Synthesis and pharmacological evaluation of 1-Alkyl-N-[(1R)-1-(4- fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives as novel antihypertensive agents

Article abstract of DOI:10.1248/cpb.59.1376

We synthesized and evaluated inhibitory activity against T-type Ca ²⁺ channels for a series of 1-alkyl-N- [(1R)-1-(4-fluorophenyl)-2- methylpropyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that the isopropyl substituent at the benzylic position plays an important role in exerting potent inhibitory activity, and the absolute configuration of the benzylic position was found to be opposite that of mibefradil, which was first launched as a new class of T-type Ca²⁺ channel blocker. Oral administration of N- [(1R)-1-(4-fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxyphenyl)ethyl] piperidine-4-carboxamide (17f) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, an adverse effect often caused by traditional L-type Ca²⁺ channel blockers.

Full text of DOI:10.1248/cpb.59.1376

1376
Regular Article
Chem. Pharm. Bull. 59(11) 1376—1385 (2011)
Vol. 59, No. 11
Synthesis and Pharmacological Evaluation of 1-Alkyl-N-[(1R)-1-(4-
fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide
Derivatives as Novel Antihypertensive Agents
Susumu WATANUKI, ,a Keisuke MATSUURA,a Yuichi TOMURA,a Minoru OKADA,b Toshio OKAZAKI,c
*
a
Mitsuaki OHTA,a and Shin-ichi TSUKAMOTO
a Drug Discovery Research, Astellas Pharma Inc.; 21 Miyukigaoka, Tsukuba, Ibaraki 305–8585, Japan: b Technology,
Astellas Pharma Inc.; 160–2 Akahama, Takahagi, Ibaraki 318–0001, Japan: and c QA, RA and Pharmacovigilance,
Astellas Pharma Inc.; 3–17–1 Hasune, Itabashi-ku, Tokyo 174–8612, Japan.
Received August 1, 2011; accepted August 24, 2011; published online August 25, 2011
We synthesized and evaluated inhibitory activity against T-type Ca2ꢀ channels for a series of 1-alkyl-N-
[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives. Structure–activity relationship
studies have revealed that the isopropyl substituent at the benzylic position plays an important role in exerting
potent inhibitory activity, and the absolute configuration of the benzylic position was found to be opposite that of
mibefradil, which was first launched as a new class of T-type Ca2ꢀ channel blocker. Oral administration of N-
[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxyphenyl)ethyl]piperidine-4-carboxamide (17f) lowered
blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, an adverse effect often
caused by traditional L-type Ca2ꢀ channel blockers.
Key words antihypertensive agent; T-type Ca2ꢀ channel; mibefradil; piperidine-4-carboxamide
Calcium ions are essential for life and the most common potent inhibitory activity against T-type Ca2ꢀ channels with
signal transduction element in cells, transmitting signals by an IC50 value of 0.089 mM in Ca2ꢀ influx assay and elicited in
entering cells through ion channels on the plasma membrane vivo antihypertensive effects in spontaneously hypertensive
in response to membrane depolarization.1) Investigation into rats without inducing reflex tachycardia by oral administra-
the different subtypes of voltage-dependent Ca2ꢀ channels tion (Fig. 1). We further optimized compound 2 in an attempt
has resulted in definition of two main classes: one responding to improve its in vivo potency, as the antihypertensive effect
to strong depolarization known as a high-voltage-activated of 2 was less potent than that of mibefradil. We considered
(HVA) Ca2ꢀ channel, and another responding to weak depo- that the low in vivo efficacy of compound 2 was caused by its
larization, known as low-voltage-activated (LVA) Ca2ꢀ chan- high lipophilicity. Compound 2 should be slightly lipophilic
nel. Based on results of several functional and pharmacologi- (c log Pꢁ5.00) to maintain its blood concentration because
cal studies, HVA Ca2ꢀ channels may be further subdivided highly lipophilic compound is easily metabolized by P450
into L-, N-, P/Q-, and R-types, with LVA Ca2ꢀ channel other- enzymes, in general (Lipinski’s rule of five). Therefore, we
wise known as T-type channels.2,3) Among these subdivi- designed compound 3a, in which one methylene group of 2
sions, T-type Ca2ꢀ channels are believed to play an important was eliminated (c log Pꢁ4.84), and found it to be as potent a
role in initial depolarization of the sinus and atrioventricular T-type Ca2ꢀ channel blocker as compound 2. Encouraged by
(AV) nodes4) and are therefore regarded as important thera- these data, we planned further optimization studies of com-
peutic targets for treating various cardiovascular diseases pound 3a.
such as hypertension, angina, heart failure, and arrhythmia.
Here, we describe the synthesis, structure–activity rela-
Mibefradil (1) was first launched as a new class of selec- tionships, and pharmacological properties of 1-alkyl-N-
tive T-type Ca2ꢀ channel blocker.5) This compound has dif-
ferent structural and pharmacological characteristics from
traditional L-type Ca2ꢀ channel blockers. In additon to caus-
ing vasodilation, blockade of T-type Ca2ꢀ channels slows the
sinus rate and prolongs AV nodal conduction without adverse
negative inotropic or positive chronotropic cardiac actions.6,7)
However, despite its excellent antihypertensive effects,
mibefradil was withdrawn from the market in 1998 due to its
pharmacokinetic interactions with other drugs metabolized
by cytochrome P450.8,9) Since the withdrawal of mibefradil,
increased interest in T-type Ca2ꢀ channels as a therapeutic
target has fueled significant efforts to discover novel T-type
Ca2ꢀ channel blockers.10—40)
We recently described the synthesis and pharmacological
evaluation of a novel set of T-type Ca2ꢀ channel blockers and
described the relationship between blockade of T-type Ca2ꢀ
channels and cardiovascular effects such as bradycardic ac-
tivity and antihypertensive effects.41,42) Compound 2 showed Fig. 1. Chemical Structures of T-Type Ca2ꢀ Channel Blocker
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: susumu.watanuki@jp.astellas.com

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[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-car- ethane, reduction of the nitrile group with DIBAL-H, and re-
boxamide derivatives as novel antihypertensive agents. oxidation with NaClO2. The Curtius rearrangement of car-
Synthesis The preparation of N-(1-ethyl-1-phenyl- boxylic acid 8 with diphenylphosphoryl azide (DPPA) and
propyl)-1-(2-phenylethyl)piperidine-4-carboxamide deriva- benzyl alcohol followed by deprotection of the benzyloxycar-
tives is outlined in Chart 1. Dialkylation of methyl benzoates bonyl (Cbz) group afforded the corresponding amine, which
4a—f with ethylmagnesium bromide followed by Ritter reac- was then coupled with 1-(Boc)piperidine-4-carboxylic acid
tion with chloroacetonitrile43) afforded chloroacetamides to give compound 9. Deprotection followed by alkylation
5a—f, which were then subsequently converted to piperidines resulted in the target compound 3g .
6a—f in a three-step sequence consisting of deprotection of
The compound bearing a cyclopentyl moiety at the ben-
the chloroacetyl group with thiourea, condensation with 1- zylic position (13) was synthesized as illustrated in Chart 3.
tert-butoxycarbonyl(Boc)piperidine-4-carboxylic acid in the Treatment of 4-fluorophenylacetonitrile 10 with 1,4-dibro-
presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodi- mobutane and NaH followed by acid hydrolysis of the nitrile
imide hydrochloride (WSCD) and 1-hydroxybenzotriazole group afforded carboxylic acid 11. Curtius rearrangement
(HOBt), and deprotection of the Boc group by treatment with followed by deprotection of the Cbz group then produced the
hydrogen chloride. Alkylation of piperidines 6a—f was ac- amine, which was subsequently treated with 1-(Cbz)piperi-
complished by reductive amination with phenylacetaldehyde dine-4-carbonyl chloride to provide compound 12. Hydro-
and sodium triacetoxyborohydride to afford the final com- genation followed by alkylation produced compound 13.
pounds 3a—f.
The synthesis of isopropyl analogues 17a—k is depicted
Obtaining compound 3g, which bears a 4-methoxy sub- in Chart 4. Curtius rearrangement of optically active car-
stituent at the benzene ring, was impossible using the method boxylic acid 1444) followed by deprotection of the Boc group
shown in Chart 1, possibly because the 4-methoxy-substi- yielded amine 15. Condensation of this amine 15 with 1-
tuted benzylic carbocation was not reactive enough to un- (Boc)piperidine-4-carboxylic acid and deprotection provided
dergo the Ritter reaction. We therefore synthesized com- the key intermediate 16. Alkylation of the piperidine 16 was
pound 3g as follows (Chart 2): 4-methoxyphenylacetonitrile carried out via two general methods, A and B. Compounds
7 was converted to carboxylic acid 8 in a three-step sequence 17a—e, 17h—k were synthesized by Method A, which in-
involving dialkylation of the benzylic position with iodo- volved reductive amination of 16 with corresponding aldehy-
Chart 1
Chart 2

1378
Vol. 59, No. 11
Chart 3
Chart 4
Chart 5
des, whereas compounds 17f, g were prepared by Method B, ing aldehydes (19a, b) and sodium triacetoxyborohydride
which involved alkylation of 16 with the corresponding tosy- subsequently produced compounds 17l and m, respectively.
lates under basic conditions.
LiAlH4 reduction of the ester group afforded the compound
Compounds 17l—n were synthesized as shown in Chart 5. 17n.
Alkylation of 3-hydroxybenzaldehyde 18 with corresponding
bromides followed by transformation of the benzaldehyde Results and Discussion
moiety to phenylacetaldehyde 19 by Wittig reaction and
The inhibitory activities of the synthesized compounds
treatment with formic acid yielded compounds 19a and b. against T-type Ca2ꢀ channels were assessed by measuring the
Alkylation of piperidine 16 by reaction with the correspond- inhibition of Ca2ꢀ influx in HEK293 cells stably expressing

November 2011
1379
human Cav3.1 (a1G).
fold compared to 3a. To reduce the lipophilicity of these
We first investigated the effect of substituents on the ben- compounds, an isopropyl group was introduced instead of the
zene ring on the left-hand side of 3a (Table 1). The inhibitory diethyl group. We initially evaluated the S-configured com-
activity of the parent compound 3a, with a fluorine atom at pound (ent-17a), which shared same absolute configuration
the 4-position, was found to be as potent as that of compound as mibefradil, and surprisingly found it to be less potent than
2 (IC50ꢁ0.13 mM). Elimination of this fluorine reduced the 3a. In contrast, the R-configured compound (17a) had similar
inhibitory activity (3b), and transposition to the 2- or 3-posi- inhibitory activity to 3a (IC50ꢁ0.15 mM). These results re-
tion (3c, d) also reduced the activity compared to 3a by 3- vealed that the stereochemistry of the substituent at the ben-
and 4-fold, respectively. While introduction of a methoxy zylic position strongly influences the inhibitory activity
group (3e—g) improved activity over that of the unsubsti- against T-type Ca2ꢀ channels and that the more potent com-
tuted compound (3b), these substituted compounds were pound had an R configuration, opposite that of mibefradil.
slightly less potent than the parent compound (3a) bearing a
Finally, we modified the pendant benzene ring of 17a of
fluorine at the 4-position. Taken together, these results indi- the phenethyl side chain (Table 3). The introduction of triflu-
cated that the introduction of a fluorine atom at the 4-position oromethyl groups reduced activity compared to the unsubsti-
on the benzene ring of 3b is optimal for conferring potent T- tuted compound (17b—d). Further, while introduction of
type Ca2ꢀ channel inhibitory activity.
methoxy groups at the 2- and 4-positions retained the in-
We then evaluated the compounds with several sub- hibitory activity (17e, g), 3-methoxy substitution increased
stituents at the benzylic position of 3a (Table 2). Inhibitory the activity. Indeed, the 3-methoxy derivative (17f) was the
activity of the cyclopentyl derivative (13) was reduced by 2- most potent in our series with an IC50 value of 0.076 mM.
These results indicated that the introduction of an electron-
Table 1. T-Type Ca2ꢀ Channel-Blocking Activity of 1-(2-Phenylethyl)-N-
(3-phenylpentan-3-yl)piperidine-4-carboxamide Derivatives (3a—g)
donating substituent was effective in enhancing the T-type
Ca2ꢀ channel blocking ability. We further explored electron-
donating substitution on the phenyl ring and found that con-
version of the methoxy group to ethoxycarbonylmethyloxy
(17l), 2-methoxyethoxy (17m), or hydroxyethoxy (17n)
groups decreased the activity compared to 17f, respectively.
While additional substituents were introduced to enhance the
inhibitory activity of 17f, introduction of another methoxy
group resulted in a decrease in activity compared to 17f
(17h—k). These results revealed that the ability to inhibit T-
type Ca2ꢀ channels is sensitive to the bulkiness of the sub-
stituents on the pendant benzene ring and that the intro-
duction of an additional substituent to 17f had a negligible
influence on inhibitory activity.
Compound
Structure
IC50 (mM)a)
3a
3b
3c
3d
3g
3e
3f
Rꢁ4-F
RꢁH
Rꢁ3-F
Rꢁ2-F
Rꢁ4-OMe
Rꢁ3-OMe
Rꢁ2-OMe
0.13
0.55
0.53
0.39
0.26
0.26
0.33
Based on the findings described above, we selected com-
pound 17f for the evaluation of the bradycardic activity in
isolated guinea pig right atria (Table 4). Compound 17f was
a) Inhibition of Ca2ꢀ influx through T-type Ca2ꢀ channels. See Experimental.
Table 2. T-Type Ca2ꢀ Channel-Blocking Activity of 1-(2-Phenylethyl)-
Table 3. T-Type Ca2ꢀ Channel-Blocking Activity of N-[(1R)-1-(4-Fluoro-
phenyl)-2-methylpropyl]-1-(2-phenylethyl)piperidine-4-carboxamide Deriva-
tives (17a—n)
piperidine-4-carboxamide Derivatives (3a, 13, ent-17a, 17a)
Compound
R
IC50 (mM)a)
Compound
Structure
IC50 (mM)a)
3a
0.13
17a
17b
17c
17d
17e
17f
17g
17l
17m
17n
17h
17i
RꢁH
Rꢁ2-CF3
Rꢁ3-CF3
Rꢁ4-CF3
Rꢁ2-OMe
Rꢁ3-OMe
Rꢁ4-OMe
Rꢁ3-OCH2CO2Et
Rꢁ3-OCH2CH2OMe
Rꢁ3-OCH2CH2OH
Rꢁ2,3-diOMe
Rꢁ3,4-diOMe
Rꢁ3,5-diOMe
Rꢁ2,5-diOMe
0.15
0.21
0.16
0.26
0.11
0.076
0.13
0.13
0.15
0.42
0.13
0.12
0.13
0.21
13
0.30
0.73
0.15
ent-17a
17a
17j
17k
a) Inhibition of Ca2ꢀ influx through T-type Ca2ꢀ channels. See Experimental.
a) Inhibition of Ca2ꢀ influx through T-type Ca2ꢀ channels. See Experimental.

1380
Vol. 59, No. 11
tent inhibitory activity against T-type Ca2ꢀ channels and that
the absolute configuration of the benzylic asymmetric center
was opposite that of mibefradil. We also found that 4-fluoro
substitution on the phenyl ring of the benzyl moiety and 3-
methoxy substitution on the phenyl ring in the phenethyl
moiety optimally improved T-type Ca2ꢀ channel blocking ac-
tivity. Of this series, N-[(1R)-1-(4-fluorophenyl)-2-methyl-
propyl]-1-[2-(3-methoxyphenyl)ethyl]piperidine-4-carbox-
amide (17f) exerted an antihypertensive effect without unde-
sirable reflex tachycardia on oral administration to sponta-
neously hypertensive rats. Further, the magnitude and dura-
tion of the reduction in blood pressure effected by the com-
pound (17f) were equipotent to those induced by mibefradil.
Further research to identify novel antihypertensive agents su-
perior in efficacy to currently available agents is underway
and will be reported in due course.
Table 4. Pharmacological Properties of Selected Compounds (17f, 1)
T-Typea)
IC50 (mM)
Bradycardic activityb)
Compound
EC30 (mM)
17f
Mibefradil (1)
0.076
0.20
2.1
2.9
a) Inhibition of Ca2ꢀ influx through T-type Ca2ꢀ channels. See Experimental. b)
Concentration required to elicit a 30% reduction in spontaneous beat rates from base-
line in isolated guinea pig right atria. See Experimental.
Experimental
1H-NMR spectra were obtained on a JEOL JNM-EX400 spectrometer and
the chemical shifts are expressed in d (ppm) values with tetramethylsilane as
an internal standard. Abbreviations of 1H-NMR signal patterns are as fol-
lows: s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multi-
plet; br, broad. Mass spectra were obtained on a JEOL JMS-DX300 or
HITACHI M-80 spectrometer. Column chromatography on silica gel was
performed with Kieselgel 60 (E. Merck).
2-Chloro-N-[3-(4-fluorophenyl)pentan-3-yl]acetamide (5a) To a solu-
tion of methyl 4-fluorobenzoate (4a, 10.0 g, 59.5 mmol) in tetrahydrofuran
(THF) (50 ml) was added portionwise ethylmagnesium bromide (3.0 M in
Et2O; 65 ml, 195 mmol) at ꢂ20 °C and the mixture was gradually warmed to
0 °C for 2 h. The mixture was poured onto ice-cooled aqueous ammonium
chloride solution and then extracted with AcOEt. The organic layer was
washed with brine, dried over Na2SO4, and evaporated in vacuo to give 3-(4-
fluorophenyl)pentan-3-ol (11.2 g) as a colorless oil, which was used for the
next step without further purification. To an ice-cooled solution of the alco-
hol obtained above (11.2 g, 59.5 mmol) and chloroacetonitrile (10 ml,
159 mmol) in AcOH (30 ml) was added slowly sulfuric acid (12 ml,
225 mmol) and the mixture was stirred at room temperature for 4 h. The
mixture was poured onto ice-water and the resulting precipitate was col-
lected by filtration to give the title compound 5a (13.8 g, 2 steps 90%) as a
colorless solid. 1H-NMR (CDCl3) d: 0.75 (6H, t, Jꢁ7.6 Hz), 2.00—2.21
(4H, m), 4.02 (2H, s), 6.69 (1H, s), 7.03 (2H, dd, Jꢁ8.4, 8.8 Hz), 7.26 (2H,
dd, Jꢁ4.8, 8.8 Hz). MS (FAB) m/z: 256 (Mꢀꢂ1).
Fig. 2. Effects of 17f and Mibefradil (1) on Mean Blood Pressure (MBP)
and Heart Rate (HR) in Conscious Spontaneously Hypertensive Rats
The compounds were orally administered at 0 h. The values are meansꢃstandard
error of the mean from at least three experiments.
found to exert potent bradycardic activity, with an EC30 value
of 2.1 mM, a value of comparable to that of mibefradil
(EC30ꢁ2.9 mM).
Given its potent inhibitory activity against T-type Ca2ꢀ
channels and the bradycardic activity displayed in isolated
guinea pig right atria, 17f was submitted for further pharma-
2-Chloro-N-(3-phenylpentan-3-yl)acetamide (5b) The title compound
was prepared in the same manner as described for 5a using 4b instead of 4a,
in 80% yield. 1H-NMR (CDCl3) d: 0.74 (6H, t, Jꢁ7.2 Hz), 2.15 (4H, q,
Jꢁ7.2 Hz), 4.04 (2H, s), 6.74 (1H, s), 7.23—7.38 (5H, m). MS (FAB) m/z:
cological evaluations. Mibefradil and 17f were orally admin- 240 (Mꢀꢀ1).
2-Chloro-N-[3-(3-fluorophenyl)pentan-3-yl]acetamide (5c) The title
istered to spontaneously hypertensive rats and the effects on
mean blood pressure (MBP) and heart rate (HR) were exam-
ined (Fig. 2). Compound 17f significantly reduced MBP, with
efficacy sustained for at least 8 h. In addition, no reflex tachy-
cardia was observed despite the potent antihypertensive ac-
tivity of the compounds. The magnitude and duration of re-
duction in blood pressure effected by 17f were not only more
potent than compound 2 by 3-fold, but also equipotent to
those induced by mibefradil. Given these findings, we hy-
pothesize that this enhanced in vivo efficacy of 17f is due to
the compound’s improved pharmacokinetic profile in sponta-
neously hypertensive rats.
compound was prepared in the same manner as described for 5a using 4c in-
stead of 4a, in 34% yield. 1H-NMR (CDCl3) d: 0.76 (6H, t, Jꢁ7.6 Hz),
2.00—2.25 (4H, m), 4.03 (2H, s), 6.70 (1H, s), 6.92—7.09 (3H, m), 7.26—
7.34 (1H, m). MS (FAB) m/z: 256 (Mꢀꢂ1).
2-Chloro-N-[3-(2-fluorophenyl)pentan-3-yl]acetamide (5d) The title
compound was prepared in the same manner as described for 5a using 4d in-
stead of 4a, in 73% yield. 1H-NMR (CDCl3) d: 0.77 (6H, t, Jꢁ7.6 Hz),
2.10—2.34 (4H, m), 4.00 (2H, s), 6.80 (1H, s), 6.97—7.05 (1H, m), 7.09—
7.15 (1H, m), 7.20—7.32 (2H, m). MS (FAB) m/z: 256 (Mꢀꢂ1).
2-Chloro-N-[3-(3-methoxyphenyl)pentan-3-yl]acetamide (5e) The
title compound was prepared in the same manner as described for 5a using
4e instead of 4a, in 67% yield. 1H-NMR (CDCl3) d: 0.74 (6H, t, Jꢁ7.6 Hz),
2.13 (4H, q, Jꢁ7.6 Hz), 3.97 (3H, s), 4.06 (2H, s), 6.73 (1H, s), 6.74—6.90
(3H, m), 7.25—7.29 (1H, m). MS (FAB) m/z: 270 (Mꢀꢀ1).
2-Chloro-N-[3-(2-methoxyphenyl)pentan-3-yl]acetamide (5f) The
title compound was prepared in the same manner as described for 5a using
4f instead of 4a, in 36% yield. 1H-NMR (CDCl3) d: 0.72 (6H, t, Jꢁ7.6 Hz),
2.05—2.20 (2H, m), 2.34—2.44 (2H, m), 3.85 (3H, s), 3.98 (2H, s), 6.90—
6.99 (2H, m), 7.15—7.33 (2H, m), 7.77 (1H, s). MS (FAB) m/z: 270
(Mꢀꢀ1).
Conclusion
A series of 1-alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methyl-
propyl]piperidine-4-carboxamide were synthesized and eval-
uated. Structure–activity relationship studies of this novel
class of compounds revealed that the isopropyl substituent at
N-[3-(4-Fluorophenyl)pentan-3-yl]piperidine-4-carboxamide Hy-
the benzylic position plays an important role in imbuing po- drochloride (6a) To a solution of 5a (1.0 g, 3.88 mmol) and AcOH

November 2011
1381
(1.0 ml) in EtOH (10 ml) was added thiourea (0.40 g, 5.25 mmol) and the
mixture was refluxed for 16 h. After the mixture was cooled to room temper-
ature, resulting precipitate was removed by filtration and the filtrate was con-
centrated in vacuo. The resulting residue was partitioned between aqueous
potassium carbonate solution and AcOEt. The organic layer was washed
with brine, dried over Na2SO4, and evaporated in vacuo to give 3-(4-fluo-
rophenyl)pentan-3-amine (0.77 g) as a colorless oil, which was used for the
next step without further purification. To an ice-cooled mixture of the amine
obtained above (0.77 g), 1-(Boc)piperidine-4-carboxylic acid (0.95 g,
4.14 mmol), and HOBt (0.55 g, 4.07 mmol) in CH3CN (10 ml) was added
WSCD (0.80 g, 4.18 mmol) and the mixture was stirred at room temperature
piperidine-4-carboxamide (0.53 g) as a colorless solid. The compound was
converted to its fumarate by treating it with fumaric acid (0.16 g, 1.38
mmol). The crude salt was suspended with CH3CN and filtered to give the
1
title compound 3a (0.54 g, 76%) as a colorless powder. H-NMR (DMSO-
d6) d: 0.62 (6H, t, Jꢁ7.2 Hz), 1.55—1.69 (2H, m), 1.70—1.86 (4H, m),
1.96—2.08 (2H, m), 2.25—2.35 (2H, m), 2.35—2.45 (1H, m), 2.70—2.85
(4H, m), 3.17—3.26 (2H, m), 6.58 (2H, s), 7.08 (2H, dd, Jꢁ8.4, 8.8 Hz),
7.17—7.32 (7H, m), 7.67 (1H, s). MS (FAB) m/z: 397 (Mꢀꢀ1). Anal. Calcd
for C25H33N2OF·C4H4O4·0.7H2O: C, 66.32; H, 7.37; N, 5.33; F, 3.62.
Found: C, 66.39; H, 7.08; N, 5.14; F, 3.49.
N-(3-Phenylpentan-3-yl)-1-(2-phenylethyl)piperidine-4-carboxamide
for 3 d. The reaction mixture was concentrated in vacuo and partitioned be- Fumarate (3b) The title compound was prepared in the same manner as
tween H2O and AcOEt. The organic layer was washed successively with 5%
aqueous citric acid solution, saturated aqueous sodium bicarbonate solution,
and brine, dried over Na2SO4, and evaporated in vacuo. The resulting residue
described for 3a using 6b instead of 6a, in 83% yield. 1H-NMR (DMSO-d6)
d: 0.62 (6H, t, Jꢁ7.2 Hz), 1.56—1.69 (2H, m), 1.70—1.89 (4H, m), 1.97—
2.09 (2H, m), 2.24—2.34 (2H, m), 2.36—2.46 (1H, m), 2.71—2.85 (4H, m),
was purified by column chromatography on silica gel (AcOEt/hexaneꢁ1/2) 3.12—3.21 (2H, m), 6.57 (2H, s), 7.12—7.32 (10H, m), 7.61 (1H, s). MS
to give tert-butyl 4-{[3-(4-fluorophenyl)pentan-3-yl]carbamoyl}piperidine- (FAB) m/z: 379 (Mꢀꢀ1). Anal. Calcd for C25H34N2O·C4H4O4·0.2H2O: C,
1-carboxylate (1.10 g, 2 steps 72%) as a colorless solid. To an ice-cooled so-
lution of the N-Boc derivative obtained above (1.10 g, 2.80 mmol) in AcOEt
(10 ml) was added 4 M HCl–AcOEt (5.0 ml, 20.0 mmol) and the mixture was
69.91; H, 7.77; N, 5.62. Found: C, 69.82; H, 7.69; N, 5.44.
N-[3-(3-Fluorophenyl)pentan-3-yl]-1-(2-phenylethyl)piperidine-4-car-
boxamide Fumarate (3c) The title compound was prepared in the same
1
stirred at room temperature for 2 h. After concentration of the reaction mix- manner as described for 3a using 6c instead of 6a, in 67% yield. H-NMR
ture, the resulting solid was suspended with AcOEt and collected by filtra-
(DMSO-d6) d: 0.63 (6H, t, Jꢁ7.2 Hz), 1.52—1.66 (2H, m), 1.67—1.87 (4H,
m), 1.95—2.09 (2H, m), 2.17—2.28 (2H, m), 2.33—2.44 (1H, m), 2.65—
2.83 (4H, m), 3.06—3.18 (2H, m), 6.59 (2H, s), 6.97—7.05 (2H, m), 7.08
tion to give the title compound 6a (0.93 g, quantitative) as a light yellow
1
solid. H-NMR (DMSO-d6) d: 0.62 (6H, t, Jꢁ7.6 Hz), 1.59—1.75 (2H, m),
1.77—1.92 (4H, m), 1.98—2.10 (2H, m), 2.50—2.62 (1H, m), 2.73—2.92 (1H, d, Jꢁ8.0 Hz), 7.17—7.35 (6H, m), 7.69 (1H, s). MS (FAB) m/z: 397
(2H, m), 3.22—3.38 (2H, m), 7.08 (2H, dd, Jꢁ8.4, 8.8 Hz), 7.26 (2H, dd, (Mꢀꢀ1). Anal. Calcd for C25H33N2OF·1.5C4H4O4: C, 66.25; H, 6.89; N,
Jꢁ4.8, 8.8 Hz), 7.78 (1H, s), 8.43 (1H, br s), 8.78 (1H, br s). MS (FAB) m/z: 4.91; F, 3.33. Found: C, 65.10; H, 6.99; N, 4.93; F, 3.40.
293 (Mꢀꢀ1).
N-[3-(2-Fluorophenyl)pentan-3-yl]-1-(2-phenylethyl)piperidine-4-car-
boxamide Fumarate (3d) The title compound was prepared in the same
manner as described for 3a using 6d instead of 6a, in 83% yield. H-NMR
N-(3-Phenylpentan-3-yl)piperidine-4-carboxamide Hydrochloride (6b)
The title compound was prepared in the same manner as described for 6a
using 5b instead of 5a, in 64% yield. H-NMR (DMSO-d6) d: 0.62 (6H, t,
Jꢁ7.6 Hz), 1.59—1.75 (2H, m), 1.77—1.90 (4H, m), 1.99—2.10 (2H, m), m), 1.85—1.96 (2H, m), 2.07—2.18 (2H, m), 2.27—2.43 (3H, m), 2.73—
1
1
(DMSO-d6) d: 0.65 (6H, t, Jꢁ7.2 Hz), 1.56—1.68 (2H, m), 1.69—1.75 (2H,
2.55—2.64 (1H, m), 2.75—2.90 (2H, m), 3.22—3.38 (2H, m), 7.10—7.20 2.86 (4H, m), 3.14—3.31 (2H, m), 6.58 (2H, s), 7.01—7.12 (2H, m), 7.17—
(1H, m), 7.20—7.30 (4H, m), 7.75 (1H, s), 8.57 (1H, br s), 9.02 (1H, br s).
7.32 (7H, m), 7.71 (1H, s). MS (FAB) m/z: 397 (Mꢀꢀ1). Anal. Calcd for
C25H33N2OF·C4H4O4·0.2H2O: C, 67.47; H, 7.30; N, 5.43; F, 3.68. Found: C,
MS (FAB) m/z: 275 (Mꢀꢀ1).
N-[3-(3-Fluorophenyl)pentan-3-yl]piperidine-4-carboxamide Hydro- 67.51; H, 7.30; N, 5.42; F, 3.57.
chloride (6c) The title compound was prepared in the same manner as de-
N-[3-(3-Methoxyphenyl)pentan-3-yl]-1-(2-phenylethyl)piperidine-4-
scribed for 6a using 5c instead of 5a, in 63% yield. 1H-NMR (DMSO-d6) d: carboxamide Fumarate (3e) The title compound was prepared in the
1
0.63 (6H, t, Jꢁ7.6 Hz), 1.60—1.75 (2H, m), 1.76—1.90 (4H, m), 1.98— same manner as described for 3a using 6e instead of 6a, in 81% yield. H-
2.10 (2H, m), 2.55—2.64 (1H, m), 2.75—2.90 (2H, m), 3.22—3.35 (2H, m), NMR (DMSO-d6) d: 0.62 (6H, t, Jꢁ7.2 Hz), 1.53—1.66 (2H, m), 1.69—
6.96—7.03 (2H, m), 7.08 (1H, d, Jꢁ7.2 Hz), 7.28—7.34 (1H, m), 7.84 (1H, 1.84 (4H, m), 1.95—2.05 (2H, m), 2.23—2.35 (2H, m), 2.38—2.48 (1H, m),
s), 8.56 (1H, br s), 9.01 (1H, br s). MS (FAB) m/z: 293 (Mꢀꢀ1).
2.73—2.86 (4H, m), 3.12—3.20 (2H, m), 3.71 (3H, s), 6.58 (2H, s), 6.71—
N-[3-(2-Fluorophenyl)pentan-3-yl]piperidine-4-carboxamide Hydro- 6.78 (2H, m), 6.83 (1H, d, Jꢁ7.6 Hz), 7.16—7.31 (6H, m), 7.59 (1H, s). MS
chloride (6d) The title compound was prepared in the same manner as de-
(FAB) m/z: 409 (Mꢀꢀ1). Anal. Calcd for C26H36N2O2·C4H4O4·0.7H2O: C,
scribed for 6a using 5d instead of 5a, in 62% yield. 1H-NMR (DMSO-d6) d: 67.07; H, 7.77; N, 5.21. Found: C, 67.12; H, 7.51; N, 5.10.
0.65 (6H, t, Jꢁ7.6 Hz), 1.60—1.73 (2H, m), 1.77—1.98 (4H, m), 2.08— N-[3-(2-Methoxyphenyl)pentan-3-yl]-1-(2-phenylethyl)piperidine-4-
2.18 (2H, m), 2.52—2.61 (1H, m), 2.76—2.90 (2H, m), 3.21—3.30 (2H, m), carboxamide Fumarate (3f) The title compound was prepared in the
1
7.01—7.12 (2H, m), 7.20—7.28 (2H, m), 7.82 (1H, s), 8.52 (1H, br s), 8.94 same manner as described for 3a using 6f instead of 6a, in 73% yield. H-
(1H, br s). MS (FAB) m/z: 293 (Mꢀꢀ1).
NMR (DMSO-d6) d: 0.60 (6H, t, Jꢁ7.2 Hz), 1.51—1.66 (2H, m), 1.69—
1.76 (2H, m), 1.95—2.20 (4H, m), 2.23—2.34 (2H, m), 2.38—2.46 (1H, m),
2.70—2.82 (4H, m), 3.10—3.15 (2H, m), 3.74 (3H, s), 6.57 (2H, s), 6.85
(1H, dd, Jꢁ6.8, 8.0 Hz), 6.94 (1H, d, Jꢁ8.0 Hz), 7.10—7.31 (7H, m), 7.36
N-[3-(3-Methoxyphenyl)pentan-3-yl]piperidine-4-carboxamide Hy-
drochloride (6e) The title compound was prepared in the same manner as
described for 6a using 5e instead of 5a, in 66% yield. 1H-NMR (DMSO-d6)
d: 0.63 (6H, t, Jꢁ7.6 Hz), 1.65—1.73 (2H, m), 1.76—1.84 (4H, m), 1.90— (1H, s). MS (FAB) m/z: 409 (Mꢀꢀ1). Anal. Calcd for C26H36N2O2·C4H4O4·
2.08 (2H, m), 2.52—2.64 (1H, m), 2.78—2.90 (2H, m), 3.21—3.35 (2H, m), 0.4H2O: C, 67.75; H, 7.73; N, 5.27. Found: C, 67.84; H, 7.81; N, 5.30.
3.72 (3H, s), 6.71—6.76 (2H, m), 6.83 (1H, d, Jꢁ7.6 Hz), 7.19 (1H, dd,
2-Ethyl-2-(4-methoxyphenyl)butanoic Acid (8) To an ice-cooled mix-
Jꢁ7.6, 8.0 Hz), 7.72 (1H, s), 8.53 (1H, br s), 8.97 (1H, br s). MS (FAB) m/z: ture of sodium hydride (60% dispersion in mineral oil; 1.30 g, 32.5 mmol)
305 (Mꢀꢀ1).
and iodoethane (3.0 ml, 37.3 mmol) in N,N-dimethylformamide (DMF)
(30 ml) was added dropwise a solution of 7 (2.0 g, 13.6 mmol) and DMF
(10 ml) and the mixture was stirred at room temperature for 20 h. The mix-
N-[3-(2-Methoxyphenyl)pentan-3-yl]piperidine-4-carboxamide Hy-
drochloride (6f) The title compound was prepared in the same manner as
1
described for 6a using 5f instead of 5a, in 69% yield. H-NMR (DMSO-d6) ture was poured onto ice-water and then extracted with PhMe. The organic
d: 0.60 (6H, t, Jꢁ7.6 Hz), 1.64—1.73 (2H, m), 1.79—1.85 (2H, m), 2.00— layer was washed with brine, dried over Na2SO4, and evaporated in vacuo.
2.16 (4H, m), 2.52—2.64 (1H, m), 2.78—2.88 (2H, m), 3.23—3.30 (2H, m), The resulting residue was purified by column chromatography on silica gel
3.74 (3H, s), 6.82—6.96 (2H, m), 7.10—7.22 (2H, m), 7.48 (1H, s), 8.45 (AcOEt/hexaneꢁ1/20) to give 2-ethyl-2-(4-methoxyphenyl)butanenitrile
(1H, br s), 8.80 (1H, br s). MS (FAB) m/z: 305 (Mꢀꢀ1).
(2.68 g, 97%) as a colorless oil. To an ice-cooled solution of the nitrile ob-
N-[3-(4-Fluorophenyl)pentan-3-yl]-1-(2-phenylethyl)piperidine-4-car- tained above (2.68 g, 13.2 mmol) in toluene (20 ml) was added dropwise
boxamide Fumarate (3a) To an ice-cooled mixture of 6a (0.45 g,
1.37 mmol), phenylacetaldehyde (0.20 ml, 1.97 mmol), and sodium acetate
(0.30 g, 3.66 mmol) in CH2Cl2 (10 ml) was added sodium triacetoxyborohy-
dride (0.45 g, 2.12 mmol) and the mixture was stirred at room temperature
DIBAL-H (1.01 M in toluene; 15 ml, 15.2 mmol) and the mixture was stirred
at 0 °C for 16 h. The mixture was poured onto 1 M HCl aq. and then extracted
with AcOEt. The organic layer was washed with brine, dried over Na2SO4,
and evaporated in vacuo to give 2-ethyl-2-(4-methoxyphenyl)butanal (2.68 g,
for 15 h. The reaction mixture was concentrated in vacuo and partitioned be- 98%) as a colorless oil, which was used for the next step without further pu-
tween saturated aqueous sodium bicarbonate solution and CHCl3. The or-
ganic layer was dried over Na2SO4 and evaporated in vacuo. The resulting
residue was purified by column chromatography on silica gel (MeOH/
rification. To an ice-cooled mixture of the aldehyde obtained above (2.68 g,
13.0 mmol), NaH2PO4·2H2O (3.0 g, 19.2 mmol), 2-methyl-2-butene (5.0 ml,
47.1 mmol), and H2O (5.0 ml) in tBuOH (20 ml) was added NaClO2 (80%;
CHCl3ꢁ3/97) to give N-[3-(4-fluorophenyl)pentan-3-yl]-1-(2-phenylethyl)- 1.80 g, 15.9 mmol) and the mixture was stirred at room temperature for 18 h.

1382
Vol. 59, No. 11
m/z: 207 (Mꢀꢂ1).
The reaction mixture was concentrated in vacuo and partitioned between
H2O and AcOEt. The organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was partitioned between 1 M
NaOH aq. and Et2O, the aqueous layer was acidified with HCl aq., and then
extracted with AcOEt. The organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo to give the title compound 8 (2.26 g, 78%)
Benzyl 4-{[1-(4-Fluorophenyl)cyclopentyl]carbamoyl}piperidine-1-
carboxylate (12) To a mixture of 11 (1.0 g, 4.80 mmol), BuOH (3.0 ml,
29.0 mmol), and Et3N (1.5 ml, 10.8 mmol) in PhMe (10 ml) was added drop-
wise a solution of diphenylphosphoryl azide (1.7 g, 6.18 mmol) and PhMe
(5.0 ml) and the mixture was stirred at 100 °C for 24 h. The mixture was
poured onto ice-water and then extracted with PhMe. The organic layer was
washed successively with saturated aqueous sodium bicarbonate solution
and brine, dried over Na2SO4, and evaporated in vacuo. The resulting residue
was purified by column chromatography on silica gel (AcOEt/hexaneꢁ1/8)
to give benzyl [1-(4-fluorophenyl)cyclopentyl]carbamate (1.32 g, 88%) as a
colorless soild. To a solution of the benzyl carbamate obtained above
(1.32 g, 4.21 mmol) in AcOEt (15 ml) was added 10% Pd/C (10 w/w %;
0.20 g) and the mixture was stirred under hydrogen atmosphere at room tem-
perature for 4 h. The catalyst was removed by filtration and the filtrate was
concentrated in vacuo to give 1-(4-fluorophenyl)cyclopentanamine (0.75 g)
as a colorless oil, which was used for the next step without further purifica-
1
as a colorless oil. H-NMR (CDCl3) d: 0.77 (6H, t, Jꢁ7.6 Hz), 1.94—2.15
(4H, m), 3.80 (3H, s), 6.88 (2H, d, Jꢁ8.8 Hz), 7.24 (2H, d, Jꢁ8.8 Hz). MS
(FAB) m/z: 221 (Mꢀꢂ1).
tert-Butyl 4-{[3-(4-Methoxyphenyl)pentan-3-yl]carbamoyl}piperidine-
1-carboxylate (9) To a mixture of 8 (2.26 g, 10.2 mmol), BuOH (5.5 ml,
53.1 mmol), and Et3N (2.0 ml, 14.3 mmol) in PhMe (20 ml) was added drop-
wise a solution of diphenylphosphoryl azide (3.5 g, 13.6 mmol) and PhMe
(10 ml) and the mixture was stirred at 100 °C for 24 h. The mixture was
poured onto ice-water and then extracted with PhMe. The organic layer was
washed successively with saturated aqueous sodium bicarbonate solution
and brine, dried over Na2SO4, and evaporated in vacuo. The resulting residue
was purified by column chromatography on silica gel (AcOEt/hexaneꢁ1/8)
to give benzyl [3-(4-methoxyphenyl)pentan-3-yl]carbamate (2.74 g, 82%) as
a yellow oil. To a solution of the benzyl carbamate obtained above (2.74 g,
8.37 mmol) in AcOEt (20 ml) was added 10% Pd/C (10 w/w %; 0.50 g) and
the mixture was stirred under hydrogen atmosphere at room temperature for
5 h. The catalyst was removed by filtration and the filtrate was concentrated
in vacuo to give 3-(4-methoxyphenyl)pentan-3-amine (1.53 g, 95%) as a col-
orless oil, which was used for the next step without further purification. To
an ice-cooled mixture of the amine obtained above (1.53 g, 7.92 mmol), 1-
(Boc)piperidine-4-carboxylic acid (1.90 g, 8.29 mmol), and HOBt (1.10 g,
8.14 mmol) in CH3CN (20 ml) was added WSCD (1.60 g, 8.36 mmol) and
the mixture was stirred at room temperature for 20 h. The reaction mixture
was concentrated in vacuo and partitioned between H2O and AcOEt. The or-
ganic layer was washed successively with 5% aqueous citric acid solution,
saturated aqueous sodium bicarbonate solution, and brine, dried over
Na2SO4, and evaporated in vacuo. The resulting residue was purified by col-
umn chromatography on silica gel (AcOEt/hexaneꢁ1/2) to give the title
compound 9 (2.41 g, 75%) as a colorless foam. 1H-NMR (CDCl3) d: 0.70
(6H, t, Jꢁ7.2 Hz), 1.45 (9H, s), 1.57—1.70 (2H, m), 1.80—1.95 (2H, m),
1.99—2.16 (4H, m), 2.22—2.32 (1H, m), 2.71—2.91 (2H, m), 3.79 (3H, s),
4.11—4.19 (2H, m), 5.50 (1H, s), 6.86 (2H, d, Jꢁ8.8 Hz), 7.18 (2H, d,
Jꢁ8.8 Hz). MS (FAB) m/z: 405 (Mꢀꢀ1).
N-[3-(4-Methoxyphenyl)pentan-3-yl]-1-(2-phenylethyl)piperidine-4-
carboxamide Fumarate (3g) To an ice-cooled solution of 9 (2.41 g,
5.96 mmol) in AcOEt (10 ml) was added 4 M HCl–AcOEt (10 ml,
40.0 mmol) and the mixture was stirred at room temperature for 16 h. After
concentration of the reaction mixture, the resulting solid was suspended with
AcOEt and collected by filtration to give N-[3-(4-methoxyphenyl)pentan-3-
yl]piperidine-4-carboxamide hydrochloride (1.80 g, 89%) as a light yellow
solid. The title compound was prepared in the same manner as described for
3a using N-[3-(4-methoxyphenyl)pentan-3-yl]piperidine-4-carboxamide hy-
drochloride instead of 6a, in 64% yield. 1H-NMR (DMSO-d6) d: 0.61 (6H, t,
Jꢁ7.2 Hz), 1.50—1.64 (2H, m), 1.66—1.74 (2H, m), 1.74—1.86 (2H, m),
1.95—2.08 (2H, m), 2.10—2.23 (2H, m), 2.30—2.41 (1H, m), 2.62—2.70
(2H, m), 2.73—2.82 (2H, m), 3.04—3.14 (2H, m), 3.72 (3H, s), 6.58 (2H,
s), 6.82 (2H, d, Jꢁ8.0 Hz), 7.12—7.32 (7H, m), 7.51 (1H, s). MS (FAB) m/z:
409 (Mꢀꢀ1). Anal. Calcd for C26H36N2O2·C4H4O4·0.5H2O: C, 67.52; H,
7.74; N, 5.25. Found: C, 67.70; H, 7.68; N, 5.34.
tion. To
a solution of 1-(Cbz)piperidine-4-carboxylic acid (1.28 g,
4.86 mmol) and DMF (1 drop) in CH2Cl2 (20 ml) was added (COCl)2
(0.80 ml, 9.79 mmol) and the mixture was stirred at room temperature for
6 h. The reaction mixture was concentrated in vacuo to give the correspond-
ing acid chloride as a colorless oil, which was used for the next step without
further purification. To an ice-cooled solution of the amine obtained above
(0.75 g) and Et3N (1.4 ml, 10.0 mmol) in CH2Cl2 (10 ml) was added a solu-
tion of the acid chloride obtained above and CH2Cl2 (10 ml) and the mixture
was stirred at room temperature for 24 h. The reaction mixture was concen-
trated in vacuo and partitioned between H2O and AcOEt. The organic layer
was washed successively with 5% aqueous citric acid solution, saturated
aqueous sodium bicarbonate solution, and brine, dried over Na2SO4, and
evaporated in vacuo. The resulting residue was purified by column chro-
matography on silica gel (AcOEt/hexaneꢁ1/1) to give the title compound 12
1
(1.49 g, 2 steps 83%) as a colorless foam. H-NMR (CDCl3) d: 1.52—1.65
(2H, m), 1.72—1.85 (6H, m), 1.98—2.10 (2H, m), 2.15—2.23 (1H, m),
2.28—2.36 (2H, m), 2.76—2.90 (2H, m), 4.10—4.27 (2H, m), 5.11 (2H, s),
5.61 (1H, s), 6.97 (2H, dd, Jꢁ8.8, 8.8 Hz), 7.29—7.38 (7H, m). MS (FAB)
m/z: 425 (Mꢀꢀ1).
N-[1-(4-Fluorophenyl)cyclopentyl]-1-(2-phenylethyl)piperidine-4-car-
boxamide Fumarate (13) To a solution of 12 (1.49 g, 3.51 mmol) in EtOH
(20 ml) was added 10% Pd/C (10 w/w %; 0.20 g) and the mixture was stirred
under hydrogen atmosphere at room temperature for 2 h. The catalyst was
removed by filtration and the filtrate was concentrated in vacuo to give N-[1-
(4-fluorophenyl)cyclopentyl]piperidine-4-carboxamide (1.0 g, 98%) as a col-
orless solid, which was used for the next step without further purification. To
an ice-cooled solution of the amine obtained above (0.30 g, 1.03 mmol),
phenylacetaldehyde (0.20 ml, 1.79 mmol), and AcOH (0.50 ml) in CH2Cl2
(10 ml) was added sodium triacetoxyborohydride (0.40 g, 1.89 mmol) and
the mixture was stirred at room temperature for 15 h. The reaction mixture
was concentrated in vacuo and partitioned between saturated aqueous
sodium bicarbonate solution and CHCl3. The organic layer was dried over
Na2SO4 and evaporated in vacuo. The resulting residue was purified by col-
umn chromatography on silica gel (MeOH/CHCl3ꢁ3/97) to give N-[1-(4-
fluorophenyl)cyclopentyl]-1-(2-phenylethyl)piperidine-4-carboxamide
(0.45 g) as a colorless solid. The compound was converted to its fumarate by
treating it with fumaric acid (0.12 g, 1.03 mmol). The crude salt was sus-
pended with CH3CN and filtered to give the title compound 13 (0.47 g, 90%)
1
1-(4-Fluorophenyl)cyclopentanecarboxylic Acid (11) To an ice-
cooled solution of 10 (5.0 g, 37.0 mmol) and 1,4-dibromobutane (4.7 ml,
39.8 mmol) in DMF (50 ml) was added portionwise sodium hydride (60%
dispersion in mineral oil; 3.2 g, 80.0 mmol) and the mixture was stirred at
room temperature for 3 h. The mixture was poured onto ice-water and then
extracted with PhMe. The organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. The resulting residue was purified by col-
umn chromatography on silica gel (AcOEt/hexaneꢁ1/10) to give 1-(4-fluo-
rophenyl)cyclopentanecarbonitrile (6.52 g, 93%) as a colorless oil. To a mix-
ture of the nitrile obtained above (6.52 g, 34.5 mmol) and H2O (20 ml) was
added H2SO4 (20 ml) and the mixture was stirred 150 °C for 5 h. The mix-
ture was poured onto ice-water and then extracted with AcOEt. The organic
layer was washed with brine, dried over Na2SO4, and evaporated in vacuo.
The residue was partitioned between 1 M NaOH aq. and Et2O, the aqueous
layer was acidified with HCl aq., and then extracted with AcOEt. The or-
ganic layer was washed with brine, dried over Na2SO4, and evaporated in
as a colorless powder. H-NMR (DMSO-d6) d: 1.48—1.61 (2H, m), 1.62—
1.76 (6H, m), 1.76—1.86 (2H, m), 2.12—2.34 (5H, m), 2.61—2.70 (2H, m),
2.73—2.82 (2H, m), 3.02—3.13 (2H, m), 6.58 (2H, s), 7.07 (2H, dd, Jꢁ8.8,
8.8 Hz), 7.15—7.36 (7H, m), 7.94 (1H, s). MS (FAB) m/z: 395 (Mꢀꢀ1).
Anal. Calcd for C25H31N2OF·C4H4O4·1.5H2O: C, 64.79; H, 7.12; N, 5.21; F,
3.53. Found: C, 64.62; H, 7.14; N, 5.21; F, 3.51.
(1R)-1-(4-Fluorophenyl)-2-methylpropan-1-amine Hydrochloride (15)
To a mixture of 1444) (13.2 g, 67.3 mmol) and Et3N (12 ml, 86.0 mmol) in
tBuOH (150 ml) was added dropwise diphenylphosphoryl azide (20 g,
72.7 mmol) and the mixture was stirred at 100 °C for 20 h. The mixture was
poured onto ice-water and then extracted with PhMe. The organic layer was
washed successively with saturated aqueous sodium bicarbonate solution
and brine, dried over Na2SO4, and evaporated in vacuo to give tert-butyl
[(1R)-1-(4-fluorophenyl)-2-methylpropyl]carbamate (19.6 g) as a light yel-
low soild. To an ice-cooled mixture of the N-Boc derivative obtained above
(19.6 g) in AcOEt (100 ml) was added 4 M HCl–AcOEt (100 ml, 400 mmol)
and the mixture was stirred at room temperature for 16 h. After concentra-
tion of the reaction mixture, the resulting solid was suspended with AcOEt
and collected by filtration to give the title compound 15 (11.3 g, 2 steps
1
vacuo to give the title compound 11 (6.65 g, 93%) as a colorless solid. H-
NMR (CDCl3) d: 1.71—1.79 (4H, m), 1.83—1.94 (2H, m), 2.60—2.70 (2H,
m), 6.99 (2H, dd, Jꢁ8.8, 8.8 Hz), 7.35 (2H, dd, Jꢁ4.8, 8.8 Hz). MS (FAB)

November 2011
1383
82%) as a colorless solid. [a]D25 ꢂ4.45 (cꢁ1.00, H2O). 1H-NMR (DMSO-d6)
d: 0.69 (3H, d, Jꢁ7.2 Hz), 1.02 (3H, d, Jꢁ7.2 Hz), 2.08—2.22 (1H, m), 3.99
(1H, d, Jꢁ8.4 Hz), 7.27 (2H, dd, Jꢁ8.2, 8.4 Hz), 7.53 (2H, dd, Jꢁ5.6,
8.4 Hz), 8.60 (3H, s). MS (FAB) m/z: 168 (Mꢀꢀ1).
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-1-{2-[4-(trifluo-
romethyl)phenyl]ethyl}piperidine-4-carboxamide Oxalate (17d) The
title compound was prepared in the same manner as described for 17a using
4-trifluoromethylphenylacetaldehyde instead of phenylacetaldehyde, in 65%
yield. 1H-NMR (DMSO-d6) d: 0.70 (3H, d, Jꢁ6.8 Hz), 0.89 (3H, d,
Jꢁ6.8 Hz), 1.65—1.98 (5H, m), 2.41—2.52 (1H, m), 2.70—2.90 (2H, m),
3.00—3.10 (2H, m), 3.12—3.23 (2H, m), 3.35—3.51 (2H, m), 4.53 (1H, dd,
Jꢁ8.4, 8.4 Hz), 7.13 (2H, dd, Jꢁ8.0, 8.4 Hz), 7.30 (2H, dd, Jꢁ5.6, 8.0 Hz),
7.51 (2H, d, Jꢁ8.4 Hz), 7.70 (2H, d, Jꢁ8.4 Hz), 8.30 (1H, d, Jꢁ8.4 Hz). MS
(FAB) m/z: 451 (Mꢀꢀ1). Anal. Calcd for C25H30N2OF4·C2H2O4·0.2H2O: C,
59.60; H, 6.00; N, 5.15; F, 13.97. Found: C, 59.61; H, 6.00; N, 5.13; F,
14.04.
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-1-[2-(2-methoxylphenyl)-
ethyl]piperidine-4-carboxamide Fumarate (17e) The title compound
was prepared in the same manner as described for 17a using 2-
methoxyphenylacetaldehyde instead of phenylacetaldehyde, in 64% yield.
1H-NMR (DMSO-d6) d: 0.69 (3H, d, Jꢁ6.8 Hz), 0.88 (3H, d, Jꢁ6.8 Hz),
1.51—1.80 (4H, m), 1.83—1.97 (1H, m), 2.15—2.34 (3H, m), 2.59—2.68
(2H, m), 2.72—2.81 (2H, m), 3.04—3.16 (2H, m), 3.77 (3H, s), 4.52 (1H,
dd, Jꢁ8.4, 9.2 Hz), 6.57 (2H, s), 6.86 (1H, dd, Jꢁ7.6, 7.6 Hz), 6.95 (1H, d,
Jꢁ8.0 Hz), 7.08—7.22 (4H, m), 7.30 (2H, dd, Jꢁ5.6, 8.0 Hz), 8.17 (1H, d,
Jꢁ9.2 Hz). MS (FAB) m/z: 413 (Mꢀꢀ1). Anal. Calcd for
C25H33N2O2F·C4H4O4·0.2H2O: C, 65.45; H, 7.08; N, 5.26; F, 3.57. Found:
C, 65.35; H, 7.12; N, 5.29; F, 3.61.
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]piperidine-4-carbox-
amide Hydrochloride (16) To an ice-cooled mixture of 15 (10.4 g,
51.1 mmol), Et3N (15 ml, 108 mmol), 1-(Boc)piperidine-4-carboxylic acid
(12 g, 52.3 mmol), and HOBt (7.0 g, 50.7 mmol) in CH3CN (100 ml) was
added WSCD (10.5 g, 54.9 mmol) and the mixture was stirred at room tem-
perature for 3 d. The reaction mixture was concentrated in vacuo and parti-
tioned between H2O and AcOEt. The organic layer was washed successively
with 5% aqueous citric acid solution, saturated aqueous sodium bicarbonate
solution, and brine, dried over Na2SO4, and evaporated in vacuo to give tert-
butyl 4-{[(1R)-1-(4-fluorophenyl)-2-methylpropyl]carbamoyl}piperidine-1-
carboxylate (19.5 g) as a colorless foam. To an ice-cooled solution of the N-
Boc derivative obtained above (19.5 g) in AcOEt (100 ml) was added 4 M
HCl–AcOEt (100 ml, 400 mmol) and the mixture was stirred at room tem-
perature for 16 h. After concentration of the reaction mixture, the resulting
solid was suspended with acetone and collected by filtration to give the title
1
compound 16 (15.5 g, 2 steps 96%) as a colorless solid. H-NMR (DMSO-
d6) d: 0.69 (3H, d, Jꢁ6.4 Hz), 0.88 (3H, d, Jꢁ6.4 Hz), 1.58—1.81 (3H, m),
1.84—1.97 (2H, m), 2.52—2.57 (1H, m), 2.75—2.92 (2H, m), 3.18—3.31
(2H, m), 4.51 (1H, dd, Jꢁ8.8, 8.8 Hz), 7.13 (2H, dd, Jꢁ8.0, 8.4 Hz), 7.31
(2H, dd, Jꢁ5.6, 8.0 Hz), 8.38 (1H, d, Jꢁ8.8 Hz), 8.61 (1H, br s), 9.04 (1H,
br s). MS (FAB) m/z: 279 (Mꢀꢀ1).
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxylphenyl)-
ethyl]piperidine-4-carboxamide Oxalate (17f) (Method B) To a mixture
of 16 (0.41 g, 1.30 mmol) and K2CO3 (0.27 g, 1.95 mmol) in CH3CN (10 ml)
was added 2-(3-methoxyphenyl)ethyl p-toluenesulfonate (0.52 g, 1.70 mmol)
and the mixture was stirred at 70 °C for 24 h. The reaction mixture was con-
centrated in vacuo and the resulting residue was partitioned between H2O
and CHCl3. The organic layer was dried over Na2SO4 and evaporated in
vacuo. The resulting residue was purified by column chromatography on sil-
ica gel (MeOH/CHCl3ꢁ5/95) to give N-[(1R)-1-(4-fluorophenyl)-2-methyl-
propyl]-1-[2-(3-methoxylphenyl)ethyl]piperidine-4-carboxamide (0.45 g) as
a colorless oil. The compound was converted to oxalate by treating it with
oxalic acid (0.12 g, 1.31 mmol). The crude salt was suspended with acetone
and filtered to give the title compound 17f (0.46 g, 70%) as a colorless pow-
der. 1H-NMR (DMSO-d6) d: 0.70 (3H, d, Jꢁ6.8 Hz), 0.89 (3H, d,
Jꢁ6.8 Hz), 1.66—1.98 (5H, m), 2.42—2.54 (1H, m), 2.76—2.96 (4H, m),
3.09—3.20 (2H, m), 3.36—3.50 (2H, m), 3.74 (3H, s), 4.53 (1H, dd, Jꢁ8.4,
8.8 Hz), 6.78—6.86 (3H, m), 7.13 (2H, dd, Jꢁ8.0, 8.4 Hz), 7.23 (1H, dd,
Jꢁ7.6, 7.6 Hz), 7.31 (2H, dd, Jꢁ5.6, 8.0 Hz), 8.31 (1H, d, Jꢁ8.8 Hz). MS
(FAB) m/z: 413 (Mꢀꢀ1). Anal. Calcd for C25H33N2O2F·C4H4O4·0.8H2O: C,
62.73; H, 7.14; N, 5.42; F, 3.67. Found: C, 62.95; H, 7.03; N, 5.47; F, 3.83.
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-1-[2-(4-methoxylphenyl)-
ethyl]piperidine-4-carboxamide Fumarate (17g) The title compound
was prepared in the same manner as described for 17f using 2-(4-
methoxyphenyl)ethyl p-toluenesulfonate instead of 2-(3-methoxy-
phenyl)ethyl p-toluenesulfonate, in 89% yield. 1H-NMR (DMSO-d6) d:
0.69 (3H, d, Jꢁ6.8 Hz), 0.88 (3H, d, Jꢁ6.8 Hz), 1.51—1.80 (4H, m), 1.83—
1.97 (1H, m), 2.15—2.33 (3H, m), 2.62—2.77 (4H, m), 3.05—3.16 (2H, m),
3.71 (3H, s), 4.52 (1H, dd, Jꢁ8.4, 9.2 Hz), 6.57 (2H, s), 6.84 (2H, d,
Jꢁ8.0 Hz), 7.09—7.16 (4H, m), 7.30 (2H, dd, Jꢁ5.6, 8.0 Hz), 8.18 (1H, d,
Jꢁ9.2 Hz). MS (FAB) m/z: 413 (Mꢀꢀ1). Anal. Calcd for C25H33N2O2F·
C4H4O4: C, 65.89; H, 7.06; N, 5.30; F, 3.59. Found: C, 65.53; H, 7.11; N,
5.25; F, 3.59.
1-[2-(2,3-Dimethoxylphenyl)ethyl]-N-[(1R)-1-(4-fluorophenyl)-2-
methylpropyl]piperidine-4-carboxamide Oxalate (17h) The title com-
pound was prepared in the same manner as described for 17a using 2,3-
dimethoxyphenylacetaldehyde instead of phenylacetaldehyde, in 50% yield.
1H-NMR (DMSO-d6) d: 0.70 (3H, d, Jꢁ6.8 Hz), 0.89 (3H, d, Jꢁ6.8 Hz),
1.66—1.99 (5H, m), 2.42—2.52 (1H, m), 2.77—2.96 (4H, m), 3.04—3.13
(2H, m), 3.39—3.54 (2H, m), 3.74 (3H, s), 3.79 (3H, s), 4.53 (1H, dd,
Jꢁ8.4, 8.8 Hz), 6.81 (1H, dd, Jꢁ1.6, 7.6 Hz), 6.95 (1H, dd, Jꢁ1.6, 8.4 Hz),
7.02 (1H, dd, Jꢁ7.6, 8.4 Hz), 7.13 (2H, dd, Jꢁ8.0, 8.4 Hz), 7.30 (2H, dd,
Jꢁ5.6, 8.0 Hz), 8.32 (1H, d, Jꢁ8.8 Hz). MS (FAB) m/z: 443 (Mꢀꢀ1). Anal.
Calcd for C26H35N2O3F·C2H2O4·0.5H2O: C, 62.09; H, 7.07; N, 5.17; F,
3.51. Found: C, 61.95; H, 7.03; N, 5.12; F, 3.53.
1-[2-(3,4-Dimethoxylphenyl)ethyl]-N-[(1R)-1-(4-fluorophenyl)-2-
methylpropyl]piperidine-4-carboxamide Oxalate (17i) The title com-
pound was prepared in the same manner as described for 17a using 3,4-
dimethoxyphenylacetaldehyde instead of phenylacetaldehyde, in 32% yield.
1H-NMR (DMSO-d6) d: 0.70 (3H, d, Jꢁ6.8 Hz), 0.89 (3H, d, Jꢁ6.8 Hz),
1.68—2.00 (5H, m), 2.43—2.53 (1H, m), 2.77—2.94 (4H, m), 3.11—3.20
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-1-(2-phenylethyl)piperi-
dine-4-carboxamide Hydrochloride (17a) (Method A) To an ice-cooled
mixture of 16 (0.34 g, 1.08 mmol), phenylacetaldehyde (0.20 ml, 1.79
mmol), and AcONa (0.10 g, 1.22 mmol) in CH2Cl2 (10 ml) was added
sodium triacetoxyborohydride (0.46 g, 2.17 mmol) and the mixture was
stirred at room temperature for 15 h. The reaction mixture was concentrated
in vacuo and partitioned between saturated aqueous sodium bicarbonate so-
lution and CHCl3. The organic layer was dried over Na2SO4 and evaporated
in vacuo. The resulting residue was purified by column chromatography on
silica gel (MeOH/CHCl3ꢁ3/97) to give N-[(1R)-1-(4-fluorophenyl)-2-
methylpropyl]-1-(2-phenylethyl)piperidine-4-carboxamide (0.24 g) as a col-
orless solid. The compound was converted to its hydrochloride salt by treat-
ing it with 4 M HCl–AcOEt (0.20 ml, 800 mmol). The crude salt was sus-
pended with AcOEt and filtered to give the title compound 17a (0.22 g,
53%) as
a
colorless powder. 1H-NMR (DMSO-d6) d: 0.70 (3H, d,
Jꢁ6.8 Hz), 0.89 (3H, d, Jꢁ6.8 Hz), 1.78—2.07 (5H, m), 2.46—2.53 (1H,
m), 2.85—2.96 (2H, m), 3.01—3.08 (2H, m), 3.22—3.30 (2H, m), 3.52—
3.64 (2H, m), 4.53 (1H, dd, Jꢁ8.4, 9.2 Hz), 7.13 (2H, dd, Jꢁ8.0, 8.4 Hz),
7.23—7.38 (7H, m), 8.40 (1H, d, Jꢁ9.2 Hz), 10.36 and 10.74 (1H, br s). MS
(FAB) m/z: 383 (Mꢀꢀ1). Anal. Calcd for C24H31N2OF·HCl·0.3H2O: C,
67.92; H, 7.74; N, 4.48; Cl, 8.35; F, 4.90. Found: C, 68.05; H, 7.61; N, 6.25;
Cl, 8.32; F, 4.50.
N-[(1S)-1-(4-Fluorophenyl)-2-methylpropyl]-1-(2-phenylethyl)piperi-
dine-4-carboxamide Hydrochloride (ent-17a) The title compound was
prepared in the same manner as described in Chart 4 using (2S)-2-(4-fluo-
rophenyl)-3-methylbutanoic acid instead of 14.
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-1-{2-[2-(trifluo-
romethyl)phenyl]ethyl}piperidine-4-carboxamide Oxalate (17b) The
title compound was prepared in the same manner as described for 17a using
2-trifluoromethylphenylacetaldehyde instead of phenylacetaldehyde, in 67%
yield. 1H-NMR (DMSO-d6) d: 0.70 (3H, d, Jꢁ6.8 Hz), 0.89 (3H, d,
Jꢁ6.8 Hz), 1.66—1.98 (5H, m), 2.41—2.51 (1H, m), 2.74—2.90 (2H, m),
3.11 (4H, br s), 3.37—3.50 (2H, m), 4.53 (1H, dd, Jꢁ8.4, 9.2 Hz), 7.13 (2H,
dd, Jꢁ8.0, 8.4 Hz), 7.31 (2H, dd, Jꢁ5.6, 8.0 Hz), 7.48 (1H, dd, Jꢁ7.6,
8.4 Hz), 7.55 (1H, d, Jꢁ7.6 Hz), 7.67 (1H, dd, Jꢁ7.6, 7.6 Hz), 7.72 (1H, d,
Jꢁ8.4 Hz), 8.30 (1H, d, Jꢁ9.2 Hz). MS (FAB) m/z: 451 (Mꢀꢀ1). Anal.
Calcd for C25H30N2OF4·C2H2O4·0.2H2O: C, 59.60; H, 6.00; N, 5.15; F,
13.97. Found: C, 59.68; H, 6.00; N, 5.16; F, 13.91.
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-1-{2-[3-(trifluo-
romethyl)phenyl]ethyl}piperidine-4-carboxamide Oxalate (17c) The
title compound was prepared in the same manner as described for 17a using
3-trifluoromethylphenylacetaldehyde instead of phenylacetaldehyde, in 63%
yield. 1H-NMR (DMSO-d6) d: 0.70 (3H, d, Jꢁ6.8 Hz), 0.89 (3H, d,
Jꢁ6.8 Hz), 1.68—2.00 (5H, m), 2.43—2.53 (1H, m), 2.76—2.93 (2H, m),
3.02—3.11 (2H, m), 3.15—3.25 (2H, m), 3.38—3.52 (2H, m), 4.53 (1H, dd,
Jꢁ8.4, 8.8 Hz), 7.13 (2H, dd, Jꢁ8.0, 8.4 Hz), 7.31 (2H, dd, Jꢁ5.6, 8.0 Hz),
7.53—7.68 (4H, m), 8.32 (1H, d, Jꢁ8.8 Hz). MS (FAB) m/z: 451 (Mꢀꢀ1).
Anal. Calcd for C25H30N2OF4·C2H2O4·0.5H2O: C, 59.01; H, 6.05; N, 5.10;
F, 13.83. Found: C, 59.01; H, 6.05; N, 5.09; F, 13.97.

1384
Vol. 59, No. 11
(2H, m), 3.38—3.52 (2H, m), 3.72 (3H, s), 3.74 (3H, s), 4.53 (1H, dd,
Jꢁ8.4, 8.8 Hz), 6.76 (1H, dd, Jꢁ2.0, 8.0 Hz), 6.86—6.91 (2H, m), 7.13 (2H,
dd, Jꢁ8.0, 8.4 Hz), 7.30 (2H, dd, Jꢁ5.6, 8.0 Hz), 8.32 (1H, d, Jꢁ8.8 Hz).
MS (FAB) m/z: 443 (Mꢀꢀ1). Anal. Calcd for C26H35N2O3F·C2H2O4·H2O:
C, 61.08; H, 7.14; N, 5.09; F, 3.45. Found: C, 61.09; H, 7.06; N, 5.07; F,
3.49.
d6) d: 0.70 (3H, d, Jꢁ6.8 Hz), 0.89 (3H, d, Jꢁ6.8 Hz), 1.78—2.08 (5H, m),
2.45—2.54 (1H, m), 2.80—3.06 (4H, m), 3.20—3.32 (2H, m), 3.31 (3H, s),
3.50—3.62 (2H, m), 3.62—3.68 (2H, m), 4.05—4.11 (2H, m), 4.53 (1H, dd,
Jꢁ8.4, 8.8 Hz), 6.80—6.90 (3H, m), 7.13 (2H, dd, Jꢁ8.0, 8.4 Hz), 7.24 (1H,
dd, Jꢁ7.6, 7.6 Hz), 7.32 (2H, dd, Jꢁ5.6, 8.0 Hz), 8.41 (1H, d, Jꢁ8.8 Hz),
10.37 and 10.74 (1H, s). MS (FAB) m/z: 457 (Mꢀꢀ1). Anal. Calcd for
C27H37N2O3F·HCl·0.2H2O: C, 65.29; H, 7.72; N, 5.64; Cl, 7.14; F, 3.83.
Found: C, 65.32; H, 7.90; N, 5.65; Cl, 7.13; F, 3.83.
1-[2-(3,5-Dimethoxylphenyl)ethyl]-N-[(1R)-1-(4-fluorophenyl)-2-
methylpropyl]piperidine-4-carboxamide Oxalate (17j) The title com-
pound was prepared in the same manner as described for 17a using 3,5-
dimethoxyphenylacetaldehyde instead of phenylacetaldehyde, in 14% yield.
1H-NMR (DMSO-d6) d: 0.70 (3H, d, Jꢁ6.8 Hz), 0.89 (3H, d, Jꢁ6.8 Hz),
1.66—1.98 (5H, m), 2.42—2.53 (1H, m), 2.74—2.94 (4H, m), 3.12—3.21
(2H, m), 3.38—3.52 (2H, m), 3.73 (6H, s), 4.53 (1H, dd, Jꢁ8.4, 8.8 Hz),
6.38 (1H, t, Jꢁ2.0 Hz), 6.43 (2H, d, Jꢁ2.0 Hz), 7.13 (2H, dd, Jꢁ8.0,
8.4 Hz), 7.30 (2H, dd, Jꢁ5.6, 8.0 Hz), 8.31 (1H, d, Jꢁ8.8 Hz). MS (FAB)
m/z: 443 (Mꢀꢀ1). Anal. Calcd for C26H35N2O3F·C2H2O4·0.3H2O: C, 62.51;
H, 7.04; N, 5.21; F, 3.53. Found: C, 62.53; H, 7.07; N, 5.15; F, 3.55.
1-[2-(2,5-Dimethoxylphenyl)ethyl]-N-[(1R)-1-(4-fluorophenyl)-2-
methylpropyl]piperidine-4-carboxamide Oxalate (17k) The title com-
pound was prepared in the same manner as described for 17a using 2,5-
dimethoxyphenylacetaldehyde instead of phenylacetaldehyde, in 71% yield.
1H-NMR (DMSO-d6) d: 0.70 (3H, d, Jꢁ6.4 Hz), 0.89 (3H, d, Jꢁ6.4 Hz),
1.66—1.98 (5H, m), 2.42—2.52 (1H, m), 2.73—2.93 (4H, m), 3.02—3.12
(2H, m), 3.35—3.50 (2H, m), 3.69 (3H, s), 3.74 (3H, s), 4.52 (1H, dd,
Jꢁ8.4, 9.2 Hz), 6.77—6.85 (2H, m), 6.91 (1H, d, Jꢁ8.4 Hz), 7.13 (2H, dd,
Jꢁ8.0, 8.4 Hz), 7.30 (2H, dd, Jꢁ5.6, 8.0 Hz), 8.31 (1H, d, Jꢁ9.2 Hz). MS
(FAB) m/z: 443 (Mꢀꢀ1). Anal. Calcd for C26H35N2O3F·C2H2O4: C, 63.14;
H, 7.00; N, 5.26; F, 3.57. Found: C, 63.35; H, 7.06; N, 5.26; F, 3.64.
Ethyl [3-(2-Oxoethyl)phenoxy]acetate (19a) To an ice-cooled mixture
of 18 (1.0 g, 8.19 mmol) and K2CO3 (1.4 g, 10.1 mmol) in CH3CN (10 ml)
was added ethyl bromoacetate (1.5 g, 8.98 mmol) and the mixture was stirred
at room temperature for 24 h. The reaction mixture was concentrated in
vacuo and the resulting residue was partitioned between H2O and AcOEt.
The organic layer was washed with brine, dried over Na2SO4, and evaporated
in vacuo. The resulting residue was purified by column chromatography on
silica gel (AcOEt/hexaneꢁ1/4) to give ethyl (3-formylphenoxy)acetate
(1.7 g, 100%) as a colorless oil. To an ice-cooled mixture of (methoxymethyl)-
triphenylphosphonium chloride (5.0 g, 14.6 mmol) in THF (50 ml) was added
tBuOK (1.6 g, 14.3 mmol) and the mixture was stirred at 0 °C for 10 min. To
this ice-cooled mixture was added the aldehyde obtained above (1.7 g,
8.16 mmol) and the mixture was stirred at room temperature for 30 min. The
mixture was poured onto ice-water and then extracted with AcOEt. The or-
ganic layer was washed with brine, dried over Na2SO4, and evaporated in
vacuo. The resulting residue was purified by column chromatography on
silica gel (CHCl3/hexaneꢁ1/4) to give ethyl [3-(2-methoxy)vinyl]phenoxy-
acetate (1.11 g, 58%) as a yellow oil. To the methyl ether obtained above
(1.11 g, 4.70 mmol) was added formic acid (10 ml) and the mixture was
stirred at room temperature for 30 min. The reaction mixture was concen-
trated in vacuo and the resulting residue was partitioned between H2O and
AcOEt. The organic layer was washed with brine, dried over Na2SO4, and
evaporated in vacuo to give the title compound 19a (1.0 g, 96%) as a yellow
oil. This compound was directly used for the next step.
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-1-{2-[3-(2-hydroxy-
ethoxy)phenyl]ethyl}piperidine-4-carboxamide Hydrochloride (17n)
To a mixture of 17l (0.20 g, 348 mmol) in CHCl3 (10 ml) was added saturated
aqueous sodium bicarbonate solution (10 ml) and the mixture was stirred at
room temperature for 15 min. The organic layer was separated, dried over
Na2SO4, and evaporated in vacuo to give ethyl {3-[2-(4-{[(1R)-1-(4-fluo-
rophenyl)-2-methylpropyl]carbamoyl}piperidin-1-yl)ethyl]phenoxy}acetate
(0.17 g) as a colorless foam, which was used for the next step without fur-
ther purification. To a solution of the ester obtained above (0.17 g,
348 mmol) in THF (10 ml) was added LiAlH4 (40 mg, 1.05 mmol) at ꢂ40 °C
and the mixture was gradually warmed to 0 °C for 2 h. The reaction was
quenched with Na2SO4·10H2O (1.0 g) and stirred at room temperature for
15 h. The precipitate was removed by filtration and the filtrate was concen-
trated in vacuo. The resulting residue was purified by column chromatogra-
phy on silica gel (MeOH/CHCl3ꢁ10/90) to give N-[(1R)-1-(4-fluorophenyl)-
2-methylpropyl]-1-{2-[3-(2-hydroxyethoxy)phenyl]ethyl}piperidine-4-car-
boxamide (0.18 g) as a colorless oil. The compound was converted to its hy-
drochloride salt by treating it with 4 M HCl–AcOEt (0.20 ml, 800 mmol). The
crude salt was suspended with acetone and filtered to give the title com-
pound 17n (89 mg, 53%) as a colorless powder. 1H-NMR (DMSO-d6) d:
0.70 (3H, d, Jꢁ6.8 Hz), 0.89 (3H, d, Jꢁ6.8 Hz), 1.76—2.07 (5H, m), 2.45—
2.54 (1H, m), 2.82—3.06 (4H, m), 3.20—3.32 (2H, m), 3.51—3.62 (2H, m),
3.67—3.74 (2H, m), 3.97 (2H, t, Jꢁ5.2 Hz), 4.53 (1H, dd, Jꢁ8.4, 9.2 Hz),
4.88 (1H, s), 6.80—6.89 (3H, m), 7.13 (2H, dd, Jꢁ8.0, 8.4 Hz), 7.24 (1H,
dd, Jꢁ7.6, 7.6 Hz), 7.32 (2H, dd, Jꢁ5.6, 8.0 Hz), 8.40 (1H, d, Jꢁ9.2 Hz),
10.31 and 10.68 (1H, s). MS (FAB) m/z: 443 (Mꢀꢀ1). Anal. Calcd for
C26H35N2O3F·HCl·0.3H2O: C, 64.46; H, 7.62; N, 5.78; Cl, 7.32; F, 3.92.
Found: C, 64.53; H, 7.55; N, 5.80; Cl, 7.46; F, 3.93.
T-Type Ca2ꢀ Channel-Blocking Activity Study HEK293 cells stably
expressing human Cav3.1 (a1G) were maintained in D-MEM supplemented
with 10% (v/v) fetal bovine serum, penicillin (100 U/ml), streptomycin
(100 mg/ml), geneticin (600 mg/ml) at 37 °C in a humid atmosphere of 5%
CO2 and 95% air. One day prior to performing the assay, cells were plated
into black-walled poly-D-lysine-coated 96-well assay plates at 25000
cells/well. Hanks balanced salt solution, containing 1.3 mM CaCl2, 20 mM N-
(2-hydroxyethyl)piperazine-Nꢄ-2-ethanesulfonic acid (HEPES) and 2.5 mM
probenecid was used as the assay buffer. The growth medium was removed
and replaced with dye loading buffer (100 ml/well) containing 4 mM fluo-3
AM, 0.04% Pluronic acid F-127, and 1% fetal bovine serum in the assay
buffer. After one-hour incubation in dye loading buffer, the cells were
washed four times with the assay buffer using an automated cell washer, giv-
ing a final volume of 100 ml of assay buffer in each well. The plates were left
to stand at room temperature for 10 min before assay, after which the plates
were placed into a FLIPRTM apparatus (Molecular Devices, Berkshire, U.K.)
to monitor cell fluorescence. Test compounds (50 ml each) were added to
each well, and the decrease in intercellular calcium concentrations as area
under the curve (AUC) was detected up to 5 min after addition of test com-
pounds. The maximum decrease, expressed as 100% inhibition was achieved
with mibefradil at 3ꢀ mM. The IC50 value was calculated using a nonlinear
regression method, taking the maximum reaction value as 100%.
[3-(2-Methoxyethoxy)phenyl]acetaldehyde (19b) The title compound
was prepared in the same manner as described for 19a using 2-bromoethyl
methyl ether instead of ethyl bromoacetate, in 97% yield. 1H-NMR (CDCl3)
d: 3.45 (3H, s), 3.64 (2H, d, Jꢁ2.0 Hz), 3.75 (2H, t, Jꢁ4.8 Hz), 4.12 (2H, t,
Jꢁ4.8 Hz), 6.79—6.83 (2H, m), 6.87 (1H, dd, Jꢁ2.8, 7.6 Hz), 7.25—7.30
(1H, m), 9.73 (1H, t, Jꢁ2.0 Hz). MS (EI) m/z: 194 (Mꢀ).
Ethyl {3-[2-(4-{[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]carbamoyl}-
piperidin-1-yl)ethyl]phenoxy}acetate Oxalate (17l) The title compound
was prepared in the same manner as described for 17a using 19a instead of
phenylacetaldehyde, in 23% yield. 1H-NMR (DMSO-d6) d: 0.70 (3H, d,
Jꢁ6.8 Hz), 0.89 (3H, d, Jꢁ6.8 Hz), 1.21 (3H, t, Jꢁ7.2 Hz), 1.65—1.98 (5H,
m), 2.42—2.54 (1H, m), 2.72—2.96 (4H, m), 3.10—3.22 (2H, m), 3.36—
3.51 (2H, m), 4.12 (2H, q, Jꢁ7.2 Hz), 4.53 (1H, dd, Jꢁ8.4, 8.8 Hz), 4.76
(2H, s), 6.80 (1H, dd, Jꢁ2.4, 8.0 Hz), 6.84—6.89 (2H, m), 7.13 (2H, dd,
Jꢁ8.0, 8.4 Hz), 7.24 (1H, dd, Jꢁ8.0, 8.0 Hz), 7.30 (2H, dd, Jꢁ5.6, 8.0 Hz),
8.30 (1H, d, Jꢁ8.8 Hz). MS (FAB) m/z: 485 (Mꢀꢀ1). Anal. Calcd for
C28H37N2O4F·C2H2O4: C, 62.70; H, 6.84; N, 4.87; F, 3.31. Found: C, 62.34;
H, 6.82; N, 4.75; F, 3.30.
Pharmacology in Vitro Study Male Hartley guinea pigs (250—400 g)
were sacrificed by decapitation under isoflurane anesthesia, and their hearts
were quickly removed. Right atria were dissected and mounted vertically in
a 30-ml organ bath containing Tyrode solution (130 mM NaCl, 5.6 mM KCl,
2.15 mM CaCl2·2H2O, 1.1 mM MgCl2·6H2O, 0.6 mM NaH2PO4·2H2O, 11 mM
D-glucose, 20 mM NaHCO3) at 37 °C and babbled with 95% O2 and 5% CO2.
The resting tension on the muscles was approximately 1 g and was kept con-
stant throughout the experiments. Under these conditions, the right atria
were allowed to equilibrate for 60 min with exchange of bath solution every
20 min before drug administration. Amplitude of constriction was measured
isometrically using a force-displacement transducer (Nihon Kohden SB-1T)
to obtain the spontaneous beat rate with a tachometer (Nihon Kohden AT-
600G) that was triggered by the contractile pulse. After the initial sponta-
neous beat rate was recorded, test compounds dissolved in dimethyl sulfox-
ide (DMSO) and diluted with saline to the desired concentration were added
to the bath solution cumulatively at 30-min intervals to construct a concen-
N-[(1R)-1-(4-Fluorophenyl)-2-methylpropyl]-1-{2-[3-(2-methoxy-
ethoxy)phenyl]ethyl}piperidine-4-carboxamide Hydrochloride (17m)
The title compound was prepared in the same manner as described for 17a
1
using 19b instead of phenylacetaldehyde, in 72% yield. H-NMR (DMSO-

November 2011
1385
tration–response curve. The EC30 value for the concentration of the com-
pounds producing a 30% reduction from initial spontaneous beat rate was
determined via linear regression.
Kang J. H., Pae A. N., Rhim H., Lee J. Y., Bioorg. Med. Chem. Lett.,
17, 471—475 (2007).
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Doddareddy M. R., Pae A. N., Kang J., Roh E. J., Bioorg. Med. Chem.,
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Joo D. J., Lee J. Y., Bioorg. Med. Chem. Lett., 17, 5740—5743 (2007).
26) Hangeland J. J., Cheney D. L., Friends T. J., Swartz S., Levesque P. C.,
Rich A. J., Sun L., Bridal T. R., Adam L. P., Normandin D. E., Mu-
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Pharmacology in Vivo Study ( per os ( p.o.)) Male SHR rats (300—
350 g) were anesthetized with pentobarbital (60 mg/kg intraperitoneally
(i.p.)), and a polyethylene cannula (PE-50) was implanted in the common
carotid artery with the opposite end of the catheter then routed to an exit site
at the back of the neck. Animals were allowed a one- to two-day recovery
period after the operation, during which time they were housed individually
with free access to rat chow and water. Blood pressure was measured using a
pressure transducer (Nihon Kohden DX-100) coupled to the carotid artery
cannula and a pressure amplifier (Nihon Kohden AP-621G) and was contin-
uously recorded using a polygraph system. Heart rate was measured with a
cardiotachometer (Nihon Kohden AT-600G) triggered by the blood pressure
pulsewave. After a 30-min measurement period to establish baseline values,
test compounds were orally administrated as an aqueous solution by gavage
at 10 and 30 mg/kg (salt form).
27) Oh Y., Kim Y., Seo S. H., Lee J. K., Rhim H., Pae A. N., Jeong K.-S.,
Choo H., Cho Y. S., Bull. Korean Chem. Soc., 29, 1881—1882 (2008).
28) Shipe W. D., Barrow J. C., Yang Z.-Q., Lindsley C. W., Yang F. V.,
Schlegel K.-A. S., Shu Y., Rittle K. E., Bock M. G., Hartman G. D.,
Tang C., Ballard J. E., Kuo Y., Adarayan E. D., Prueksaritanont T.,
Zrada M. M., Uebele V. N., Nuss C. E., Connolly T. M., Doran S. M.,
Fox S. V., Kraus R. L., Marino M. J., Graufelds V. K., Vargas H. M.,
Bunting P. B., Hasbun-Manning M., Evans R. M., Koblan K. S.,
Renger J. J., J. Med. Chem., 51, 3692—3695 (2008).
Acknowledgements We thank Dr. Fukushi Hirayama for his helpful
support in preparing this manuscript. We are also grateful to Dr. Hironori
Harada, Dr. Masakazu Imamura, and Mr. Kyoichi Maeno for their useful
advice. Finally, we wish to thank Mr. Kazuhiko Mizukami, Miss Yuriko
Komiya, Dr. Noriyasu Kanie, Mr. Satoshi Konagai, and Mr. Eisaku Yama-
moto for performing the biological experiments, and the members of the Di-
vision of Analytical Science Laboratories for elemental analysis and spectral
measurements.
29) Heo J. H., Seo H. N., Choe Y. J., Kim S., Oh C. R., Kim Y. D., Rhim
H., Choo D. J., Kim J., Lee J. Y., Bioorg. Med. Chem. Lett., 18, 3899—
3901 (2008).
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