HLM, human liver microsomes; RLM, rat liver mi-
crosomes; h293, human embryonic kidney 293 cells; HSA, human serum
albumin; NADP, nicotinamide adenine dinucleotide phosphate; Cp,
cyclopropyl.
10.1021/jm800310g CCC: $40.75
2008 American Chemical Society
Published on Web 06/14/2008

3954 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Julian et al.
Scheme 2. Synthesis of 4-Fluorocyclohexanone 19a
a Reagents and conditions: (a) diethylaminosulfur trifluoride (DAST),
CH2Cl2, -78 °C to room temp (19%); (b) LiOH, MeOH, THF (93%); (c)
PCC, CH2Cl2 (71%).
Figure 2. An initial benzamide compound.
Scheme 1. General Synthesis of Benzamide 11ꢀ-HSD1
Inhibitorsa
In the cellular assays, inhibitors were tested in the presence and
absence of human serum albumin (HSA) to measure the impact
of protein binding. The 11ꢀ-hydroxysteroid dehydrogenase
selectivity profile of compounds was determined by measuring
11ꢀ-HSD2 activity using the SPA assay and comparing the
results to 11ꢀ-HSD1 enzyme activity.
Initial characterization of compound 2 revealed that it was
rapidly metabolized in vitro, showing nearly complete consump-
tion in both human and rat liver microsomes after a 30 min
incubation period.12 In vivo pharmacokinetic data also showed
compound 2 to be rapidly cleared in rats (CL ) 3.1 L/h/kg).
The identification and quantification of metabolites formed from
human and rat liver microsomes (HLM and RLM, respectively)
showed three major routes of oxidative metabolism: N-dealky-
lation (2a) and oxidation of both the N-ethyl (2b) and N-
cyclohexyl (2c) substituents (Figure 3). Furthermore, the
metabolite identification data revealed significant species dif-
ferences. Specifically, N-dealkylation was primarily observed
in humans, shown from quantification of 2a (26% from HLM
and <1% from RLM). The amount of N-ethyl oxidation was
comparable in both species (i.e., 2b); however, oxidation of the
cyclohexyl ring occurred more extensively in rat, (2c, 62% from
RLM vs 44% from HLM). With these data in hand, we sought
to improve the metabolic stability of compound 2 via modifica-
tions to the ethyl and cyclohexyl substituents. We planned to
use our in vitro assay to measure initial improvements in
metabolic stability of synthesized compounds. Promising ana-
logues would then be advanced to rodent pharmacokinetic
studies.
Analogues containing N-ethyl replacements were initially
explored, and it was found that the different nitrogen substituents
were generally tolerated in regard to potency (Table 1).
Compound 8 showed a slight reduction in potency, especially
in the cellular assays; however, this compound was tested as a
racemic mixture. On the basis of our metabolite identification
studies described above, we expected improvements in stability
to be greater in human liver microsomes over rat liver
microsomes. Indeed, compounds 7-9 all showed improvements
in HLM stability, while no stability gains were observed when
evaluated in the rat microsome assay. Compound 9, containing
the N-cyclopropyl substituent, was found to be optimal in the
HLM stability assay (81% remaining after 30 min). In addition
to improved microsomal stability, the cyclopropyl-substituted
analogue 9 showed a slight increase in potency (11ꢀ-HSD1 IC50
) 0.8 nM) compared to the parent compound 2.
a Reagents and conditions: (a) NH2R2, NaBH(OAc)3, dichloroethane
(16-99%); (b) 17, EDCI, HOAt, NaHCO3, DMF (10-63%); (c)
(CF3CO)2O, pyridine (88%); (d) BH3, THF; (e) 17, SOCl2, THF, 80 °C,
then amine (29%, two steps); (f) TMSCF3, TBAF, THF; (g) 5 M NaOH,
75 °C (78%, two steps); (h) recrystallization with chinconidine, optical purity
>99% ee (24% from racemic material).
standard amide coupling conditions to afford the targeted
analogues 2, 8, and 9. Compound 7 was prepared via a different
synthetic route starting from cyclohexylamine 5. Acylation of
cyclohexylamine with trifluoroacetic anhydride, followed by
reduction of the resultant amide carbonyl with borane, gave the
N-(2,2,2-trifluoroethyl)cyclohexylamine 6, which was coupled
to (S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid 17
through intermediate formation of the more reactive acid
chloride.
The synthesis of 4-substituted cyclohexane benzamides was
accomplished in a straightforward manner, starting with the
appropriate 4-substituted cyclohexanone 3 (R1 * H) (Scheme
1). For compounds 10-12, the commercially available 4-phenyl-
and 4-(4-cyano)phenylcyclohexanones (3, R1 ) Ph and 4-CNPh,
respectively) were elaborated to the corresponding benzamides
in two steps via reductive amination with cyclopropylamine
followed by amide bond formation.8 For analogues 13 and 14,
the 4-substituted cyclohexanone intermediates (3, R1 ) 3-pyridyl
and CH2CH2CN, respectively) were prepared according to
literature prodecures.9,10 The preparation of 4-fluorocyclohex-
anone 19, a precursor to derivative 15, was achieved in three
steps from known 4-hydroxycyclohexyl benzoate 18 as detailed
in Scheme 2.11
Having improved the in vitro stability in human liver
microsomes, we then turned our attention to the optimization
of metabolic stability in rats. The N-cyclopropyl group was
maintained in subsequent analogues, which was predicted to
have an additive effect with any improvements made in rat
microsomal stability. It was found that, in general, substitution
at the 4-position on the cyclohexane ring resulted in significant
improvements in microsomal stability. The stereochemistry of
this substituent was determined to be important because only
Results and Discussion
All compounds were screened for 11ꢀ-HSD1 enzyme activity
in a scintillation proximity assay (SPA).7 Select compounds were
then tested for cellular activity in human embryonic kidney 293
cells (HEK 293 or h293) that stably express recombinant full-
length human 11ꢀ-HSD1 and nontransfected human fat stromal
cells (adipocytes) expressing endogenous levels of 11ꢀ-HSD1.12

Benzamide Inhibitors of 11ꢀ-HSD1
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3955
Figure 3. Major metabolites of compound 2.
Table 1. Effect of N-Ethyl Modifications on in Vitro Metabolic
Stability and Potency
measured. Typically, IC50 values measured in adipocytes were
comparable to the noncellular biochemical potency data. The
trans-4-substituted cyclohexane benzamides were also tested
against the 11ꢀ-HSD2 enzyme in the SPA assay to determine
11ꢀ-HSD selectivity. In all cases, the compounds were inactive
(>10 µM).
Since compounds 12-14 demonstrated satisfactory in vitro
metabolic stability, these compounds were examined in rodent
pharmacokinetic experiments (Table 3). It was found that in
vivo results exhibited a correlation to the in vitro microsomal
stability data. For example, the 4-(4-cyano)phenyl derivative
12 was found to have a very low clearance in rats (CL ) 0.11
L/h/kg) as predicted from the rat liver microsome data (>90%
remaining after 30 min). Analogues 13 and 14 were found to
have moderate clearance in rats (CL ) 1.0 and 1.28 L/h/kg,
respectively), also reflected in the in vitro data (Table 2). Further
pharmacokinetic evaluation of compound 13 was carried out
in two separate species, cynomolgus monkey and dog. The
measured clearance of 13 in cynomolgus monkey and dog (CL
) 0.50 and 0.60 L/h/kg, respectively) was found to be about
2-fold lower than the rat clearance, which resulted in a low
predicted clearance in humans based on allometric scaling.13
Pyridine analogue 13 had excellent oral bioavailability in rats
(F ) 72%) and cynomolgus monkeys (F ) 64%), but the
bioavailability in dogs was poor (4%).14 Overall, molecules 12
and 13 showed the most promising pharmacokinetic profiles,
characterized by low clearances, long half-lives, and high
exposures.
a IC50 values determind by scintillation proximity assay (SPA). b All
potency data are reported as the average of at least two determinations.
c h293 ) HEK 293 cells stably transfected with full length human
11ꢀ-HSD1. d HSA ) human serum albumin. e Racemic mixture; synthesized
from racemic 17.
the trans isomers showed improved microsomal stability. For
example, the 4-phenyl trans derivative 10 was stable in both
human and rat liver microsomes (>90% remaining after 30 min),
while the corresponding cis analogue 11 was rapidly consumed
(9% and <5% remaining in HLM and RLM after 30 min,
respectively, Table 2). These results demonstrated that con-
comitant modifications to the N-ethyl and N-cyclohexane groups
led to highly improved stability in the in vitro microsomal
clearance assay in humans and rats, as predicted from the
metabolic identification studies of parent compound 2.
In addition to significant improvements measured in the
microsomal stability assay, compounds containing a substituent
at the 4-cyclohexane position were highly potent. It was found
that trans aryl (10, 12), heteroaryl (13), alkyl (14), and fluorine
(15) substituents were tolerated. The 4-phenyl cis analogue 11
showed slightly diminished 11 ꢀ-HSD1 activity (∼5-fold)
relative to the corresponding trans derivative 10 in the noncel-
lular assay, and this result exemplified the general SAR trend
for the cis and trans stereoisomers. A shift in potency was
observed in h293 cells for all compounds tested, ranging from
2-fold to 17-fold. The cellular potency was further lowered in
the presence of HSA, ranging from 4-fold to 21-fold. The
potency profile of pyridyl compound 13 exemplified the general
trend: 11ꢀ-HSD1 (SPA) IC50 ) 1.4 nM, h293 11ꢀ-HSD1 IC50
) 5.8 nM (4-fold shift), and h293 (+3% HSA) 11ꢀ-HSD1 IC50
) 124 nM (21-fold shift).
In addition to the excellent potency and pharmacokinetic
profile, compound 13 had suitable activity in a recombinant
cynomolgus monkey 11ꢀ-HSD1 enzyme assay (IC50 ) 39 nM).
We selected compound 13 for further evaluation in our
cynomolgus ex vivo pharmacodymanic model in which we
measured, in vitro, the 11ꢀ-HSD1 enzyme activity in intact fat
tissues collected from animals dosed with the molecule. This
ex vivo model is useful in that it can quantify the 11ꢀ-HSD1
activity not only in the tissue of choice but also at a time point
of choice.
In the ex vivo study, cynomolgus monkeys were dosed orally
with 2 and 10 mg/kg of inhibitor 13. At 2 h postdose, the
animals were sacrificed and the mesenteric fat tissue was
removed. Following incubation of these tissues in media
containing [3H]cortisone, 11ꢀ-HSD1 activity was measured
through detection of tritiated cortisol levels using a scintillation
proximity assay. Relative to controls, both dose groups showed
a decrease in [3H]cortisol production in mesenteric fat, corre-
sponding to an ED50 in cynomolgus monkey of 2 mg/kg12
(Figure 4). Compound exposure levels were measured to be
approximately 2.5 times greater in the adipose (levels ranged
from 1510 to 2890 ng/g) than in the plasma, which showed
that the compound effectively distributed to the target fat tissue.
These results demonstrated that inhibitor 13 was effective in
11ꢀ-HSD1 enzyme inhibition in the adipose tissue is believed
to be important for achieving efficacy in vivo.4 Thus, we
measured the ability for compounds to inhibit 11ꢀ-HSD1 activity
in human adipocytes (Table 2). The ꢀ-cyanoethyl analogue 14
showed exquisite potency across all assays, including in the
adipocyte assay where subnanomolar potency of 0.2 nM was

3956 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Julian et al.
Table 2. SAR of 4-Substituted Cyclohexane Benzamide Inhibitors 9-15
a IC50 values determind by scintillation proximity assay (SPA). b All potency data are reported as the average of at least two determinations. c h293 )
HEK 293 cells stably transfected with full length human 11ꢀ-HSD1. d HSA ) human serum albumin. e ND ) not determined.
Table 3. Pharmacokinetic Profiles of Compounds 12-14
CL
t1/2
Vdss
AUC
F
compd species (iv, L/h/kg) (iv, h) (iv, L/kg) (iv, mg ·h/L (po, %)
12
13
13
13
14
rata
0.11
1.0
0.50
0.60
1.28
15.7
4.5
11.2
9.3
2.5
6.7
8.1
3.5
0.91
1590
481
1010
915
29
72
64
4
ratb
cynob
dogb
rata
0.5
393
83
a Dosed iv 0.17 mg/kg, po 2.0 mg/kg. b Dosed iv 0.5 mg/kg, po 2.0
mg/kg.
lowering 11ꢀ-HSD1 adipose activity in cynomolgus monkeys
when administered orally.
Insight into the binding mode of the benzamide class of 11ꢀ-
HSD1 inhibitors was obtained by X-ray crystallography, and
the data were compared to our previously studied sulfonamide
inhibitors (e.g., compound 20, Figure 5d).6c,15 Specifically, an
X-ray cocrystal structure of compound 13 with human 11ꢀ-
HSD1 enzyme containing NADP cofactor was generated (Figure
5). Benzamide 13 binds in a V-shaped conformation in the
steroid substrate binding pocket with the amide carbonyl forming
a central hydrogen bond interaction with hydroxyl of S170
(Figure 5a), one of the three residues that define the catalytic
triad for 11ꢀ-HSD1 activity.16 The rest of the molecule forms
a number of van der Waals (VDWs) contacts with the enzyme
as well as the cofactor NADP. The pyridine ring is positioned
toward the solvent exposed area of the dimer interface region
of the protein and does not make any specific interactions, which
may explain the tolerability of polar groups at this position
(Figure 5b). The cyclopropyl moiety forms close van der Waals
interactions with the side chains of L171 and Y177 and the
Figure 4. Exposure and activity of compound 13 as measured in a
cynomolgus monkey enzyme inhibition ex vivo assay.
backbone of L215, and the trifluoromethyl tertiary alcohol
positions toward the cofactor NADP with the trifluoromethyl
group in close VDWs contacts with T124, S125, L126, and
A226.
In comparison to the benzamide compound, our previously
reported sulfonamide inhibitor 20 also binds in the active site
with a similar V-shape binding mode.15 The cyclopropane
carboxamide group points toward the dimer interface region,

Benzamide Inhibitors of 11ꢀ-HSD1
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3957
Figure 5. X-ray cocrystal structures of benzamide 13 and sulfonamide 20 with human 11ꢀ-HSD1. (a) Binding mode of inhibitor 13 in the active
site of 11ꢀ-HSD1. The key hydrogen bonding interaction of 13 to the enzyme is shown with the magenta dashed line. The color scheme is red for
oxygen atoms, blue for nitrogen atoms, orange for sulfur atoms, magenta for fluorine atoms. Carbon atoms are in gray for the enzyme, beige for
NADP, and cyan for the inhibitor. The key residues in the catalytic triad are highlighted in yellow sticks, with hydrogen bond interactions indicated
by gray dashed lines. (b) Molecular surface representation of a side view of 13 in the active site. (c) Binding mode of inhibitor 20 to the enzyme
with inhibitor 13 overlaid on it. The key hydrogen bonding interaction of 20 to the enzyme is shown with the magenta dashed line. The carbon
atoms are in green for inhibitor 20. The water molecules in the active site are shown in red spheres. (d) Chemical structures of pyridine 13 and
sulfonamide 20.
solvents (DriSolv) were purchased from EMD Chemicals and
packaged under nitrogen in Sure Seal bottles. Reactions were
monitered using thin-layer chromatography on 250 µm plates or
using Agilent 1100 series LCMS with UV detection at 254 nm
and a low resonance electrospray mode (ESI). Purification of title
compounds was accomplished by flash column chromatography
using silica gel 60 (particle size 0.04-0.063 mm, 230-400 mesh)
or medium pressure liquid chromatography on a CombiFlash
Companion (Teledyne Isco) with RediSep normal phase silica gel.
1H NMR spectra were recorded on a Bruker spectrometer (400 or
500 MHz) at ambient temperature, with the exception of compounds
2, 7, and 8, which were recorded at 120 °C. Compounds 2, 7, and
8 exist as a mixture of amide rotamers, which results in broad peaks
at ambient temperature. Chemical shifts are reported in ppm relative
to CDCl3 or DMSO and coupling constants (J) are reported in hertz
(Hz).
similar to the area occupied by the pyridyl ring in 13 (Figure
5c). However, the isosteric sulfonamide core moiety does not
form any direct hydrogen bond interactions to the catalytic triad
residues, as observed in the cocrystal structure of inhibitor 13.
Instead, the sulfonamide oxygen forms a hydrogen bond with
the backbone amide of A172, which represents a notable
difference in the key binding interactions of the benzamide and
sulfonamide inhibitors.
Conclusion
In summary, we have identified a novel class of 11ꢀ-HSD1
inhibitors containing a benzamide core structure. Our initial lead
compound 2, in the benzamide series, was highly potent, but
showed poor metabolic stability. Significant improvements in
metabolic stability were achieved by identifying the primary
metabolites of compound 2 and utilizing these data to systemati-
cally modify the proposed structural liabilities. Modification of
the parent compound 2, which included incorporation of an
N-cyclopropyl group and a trans-disposed substituent at the
4-position on the N-cyclohexyl ring, resulted in dramatically
improved metabolic stability, as exemplified by compound 13.
In vitro microsomal stability data were predictive of pharma-
cokinetics and were used as a tool to select compounds for in
vivo experiments. Pyridyl compound 13 possessed a desirable
pharmocokinetic profile in three different species (rat, cyno-
molgus monkey, and dog) and was demonstrated to be orally
efficacious in lowering adipose 11ꢀ-HSD1 activity in a monkey
ex vivo model. Finally, X-ray cocrystallographic data of
compound 13 with 11ꢀ-HSD1 revealed key interactions im-
portant for inhibitor binding.
2-(S)-2-Methyl-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phe-
nylsulfonyl)piperidine (1). To a solution of 2-(S)-2-methylpiperi-
dine17 (1.69 g, 17.1 mmol) and triethylamine (10 mL, 71.9 mmol)
in CH2Cl2 (35 mL) was added 4-acetylbenzenesulfonyl chloride
(4.0 g, 18.3 mmol). After being stirred for 14 h, the reaction mixture
was diluted with saturated aqueous NaHCO3, extracted with CH2Cl2
(×2), dried with Na2SO4, and concentrated under reduced pressure.
Purification of the crude material by flash column chromatography
(SiO2, 1% MeOH/CH2Cl2) gave the product (3.27 g, 68%) as a
white solid.
The 4-acetylbenzenesulfonamide prepared above (1.60 g, 5.69
mmol) was dissolved in THF (30 mL) followed by the addition of
TMSCF3 (22.7 mL, 0.5 M solution in THF). After 30 min,
tetrabutylammonium fluoride hydrate (6.3 mL, 1 M in THF) was
added. After being stirred for 3 h, the reaction mixture was diluted
with saturated aqueous NaHCO3, extracted with EtOAc (×2), dried
with MgSO4, and concentrated under reduced pressure. Purification
of this material by flash column chromatography (SiO2, 0.5%
MeOH/CH2Cl2) gave the product (902 mg, 45%) as a viscous
yellow oil: 1H NMR (DMSO-d6, 400 MHz) δ 7.80 (d, J ) 9.0 Hz,
2 H), 7.79 (d, J ) 9.0 Hz, 2 H), 6.85 (s, 1 H), 4.10 (m, 1 H), 3.59
Experimental Section
Unless otherwise noted, all materials were obtained from
commercial suppliers and used without purification. Dry organic

3958 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Julian et al.
(m, 1 H), 2.96 (ddd, J ) 13.2, 13.2, 2.6 Hz, 1 H), 1.71 (s, 3 H),
1.45 (m, 5 H), 1.20 (m, 1 H), 0.99 (d, J ) 6.9 Hz, 3 H). Anal.
Calcd for C15H20F3NO3S: C, 51.27; H, 5.74; N, 3.99. Found: C,
51.37; H, 5.75; N, 4.05.
1.06 (m, 3 H). Anal. Calcd for C18H21F6NO2: C, 54.41; H, 5.33;
N, 3.52. Found: C, 54.56; H, 5.37; N, 3.48.
(S)-N-Cyclohexyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-N-cy-
clopropylmethylbenzamide (8). Compound 8 was prepared in 41%
yield (two steps) according to the procedure used for 2, substituting
(S)-N-Cyclohexyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-N-
ethylbenzamide (2). To a solution of cyclohexanone 3 (R1 ) H)
(200 mg, 2.04 mmol) in dichloroethane (6 mL) was added
ethylamine hydrochloride (249 mg, 3.06 mmol), AcOH (114 µL,
2.04 mmol), and NaBH(OAc)3 (648 mg, 3.06 mmol). After being
stirred for 12 h, the reaction mixture was quenched with 2 N NaOH
and extracted with CH2Cl2 (×1). The combined organic layers were
washed with brine (×1), dried with MgSO4, and concentrated in
vacuo to afford the crude amine, which was used without purifica-
tion in the following reaction.
1
cyclopropylmethylamine for ethylamine hydrochloride. H NMR
(DMSO-d6, 500 MHz, 120 °C) δ 7.65 (d, J ) 8.1 Hz, 2 H), 7.34
(d, J ) 8.1 Hz, 2 H), 6.24 (s, 1 H), 3.65 (m, 1 H), 3.21 (m, 2 H),
1.74 (s, 3 H), 1.72 (m, 6 H), 1.58 (m, 1 H), 1.13 (m, 3 H), 1.01 (m,
1 H), 0.47 (m, 2 H), 0.17 (m, 2 H). Anal. Calcd for C20H26F3NO2:
C, 65.02; H, 7.09; N, 3.79. Found: C, 64.58; H, 7.16; N, 3.74.
(S)-N-Cyclohexyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-N-cy-
clopropylbenzamide (9). Compound 9 was prepared in 45% yield
(two steps) according to the procedure used for 2, substituting
cyclopropylamine for ethylamine hydrochloride. 1H NMR (CDCl3,
500 MHz) δ 7.58 (d, J ) 9.0 Hz, 2 H), 7.47 (d, J ) 9.0 Hz, 2 H),
4.09 (m, 1 H), 2.83 (s, 1 H), 2.56 (m, 1 H), 1.96 (m, 1 H), 1.85 (m,
4 H), 1.85 (s, 3 H), 1.71 (m, 2 H), 1.39 (m, 2 H), 1.18 (m, 1 H),
0.56 (m, 2 H), 0.45 (m, 2 H). Anal. (C19H24F3NO2) C, H, N.
(S)-N-(trans-4-Phenyl)cyclohexyl-4-(1,1,1-trifluoro-2-hydrox-
ypropan-2-yl)-N-cyclopropylbenzamide (10) and (S)-N-(cis-4-Phe-
nyl)cyclohexyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-N-cyclo-
propylbenzamide (11). A solution of 4-phenylcyclohexanone 3 (R1
) Ph) (500 mg, 2.87 mmol) in 1,2-dichloroethane (16 mL) was
treated at 0 °C with cyclopropylamine (298 µL, 4.31 mmol), acetic
acid (329 µL, 5.74 mmol), and NaBH(OAc)3 (1.22 g, 5.74 mmol).
After being stirred at 25 °C for 12 h, the reaction mixture was
diluted (EtOAc) and washed with 1 M NaOH (×1) and brine (×1).
The organics were dried with Na2SO4 and concentrated in vacuo
to provide 610 mg of the product as a colorless oil (2.83 mmol,
99%). The product was used in the next step without further
purification.
A solution of N-cyclopropyl-4-phenylcyclohexylamine (81 mg,
0.38 mmol) and (S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic
acid 17 (80 mg, 0.34 mmol) in DMF (1.7 mL) was treated at 0 °C
with EDCI (85 mg, 0.44 mmol), HOAt (60 mg, 0.44 mmol), and
NaHCO3 (57 mg, 0.68 mmol). After being stirred at 25 °C for 12 h,
the reaction mixture was diluted (EtOAc), washed 10% aqueous
citric acid (×1), saturated aqueous NaHCO3 (×1), and brine (×1).
The organics were dried with Na2SO4 and concentrated under
reduced pressure. Flash chromatography (SiO2, 20% EtOAc/
hexanes) gave 37 mg of the trans product 10 as a white solid (25%):
1H NMR (CDCl3, 500 MHz, trans isomer) δ 7.59 (d, J ) 8.1 Hz,
2 H), 7.49 (d, J ) 8.0 Hz, 2 H), 7.25 (m, 5 H), 4.23 (m, 1 H), 2.70
(m, 3 H), 2.04 (m, 6 H), 1.79 (s, 3 H), 1.64 (m, 2 H), 0.59 (m, 2
H), 0.51 (m, 2 H). Anal. Calcd for C25H28F3NO2: C, 69.59; H, 6.54;
N, 3.25. Found: C, 69.57; H, 6.63; N, 3.26.
Further elution using more polar solvent (SiO2, 25% EtOAc/
hexanes) afforded 39 mg of the cis isomer 11 as a white solid (27%):
1H NMR (CDCl3 500 MHz) 7.57 (d, J ) 8.5 Hz, 2 H), 7.46 (d, J
) 8.1 Hz, 2 H), 7.41 (m, 2 H), 7.34 (m, 2 H), 7.21 (m, 1 H), 4.33
(m, 1 H), 3.11 (m, 1 H), 2.76 (m, 1 H), 2.50 (m, 1 H), 2.30 (m, 1
H), 2.08 (m, 2 H) 1.95 (m, 2 H), 1.80 (m, 2 H), 1.78 (s, 3 H), 0.45
(m, 2 H), 0.35 (m, 2 H). Anal. Calcd for C25H28F3NO2: C, 69.59;
H, 6.54; N, 3.25. Found: C, 69.38; H, 6.64; N, 3.24.
(S)-N-[trans-4-(4-Cyanophenyl)cyclohexyl]-4-[1,1,1-trifluoro-2-
hydroxypropan-2-yl]-N-cyclopropylbenzamide (12). A solution of
crude 4-(4-cyanophenyl)cyclohexanone 3 (R1 ) 4-CNPh) (7.3 g,
36.6 mmol) in 1,2-dichloroethane (170 mL) was treated at 0 °C
with cyclopropylamine (3.80 mL, 54.7 mmol), acetic acid (4.19
mL, 73.2 mmol), and NaBH(OAc)3 (15.5 g, 73.2 mmol). After being
stirred at 25 °C for 12 h, the reaction mixture was diluted (EtOAc),
washed with 1 M NaOH (×1) and brine (×1), dried with Na2SO4,
and concentrated in vacuo. Flash chromatography (SiO2, 20-30%
EtOAc/hexanes containing 2.5% of TEA, gradient elution) gave
the cis amine (13.8 mmol, 37%). Further elution using more polar
solvent (30-50% EtOAc/hexanes containing 2.5% of TEA, gradient
elution) afforded 2.20 g (25%) of the trans amine as a pale-yellow
solid.
To a mixture of crude N-cyclopropylcyclohexylamine (60 mg,
0.47 mmol), (S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic
acid 17 (121 mg, 0.52 mmol), HOAt (95 mg, 0.70 mmol), EDCI
(134 mg, 0.70 mmol), and NaHCO3 (78 mg, 0.94 mmol) was added
DMF (1.5 mL). After the mixture was stirred for 12 h, the reaction
was quenched with water and the mixture was diluted with EtOAc.
The aqueous layer was extracted with EtOAc (×1), and the
combined organic layers were washed with water (×3) and brine
(×1), dried with MgSO4, and concentrated in vacuo. The crude
material was purified by flash column chromatography (SiO2, 50%
1
EtOAc/hexanes) to afford 71 mg of 2 (44%) as a white solid: H
NMR (DMSO-d6, 500 MHz, 120 °C) δ 7.65 (d, J ) 8.1 H, 2 H),
7.34 (d, J ) 8.1 Hz, 2 H), 6.24 (s, 1 H), 3.65 (m, 1 H), 3.28 (q, J
) 6.8 H, 2 H), 1.75 (m, 4 H), 1.74 (s, 3 H), 1.61 (m, 3 H), 1.12 (t,
J ) 6.8 Hz, 3 H), 1.12 (m, 3 H). Anal. Calcd for C18H24F3NO2: C,
62.96; H, 7.04; N, 4.08. Found: C, 62.59; H, 7.08; N, 4.07.
(S)-N-Cyclohexyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-N-
(2,2,2-trifluoroethyl)benzamide (7). To a solution of cyclohexy-
lamine 5 (324 mg, 3.27 mmol), pyridine (400 µL, 4.90 mmol), and
CH2Cl2 (15 mL) at 0 °C was added trifluoroacetic anhydride (549
µL, 3.92 mmol) dropwise. The ice bath was removed, and the
reaction mixture was stirred at ambient temperature for 12 h. The
reaction mixture was quenched with water and extracted with
CH2Cl2 (×1). The combined organics were washed with brine (×1),
dried with MgSO4, and concentrated in vacuo to afford the crude
N-cyclohexyl-2,2,2-trifluoroacetamide, which was used without
purification in the following reaction.
To a solution of N-cyclohexyl-2,2,2-trifluoroacetamide in THF
(2 mL) at 0 °C was slowly added BH3 ·THF (8.0 mL, 1 M in THF).
The ice bath was removed, and the reaction mixture was refluxed
for 12 h. The reaction mixture was then cooled to 0 °C, treated
with MeOH (2.5 mL), and refluxed for an additional 5 h. After
cooling to room temperature, the mixture was poured into water,
acidified to pH 2 with 2 N HCl, and extracted with CH2Cl2 (×2).
The organic layers were discarded, and the aqueous layer was
basified with 2 M NaOH. Following extraction of the aqueous layer
with CH2Cl2 (×2), the combined organics were washed with brine
(×1), dried with MgSO4, and carefully concentrated in vacuo to
afford 520 mg of the volatile N-(2,2,2-trifluoroethyl)cyclohexy-
lamine 6, which was used without purification in the following
reaction.
To a solution of (S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-
benzoic acid 17 (400 mg, 1.71 mmol), pyridine (279 µL, 3.42
mmol), and THF (4 mL) was added SOCl2 (137 µL, 1.88 mmol).
After being stirred at 80 °C for 2 h, the reaction mixture was cooled
to room temperature and N-(2,2,2-trifluoroethyl)cyclohexylamine
6 was added. After being stirred for an additional 12 h, the reaction
mixture was quenched with water. The aqueous layer was extracted
with EtOAc (×1), and the combined organic layers were washed
with water (×3) and brine (×1), dried with MgSO4, and concen-
trated in vacuo. The crude material was purified by flash column
chromatography (SiO2, 20-33% EtOAc/hexanes, gradient elution)
1
to afford 200 mg of 7 (29%) as a white solid: H NMR (DMSO-
d6, 400 MHz, 120 °C) δ 7.65 (d, 8.1 Hz, 2 H), 7.40 (dt, J ) 8.5,
1.9 Hz, 2 H), 6.27 (s, 1 H), 4.21 (q, J ) 9.4 Hz, 2 H), 3.60 (tt, J
) 11.9, 3.3 Hz, 1 H), 1.74 (m, 4 H), 1.74 (s, 3 H), 1.58 (m, 3 H),
A solution of trans-N-cyclopropyl-4-(4-cyano)phenylcyclohexy-
lamine (6.30 g, 26.2 mmol) and (S)-4-(1,1,1-trifluoro-2-hydrox-

Benzamide Inhibitors of 11ꢀ-HSD1
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3959
ypropan-2-yl)benzoic acid 17 (6.14 g, 26.2 mmol) in DMF (66 mL)
was treated at 0 °C with EDCI (6.53 g, 34.1 mmol), HOAt (4.64
g, 34.1 mmol), and NaHCO3 (4.40 g, 52.4 mmol). After being
stirred at 25 °C for 12 h, the reaction mixture was diluted (EtOAc),
washed with 1 N HCl (×2), 1 N NaOH (×2), and brine (×1), dried
with Na2SO4, and concentrated under reduced pressure. Purification
of the residue by recrystallization (3 × 50% EtOAc/hexanes)
afforded 6.70 g of the product 12 as a white solid (56%): 1H NMR
(CDCl3, 500 MHz) δ 7.59 (d, J ) 8.1 Hz, 2 H), 7.59 (d, J ) 8.1
Hz, 2 H), 7.49 (d, J ) 8.2 Hz, 2 H), 7.32 (d, J ) 8.1 Hz, 2 H),
4.25-4.15 (m, 1 H), 2.75-2.57 (m, 3 H), 1.96 (m, 6 H), 1.80 (s,
3 H), 1.64 (m, 2 H), 0.59 (m, 2 H), 0.51 (m, 2 H). Anal.
(C26H27F3NO2) C, H, N.
4-Fluorocyclohexanone 19 was converted to compound 15
following the amide coupling procedure described for compound
10. After the amide coupling reaction, the crude material was
purified by flash chromatography (SiO2, 20-35% EtOAc/hexanes,
gradient elution) to afford the title compound in 10% yield (three
steps), along with 14% of the cis isomer. Data for the trans isomer:
1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J ) 8.2 Hz, 2 H), 7.45 (d,
J ) 8.2 Hz, 2 H), 4.52 (m, 1 H), 4.09 (m, 1 H), 2.76 (m, 1 H),
2.56 (m, 1 H), 2.21 (m, 2 H), 1.95 (m, 4 H), 1.79 (s, 3 H), 1.64 (m,
2 H), 0.55 (m, 2 H), 0.43 (m, 2 H). Anal. Calcd for C19H23F4NO2:
C, 61.12; H, 6.21; N, 3.75. Found: C, 61.37; H, 6.31; N, 3.68.
(S)-4-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)benzoic Acid (17).
To a solution of 4-acetylbenzonitrile 16 (1,293 g, 8.907 mol) in
THF (6297 mL) at 20 °C was added TBAF (1.0 M in THF, 160.9
g). TMSCF3 (1712 mL, 11.58 mol) was charged dropwise over
4 h. HCl (5 N, 9440 mL) was then added to the reaction mixture
over 1 h. After the mixture was stirred for an additional 4.5 h, the
phases were separated, the lower aqueous phase was extracted with
EtOAc (×2), and the combined organic phases were concentrated
to dryness in vacuo. The yellow-brown solid was triturated with
heptane/ethyl acetate (4:1, 6465 mL), filtered, and washed with
heptane/ethyl acetate (4:1, 647 mL). The filtrate was then concen-
trated to dryness in vacuo, then slurried in heptane/ethyl acetate
(4:1, 1131 mL) at 20 °C for 30-60 min. The second crop was
filtered, washed with heptane/ethyl acetate (4:1, 200 mL), and
combined with the first crop. The combined solids were triturated
with toluene (3200 mL) at 20 °C for 30-60 min, then filtered,
washed with toluene (200 mL), and dried overnight (45 °C/27 in.
Hg) to afford 1574.8 g (82% yield) the trifluoromethyl alcohol.
The product (597.5 g, 2.777 mmol) was dissolved in methanol
(600 mL) at 50 °C. Aqueous sodium hydroxide (2790 mL, 5 N)
was added in one portion and heated to reflux with subsurface
nitrogen purge. After being stirred for 3 h, the reaction mixture
was cooled to 0 °C and charged HCl (5 N, 2790 mL) dropwise.
The mixture was polish filtered (0.45 µm PTFE) and rinsed with
600 mL of methanol. Cinchonidine (654 g, 2.222 mol) was added
to the filtrate, followed by addition of methanol (4380 mL). The
mixture was refluxed for 1-3 h, then cooled to 20 °C and vacuum
filtered. The filter cake was washed with methanol/water (1:2, 600
mL) and the product was dried overnight (40 °C/27 in. Hg) to afford
601 g of the chinconidine salt (88.9% with respect to acid, 84.6%
de).
(S)-N-(trans-4-(Pyridin-3-yl))cyclohexyl-4-(1,1,1-trifluoro-2-hy-
droxypropan-2-yl)-N-cyclopropylbenzamide (13). Compound 13
was prepared according to the procedure used for 12, substituting
4-(pyridin-3-yl)cyclohexanone 3 (R1 ) 3-pyridyl) for 4-(4-cy-
anophenyl)cyclohexanone. The crude mixture of cis and trans
amines was purified by flash column chromatography (SiO2,
40-70% EtOAc/hexanes containing 2.5% TEA to 10% MeOH/
CH2Cl2 containing 2.5% TEA, gradient elution) to provide trans-
N-cyclopropyl-4-(pyridine-3-yl)cyclohexylamine in 31% yield. After
the amide coupling reaction, compound 13 was purified by flash
column chromatography (SiO2, 3-10% MeOH/CH2Cl2, gradient
elution) to afford the title compound (63%): 1H NMR (CDCl3, 500
MHz) δ 8.49 (s, 1 H), 8.46 (d, J ) 3.6 Hz, 1 H), 7.61 (d, J ) 8.1
Hz, 2 H), 7.58 (d, J ) 7.7 Hz, 1 H), 7.50 (d, J ) 8.3 Hz, 2 H),
7.24 (dd, 1 H, overlapping with CDCl3), 4.23 (m, 1 H), 2.80 (m, 1
H), 2.62 (m, 2 H), 2.05 (m, 6 H), 1.80 (s, 3 H), 1.65 (m, 2 H), 0.60
(d, J ) 4.8 Hz, 2 H). 0.49 (m, 2H). Anal. Calcd for C24H27F3NO2:
C, 66.64; H, 6.29; N, 6.48. Found: C, 66.65; H, 6.26; N, 6.43.
(S)-N-(trans-4-(2-Cyanoethyl)cyclohexyl)-4-(1,1,1-trifluoro-2-hy-
droxypropan-2-yl)-N-cyclopropylbenzamide (14). Compound 14
was prepared according to the procedure used for 12, substituting
4-(2-cyanoethyl)cyclohexanone 3 (R1 ) CH2CH2CN) for 4-(4-
cyanophenyl)cyclohexanone. The crude mixture of cis and trans
amines was purified by flash column chromatography (SiO2, 30%
EtOAc/hexanes containing 2.5% TEA) to provide trans-N-cyclo-
propyl-4-(2-cyanoethyl)cyclohexylamine in 16% yield. After the
amide coupling reaction, the crude material was purified by flash
column chromatography (SiO2, 50-75% EtOAc/hexanes, gradient
1
elution) to afford the title compound 14: H NMR (CDCl3, 400
The material could be further enriched by recrystallization with
cinchonidine: The crude salt (10.0 g, 18.92 mmol) was dissolved
in acetonitrile/water (1:1, 385 mL) at reflux. After the mixture was
cooled to 65 °C, it was seeded with the enantiomerically pure
material (0.100 g, 0.1892 mmol), held at 65 °C for 1 h, then cooled
to 0 °C at 20 °C/min and held for 1 h. The mixture was filtered,
washed with acetonitrile/water (1:2, 20 mL), and dried overnight
(40 °C/27 in. Hg) to afford 5.458 g pure (S)-4-(1,1,1-trifluoro-2-
hydroxypropan-2-yl)benzoic acid 17 (24.2% with respect to acid,
99% de). 1H NMR (DMSO-d6, 400 MHz) δ 13.00 (br s, 1H), 7.96
(d, J ) 8.6 Hz, 2H), 7.71 (d, J ) 8.6 Hz, 2H), 6.75 (s, 1H), 1.70
(s, 3H). Anal. (C10H9F3O3) C, H.
MHz) δ 7.59 (d, J ) 8.2 Hz, 2H), 7.49 (dt, J ) 8.6, 2.0 Hz, 2H),
4.13 (m, 1H), 2.58 (s, 1H), 2.57 (m, 1H), 2.40 (t, J ) 7.0 Hz, 2H),
1.92 (m, 6H), 1.80 (s, 3H), 1.61 (q, J ) 7.0 Hz, 2H), 1.49 (m, 1H),
1.14 (m, 2H), 0.56 (m, 2H), 0.45 (m, 2H). Anal. Calcd for
C22H27F3NO2: C, 64.69; H, 6.66; N, 6.86. Found: C, 64.72; H, 6.69;
N, 6.76.
(S)-N-(trans-4-Fluorocyclohexyl)-4-(1,1,1-trifluoro-2-hydrox-
ypropan-2-yl)-N-cyclopropylbenzamide (15). A solution of trans-
4-hydroxycyclohexyl benzoate 18 (5.26 g, 23.9 mmol) in CH2Cl2
(120 mL) at -78 °C was treated with a solution of DAST (2.0
mL, 15.4 mmol) in CH2Cl2 (120 mL). After being stirred at -78
°C for 10 min, 0 °C for 1 h, and 25 °C for 2 h, the reaction mixture
was diluted with CH2Cl2, washed with brine (×1), dried with
Na2SO4, and concentrated in vacuo. The crude material was purified
by flash column chromatography (SiO2, 5% MTBE/hexanes) to
afford 1.01 g of the product as a white solid.
To a solution of cis-4-fluorocyclohexyl benzoate (300 mg, 1.35
mmol) in 1:1 THF/MeOH (5.4 mL) was added LiOH (1.4 mL, 1.2
M in H2O). After being stirred for 5 h, the reaction mixture was
diluted with water, extracted with 10% MeOH/CH2Cl2 (×5), dried
with Na2SO4, and concentrated in vacuo to provide 150 mg of the
alcohol as a yellow solid. This material was used in the subsequent
step without further purification.
Acknowledgment. We thank Dr. Smriti Khera and David
Chow for recording the high-temperature NMR spectra of
compounds 2, 7, and 8 and David Meininger, Haoda Xu, and
Shelley Rabel Riley for technical assistance.
Supporting Information Available: Elemental analysis data and
experimental details for the biological assays and cocrystallization.
This material is available free of charge via the Internet at http://
pubs.acs.org.
To a mixture of PCC (437 mg, 2.03 mmol) and 4 Å molecular
sieves in CH2Cl2 (10 mL) was added a solution of 4-fluorocyclo-
hexanol (150 mg, 1.26 mmol). After being stirred for 1 h, the
reaction mixture was diluted with ether, filtered through silica gel,
and concentrated under reduced pressure to provide 103 mg of
4-fluorocyclohexanone 19 as a yellow oil.
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