Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist 'CJ-17,493'

Article abstract of DOI:10.1016/j.bmc.2008.06.047

A novel central nervous system (CNS) selective neurokinin-1 (NK₁) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine 'CJ-17,493' (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (K_i = 0.2 nM) for the human NK₁ receptor in IM-9 cells, potent activity in the [Sar⁹, Met(O₂)¹¹]SP-induced gerbil tapping model (ED₅₀ = 0.04 mg/kg, sc) and in the ferret cisplatin (10 mg/kg, ip)-induced anti-emetic activity model (vomiting: ED₉₀ = 0.07 mg/kg, sc), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721.

Full text of DOI:10.1016/j.bmc.2008.06.047

Bioorganic & Medicinal Chemistry 16 (2008) 7193–7205
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Discovery and stereoselective synthesis of the novel isochroman
neurokinin-1 receptor antagonist ‘CJ-17,493’
Yuji Shishido ,à, Hiroaki Wakabayashi à, Hiroki Koike, Naomi Ueno, Seiji Nukui , Tatsuya Yamagishi à,
*
Yoshinori Murata, Fumiharu Naganeo, Mayumi Mizutani à, Kaoru Shimada à, Yoshiko Fujiwara,
Ayano Sakakibara à, Osamu Suga, Rinko Kusano, Satoko Ueda, Yoshihito Kanai, Megumi Tsuchiya,
Kunio Satake à
Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2394, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel central nervous system (CNS) selective neurokinin-1 (NK1) receptor antagonist, (2S,3S)-3-[(1R)-6-
Received 4 April 2008
Revised 23 June 2008
Accepted 24 June 2008
Available online 26 June 2008
methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine
‘CJ-17,493’
(compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step.
Compound (+)-1 displayed high and selective affinity (Ki = 0.2 nM) for the human NK1 receptor in IM-9
cells, potent activity in the [Sar9, Met(O2)11]SP-induced gerbil tapping model (ED50 = 0.04 mg/kg, sc)
and in the ferret cisplatin (10 mg/kg, ip)-induced anti-emetic activity model (vomiting: ED90 = 0.07 mg/
kg, sc), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited
linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result pro-
vides a potential solution for the clinical issue observed with CP-122,721.
Keywords:
Neurokinin-1
Antagonist
CP-122,721
CYP2D6
Ó 2008 Elsevier Ltd. All rights reserved.
Kinetic resolution
Lipase PS
CJ-17,493
1. Introduction
(Fig. 1).4 Using the piperidine derivatives CP-99,994 and GR-
203040 (Glaxo), it was soon demonstrated that NK1 antagonism re-
The neurokinin-1 (NK1) receptor is a member of the seven-
transmembrane G-protein coupled family of receptors and is asso-
ciated with sensory neurons in the peripheral and specific areas of
the central nervous system. The neuropeptide ‘Substance P’ and its
human neurokinin-1 (hNK1) receptor have been associated with
various biological disorders such as anxiety, depression, emesis,
asthma and inflammatory bowel disease (IBD).1 Recently, two
selective NK1 receptor antagonists have been approved: aprepitant
(Merck; EmendÒ),2 as part of a combination therapy with a cortico-
steroid and a 5-HT3 receptor antagonist for the prevention of acute
and delayed chemotherapy-induced nausea and vomiting (CINV)
in humans; and maropitant (Pfizer; CereniaÒ)3 as a veterinary
medication to prevent and treat acute vomiting in dogs (Fig. 1).
The Pfizer compounds CP-99,994 and CP-96,345 were the first
non-peptide neurokinin-1 receptor antagonists to be disclosed
sults in the inhibition of cisplatin-induced emesis in humans and
animals and that the site of action is a part of the central nervous
system.5 Subsequently, CP-122,721, derived from CP-99,994 by the
introduction of a trifluoromethoxy group, demonstrated anti-eme-
tic activity at one-tenth the effective dose of CP-99,994. However,
CP-122,721 exhibited strong competitive inhibition (Ki = 0.02 lM
against metabolic oxidation of bufuralol) of the CYP2D6 enzyme.
Furthermore, a comparison of half-lives of CP-122,721 upon expo-
sure to CYP2D6-deficient human liver microsomes (HLM) with or
without addition of exogenous CYP2D6 enzyme (hereinafter called
the CYP2D6 +/ꢀ assay) revealed that the half-life of the compound
decreased more than 3-fold upon addition of exogenous CYP2D6.
The first step of the major metabolic pathway for CP-122,721
was identified as the CYP2D6 catalyzed O-demethylation on the
2-methoxy moiety.6
Based on the prototype NK1 receptor antagonist ‘CP-122,721’,
we initiated a program aimed at lowering the effective dose in
the anti-emetic model and addressing the high affinity of CP-
122,721 for the CYP2D6 enzyme. In order to address these major
issues, our initial approach focused on the modification at the 5
(or 4, 5)-position(s) of the benzylamine moiety by introduction
of fluorine atoms as in the 5-trifluoromethoxy group of
* Corresponding author.
E-mail address: yuji.shishido@raqualia.com (Y. Shishido).
Present address: Pfizer Global Research & Development, La Jolla Laboratories,
10614 Science Center Drive, San Diego, CA 92121, USA.
à
Present address: RaQualia Pharma Inc. 5-2 Taketoyo, Aichi, 470-2341, Japan.
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.06.047

7194
Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
Figure 1. NK1 receptor antagonists as anti-emetic drugs for humans and animals (dog).
Figure 2. Approach to compound (+)-1 starting from CP-99,994 and CP-122,721.
CP-122,721, while retaining the 2-methoxy moiety which plays an
important role in the antagonistic activity (Fig. 2). As a result, the
highly potent and metabolically stable compound (+)-1 was found
among a series of synthesized 4,5-fused derivatives containing an
oxygen atom. (+)-1 showed anti-emetic activity comparable to that
of CP-122,721 in the gerbil tapping assay, known to be connected
to the central NK1 receptor site, and in the cisplatin-induced ferret
emesis and vomiting model. In addition, compound 21 (5:1 diaste-
reomer mixture of compound (+)-1) displayed a 6-fold lower affin-
ity for the CYP2D6 enzyme and a 3-fold improvement in the
CPY2D6 +/ꢀ assay, comparing favorably to the high affinity for
CYP2D6 which had identified as a major issue for CP-122,721. This
report summarizes our SAR pursuit from CP-122,721 to compound
(+)-1, a compound with enhanced safety potential which may
prove useful as an anti-emetic drug, and outlines the first synthetic
method of optically active (+)-1 using a kinetic resolution by li-
pase-PS.7
fluoroalkyl moiety led to an improvement in the affinity for IM-9
cells and in the specific interaction to CYP2D6, while conserving
the hNK1 receptor antagonistic activity in vitro (Table 1). In partic-
ular, the introduction of geminal-methyl groups or of fluorine
groups (F, CF3) at the 5-benzylic position of CP-122,721 (com-
pounds 4, 6 and 7) resulted in moderate inhibition of the metabolic
oxidation of bufuralol at 5 lM substrate, while retaining the intrin-
sic activity in the gerbil tapping assay as shown in Table 1. Further-
more, the 5- and 6-membered cyclized trifluoromethyl derivatives
(10–13, 15–17, and 21) showed comparable to or improved activ-
ity over CP-122,721 in the gerbil tapping assay, while the introduc-
tion of an oxygen atom in the 5- and 6-membered derivatives (15
and 21) resulted in a significant increase in inhibitory activity
(ED90 < 0.1 mg/kg, sc) in the cisplatin-induced emesis assay, as
shown in Tables 2 and 3. Compound 21 was evaluated as a 5:1
R/S mixture at the 6-position. The lower activity in vivo of these
in vitro potent compounds (in the binding assay) can be explained
by a lower CNS penetration, as evidenced by the ratio of free frac-
tion concentration in brain (or CSF) versus plasma.
CP-122,721 demonstrated super dose-proportional kinetics
among poor metabolizers (PMs) of CYP2D6 in a human PK study
of healthy male subjects,6 while the quinuclidine compound CJ-
11,974 showed dose-proportional pharmacokinetics in clinical
data. An in vitro assay of these compounds confirmed the differ-
ence in Km values for CP-122,721 and CJ-11,974 in human liver
microsomes.8 We therefore hypothesized that it is possible to pre-
2. Discussion and results
The results of our modifications around the 5 (or 4, 5)-posi-
tion(s) of the benzylamine moiety are summarized in SAR Tables
1–3, focusing in turn on non-cyclic analogs (Table 1), 5-ring mem-
bered analogs (Table 2), and 6-ring membered analogs (Table 3).
The conversion of the trifluoromethoxy group of CP-122,721 to a

Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
7195
Table 1
Non-cyclic analogs based on CP-122,721
Compound
IM-9 binding
(IC50, nM)
Affinity to CYP2D6
Gerbil tapping assay
Cisplatin-induced emesis in ferrets
(% inh. at 5
lM)
ED50 (mg/kg, sc) or % inhibition (dose, mg/kg)
ED100 (mg/kg, sc)
ED90 (mg/kg, sc)
CP-122,721
0.4
0.9
0.4
0.2
<0.1
0.7
<0.1
<0.1
<0.1
95.6
95.9
65.9
54.8
92.9
46.6
43.1
NT
0.28 (n = 3)
0.03
0.82
0.12
67% (1)
0.16
0.33
P0.3
0.1
P1.0
1
0.09
<0.1
0.3
0.21
NT
2
3
4
5
6
7
8
9
NT
97% inh. (0.1 mg/kg)
0.90
NT
0.48
NT
57% (1), 30% (0.1)
55% (1), 63% (0.1)
62.6
15% inh. (0.1 mg/kg)
Table 2
5-Membered ring analogs based on CP-122,721
Compound
IM-9 binding
(IC50, nM)
Affinity to CYP2D6
Gerbil tapping assay
Cisplatin-induced emesis in ferrets
(% inh. at 5
lM)
ED50 (mg/kg, sc) or % inhibition (dose, mg/kg)
ED100 (mg/kg, sc)
ED90 (mg/kg, sc)
0.12
10
11
12
13
14
15
16
0.9
0.4
74.2
75.9
NT
66.4
41.8
73
0.11
1
88 (1), 79 (0.1)
80 (1), 68 (0.1)
84 (0.1)
69 (1), 15 (0.1)
77 (0.1)
100% inh. (1 mg/kg)
<0.1
<0.1
<0.1
<0.1
0.16
NT
NT
99% inh. (0.1 mg/kg)
NT
0.3
NT
0.05
81
94 (1), 87 (0.1)
99% inh. (0.3 mg/kg)
dict the kinetic behavior of compounds in this series by their Ki val-
ues and the ratio of their half-life in the CYP2D6 +/ꢀ assay. Thus a
new screening sequence was devised, consisting of an inhibitory
(Ki > 0.5 lM vs 0.02 lM) in Table 4, compound 11 and 17 dem-
onstrated hypermetabolism in CYP2D6 +/ꢀ assay. A possible
explanation for the 10-fold jump for 11 in the CYP2D6 +/ꢀ assay
is a rapid metabolite formation despite its low affinity for the
CYP2D6 enzyme.
Finally, in order to study the relationship between pharmaco-
logical activity in vivo and affinity to CYP2D6 in vitro, the 5- and
6-membered derivatives (15 and 21) were selected. Since the
assay of the 10-hydroxylation of bufuralol at 5
lM concentration
of substrates, followed by a full inhibition assay to determine the
inhibition constant (Ki) of the compound for the inhibition of buf-
uralol by CYP2D6 instead of the cumbersome measurement of Km
values. In addition to the Ki value, the T1/2 ratio in HLM in the
CPY2D6 +/ꢀ assay or HLM in the quinidine +/ꢀ was also
determined.9
respective Ki values of 0.66 and 0.12
lM for 15 and 21 indicate a
6- to 30-fold lower affinity compared to the Ki value (0.02
lM)
Compounds with potent anti-emetic efficacy were selected
and compared for their effect on CYP2D6, as shown in Table 4.
Compounds 2, 3, 15 and 21 showed high specific interaction
for CP-122,721, we predicted that compound 21 would not demon-
strate appreciable super dose-proportionality in humans at phar-
macologically relevant doses. The half-life ratio in the CPY2D6 +/ꢀ
of compound 21 is also 3-fold lower than the corresponding ratio
(6.00) for CP-122,721. Furthermore, although the profile of com-
pound 21 is comparable to that of the 5-membered-ring compound
15, the pharmacokinetics of compound 21 showed a 2- to 4-fold
superiority in AUC, Cmax and half-life (dog, 5 mg/kg, po). Thus our
effort shifted to the development of an efficient synthesis of opti-
cally active (+)-1.
(>60% inhibition at 5
l
M, Ki < 1.0
lM) with the CYP2D6 enzyme
in the 50% inhibition assay using bufuralol at 5
l
M concentration
of substrates, and low Ki values in the bufuralol metabolism as-
say by human CYP2D6, while tetrahydronaphthalene derivative
19 (a C-analog of compound 21) showed a definite improvement
over 21. Among the compounds with inhibition constants more
than 25 times greater than the Ki value for CP-122,721

7196
Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
Table 3
6-Membered ring analogs based on CP-122,721
Compound
IM-9 Binding
(IC50, nM)
Affinity to CYP2D6
Gerbil tapping assay
Cisplatin-induced emesis in ferrets (vomiting)
(% inh. at 5
lM)
ED50 (mg/kg, sc) or % inhibition (dose, mg/kg)
ED100 (mg/kg, sc)
ED90 (mg/kg, sc)
17
18
19
20
21
22
(+)-1
0.5
76.5
85.4
42
42
90
77% (1), 55% (0.1)
4% (1)
1
NT
NT
NT
0.17
NT
NT
<0.1
0.21
<0.1
<0.1
0.34
0.2*
85% (1), 21% (0.1)
65% (1), 0% (0.1)
91% (1), 86% (0.1)
87% (1), 26% (0.1)
0.043
NT
97% inh. (0.1 mg/kg)
NT
90
NT
NT
0.07
*Ki value.
Table 4
Evaluation of bufuralol turnover (Ki) and CYP2D6 +/ꢀ assay among key compounds
Compound
In vitro
In vivo
Cisplatin-induced emesis (vomiting)
ED90 (mg/kg, sc) ED100 (mg/kg, sc)
b
Affinity to CYP2D6
CYP2D6 +/ꢀ
Bufuralol turnover by human CYP2D6
(Ki M)
(% inh. at 5
lM)
l
CP-122,721
2
3
4
6
7
11
15
17
19
21
CJ-11,974
95.6
95.9
65.9
54.8
46.6
43.1
75.9
73
6.0–6.20
4.25
0.02
0.07
0.84
1.34
0.09
0.09
0.3
0.17
P0.3
0.1
P1.0
1
2.2/1.0a
1.16
1.83
2.0
10.6
2.1
7.35
1.58
1.8
1.8–3.80
cal. 1.86c
2.1
97% inh. (0.3 mg/kg)
0.48
NT
0.05
NT
NT
0.9
NT
0.3
NT
NT
cal. 0.52
0.66
cal. 0.5
cal. 2.24
0.12
76.5
42.0
90
97% inh. (0.1 mg/kg)
2.1
64.1
0.42–0.57
a
Quinidine +/ꢀ assay.
b
c
CYP2D6 +/ꢀ means the ratio of half-lives between CYP2D6-deficient HLM and CYP2D6-deficient HLM upon addition of exogenous CYP2D6.
Calculated Ki value was estimated from the one point measurement at 5 M substrate concentration: % inhibition (5
M) = 5/(5 + 3.08Ki) ꢂ 100.
l
l
Finally, the important Km value for synthesized compound (+)-1
was then effected by selective lithiation at the 4-position using
n-butyl lithium at ꢀ100 °C followed by the addition of 1,1,1-triflu-
oroacetone, affording a 3.9:1 mixture of 26 and 3-methoxyphene-
tyl chloride. The by-product was converted to 1-methoxy-3-
vinylbenzene using DBU, after which distillation of the crude prod-
uct gave pure 26 in 77% yield. After conversion of 26 to 28, com-
pound 28 was subjected to kinetic resolution using lipase-PS,
leading to the optically active O-acetyl derivative 29 with an enan-
tiomeric excess of 94%.10 Compound 29 was converted to the 1-
methoxy derivative in two steps to furnish 32, which was formy-
lated regioselectively at the 7-position using a combination of alu-
minum(III) chloride and dichloromethyl n-butyl ether (ratio in 5-/
7-position = 5.3:1, isolated yield 54%) (Table 7, entry 5). The reduc-
tive amination of 34 with (2S,3S)-3-amino-2-phenylpiperidine led
to compound 1, which was treated with 10% hydrochloric metha-
nol to give (+)-1ꢁdihydrochloride. The optical purity of the obtained
(+)-1ꢁdihydrochloride was then increased to >99% de by two suc-
cessive recrystallizations.
was measured directly based on the results for the affinity to
CYP2D6 enzyme for compound 21 (active-enriched 5:1 diastereo-
mer mixture). While the major metabolite of CP-122,721 is O-
demethylation in human liver microsomes, the metabolic routes
for CJ-17,493 are 4-hydroxylation on the benzylamine moiety
(not demethylation in 6-position as in the metabolism of CP-
122,721) and N-dealkylation on the 3-carbon atom between the
benzylic NH moiety and the piperidine skeleton. The Km values in
human liver microsomes were 16.6 and 2.3 lM for hydroxylation
and N-dealkylation, that is, 10- to 70-fold higher than the Km of
CP-122,721 in human liver microsomes. This Km ratio between
CP-122,721 and CJ-17,493 was considered to be sufficient to pre-
dict a lack of super-proportional kinetics. In fact, the FIH study of
CJ-17,493 confirmed the dose-proportionality in a PK study at
doses ranging from 30 to 380 mg (individual subjects dose-ad-
justed AUC(0–inf)s were similar) and no differences between CYP2D6
EMs (n = 20) and PMs (n = 4).
The following Table 5 summarizes the screening of lipases for the
kinetic resolution of racemic compound 28.11 The lipase PS series of
standard and immobilized reagents produced the optically active
acetate 29 in more than 60% enantiomer excess (ee). Thus the inex-
pensive standard lipase PS was selected, and we proceeded to study
the limited solvent choices, as shown in Table 6. Although the com-
3. Chemistry
Regioselective mono-bromination of the commercially available
23 was followed by chlorination of the hydroxyl group (Scheme 1).
The conversion of 25 to 3,4-dihydro-1H-isochromen derivative 26

Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
7197
Scheme 1. Synthesis of compound (+)-1 (CJ-17,493). Reagents and conditions: (a) bromine, pyridine (1.1 equiv), CH2Cl2 (100%); (b) CCl4, triphenylphosphine, 85 °C, 75%; (c) n-
butyllithium, THF/hexane (3:1), ꢀ100 °C then 1,1,1-trifluoroacetone, ꢀ70 °C–rt; (d) DBU, toluene, reflux, 77% from 25; (e) 48% HBr aq AcOH, reflux, 100%; (f) AcCl, triethylamine,
THF, rt, 89%; (g) lipase-PS, 10% sec-butanol/hexane, rt, 24 h, 45%; (h) K2CO3, methanol/H2O (2.5:1), rt, 93%, 94% ee; (i) MeI, 60% NaH, DMF, rt, 98%; (j) dichloromethyl n-butyl ether,
AlCl3, CH2Cl2, 74%; (k) (2S,3S)-3-amino-2-phenylpiperidine, NaBH(OAc)3, CH2Cl2, rt, 24 h, 100% (crude yield); (l) 10% HCl/methanol, methanol, 78%.
Table 5
Lipase kinetic resolution: lipase screeninga
Entry
Lipases
Time (h)
Conversion (%)
ee (acetate 29)
ee (phenol 30)
1
2
3
4
5
6
Lipase PS
2
1.5
13
13
13
4
51.3
52.6
41.5
42.4
32
69.6
3.5
50.4
23.9
30.7
2.5
67.4
2.3
84.0
34.2
64.9
1
Lipase AY
Lipase AH
CHE
LPL-A (TOYOBO)
Steapsin (TCI)
54.3
a
28 (50 mg) and lipases (50 mg)/IPE-saturated water (2 mL)/rt.
binationsof10%alcoholswithhexaneonlymoderatelyincreasedthe
enantiomeric excess (ee) of compound 29, this combination of sol-
vents allowed a better control of the rate of the kinetic resolution
than thecombination of alcoholsand buffer solution. Theconversion
rate (%) at ambient temperature was carefully investigated on a 15 g
scale for 28 and the 50% conversion time was determined to be ca.
20–23 h. Finally, a combination of lipase-PS using 10% sec-butanol/
hexane as the solvent gave the optical acetate 29 in 94% ee (51% con-
version) on multigram scale: 28 (38.4 g)/lipase PS (35 g)/10% sec-
BuOH/hexane (1.3 L)/rt 23 h (Table 6, entry 5).
Another issue in the synthesis of compound (+)-1 was the need to
improve the regioselectivity in the formylation of compound 32 (Ta-
ble 7). A 34/33 ratio of 1.5:1 was obtained using titanium chloride
and dichloromethyl methyl ether,12 compared with a 10–15:1 ratio
when this combination of reagents was used to produce the 5-mem-
Table 6
Lipase PS kinetic resolution: solvent screeninga
Entry Solvents
Time
Conversion
(%)
ee
(29)
ee
(30)
(h)
1
2
Phosphate buffer pH 7.0
20% Acetone-phosphate buffer
pH 7.0
20% t-BuOH/phosphate buffer
pH 7.0
10% sec-BuOH/hexane
10% sec-BuOH/hexane
10% MeOH-IPE
1
32.9
55.3
33
100
63.5
74.3
0.5
0.5
13
23
20
13
3
65.7
100
50.4
4
41.1
51.0
46.2
40.5
61.8
94c
51.1
54.9
100
83
63.4
100
5b
6
7
IPE saturated with H2O
a
28 (30 mg) and lipase-PS (30 mg)/solvents (2 mL)/rt.
28 (38 g) and lipase-PS (35 g)/solvents (1.3 L).
Ref. [10b].
b
c

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Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
bered analog 40 in scheme 2. After testing various reagent combina-
tions, we found that the combination of aluminum chloride (2.3
equiv) and dichloromethyl n-butyl ether (2.0 equiv) in dichloro-
methane with dry ice/methanol cooling increased the regioselectiv-
ity of the formylation to a ratio of 5–6: 1 (Table 7, entry 5).
Compound 15 was also synthesized according to the same se-
quence as compound 1 (Scheme 2). Cyclization of 38 to 39 afforded
a 13:1 mixture of 38 and 37, which was treated with glycine13 to
give a single compound 38 in 69% yield. The subsequent formyla-
tion of 39 using titanium chloride/dichloromethyl methyl ether
gave 6-formyl derivative 40 (82% yield) in a ratio of 15:1, as com-
pared to the 5.3:1 ratio obtained in the formylation of compound
32 under the same conditions. The reductive amination of 40 with
(2S,3S)-3-amino-2-phenylpiperidine led to compound 15 as a 1:1
diastereomer mixture, which was treated with 10% hydrochloric
methanol to give 15ꢁdihydrochloride. Finally, triple recrystalliza-
tion of 15ꢁdihydrochloride allowed the isolation of the enriched
1R diastereomer as a 49:1 mixture without the need for any kinetic
resolution of an intermediate.
For the synthesis of the carbocyclic analogs 12 and 19, the fol-
lowing general protocol was used (Scheme 3). The ketones (42
and 43) were transformed into the trifluoromethyl tertiary alco-
hols (44 and 45) using Ruppert’s reagent (TMS-CF3) followed by
acidic hydrolysis.14 Next, chlorination of the cyclic tertiary alcohols
using titanium(IV) chloride (2 equiv) at ꢀ78 °C followed by addi-
tion of dimethylzinc (2 equiv), all in one pot, afforded the desired
products (48 and 49) in high yield.15 These were converted to
the desired formyl derivatives 52 and 53 using titanium(IV) chlo-
ride and dichloromethyl methyl ether as the first-line choice, the
two compounds giving different regioselectivity results. The reduc-
tive amination of these formyl derivatives with (2S,3S)-tert-butyl
3-amino-2-phenylpiperidine-1-carboxylate led to compounds 12
and 19, which were treated with 10% hydrochloric methanol to
give 12ꢁdihydrochloride and 19ꢁdihydrochloride, respectively.
Table 7
Regioselective formylation of compound 32
Entry
Reagent 1
Reagent 2
Time/temp (°C)
Solvent
Regioselectivity
34
33
1
2
3
4
5
6
7
TiCl4 (2.2)
TiCl2 (O-i-Pr)2 (2.2)
TiCl4 (2.2)
AlCl3 (2.2)
AlCl3 (2.3)
Cl2CHOMe (2.0)
Cl2CHOMe (2.0)
Cl2CHO-n-Bu (2.0)
Cl2CHOMe (2.0)
Cl2CHO-n-Bu (2.0)
1 h/ꢀ78
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
1.6–1.8
NR
1.6–1.8
2.3
4.7–5.5
NR
5
1
4 h/ꢀ78–rt
1 h/ꢀ78
1
1
1
1 h/ꢀ78
1 h/ꢀ78
POCl3 (5.0)
HMTA (6.0)
6h/120–160
15 h, reflux
CF3CO2H
1
The parenthetic number means the mol ratio (equiv.) of reagent against 32.
Scheme 2. Synthesis of compound 15. Reagents and conditions: (a) bromine, pyridine (1.2 equiv)/CH2Cl2, 0 °C–rt, 18 h; (b) n-butyllithium, THF/hexane (3:1), ꢀ100 °C then
1,1,1-trifluoroacetone, ꢀ70 to ꢀ30 °C (39/37 = 13.2:1); (c) glycine, KOH, EtOH/H2O (3:2), reflux, 2 h then distillation (bp 94–96 °C/1.5 mm Hg), 69% from 37; (d)
dichloromethyl methyl ether, TiCl4, CH2Cl2, 82% (40/41 = 15:1); (e) (2S,3S)-3-amino-2-phenylpiperidine, NaBH(OAc)3, CH2Cl2, rt, 24 h, 100% (crude yield); (f) 10% HCl/
methanol, ethyl acetate, 21% after three times recrystallization.

Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
7199
Scheme 3. Synthesis of compound 12, 19 and 20 (indane and tetraline derivatives). Reagents and conditons: (a) TMSCF3, TBAF (cat.), THF, rt, then dil HCl aq; (b) TiCl4 (2.2
equiv), CH2Cl2, ꢀ78 °C; (c) 1.0 M Me2Zn in hexane solution (2.0 equiv) (n = 1:87%; n = 2:92%); (d) TiCl4 (2.2 equiv), Cl2CHOMe (2.2 equiv), CH2Cl2, 0 °C (n = 1:85%; n = 2: 40%);
(e) (2S,3S)-tert-butyl 3-amino-2-phenylpiperidine-1-carboxylate, NaBH(OAc)3, CH2Cl2, rt, 24 h; (f) 2 M HCl aq/ethyl acetate (n = 1:86%; n = 2:94% from 52 and 53); (g) 10%
HCl/methanol.
agent, elicits acute emetic episodes such as retching, vomiting and
gagging in the ferret. (+)-1, given sc 30 min before cisplatin, inhib-
ited the emesis response in a dose-dependent manner with ED90
values of 0.03 and 0.07 mg/kg, sc for retching and vomiting/gag-
ging, respectively (Fig. 3).
4. Evaluation of compound(+)-1 (CJ-17,493)
4.1. In vitro data of compound (+)-1 (CJ-17,493)
Compound (+)-1 binds with high affinity (Ki = 0.2 nM) to the
NK1 receptor labeled by [3H]SP in the IM-9 human lymphoblas-
toma cell line. (The IC50 values in human IM-9 cell were <0.1,
0.34 and 0.79 nM for compound (+)-1, the 1S epimer of compound
(+)-1 and substance P, respectively). On the other hand, it pos-
sesses moderate affinity to the verapamil binding site at the L-type
Ca2+ channel labeled by [3H]desmethoxyverapamil (IC50 = 164 nM)
and the sodium channel site 2 labeled by [3H]batrachotoxinin
(IC50 = 48 nM). The functional activity of compound (+)-1 against
the sodium channel was examined by whole-cell patch clamp
using CHO-CNaIIA cells stably transfected with the rat Na+-channel
type IIA-subunit. The compound had no significant activity against
4.3. PK profile of compound (+)-1 (CJ-17,493)
In rats, the systemic plasma clearance (CL), volume of distri-
bution at steady-state (Vdss), and half-life (T1/2) of optically active
(+)-1 (0.3 mg/kg, iv) were 0.66 L/h/kg, 7 L/kg, and 8.8 h, respec-
tively. After oral administration (1–30 mg/kg), exposure to com-
pound (+)-1 increased with dose and maximum drug
concentrations (Cmax) occurred within 0.5 h post dose. Oral bio-
availability of optically active (+)-1 administered as the hydro-
chloride salt dissolved in water was lower than 1% at the
tested doses. In dogs, optically active (+)-1 at 1 mg/kg, iv gave
CL, Vdss, and T1/2 of 1.9 L/h/kg, 11 L/kg, and 3.8 h, respectively.
Exposure in dogs after oral administration was significantly
higher than that in rats and the oral bioavailability at 5 mg/kg,
administered p.o. as a water solution was 9.8%. Finally, the FIH
study of compound (+)-1 confirmed the dose-proportionality in
PK from 30 to 380 mg doses (individual subjects dose-adjusted
AUC(0–inf)s were similar) and no differences between CYP2D6
EMs (n = 20) and PMs (n = 4).
the sodium channel at up to 1 lM concentration (13% inh.), and
88% inhibition was observed at a concentration of 10 lM.
4.2. Pharmacology of compound (+)-1 (CJ-17,493)
The activity of optically active compound (+)-1 in the CNS was
assessed by the intracelebroventricular injection of a stable NK1
receptor agonist, that is, the gerbil [Sar9, Met(O2)11]SP-induced
tapping model. Compound (+)-1, dosed sc 30 min before the ago-
nist injection, inhibited the tapping response in a dose-dependent
manner. The ED50 was 0.043 0.003 mg/kg, sc (mean SEM, n = 3).
Capsaicin elicits plasma extravasation in a variety of tissues
through the release of endogenous SP from sensory afferents. In
the guinea pig ureter, intraperitoneally injected capsaicin
5. Conclusion
As a result of our search for a new anti-emetic drug based on
prototype ‘CP-122,721’, we have found a compound with high po-
tency and selectivity (Ki = 0.2 nM) for the NK1 receptor in IM-9 cells
and potent anti-emetic activity in the cisplatin (10 mg/kg, ip)-in-
duced anti-emetic ferret assay (vomiting: ED90 = 0.07 mg/kg, sc)
comparable with CP-122,721, while lowering the affinity for the
CYP2D6 enzyme. Thus compound (+)-10 CJ-17,4930 was identified
as an anti-emetic candidate that addresses the PK issue of CP-
122,721 in poor metabolizers (PMs).
(30 lM) produces a plasma protein leakage which is likely to be
mediated by activation of the peripheral NK1 receptor. In this mod-
el, (+)-1 showed dose-dependent inhibition with an ED50 of
0.005 mg/kg, po. NK1 receptor antagonists have been shown to
block retching and vomiting responses induced by a wide range
of centrally and peripherally acting emetogens in the ferret. Intra-
peritoneal injection of cisplatin (10 mg/kg ip), a chemotherapeutic

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Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
Vomiting/Gagging
30
25
20
15
10
5
Retching
120
100
80
60
40
20
0
Vehicle
Compound (+)-1
Vehicle
Compound (+)-1
∗
∗∗
∗∗
∗∗
0
Control 0.01
0.03
0.1
Control
0.01
0.03
0.1
Dose (mg/kg, s.c.)
Dose (mg/kg, s.c.)
Figure 3. Activity of optically active (+)-1 on retching and vomiting/gagging induced by cisplatin (10 mg/kg, ip) in ferrets. *P < 0.05 and **P < 0.01 versus control by Student’s-
test. Data are mean SEM, n = 4–5.
chloride (940 mL) was added triphenylphosphine (190.0 g,
0.72 mol) portionwise at ambient temperature and the organic
solution was stirred at 84 °C for 4 h. After cooling the mixture to
room temperature, additional triphenylphosphine (8.5 g,
32.0 mmol) was added to the solution and the reaction mixture
was stirred at 84 °C for 10 h. The reaction mixture was filtered
through Celite, and the filter cake was washed with carbon tetra-
chloride (5ꢂ 50 mL). The combined filtrate and washings were
washed with saturated aqueous sodium bicarbonate (100 mL),
brine (100 mL), dried over magnesium sulfate, and concentrated
in vacuo. The crude product was purified by flash chromatography
(Silica-gel, 12 ꢂ 9 cm, 2–3% ethyl acetate in hexane) to afford the
compound 25 (281.0 g, 85%), which was distilled (bp 133 °C/
1.9 mm Hg), to provide the compound 25 (247.0 g, 75%).
1H NMR (CDCl3): d 7.43 (d, J = 8.7 Hz, 1H), 6.83 (d, J = 3.0 Hz,
1H), 6.69 (dd, J = 8.7, 3.0 Hz, 1H), 3.79 (s, 3H), 3.73 (t, J = 7.1 Hz,
2H), 3.16 (t, J = 7.1 Hz, 2H).
6. Experimental
6.1. General
Proton nuclear magnetic resonance (1H NMR) spectra were
measured on a JEOL FX270 by using deuterochloroform or dimeth-
ylsulfoxide-d6, and proton chemical shifts are reported as d values
in parts per million (ppm) relative to tetramethylsilane as an inter-
nal standard. Spin multiplicities are given as s (singlet), d (doublet),
t (triplet), q (quartet), dd (doublet of doublet), m (multiplet), and br
s (broad singlet). Gas chromatography analysis was determined
using Column: J&DB-1 30 m ꢂ 0.25 mm (Film thickness
0.25 mm), Carrier gas: He, 20 psi (138 kPa), Injector: split (ca.
100:1), T = 250 °C, Detector: FID: T = 250 °C, Oven 170 °C
(10 min). The electron spray ionization mass spectra (ESI-MS) were
obtained with Quattro-II triplequadrupole mass spectrometer
(micromass, UK). Melting points were determined on a Yanagimot-
o micro-melting-point apparatus and were uncorrected. The re-
sults of elemental analyses were within 0.4% of the theoretical
values and reported only with symbols. Reactions were followed
by TLC on Silica-gel 60 F254 precoated TLC plates (E. Merck) or
NH2 HPTLC F254s plates (E. Merck). Chromatographic separations
were carried out on silica-gel (E. Merck, 70–230 mesh) using the
indicated eluents. The color fixing agent of TLC plates was used
Dragendorf’s reagent in the case of the basic compounds.
GC retention time: 5.64 min (compound 25).
6.1.1.3. 6-Methoxy-1-methyl-1-trifluoromethylisochroman
(26). To a stirred solution of compound 25 (80.0 g, 0.32 mol) in
anhydrous tetrahydrofuran (1300 mL)/hexane (450 mL) was
added n-butyllithium (230 mL, 0.35 mol) dropwise under nitro-
gen at ꢀ100 °C (internal temperature). The reaction mixture
was stirred at ꢀ93 °C for 2 h. To the reaction mixture was added
a solution of 1,1,1-trifluoroacetone (37 mL, 0.42 mol) in anhy-
drous tetrahydrofuran (120 mL)/hexane (40 mL) dropwise at
ꢀ105 °C to ꢀ70 °C (internal temperature) for 40 min using a
dropping funnel and stirred overnight at ꢀ70 °C to room temper-
ature (The temperature was gradually raised to room tempera-
ture overnight). This was quenched by water (100 mL), and
extracted with dichloromethane. The combined organic extracts
were dried over magnesium sulfate, and concentrated in vacuo
to give a crude product. The ratio of desired compound and 3-
methoxyphenethyl chloride was 3.9:1 as determined by 1H
NMR and GC. To remove the by-product (3-methoxyphenethyl
chloride), the residue was diluted with toluene (530 mL) and
to the mixture was added 1,8-diazabicyclo[5.4.0]undec-7ene
(DBU) (37 mL, 0.24 mol). After the solution was stirred at
110 °C for 16 h, aqueous 2 M hydrochloric acid (200 mL) was
added to the stirred solution mixture at 0 °C. The organic layer
was extracted with ethyl acetate (500 mL), washed with aqueous
2 M hydrochloric acid (100 mL), saturated aqueous sodium bicar-
bonate (100 mL), brine (100 mL), dried over magnesium sulfate,
and concentrated in vacuo. The residue was passed through a
short column (Silica-gel, 12 ꢂ 9 cm, 5% ethyl acetate in hexane)
to remove the baseline compound. The mixture was distilled to
provide compound 26 (61.0 g, 77%) (bp 106 °C/0.9 mm Hg) as a
colorless oil.
6.1.1. (2S,3S)-3-[(1R)-6-Methoxy-1-methyl-1-trifluoromethy
lisochroman-7-yl]methylamino-2-phenylpiperidine ((+)-1)
ꢁdihydrochloride
6.1.1.1. 2-Bromo-5-methoxyphenethyl alcohol (24). To a stirred
mixture of 3-methoxyphenethyl alcohol (50.0 g, 0.33 mol) and pyr-
idine (29 mL, 0.36 mol) in anhydrous dichloromethane (560 mL)
was added bromine (20 mL, 0.39 mol) dropwise under nitrogen
at 0 °C. The organic solution was stirred at ambient temperature
for 2 h. To the mixture was added additional bromine (0.85 mL,
17.0 mmol) at the same temperature to complete the reaction
and the solution was stirred for 1.5 h. The resultant mixture was
quenched by addition of 10% aqueous sodium bisulfite (100 mL),
and extracted with dichloromethane. The organic extracts were
washed with brine (100 mL), dried over magnesium sulfate, and
concentrated to give crude product 24 (76.0 g, quant.).
1H NMR (CDCl3): d 7.43 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 3.3 Hz,
1H), 6.67 (dd, J = 8.8, 3.3 Hz, 1H), 3.91–3.81 (m, 2H), 3.78 (s, 3H),
2.99 (t, J = 6.6 Hz, 2H). OH (1 proton, not observed) GC retention
time: 5.98 min (compound 24), 3.05 min (3-methoxyphenethyl
alcohol).
*
6.1.1.2. 2-Bromo-5-methoxyphenethyl chloride (25). To a stir-
red solution of compound 24 (150.0 g, 0.66 mol) in carbon tetra-

Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
7201
1H NMR (CDCl3): d 7.26 (d, J = 8.9 Hz, 1H), 6.81 (dd, J = 8.9,
2.6 Hz, 1H), 6.68 (d, J = 2.6 Hz, 1H), 4.14 (dt, J = 11, 5.8 Hz, 1H),
3.90 (dt, J = 11, 5.8 Hz, 1H), 3.81 (s, 3H), 2.87-2.81 (m, 2H), 1.64
(s, 3H).
in vacuo to afford the compound 31 (28.0 g, 93%, 94% ee) as a col-
orless oil.
The1H NMR (CDCl3) spectra of this compound was identical
with that of racemate 27.
GC retention time: 3.71 min (compound 26), 3.07 min (3-meth-
oxyphenethyl chloride), 2.21 min (3-vinylanisole).
6.1.4. (1R)-6-Methoxy-1-methyl-1-trifluoromethylisochroman
(32)
6.1.1.4. 6-Hydroxy-1-methyl-1-trifluoromethylisochroman
(27). To a stirred solution of compound 26 (71.0 g, 0.29 mol) in
acetic acid (600 mL) was added aqueous 48% HBr (300 mL) and
the mixture was stirred at 130 °C for 13 h. After the removal of sol-
vent in vacuo, the reaction mixture was treated with aqueous 8 M
sodium hydroxide until the pH became 5 to 6. The resultant solu-
tion was extracted with ethyl acetate (2ꢂ 400 mL) and the com-
bined extracts were washed with brine (100 mL), dried over
magnesium sulfate, and concentrated in vacuo, followed by flash
chromatography (Silica-gel, 15 ꢂ 20 cm, 17% ethyl acetate in hex-
ane) to afford the compound 27 (67.0 g, quant.) as a colorless oil.
1H NMR (CDCl3): d 7.22 (d, J = 9.1 Hz, 1H), 6.73 (dd, J = 9.1,
2.6 Hz, 1H), 6.63 (d, J = 2.6 Hz, 1H), 5.00 (s, 1H), 4.17–4.07 (m,
1H), 3.90 (dt, J = 11, 5.8 Hz, 1H), 2.84–2.74 (m, 2H), 1.64 (s, 3H).
GC retention time: 4.26 min (compound 27).
To a stirred mixture of 60% sodium hydride (3.47 g, 0.145 mol)
in N,N-dimethylformamide (50 mL) was added
a solution of
compound 31 (28.0 g, 0.121 mol) in DMF (370 mL) at 0 °C and
the mixture was stirred at the same temperature for 1 h. Methyl
iodide (25.8 g, 0.182 mol) was added dropwise to the resulting
mixture at 0 °C and the mixture was stirred at room temperature
for 1 h. The reaction mixture was quenched with water and diluted
with saturated aqueous ammonium chloride. This was extracted
with ethyl acetate/toluene (4:1) and the combined solution was
washed with water, brine and dried over magnesium sulfate. After
the solvent was removed in vacuo, the residue was purified by
column chromatography on silica-gel eluted with hexane/ethyl
acetate (40:1) to give the compound 32 (29.1 g, 98%) as a colorless
oil.
The 1H NMR (CDCl3) spectra of this compound was identical
with that of racemate 26.
6.1.1.5. 6-Acetoxy-1-methyl-1-trifluoromethylisochroman (28).
To a stirred solution of compound 27 (79.0 g, 0.34 mol) and triethyl-
amine (120 mL, 0.88 mol) in tetrahydrofuran (680 mL) was added
acetyl chloride (31 mL, 0.44 mol) at 0 °C, and the mixture was stir-
red at ambient temperature for 1 h. The reaction mixture was
quenched by adding aqueous 1 M hydrochloric acid (400 mL), and
the organic solution was extracted with ethyl acetate (500 mL).
The extracts were washed with aqueous saturated sodium bicarbon-
ate (100 mL) and brine (100 mL), dried over magnesium sulfate, and
concentrated in vacuo. The residue was purified by flash chromatog-
raphy (Silica-gel, 15 ꢂ 20 cm, 6% ethyl acetate in hexane) to afford
the compound 28 (83.0 g, 89%) as a colorless oil.
6.1.5. (1R)-6-Methoxy-1-methyl-1-trifluoromethylisochroman-
7-carbaldehyde (34)
To a stirred solution of compound 32 (33.2 g, 0.135 mol) in
anhydrous dichloromethane (1 L) was added powdered alumi-
num chloride (41.4 g, 0.31 mol) portionwise at ꢀ78 °C and stir-
red for 20 min. To the yellow solution was added a solution of
dichloromethyl n-butyl ether (42.3 g, 0.27 mol) in anhydrous
dichloromethane (100 mL) dropwise and the mixture was stirred
at ꢀ78 °C for 2.5 h. This was poured into ice-water and stirred at
room temperature for 1 h. The organic layer was separated and
the aqueous layer was extracted with dichloromethane (3ꢂ
300 mL). The combined organic layers were washed with brine,
dried over magnesium sulfate, and concentrated in vacuo to af-
ford a slightly yellow crystalline solid (40.3 g) as a mixture of
compound 34 (7-formyl) and compound 33 (5-formyl) in a ratio
of ca. 5.3:1, as determined by 1H NMR. The solid (40.3 g) was
recrystallized from a mixed solvent of ethyl acetate (35 mL)
and hexane (400 mL) to give the compound 34 (19.8 g, 54%) in
a pure form.
1H NMR (CDCl3): d 7.36 (d, J = 7.2 Hz, 1H), 6.98 (dd, J = 7.2,
2.5 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 4.18–4.08 (m, 1H), 3.92 (dt,
J = 11, 5.4 Hz, 1H), 2.86 (t, J = 5.4 Hz, 2H), 2.30 (s, 3H), 1.66 (s, 3H).
GC retention time: 4.95 min (compound 28).
6.1.2. (1R)-6-Acetoxy-1-methyl-1-trifluoromethylisochroman
(29) and (1S)-6-hydroxy-1-methyl-1-trifluoromethylisoch-
roman (30)
A mixture of racemic compound 28 (38.4 g, 0.14 mol), 10% sec-
butanol solution in hexane (1.3 L), and lipase PS (Amano enzyme:
lot LPSAV09512, 35 g) was stirred vigorously at ambient tempera-
ture for 23 h. After the filtration, the filtrate was concentrated
under reduced pressure to give a mixture. This was purified by sil-
ica-gel column chromatography eluted with a gradient of hexane
and ethyl acetate (15:1–5:1–2:1) to give compound 29 (first frac-
tion, 17.3 g, 45%) as a colorless oil. The second fraction gave com-
pound 30[(1S)-6-hydroxy-1-methyl-1-trifluoromethylisochroman]
(16.9 g, 52%, 83% ee).
1H NMR (CDCl3): 10.41 (s, 1H), 7.82 (s, 1H), 6.77 (s, 1H), 4.24–
3.82 (m, 2H), 3.94 (s, 3H), 3.02–2.80 (m, 2H), 1.68 (d, J = 1.2 Hz,
3H).
The filtrate was concentrated in vacuo, and the residual solid
was purified by column chromatography on silica-gel with hex-
ane/ethyl acetate (10:1–3:1). The first fraction afforded the com-
pound 33 (5.24 g, 14.2%) as a yellow crystalline solid.
1H NMR (CDCl3): 10.63 (s, 1H), 7.55 (d, J = 8.9 Hz, 1H), 6.94 (d,
J = 8.9 Hz, 1H), 4.13–3.80 (m, 2H), 3.94 (s, 3H), 3.28–3.19 (m, 2H),
1.66 (s, 3H).
The 1H NMR (CDCl3) spectra of these compounds was identical
with those of racemates 28 and 30.
The second fraction afforded a mixture containing 1-methyl-1-
trifluoromethyl-3-methyl-5-methoxy-1,3-dihydroisobenzofuran-
aldehyde (impurity-1) eluting with hexane/ethyl acetate (10:1–
7:1) as a pale yellow crystalline solid (total 2 g, maximum 5.4%
yield as impurity-1).
6.1.3. (1R)-6-Hydroxy-1-methyl-1-trifluoromethylisochroman
(31)
To a stirred mixture of compound 29 (35.5 g, 0.129 mol), meth-
anol (860 mL), and water (340 mL) was added potassium carbonate
(35.7 g, 0.258 mol) at 0 °C, then the mixture was stirred at room
temperature for 1 h. The resultant mixture was acidified with
2 M hydrochloric acid to pH 3 and evaporated in vacuo to remove
the methanol. The residue was extracted with ethyl acetate. The
organic layer was washed with water and brine, and dried over
magnesium sulfate. After filtration, the filtrate was concentrated
1H NMR (CDCl3): 10.44 (s, 1H), 7.77 (s, 1H), 6.88 (s, 1H), 5.44 (q,
J = 6.4 Hz, 1H), 3.98 (s, 3H), 1.69 (d, J = 1.0 Hz, 3H), 1.56 (d,
J = 6.4 Hz, 3H).
The third fraction, eluting with hexane/ethyl acetate (7:1–3:1),
afforded the desired compound 34 (7.44 g, 20%) as a yellow crystal-
line solid, which was recrystallized from ethyl acetate/hexane
(1:10) to give the pure compound (6.00 g, 16.2%) as a yellow crys-
talline solid.

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Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
6.1.6. (2S,3S)-3-[(1R)-6-Methoxy-1-methyl-1-trifluoromethyli-
sochroman-7-yl]methylamino-2-phenylpiperidine ((+)-1)ꢁ
dihydrochloride
6.1.7.2. 5-Methoxy-1-methyl-1-trifluoromethyl-1,3-dihydro-
isobenzofuran (39). To a stirred solution of compound 38 (13.8 g,
59 mmol) in a mixture of dry tetrahydrofuran (330 mL) and hexane
(110 mL) was added n-butyllithium (37.2 mL, 62 mmol) in hexane
dropwise over 30 min at ꢀ100 °C under nitrogen, and the reaction
mixture was stirred at ꢀ100 °C for 2.5 h. Then, to the mixture was
added a solution of 1,1,1-trifluoroacetone (6.3 mL, 71 mmol) dis-
solved in dry tetrahydrofuran (15 mL) and hexane (5 mL) dropwise
at the same temperature, and the resulting mixture was allowed to
elevate to ꢀ30 °C. This was quenched with water, and the solvent
was removed by evaporation. The residue was extracted with hex-
ane. The organic extracts were dried over magnesium sulfate, and
concentrated to give the crude product as a light yellow oil (13.6 g).
The crude product (13.6 g), glycine (575 mg, 7.66 mmol) and
potassium hydroxide (703 mg, 12.5 mmol) were dissolved in a
mixture of ethanol (30 mL) and water (20 mL), and stirred at reflux
for 2 h. After cooling, the reaction mixture was diluted with brine,
and extracted with hexane. The organic extracts were dried over
magnesium sulfate, and concentrated by evaporation to afford a
light yellow oil (12.6 g), which was purified by distillation (bp
94–98 °C/1.5 mm Hg) to give the title compound 39 as a colorless
oil (10.8 g, 78.7%).
To a stirred solution of (2S,3S)-3-amino-2-phenylpiperidine
(16.0 g, 90.8 mmol) and compound 34 (24.9 g, 90.8 mmol) in
anhydrous dichloromethane (850 mL) was added sodium triacet-
oxyborohydride (38.5 g, 181.5 mmol) portionwise under nitrogen
at ambient temperature. The reaction mixture was stirred at the
same temperature for 20 h. The reaction mixture was made basic
to pH > 10 with 2 M sodium hydroxide aqueous solution with
ice-cooling and stirred at room temperature for 30 min. The or-
ganic layer was separated and the aqueous layer was extracted
with dichloromethane (3ꢂ 300 mL). The combined organic layers
were washed with brine, dried over magnesium sulfate, and con-
centrated in vacuo to give crude product (40.2 g) as a white vis-
cous oil. H NMR of the crude mixture indicated contamination
with dialkylated compound at N-1 on the piperidine ring of
compound (+)-1 in a ratio of compound-1/dialkyl derivative = ca.
20:1 as determined by 1H NMR. To a solution of the crude oil
(40.2 g) in methanol (250 mL) was added 10% HCl/methanol
(1000 mL). The solvent was removed, and the residue was di-
luted with dry methanol (800 mL) and heated at 110 °C (bath
temperature) for 13 h. The solvent was concentrated to a volume
of ca. 500 mL, and cooled to room temperature. The white crys-
talline solid was filtered to give the compound (+)-1ꢁdihydro-
chloride (35.5 g, 77.7%).
1H NMR (CDCl3): d 7.20 (d, J = 8.4 Hz, 1H), 6.87 (dd, J = 8.4,
2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 5.21–5.09 (m, 2H), 3.82 (s,
3H), 1.65 (d, J = 1.1 Hz, 3H).
Mp 257–258 °C.
6.1.7.3. 3-Methyl-3-trifluoromethyl-6-methoxy-1,3-dihydrois-
obenzofuran-5-carbaldehyde (40). To a stirred solution of com-
pound 38 (10.8 g, 46 mmol) in dry dichloromethane (280 mL)
was added titanium(IV) chloride (11.2 mL, 102 mol) dropwise un-
der nitrogen at ꢀ78 °C, and the resulting solution was stirred for
MS (ESI): m/z 435 (M+H)+ [Quattro-II triplequadrupole mass
spectrometer].
1H NMR (free base, CDCl3): d 7.35–7.17 (m, 5H), 6.95 (s, 1H),
6.44 (s, 1H), 4.17–4.05 (m, 1H), 3.95–3.82 (m, 2H), 3.62 (d,
J = 14.0 Hz, 1H), 3.51 (s, 3H), 3.34 (d, J = 14.0 Hz, 1H), 3.34–3.22
(m, 1H), 2.88–2.72 (m, 4H), 2.15–1.80 (m, 4H), 1.70–1.52 (m,
1H), 1.59 (d, J = 0.8 Hz, 3H), 1.48–1.35 (m, 1H).
15 min.
A solution of dichloromethyl methyl ether (8.4 mL,
0.093 mol) in dry dichloromethane (20 mL) was added to the
resulting brown solution at ꢀ78 °C, and stirred for 1.5 h. This mix-
ture was poured into ice-water, and stirred at ambient tempera-
ture for 30 min. The organic layer was separated, and the
aqueous layer was extracted with dichloromethane. The combined
organic extracts were washed with brine, dried over magnesium
sulfate, and concentrated to afford the title compound 40 as a light
yellow crystalline solid (12.1 g, quant.).
13C NMR (free base, CDCl3): 157.1, 142.3, 134.7, 128.2 (2
carbons), 127.7, 127.1, 126.7, 126.4 (2carbons), 126.0, 124.0,
109.9, 76.0, 64.1, 61.4, 55.0, 54.9, 47.7, 46.6, 29.2, 28.5, 23.3,
20.2.
X-ray crystallography: the stereochemistry at 1-position on the
isochroman (Me, CF3) was determined by X-ray crystallography to
be as shown in the chemical structure.
1H NMR (CDCl3): d 10.45 (s, 1H), 7.79 (s, 1H), 6.88 (s, 1H), 5.25–
5.13 (m, 2H), 3.97 (s, 3H), 1.68 (m, 3H).
Optical rotation: ½a D27
ꢃ
+75.44° (c 0.424, methanol).
Elementary Anal. Calcd for C24H29F3N2O2ꢁ2HCl: C, 56.81%; H,
6.16%; N, 5.22%; F, 11.23%; Cl, 13.97%. Found: C, 56.76%; H,
6.16%; N, 5.63%; F, 11.35%; Cl, 13.93%.
6.1.8. (2S,3S)-3-(6-Methoxy-3-methyl-3-trifluoromethyl-1,3-
dihydroisobenzofuran-5-yl)methylamino-2-phenylpiperidine
(15)ꢁdihydrochloride
6.1.7. (2S,3S)-3-(6-Methoxy-3-methyl-3-trifluoromethyl-1,3-
dihydroisobenzofuran-5-yl)methylamino-2-phenylpiperidine
(15)ꢁdihydrochloride
To a stirred solution of (2S,3S)-2-phenyl-3-aminopiperidine
(4.1 g, 23.1 mmol) which was prepared by a method described in
WO 92/17,449 and compound 40 (6.1 g, 23.3 mmol) in dry dichlo-
romethane (200 mL) was added sodium triacetoxyborohydride
(7.8 g, 36.9 mmol) portionwise under nitrogen at ambient temper-
ature, and the resultant mixture was stirred at the same tempera-
ture for 16 h. The pH was adjusted to below 10 with a saturated
aqueous sodium bicarbonate solution, and extracted with dichlo-
romethane. The extracts were dried over magnesium sulfate, and
concentrated to afford to a light yellow amorphous solid (10.1 g).
A methanolic HCl solution was added to the crude products dis-
solved in ethyl acetate. Formed solids were collected by filtration,
dried under vacuum, and purified by crystallization from methanol
to afford the title compound as a white crystalline solid; mp 200–
207 °C.
6.1.7.1. 2-Bromo-5-methoxybenzyl chloride (38). To a stirred
solution of 3-methoxybenzyl chloride (37.2 g, 0.238 mol) and
pyridine (23.1 mL, 0.286 mol) dissolved in dry dichloromethane
(400 mL) was added bromine (23.1 mL, 0.88 mol) at 0 °C. The
resulting mixture was stirred at 0 °C for 1 h, then at ambient
temperature for 18 h. This was diluted with a saturated aqueous
solution of sodium thiosulfate, and extracted with dichlorometh-
ane. The combined extracts were washed with brine, sequen-
tially. The extracts were dried over magnesium sulfate, and
concentrated to give a crude product as a slightly yellow crystal-
line solid. This solid was taken up in ethyl acetate, and the pre-
cipitate was filtered. The filtrate was washed, and concentrated
to give a slightly yellow crystalline solid, which was washed
with hexane to afford the title compound 38 (43 g, 77%) as a
white solid.
1H NMR (major isomer, free amine, CDCl3): d 7.31–7.21 (m, 5H),
6.89 (s, 1H), 6.54 (s, 1H), 5.16–5.04 (m, 2H), 3.90 (d, J = 2.3 Hz, 1H),
3.68 (d, J = 14.3 Hz, 1H), 3.52 (s, 3H), 3.40 (d, J = 14.3 Hz, 1H), 3.29–
3.26 (m, 1H), 2.85–2.75 (m, 2H), 2.14–2.09 (m, 1H), 1.95–1.86 (m,
1H NMR (CDCl3): d 7.44 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 3.3 Hz,
1H), 6.74 (dd, J = 8.8, 3.3 Hz, 1H), 4.64 (s, 2H), 3.79 (s, 3H).

Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
7203
1H), 1.66–1.54 (m, 1H), 1.60 (s, 3H), 1.44–1.40 (m, 1H). *NH (2 pro-
ton, not observed).
over magnesium sulfate and concentrated in vacuo to give the
crude product as a yellow oil, which was purified by column chro-
matography on silica-gel (40 g) with dichloromethane/methanol
(10:1–6:1) to give the title compound 12 (1.04 g, 86%) as a pale yel-
low viscous oil.
Analysis by 1H NMR indicated a diastereomeric ratio at the 3-
position of the dihydroisobenzofuran ring of 98:2 (3R/3S). The
absolute stereochemistry of the title compound 15 was determined
by X-ray crystallography to be that of the (3R) isomer after further
purification by recrystallization.
1H NMR (CDCl3, 270 MHz) d 7.33–7.17 (m, 5H), 6.95 and 6.90
(each s, total 1H), 6.56 and 6.53 (each s, total 1H), 3.89 (d,
J = 2.2 Hz, 1H), 3.66 and 3.64 (each d, J = 13.8 Hz, total 1H), 3.48
and 3.43 (each s, total 3H), 3.38 and 3.36 (each d, J = 13.8 Hz, total
1H), 3.33–3.22 (m, 1H), 3.05–2.72 (m, 4H), 2.55–2.42 (m, 1H),
2.20–1.80 (m, 5H), 1.70–1.52 (m, 1H), 1.42 (s, 3H), 1.43–1.35 (m,
1H).
6.1.9. (2S,3S)-3-(5-Methoxy-1-methyl-1-(trifluoromethyl)indane-
6-yl)methylamino-2-phenylpiperidine (12)ꢁdihydrochloride
6.1.9.1. 5-Methoxy-1-methyl-1-(trifluoromethyl)indane (48). To
a stirred solution of alcohol 44 (980 mg, 4.22 mmol) in dry dichloro-
methane (16 mL) was added titanium chloride (8.44 mmol, 926 lL)
via a syringe at ꢀ78 °C. After 1.5 h at the same temperature, to the
mixture was added a 1.0 M hexane solution of dimethylzinc
(16.9 mmol, 16.9 mL) at ꢀ78 °C. The reaction mixture was stirred
for 40 min at ꢀ78 °C, then warmed to ambient temperature and stir-
red for 5 h. The reaction mixture was poured into ice-water and fil-
tered through a pad of Celite. The filtrate and washings were washed
with brine, dried over sodium sulfate and concentrated in vacuo to
give the crude product as a yellow oil. The crude product was puri-
fied by column chromatography on silica-gel (30 g) eluting with
hexane/ethyl acetate (80:1) to give compound 48 (847 mg, 87%) as
a colorless oil.
6.1.11. (2S,3S)-3-(5-Methoxy-1-methyl-1-(trifluoromethyl)
indane-6-yl)methylamino-2-phenylpiperidine (12)ꢁdihydrochloride
The compound 12 (1.04 g) was treated with 10% hydrochloric
methanol solution (40 mL) at ambient temperature. After the sol-
vent was evaporated in vacuo, the residue was washed with hot
ethanol (two times) to give the title compound 12ꢁ2HCl (560 mg,
46%) as a white solid; mp 236–238 °C.
Elementary Anal. Calcd for C24H29F3N2Oꢁ2HCl: C, 58.66%; H,
6.36%; N, 5.70%. Found: C, 58.66%; H, 6.68%; N, 5.69%.
MS (ESI): m/z 419.4 (M+H)+.
1H NMR (CDCl3, 270 MHz) d 7.22 (d, J = 9.2 Hz, 1H), 6.80–6.75
(m, 2H), 3.79 (s, 3H), 3.08–2.83 (m, 2H), 2.57–2.46 (m, 1H), 2.02–
1.88 (m, 1H), 1.47 (s, 3H).
6.1.12. (2S,3S)-3-[((6-Methoxy-1-methyl-1-(trifluoromethyl)-1,
2,3,4-tetrahydronaphthalene)-7-yl)]methylamino-2-phenylpi-
peridine (19)ꢁdihydrochloride
6.1.9.2. 5-Methoxy-1-methyl-1-(trifluoromethyl)indane-6-car-
boxaldehyde (52). To a stirred solution of compound 48 (1.19 g,
5.16 mmol) in dry dichloromethane (30 mL) was added tita-
nium(IV) chloride (2.15 g ꢄ 1.25 mL, 11.35 mmol) via a syringe
at ꢀ78 °C with dry ice/methanol cooling. After 10 min, to this
was added a solution of dichloromethyl methyl ether (1.19 g,
10.32 mmol) in dry dichloromethane (5 mL) dropwise at the same
temperature and the reaction mixture was stirred at ꢀ78 °C for
5 h. The mixture was poured into ice-water and stirred at ambient
temperature for 10 min. The organic layer was separated and the
aqueous layer was extracted with dichloromethane (3ꢂ). The
combined solution was washed with brine, dried over magnesium
sulfate and concentrated in vacuo to give the crude product as a
yellow solid. The crude product was purified by column chroma-
tography on silica-gel with hexane/ethyl acetate (9:1–5:1–3:1)
to give the title compound 52 (1.13 g, 85%) as a white solid.
1H NMR (CDCl3, 270 MHz) d 10.41 (s, 1H), 7.79 (s, 1H), 6.87 (s,
1H), 3.93 (s, 3H), 3.19–2.88 (m, 2H), 2.63–2.50 (m, 1H), 2.06–1.90
(m, 1H), 1.50 (s, 3H).
6.1.12.1. 6-Methoxy-1-methyl-1-(trifluoromethyl)-1,2,3,4-tetra-
hydronaphthalene (49). To a stirred solution of compound 45
(2.25 g, 9.16 mmol) in anhydrous dichloromethane (35 mL) was
added titanium(IV) chloride (2.0 mL, 18.3 mmol) via a syringe
at ꢀ78 °C. After 2 h at same temperature, to this was added
1.0 M dimethylzinc solution in hexane (36.4 mL, 36.4 mmol) via
a syringe at ꢀ78 °C. The mixture was stirred at ꢀ78 °C for
40 min then allowed to warm to ambient temperature (addi-
tional 4 h). The mixture was poured into ice-water and stirred
for 10 min and extracted with dichloromethane (3ꢂ). The com-
bined extracts were washed with brine, dried over magnesium
sulfate and concentrated in vacuo to give the crude product,
which was purified by column chromatography on silica-gel
(250 g) eluting with hexane only to give compound 49 (2.07 g,
92%) as a colorless oil.
1H NMR (CDCl3, 270 MHz) d 7.41 (d, J = 9.2 Hz, 1H), 6.76 (dd,
J = 9.2, 2.7 Hz, 1H), 6.63 (d, J = 2.7 Hz, 1H), 3.78 (s, 3H), 2.82–2.72
(m, 2H), 2.21–2.08 (m, 1H), 2.04–1.87 (m, 1H), 1.80–1.64 (m,
2H), 1.48 (s, 3H).
6.1.10. (2S,3S)-3-(5-Methoxy-1-methyl-1-(trifluoromethyl)-
indane-6-yl)methylamino-2-phenylpiperidine (12)
6.1.12.2. 6-Methoxy-1-methyl-1-(trifluoromethyl)-1,2,3,4-tetra-
hydronaphthalene-7-carbaldehyde (53). To a stirred solution of
compound 49 ( 1.61 g, 6.58 mmol) in anhydrous dichloromethane
(50 mL) was added titanium(IV) chloride (1.59 mL, 14.48 mmol)
via a syringe at ꢀ78 °C. After 10 min to this was added dichlorom-
ethyl methyl ether (1.51 g, 13.2 mmol) at the same temperature.
After 3 h at ꢀ78 °C, the mixture was diluted with water and stir-
red at ambient temperature for 15 min. The mixture was ex-
tracted with dichloromethane (3ꢂ) and the combined solution
was washed with brine, dried over magnesium sulfate and con-
centrated in vacuo to give the crude product, which was purified
by column chromatography on silica-gel (120 g) eluting with hex-
ane/ethyl acetate (5:1–3:1) to give compound53 (713 mg, 40%) as
a white solid.
To a stirred solution of (2S,3S)-tert-butyl 3-amino-2-phenylpi-
peridine-1-carboxylate (800 mg, 2.89 mmol) in dry dichlorometh-
ane (60 mL) added compound 52 (897 mg, 3.47 mol) and sodium
triacetoxyborohydride (1.23 g, 5.78 mmol) in one portion at ambi-
ent temperature. After 2 h at ambient temperature, the reaction
mixture was made basic to pH > 10 with 2 M sodium hydroxide
solution with ice-cooling. The aqueous layer was extracted with
dichloromethane and the combined organic phases were washed
with brine, dried over magnesium sulfate and concentrated in va-
cuo to give the crude product (1.60 g) as a white viscous oil. Then,
to a solution of the crude product (1.60 g) in ethyl acetate (45 mL)
was added conc. hydrochloric acid solution (4.5 mL) at room tem-
perature. After 1.5 h, the mixture was made basic to pH > 10 with
2 M sodium hydroxide solution with ice-cooling. The organic layer
was separated and the aqueous solution was extracted with ethyl
acetate (2ꢂ). The combined extracts were washed with brine, dried
1H NMR (CDCl3, 270 MHz) d 10.38 (s, 1H), 7.97 (s, 1H), 6.71 (s,
1H), 3.91 (s, 3H), 2.96–2.72 (m, 2H), 2.27–2.10 (m, 1H), 2.09–1.90
(m, 1H), 1.83–1.65 (m, 2H), 1.51 (s, 3H).

7204
Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
6.1.13. (2S,3S)-3-[((6-Methoxy-1-methyl-1-(trifluoromethyl)-
1,2,3,4-tetrahydronaphthalene)-7-yl)]methylamino-2-phenylpi-
peridine (19)
To a stirred solution of (2S,3S)-tert-butyl 3-amino-2-phenylpi-
peridine-1-carboxylate (250 mg, 0.91 mmol) in dry dichlorometh-
ane (20 mL) and compound 53 (296 mg, 1.09 mol) was added
sodium triacetoxyborohydride (384 mg, 1.81 mmol) in one portion
at ambient temperature. The same procedure as described in com-
pound 12 was performed to give the compound 19 (367 mg, 94%)
as a pale yellow viscous oil.
product as a yellow oil, which was purified by column chromatog-
raphy on silica-gel with dichloromethane/methanol (20:1–10:1) to
give the compound 4 (83 mg, 80% in two steps).
1H NMR (CDCl3, 270 MHz) d 7.32–7.16 (m, 6H), 7.15–7.09 (m,
1H), 6.65 (d, J = 8.8 Hz, 1H), 3.88 (d, J = 2.2 Hz, 1H), 3.67 (d,
J = 13.9 Hz, 1H), 3.48 (s, 3H), 3.39 (d, J = 13.9 Hz, 1H), 3.32–3.22
(m, 1H), 2.86–2.72 (m, 2H), 2.18–2.06 (m, 1H), 2.00–1.80 (m, 3H),
1.69–1.36 (m, 2H), 1.49 (s, 6H).
6.1.16. (2S,3S)-3-[5-(1,1-Dimethyl-2,2,2-trifluoroethyl)-2-methoxy-
benzylamino]-2-phenylpiperidine (4)ꢁdihydrochloride
Compound 4 (80 mg) was treated with 10% hydrochloric meth-
anol solution (30 mL). After the solvent was evaporated in vacuo,
the residue was recrystallized from ethanol/diethyl ether to give
compound 4ꢁ2HCl (73 mg, 77%) as a white solid; mp 225–226 °C.
Anal. Calcd for C23H29F3N2Oꢁ2HCl: C, 57.62%; H, 6.52%; N, 5.84%.
Found: C, 57.65%; H, 6.86%; N, 5.72%.
1H NMR (CDCl3, 270 MHz) d 7.35–7.15 (m, 5H), 7.13 and 7.09
(each s, total 1H), 6.39 and 6.36 (each s, total 1H), 3.89 (d,
J = 2.2 Hz, 1H), 3.70 and 3.61 (each d, J = 13.6 Hz, total 1H), 3.46
and 3.40 (each s, total 3H), 3.35 (d, J = 13.6 Hz, 1H), 3.35–3.22
(m, 1H), 2.90–2.65 (m, 4H), 2.35–1.82 (m, 6H), 1.80–1.52 (m,
3H), 1.43 (s, 3H), 1.50–1.35 (m, 1H).
6.1.14. (2S,3S)-3-[((6-Methoxy-1-methyl-1-(trifluoromethyl)-
1,2,3,4-tetrahydronaphthalene)-7-yl)]methylamino-2-phen-
ylpiperidine (19)ꢁdihydrochloride
MS (API): m/z 407.0 (M+H)+.
6.1.17. (2S,3S)-3-[2-Methoxy-5-(2,2,2-trifluoroethyl)benzylamino]-
2-phenylpiperidine (2)
Compound 19 (360 mg) was treated with 10% hydrochloric
methanol solution (40 mL) at ambient temperature. After the sol-
vent was evaporated in vacuo, the residue was recrystallized from
ethanol to give compound 19ꢁ2HCl (220 mg, 52.3%) as a white so-
lid; mp 235–237 °C.
1H NMR (CDCl3, 270 MHz) d 7.35–7.20 (m, 5H), 7.06 (dd, J = 8.4,
1.8 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 3.90 (d,
J = 2.2 Hz, 1H), 3.68 (d, J = 14.3 Hz, 1H), 3.49 (s, 3H), 3.42 (d,
J = 14.3 Hz, 1H), 3.35–3.24 (m, 1H), 3.20 (q, J = 11.0 Hz, 2H), 2.88–
2.73 (m, 2H), 2.20–1.85 (m, 4H), 1.68–1.52 (m, 1H), 1.50–1.37
(m, 1H).
Diastereomer ratio: R/S = 3:1.
Anal. Calcd for C25H31F3N2Oꢁ2HCl: C, 59.41%, H, 6.58%; N, 5.54%.
Found: C, 59.17%; H, 6.88%; N, 5.50%. MS (API): m/z 433.2 (M+H)+.
The filtrate was evaporated in vacuo and the residue was
recrystallized from ethanol/ether to give compound 20ꢁ2HCl
(150 mg, 35.7%) as a white solid; mp 221–223 °C.
Diastereomer ratio: R/S = 1:5.
Compound 2ꢁ2HCl: mp 209–210 °C.
Anal. Calcd for C21H25F3N2Oꢁ2HCl: C, 55.88%; H, 6.03%; N, 6.21%.
Found: C, 55.52%; H, 6.21%; N, 6.10%.
MS (EI): m/z 378 (M+).
Anal. Calcd for C25H31F3N2Oꢁ2HClꢁ2H2O: C, 58.99%; H, 6.61%; N,
5.50%. Found: C, 58.73%; H, 6.50%; N, 5.38%. MS (API): m/z 433.2
(M+H)+.
Acknowledgments
The authors thank Drs. Masami Nakane (Pfizer Global R&D, Na-
goya), R. Scott. Obach (Pfizer Global R&D, Drug Metabolism Depart-
ment, Groton) and Amano enzyme for providing helpful advice. In
addition, Dr. Seiji Nukui and Mr. Tatsuya Yamagishi contributed
significantly to the efforts in the cyclization reaction to isochroman
and the kinetic resolution by lipase-PS in the bulk synthesis of
optically active compound (+)-1, respectively.
6.1.15. (S,3S)-3-[5-(1,1-Dimethyl-2,2,2-trifluoroethyl)-2-methoxy-
benzylamino]-2-phenylpiperidine (4)ꢁdihydrochloride
6.1.15.1. 5-(1,1-Dimethyl-2,2,2-trifluoroethyl)-2-methoxybenz-
aldehyde. 1-Methoxy-4-(2,2,2-trifluoro-1,1-dimethylethyl)ben-
zene11 (1.45 g, 6.64 mmol) was converted to the aldehyde deriv-
ative using the same procedure as with compound 52. The product
was purified by column chromatography on silica-gel with hex-
ane/ethyl acetate (40:1–20:1) to give the title compound (1.49 g,
81%) as a pale yellow solid.
References and notes
1. (a) Gale, J. D.; O’Neill, B. T.; Humphrey, J. M. Expert Opin. Ther. Patents 2001, 11,
1837; (b) Lecci, A.; Maggi, C. A. Expert Opin. Ther. Target 2003, 7, 342; (c) Albert,
J. S. Expert Opin. Ther. Target 2004, 14, 1421.
2. Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski, S.; Ber,
E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.; Eirmann, G.; Tsou, N. N.; Tattersall, F.
D.; Rupniak, N. M. J.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D.
E. J. Med. Chem. 1998, 41, 4607.
1H NMR (CDCl3, 270 MHz) d 10.47 (s, 1H), 7.95 (d, J = 2.6 Hz,
1H), 7.75–7.65 (m, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H), 1.57
(s, 6H).
6.1.15.2. (2S,3S)-3-[5-(1,1-Dimethyl-2,2,2-trifluoroethyl)-2-me-
thoxybenzylamino]-2-phenylpiperidine (4). To a stirred solu-
tion of (2S,3S)-tert-butyl 3-amino-2-phenylpiperidine-1-carboxyl-
ate (71 mg, 0.256 mmol) in dry dichloromethane (6 mL) and 5-
(1,1-dimethyl-2,2,2-trifluoroethyl)-2-methoxybenzaldehyde (75 mg,
0.31 mol) was added sodium triacetoxyborohydride (109 mg,
0.51 mmol) in one portion at ambient temperature. The same pro-
cedure as described in compound 19 was performed to give the
N-Boc derivative (128 mg, 94%) as a pale yellow viscous oil. To a
stirred solution of N-Boc derivative (128 mg) in ethyl acetate
(5 mL) was added concd HCl (0.7 mL) at ambient temperature.
The reaction mixture was stirred at ambient temperature for 1 h
and the mixture was made basic to pH > 10 with 10% sodium
hydroxide aqueous solution with ice-cooling. The organic layer
was separated and the aqueous layer was extracted with ethyl ace-
tate (3ꢂ). The combined solution was washed with brine, dried
over magnesium sulfate and concentrated in vacuo to give crude
3. Ito, F.; Kondo, H.; Shimada, K.; Nakane, M.; Lowe III, J. A.; Rosen, T. J.; Yang, B. V.
WO 9221677 A1.
4. (a) Snider, R. M.; Constantine, J. W.; Lowe, J. A.; Longo, K. P.; Label, W. S.;
Woody, H. A.; Drozda, S. E.; Desai, M. C.; Vinick, F. J.; Spencer, R. W.; Hess, H.-J.
Science 1991, 251, 435; (b) Mclean, S.; Ganong, A.; Seeger, T.; Bryce, D.; Pratt, K.;
Reynolds, L.; Siok, C.; Low, J.; Heym, J. Science 1991, 251, 437.
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T.; Liang, K.; Middlemiss, D.; Mordaunt, J.; Naylor, A.; Pegg, N. A.; Vinader, P.
M.; Watson, S. P.; Bountra, C.; Evans, D. C. J. Med. Chem. 1995, 38, 4985.
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Obach, R. S.; Margolis, J. M.; Logman, M. J. Drug Metab. Pharmacokinet 2007, 22,
336.
7. Process research of CJ-17493: Caron, S.; Do, N. M.; Sieser, J. E.; Arpin, P.;
Vazquez, E. Org. Process Res. Dev. 2007, 11, 1015.
8. (a) O-Demethylation of CP-122,71: the ‘first step major metabolite’ exhibits a
Km value of 0.24 in human liver microsomes, while the two major metabolites
of CJ-11974 exhibit Km values of 80 and 88 lM in the metabolic pathway by
human liver microsomes; detailed data of CP-122,721: Ref. 6(b); detailed data
of CJ-11,974.; (b) Obach, R. S. Drug Metab. Dispos. 2000, 28, 1069.
9. Takashima, T.; Murase, S.; Iwasaki, K.; Shimada, K. Drug Metab. Pharmacokinet
2005, 20, 177.

Y. Shishido et al. / Bioorg. Med. Chem. 16 (2008) 7193–7205
7205
10. (a) Enzymes were kindly supplied by Amano enzyme. Lipase AY (Candida
rugosa), CHE (Cholesterol esterase), lipase AH (Pseudomonas, sp.), lipase PS
(Pseudomonas sp.).; (b) It was difficult to obtain the exact enantiomeric excess
of compound 29. After deacetylation, the enantiomeric excess of optical phenol
31 was analyzed by HPLC using a DICEL CHIRALCEL OJ column (4.6 ꢂ 250 mm),
No. 45-04-90412, eluent; hexane/isopropanol (95:5), flow rate: 1 mL/min,
11. Mizuguchi, E.; Takemoto, M.; Achiwa, K. Tetrahedron: Asymmetry 1993, 4,
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