Preparation of (S)-4-(1-(3,4-dichlorophenyl)-2-methoxyethyl)piperidine

Article abstract of DOI:10.1016/j.tetasy.2015.06.021

Abstract The novel triple reuptake inhibitor (S)-4-(1-(3,4-dichlorophenyl)-2-methoxyethyl)piperidine monohydrochloride 1 possesses a unique 2-phenyl-2-(piperidin-4-yl)ethanol moiety with a stereogenic center at the benzyl position. To synthesize 1 as the (S)-isomer, three possible routes were investigated; (1) the lipase-catalyzed kinetic resolution of tert-butyl 4-(1-(3,4-dichlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate 2 utilizing PS-IM from Pseudomonas sp. as the lipase; (2) the asymmetric hydrogenation of tert-butyl 4-(1-(3,4-dichlorophenyl)-2-oxoethyl)piperidine-1-carboxylate 5 utilizing dynamic kinetic resolution; and (3) the resolution of racemic [1-(tert-butoxycarbonyl)piperidin-4-yl](3,4-dichlorophenyl)acetic acid 8 with (S)-phenylethylamine. The design of the asymmetric reaction using retrosynthesis, as well as the extensive exploration of enzymes, asymmetric hydrogenation catalysts, and resolving reagents, were all important to afford the optically active compound 1 in excellent yield.

Full text of DOI:10.1016/j.tetasy.2015.06.021

Tetrahedron: Asymmetry 26 (2015) 935–942
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Preparation of (S)-4-(1-(3,4-dichlorophenyl)-2-
methoxyethyl)piperidine
a
a
a
a
Masayuki Yamashita a, , Naohiro Taya , Mitsuyoshi Nishitani , Katsuaki Oda , Tetsuji Kawamoto ,
⇑
Eiji Kimura b, Yuji Ishichi b, Jun Terauchi b, Toru Yamano a
a Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company Limited, 2-17-85, Juso-honmachi, Yodogawa-ku, Osaka 532-8686, Japan
b CNS DDU, Takeda Pharmaceutical Company Limited, 2-17-85, Juso-honmachi, Yodogawa-ku, Osaka 532-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The novel triple reuptake inhibitor (S)-4-(1-(3,4-dichlorophenyl)-2-methoxyethyl)piperidine monohy-
drochloride 1 possesses a unique 2-phenyl-2-(piperidin-4-yl)ethanol moiety with a stereogenic center
at the benzyl position. To synthesize 1 as the (S)-isomer, three possible routes were investigated; (1)
Received 1 June 2015
Accepted 29 June 2015
Available online 23 July 2015
the
lipase-catalyzed
kinetic
resolution
of
tert-butyl
4-(1-(3,4-dichlorophenyl)-2-hydrox-
yethyl)piperidine-1-carboxylate 2 utilizing PS-IM from Pseudomonas sp. as the lipase; (2) the asymmetric
hydrogenation of tert-butyl 4-(1-(3,4-dichlorophenyl)-2-oxoethyl)piperidine-1-carboxylate 5 utilizing
dynamic kinetic resolution; and (3) the resolution of racemic [1-(tert-butoxycarbonyl)piperidin-4-
yl](3,4-dichlorophenyl)acetic acid 8 with (S)-phenylethylamine. The design of the asymmetric reaction
using retrosynthesis, as well as the extensive exploration of enzymes, asymmetric hydrogenation cata-
lysts, and resolving reagents, were all important to afford the optically active compound 1 in excellent
yield.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
(3,4-dichlorophenyl)-2-methoxyethyl)piperidine monohydrochlo-
ride 1, which was created as a candidate novel antidepressant
Depression is a common mental disease, characterized by sad-
ness, loss of interest in activities, and decreased energy, which
affects more than 350 million people worldwide.1 Among the
numerous hypotheses put forward for the mechanism of depres-
sion, the monoamine hypothesis is one of the most prominent.
Currently, many drugs based on the monoamine hypothesis are
widely used, such as the tricyclic antidepressants, selective sero-
tonin reuptake inhibitors, and serotonin noradrenaline reuptake
inhibitors. As an extension of the hypothesis, ‘triple reuptake inhi-
bitors’, which inhibit the reuptake of serotonin, norepinephrine,
and dopamine, have emerged as broad-spectrum antidepressants.
Triple reuptake inhibitors are expected to show high efficacy,
including for the refractory population and those in remission,
with less side effects of sexual dysfunction, and early onset of
action.2
agent after extensive optimization efforts. The identification of a
more potent stereoisomer of 1 using a mice tail suspension test,
and the determination of its absolute configuration by X-ray single
crystal structure analysis, revealed that the potent isomer has an
(S)-configuration4 (Fig. 1).
MeO
Cl
.HCl
NH
Cl
Figure 1. The structure of triple reuptake inhibitor 1.
Our primary concept was to synthesize the enantiomerically
pure compound 1 by appropriately designing a substrate, selecting
reagents, and optimizing the reaction conditions and/or proce-
dures. The design of the substrate was conducted based on a ret-
rosynthesis approach, as depicted in Figure 2.
Optically active 2-phenyl-2-substituted ethanol derivatives are
common structural motifs found in a variety of active pharmaceu-
tical ingredients, such as the serotonin–norepinephrine reuptake
inhibitor EffexorXR3 and the triple reuptake inhibitor (S)-4-(1-
Various synthetic methods, such as asymmetric epoxidation,
asymmetric hydrogenation, diastereomeric salt resolution, enzy-
matic resolution, chiral pool synthesis, and optical resolution using
preparative HPLC, were all worth considering to effectively obtain
⇑
Corresponding author. Tel.: +81 6 6300 6561; fax: +81 6 6300 6251.
E-mail address: masayuki.yamashita@takeda.com (M. Yamashita).
http://dx.doi.org/10.1016/j.tetasy.2015.06.021
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

936
M. Yamashita et al. / Tetrahedron: Asymmetry 26 (2015) 935–942
MeO
HO
HO
Cl
Cl
Cl
Cl
Cl
Cl
enzymatic resolution
.HCl
NH
NBoc
NBoc
1
asymmetric hydrogenation
utilizing Dynamic kinetic resolution
O
O
Cl
Cl
deracemization
NBoc
NBoc
Cl
Cl
CO2H
CO2H
Cl
Cl
diastereomeric salt resolution
NBoc
NBoc
Cl
Cl
Figure 2. The design of substrates via a retrosynthetic approach.
optically active 2-phenyl-2-substituted ethanol derivatives.
Among them, three key methods, enzymatic resolution, asymmet-
ric hydrogenation, and diastereomeric salt resolution, were
selected in anticipation of scale-up synthesis.
diatomite (Amano Enzyme Inc.) gave an efficient E-value of 243
(Table 1, entry 7). Considering the availability of the lipases as well
as the conversions and selectivity, we selected lipase PS-IM
(Amano enzyme) for further optimization and scale-up synthesis.
The solubility of compound 2 and the results of the reaction in
various solvents are summarized in Table 2. Among the solvents
tested, diisopropyl ether (IPE) gave the highest E-value for esterifi-
cation (Table 2, entry 1). Although the solubility of compound 2 in
IPE is moderate, the excellent E-value encouraged us to choose IPE
as the solvent. The addition of acetone as a co-solvent was an
attractive idea to improve the solubility and obtain high enan-
tiomeric excess, but feasibility trials indicated that acetone inhib-
ited the progress of the reaction.
Preliminary optimization of the reaction on a 10 g scale synthe-
sis showed that the reaction rate dropped drastically after forty
hours. It was surmised that the major reason for this decrease in
the reaction rate was that the lipase becomes deactivated when
the essential water from it is withdrawn by the hygroscopic nature
of the organic solvent.8 However, it was then found that a stepwise
addition of lipase and vinyl acetate could keep the high reaction
rate with an excellent E-value.
Enzymatic resolution has attracted much attention due to its
ability for stereo-recognition, which enables enantiomerically pure
compounds such as alcohols and amino acids to be prepared.5 This
method is also advantageous for green chemistry because of the
reduced use of metal catalysts and the formation of by-products.
Asymmetric hydrogenation is also an attractive and straightfor-
ward technique to obtain enantiomerically enriched compounds
due to the fact that there is little wasted substrate, and it was envi-
sioned that recent advancements in the design of substrates with
good anchor groups for metals and ligand selection might enable
us to synthesize optically active 2-phenyl-2-substituted ethanol
derivatives with both high enantioselectivity and yield.
Resolution via diastereomeric salt formation is still a useful
technique on an industrial scale, since it is generally simple, clean,
and easy to reproduce laboratory-scale data on an industrial scale.
In fact, many chiral drugs on the pharmaceutical market are pro-
duced by the diastereomeric salt formation method using resolving
reagents.6
After the enzymatic resolution, compound 3 was isolated by a
simple extraction work-up using sulfur trioxide pyridine in 96%
ee with 98% purity.9 Hydrolysis of the acetyl group followed by
methylation, according to the established method, afforded com-
pound 14 (Scheme 1).
Herein we describe the process for establishing an efficient
synthetic method to afford the novel triple reuptake inhibitor
(S)-4-(1-(3,4-dichlorophenyl)-2-methoxyethyl)piperidine monohydro-
chloride 1.
2.2. Asymmetric hydrogenation
2. Results and discussion
2.1. Enzymatic resolution
Next, we investigated an asymmetric hydrogenation reaction to
obtain compound 1. A great deal of effort has been devoted to the
development of efficient and potent chiral ligands for use in asym-
metric hydrogenation.10 To elicit high performance from these
sophisticated ligands, it is necessary to design substrates with suit-
able anchor groups, which enable the substrate to chelate to a
metal, adjacent to the desired stereogenic center.11 Thus, we were
encouraged to investigate the synthesis of 1 via asymmetric hydro-
genation using dynamic kinetic resolution, considering structures
with a stereogenic center at the benzylic position, which can read-
ily be epimerized by bases. As a catalyst system, we investigated
Ru-diphosphine–diamine, which is widely utilized for the
Enzymatic resolution in a later step can be beneficial to mini-
mize the chance for racemization. Furthermore, it has been
reported that lipases are able to resolve primary alcohols.7 These
facts encouraged us to investigate the enzymatic resolution of
compound 2,4 which was a straightforward substrate for the syn-
thesis of compound 1. A preliminary enzyme screen was conducted
using 38 lipases; those with an E-value of over 10 are shown in
Table 1.
As a result, lipases from Pseudomonas sp. were found to have a
high potential for resolution (Table 1, entries 5–9), and lipase PS on

M. Yamashita et al. / Tetrahedron: Asymmetry 26 (2015) 935–942
937
Table 1
Enzyme screening for primary alcohol 2a
HO
AcO
HO
Cl
Cl
Cl
Cl
Cl
Cl
lipase, vinyl acetate
Isopropylether
+
NBoc
NBoc
NBoc
2
3
4
Ee (%)b
Conversion (%)b
E-value
Entry
Lipase
3
4
QLGc
73
91
76
92
98
97
94
89
81
>99
6
58
6
47
1
2
3
4
5
6
7
8
9
AHd
25
AH-Sd
56
11
14
23
52
53
55
45
>99
11
AK-20d
30
Pd
16
123
100
243
100
74
PSd
28
PS on diatomited
PS on Toyonited
PS-Cd
>99
>99
>99
a
Reaction conditions: 2 (1.0 mg), vinyl acetate (0.005 mL), lipase (5 mg) in solvent (IPE (1 mL)) at 35 °C for 24 h.
b Determined by HPLC analysis (CHIRALCEL OD-H column).
c Meito Sangyo Co., Ltd.
d Amano Enzyme Inc.
asymmetric hydrogenation of ketones and imines12 and also
dynamic kinetic resolution.13
2.3. Diastereomeric salts resolution
As shown in the Table 3, some Ru-diphosphine–diamine cata-
lysts gave high to moderate enantiomeric excesses and chemical
yields.
Finally, we devoted our efforts to the diastereomeric salt resolu-
tion of compound 8.4 To make the resolution highly attractive both
in terms of the yield and cost, we carefully conducted the
screening of different resolving reagents. A preliminary screening
of 28 resolving reagents indicated that (+)-dehydroabietyl amine
(82% ee), (S)-phenylethylamine (75% ee), quinine (12% ee), (R)-1-
(p-tolyl)ethylamine (54% ee), (S)-cyclohexylamine (26% ee),
(1R,2S)-cis-2-benzylamino-cyclohexanemethanol (28% ee) and
hydroquinine (22% ee) formed diastereomeric salts with consider-
able ee’s. Among them, (S)-phenylethylamine was chosen as a
promising resolving reagent due to it having some substructural
similarity with the substrate14 and, more importantly, its ready
availability.
Over the course of the optimization, we conducted solvent
screening; Table 5 shows that the enantiomeric excess of the salt
obtained from acetonitrile was up to 97% ee, with a moderate yield
(Table 5, entry 1). The volume of solvent is very important for
diastereomeric salt resolution, especially on an industrial scale.
In order to reduce the volume of solvent while keeping the high
enantiomeric excess, it was found that the addition of ethanol to
acetonitrile was effective (Table 5, entries 6 and 7).
For homogeneous ruthenium catalysts it has been shown that
the combination of diphosphines and diamines is critical to obtain
excellent enantiomeric excesses and chemical yields. Tuning the
structural and electronic properties of the diphosphines and diami-
nes is pivotal for the outcome of the reaction. In our case, the abso-
lute configuration of the diphosphines and the diamines is the key
to obtain high enantiomeric excess, while the structure of the dia-
mine ligands also seems to be important for the catalysts’ overall
performance (Table 3).
The fact that the yields exceed 50% with high enantiodiscrimi-
nation clearly indicates that epimerization of the substrate must
have occurred in the reaction, thus indicating dynamic kinetic res-
olution. As a result, we focused on the optimization of the reaction
conditions to improve the yields and ee’s.
The use of potassium tert-butoxide (t-BuOK) as
a base
was essential to the reaction (Table 4, entry 2 vs entry 3). Low
hydrogen pressure gave a low conversion (Table 4, entry 4) and
high reaction temperature did not affect the outcome of the
reaction (Table 4, entry 5). It was expected that additional investi-
gation would further improve the enantiomeric excesses and
chemical yields.
It has been reported that a hydrogen bond network exists in less
soluble diastereomeric salts,15 and that there would be a hydrogen
bond network between the carboxyl group at (S)-8 and the

938
M. Yamashita et al. / Tetrahedron: Asymmetry 26 (2015) 935–942
Table 2
Investigation of the reaction solventsa
HO
AcO
HO
Cl
Cl
Cl
Cl
Cl
Cl
PS-IM, vinyl acetate
Solvents
+
NBoc
NBoc
NBoc
2
3
4
Entry
Solvent
Solubility
(mg/mL)
Reaction time
(h)
Ee (%)b
Conversion (%)b
E-valueb
1
2
3
4
5
6
IPE
>25
24
48
48
48
24
40
98
98
93
92
48
7
525
178
37
66
THF
>300
>300
>100
>300
>100
Acetone
Acetonitirile
DMF
20
48
-
c
-
-
t-BME
91
52
107
a Reaction conditions: 2 (100 mg), vinyl acetate (2 equiv), PS-IM (10 mg)) in solvent (4 mL) at 35 °C.
b Determined by HPLC analysis (CHIRALCEL OD-H column).
c Not detected.
1. NaOH
2. MeI
AcO
MeO
HO
1. PS-IM
vinyl acetate
3. HCl
Cl
Cl
Cl
Cl
Cl
.HCl
NH
2. SO3-pyridine
NBoc
NBoc
Cl
3
1
2
96% ee, 98% purity
Scheme 1. Synthesis of 1 via enzymatic resolution.
amino group at (S)-phenylethylamine to form a 21-column. The
substructural similarity of compound 8 and phenylethylamine sug-
gests that van der Waals interactions between the 21-columns may
stabilize the diastereomeric salt.
retro-synthesis and the knowledge of resolution and asymmetric
synthesis, as well as screening for optimization, can lead to an
effective synthetic procedure for chiral compounds.
The robustness of the diastereomeric salt resolution method
was confirmed by a 612 g scale experiment, in which 97% ee with
41% yield was obtained. After recrystallization of the diastere-
omeric salt 9, 224 g of 9 were obtained successfully with >99.9%
ee. According to the established method,4 compound 1 was suc-
cessfully synthesized without any deterioration of the enan-
tiomeric excess (>99.9% ee) (Scheme 2).
4. Experimental
4.1. General
The proton nuclear magnetic resonance (1H NMR) spectra were
recorded on a Bruker AVANCE 300 (300 MHz) or Varian Gemini 200
(200 MHz) or Ultra-300spectrometer (300 MHz) or JEOL
JMTC0400/5 (400 MHz). Chemical shifts are given in d values
(ppm) using tetramethylsilane as the internal standard. Reactions
were followed by TLC on Silica gel 60 F 254 pre-coated TLC plates
(E. Merck) or NH TLC plates (Fuji Silysia Chemical Ltd).
Chromatographic separations were carried out on silica gel 60
(0.063–0.200 or 0.040–0.063 mm, E. Merck) or basic silica gel
(ChromatorexÒ NH, 100–200 mesh, Fuji Silysia Chemical Ltd) using
the indicated eluents. High-performance liquid chromatography
(HPLC) was performed with Agilent 1200 System equipped with
a G1365B MWD. Elemental analyses were carried out by Takeda
Analytical Laboratories, Ltd and were within 0.4% of theoretical
values unless otherwise noted. HPLC–MS measurements were per-
formed on Waters HPLC–MS system ZMD-1. Asymmetric
3. Conclusion
Excellent enantiomeric excess has been achieved for the novel
triple reuptake inhibitor (S)-4-(1-(3,4-dichlorophenyl)-2-methox-
yethyl)piperidine monohydrochloride 1, using three approaches;
enzymatic resolution (up to 98% ee, 48%), asymmetric hydrogena-
tion (up to 85% ee, 73%), and diastereomeric salt resolution (up to
98% ee, 40%). Each approach has scientific insights and is worth
developing for scale-up synthesis. The success of a greater than
200 g scale synthesis of 1 indicates that diastereomeric salt
resolution is a promising approach for large scale production. We
have also shown that the careful design of substrates, based on

M. Yamashita et al. / Tetrahedron: Asymmetry 26 (2015) 935–942
939
Table 3
Asymmetric hydrogenation of compound 5 with various catalystsa
HO
O
Cat.* (1 mol%)
H2 (1.0 MPa), 2-Propanol, t-BuOK(1 eq. to 5), rt, 5 h
Cl
Cl
Cl
Cl
*
NH
NBoc
6
5
Entry
Ee (%)b
Yield (%)b
Cat.*
diphosphine
diamine
(R)-Binap
(R, R)-DACH
(R, R)-DPEN
(R)-DAIPEN
(S, S)-DACH
(S, S)-DPEN
(S)-DAIPEN
1
2
3
4
5
6
65
71
30
7
rac
20
76
79
80
66
86
80
(R)-Tolbinap
(R)-Xylbinap
(R)-XylSDP
(R, R)-DACH
(R, R)-DPEN
(R)-DAIPEN
(S, S)-DACH
(S, S)-DPEN
(S)-DAIPEN
7
8
9
10
11
12
66
46
38
4
2
26
70
68
80
87
84
81
(R, R)-DACH
(R, R)-DPEN
(R)-DAIPEN
(S, S)-DACH
(S, S)-DPEN
(S)-DAIPEN
13
14
15
16
17
18
80
77
50
35
26
8
69
86
84
73
84
85
(R, R)-DACH
(R, R)-DPEN
(R)-DAIPEN
(S, S)-DACH
(S, S)-DPEN
(S)-DAIPEN
19
20
21
22
23
24
10
5
6
35
31
3
56
80
70
70
75
79
NH2
MeO
OMe
Binap : Ar=C6H5
Tolbinap : Ar=4-CH3C6H4
Xylbinap : Ar=3,5-(CH3)2C6H3
NH2
NH2
PAr2
PAr2
DACH :
DAIPEN :
H2N
H2N
H2N
PAr2
PAr2
XylSDP : Ar=3,5-(CH3)2C6H3
DPEN :
a
Reaction conducted on a 0.1 mmol scale at room temperature under 1.0 MPa of H2. Cat.⁄ were generated
in situ using [RuCl2(binaps)](dmf)n and diamines.
b Determined by HPLC analysis using CHIRALPAK AD-H column.

940
M. Yamashita et al. / Tetrahedron: Asymmetry 26 (2015) 935–942
Table 4
Asymmetric hydrogenation of compound 5 with various bases and conditionsa
HO
O
Cat.* [RuCl2{(R)-xylbinap}{(R, R)-diamine)](1 mol%)
H2, 2-Propanol, base (1 eq. to 5)
Cl
Cl
Cl
Cl
NBoc
NBoc
5
7
Entry
(R, R)-Damine
DACH
Base
H2 (MPa)
1.0
Other conditions
Ee (%)b
82
Yield (%)b
1
2
3
4
5
t-BuOK
t-BuOK
K2CO3
t-BuOK
t-BuOK
rt, 2h
77
DPEN
1.0
rt, 2h
85
68
DPEN
1.0
rt, 2h
---
no reaction
DPEN
0.2
rt, 5h
80
17c
73
DPEN
1.0
50oC, 2h
85
a
Reaction conducted on 0.1 mmol-scale under 1.0 MPa of H2.
b Determined by HPLC analysis (CHIRALPAK AD-H column).
c Compound 5 remained unchanged.
Table 5
Diastereomeric salt resolution of 8 with various solventsa
CO2H
CO2H
NH2
Cl
Cl
Cl
Cl
(S)-Phenylethylamine
Solvent
NBoc
NBoc
8
9
Resolution efficiency c
Entry
Solvent
CH3CN
MeOH
EtOH
Volume (mL)
Ee (%)b
97
Yield (%)b
1
2
3
4
5
6
7
50
5
39
41
43
68
33
46
40
76
76
82
50
63
83
78
93
10
15
5
95
Acetone
37
5%H2O/EtOH
96
EtOH/CH3CN (1/1)
EtOH/CH3CN (2/1)
10
15
90
98
a
Reaction conducted on 1.0-g scale with 1.0 equiv of (S)-phenylethylamine at room temperature.
b Determined by HPLC analysis (CHIRACEL OJ-RH column).
c Resolution efficiency = enantiomeric excess (% ee) Â yield (%) Â 2/100.
hydrogenation was carried out using standard Schlenk techniques.
for 40 h at 35 °C. To this solution were added vinyl acetate
(0.248 mL, 1.0 equiv) and lipase (PS-IM™, Amano Co. Ltd)
(25 mg) at 35 °C. The resulting mixture was stirred for 24 h at
35 °C. The lipase was filtered off and washed with IPE. The same
scale reactions were repeated three times. The resulting filtrate
and washings were combined and concentrated under reduced
pressure to give crude 3 (4.0 g, 96% ee). To a solution of crude 3
in pyridine (16 mL) was added SO3-pyr (2.73 g, 3.0 equiv) at room
temperature. The resulting mixture was stirred for 2.5 h at room
temperature and cooled to 0 °C. After the addition of water
Compounds 2 and 8 were synthesized by the reported method.4
4.2. Enzymatic resolution
4.2.1. tert-Butyl 4-((1S)-2-acetoxy-1-(3,4-dichlorophenyl)ethyl)
piperidine-1-carboxylate 3
To a solution of 2 (1000 mg, 2.67 mmol) and vinyl acetate
(0.495 mL, 2.0 equiv) in IPE (20 mL) was added lipase (PS-IM™,
Amano Co. Ltd) (50 mg) at 35 °C. The resulting mixture was stirred

M. Yamashita et al. / Tetrahedron: Asymmetry 26 (2015) 935–942
941
NH2
CO2H
CO2H
Cl
Cl
Cl
(S)-phenylethylamine
NBoc
HO
NBoc
EtOH/CH3CN (1/1), 65oC
Cl
9
8
MeO
MeO
Cl
Cl
Cl
Cl
1. HCl
MeI
HCl
.HCl
2. BH3.THF
NBoc
NBoc
NH
Cl
Cl
7
10
1
Scheme 2. Synthesis of 1 via diastereomeric salt resolution.
(32 mL), the whole mixture was extracted with IPE (20 mL, twice).
The organic layers were combined and washed successively
with a 10% aqueous NaCl solution (20 mL, three times), a 10% aque-
4.4. Diastereomeric resolution
4.4.1. [(1S)-(tert-Butoxycarbonyl)piperidin-4-yl](3,4-dichloro-
phenyl)acetic acid (S)-1-phenyl ethylamine salt 9
ous citric acid solution (20 mL, twice) and
a 10% aqueous
NaCl solution (20 mL), and concentrated under reduced pressure
to give (S)-3 (2.11 g, purity 98%) as an oil. Enantiomeric
excess (96%) was determined by HPLC analysis using racemic 3
as the external standard. (CHIRALCEL OD-H, eluted with
n-hexane/EtOH = 95/5 (v/v); flow rate, 1.0 mL/min; detection,
To a solution of [1-(tert-butoxycarbonyl)piperidin-4-yl](3,4-
dichlorophenyl)acetic acid
8
(612 g, 1.58 mol) in ethanol
(3,060 mL) and acetonitrile (3,060 mL) was added (S)-(À)-1-phenyl
ethylamine (194 g, 1.60 mol) at 65 °C. The mixture was stirred at
65 °C for 3 h, and then at room temperature for 3 h. The solids were
collected and washed with 50% EtOH in acetonitrile (800 mL) and
dried under reduced pressure to give colorless solids (331 g, 41%,
97% ee).
220 nm; temperature, 40 °C). 1H NMR (400 MHz, CDCl3)
d
1.24–1.28 (m, 2H), 1.41 (s, 9H), 1.64–1.90 (m, 3H), 1.97 (s, 3H),
2.65–2.70 (m, 4H), 3.95–4.20 (m, 1H), 4.24–4.37 (m, 2H), 7.00
(dd, J = 2.0, 8.0 Hz, 1H), 7.24–7.29 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H).
MS: 315 [MÀBoc+H]+.
To a solution of 9 (248 g, 487 mmol) in 5% aqueous EtOH
(3700 mL) was added acetonitrile (3700 mL) at 75 °C and stirred
at 50 °C for 1 h, and then at room temperature for 14 h. The result-
ing solid was filtered and washed with 50% EtOH in acetonitrile
(500 mL) and then concentrated under reduced pressure at 40 °C
to give 9 as a colorless solid (224 g, 90%, 99.9% ee). Enantiomeric
excess was determined by HPLC analysis using 8 as the external
standard. (CHIRALCEL OJ-RH, eluted with 20 mM KHPO4 (pH 2.1)
adjusted by phosphoric acid/acetonitrile = 1/1 (v/v); flow rate,
4.3. Asymmetric hydrogenation
4.3.1. tert-Butyl 4-(1-(3,4-dichlorophenyl)-2-oxoethyl)piperidine-
1-carboxylate 5
Dess–Martin reagent (4.00 g, 9.43 mmol) was added portion-
wise at 0 °C to a solution of tert-butyl 4-(1-(3,4-dichlorophenyl)-
2-hydroxyethyl)piperidine-1-carboxylate (2.21 g, 5.90 mmol) in
CH3CN (50 mL). The mixture was stirred at room temperature for
1 h and then poured into satd NaHCO3 aq and satd Na2S2O3 aq.
After being stirred for 30 min, the mixture was extracted with
EtOAc and washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by silica gel col-
umn chromatography (n-hexane/ethyl acetate = 9/1 to 2/1) to
afford 5 (1.67 g, 76%) as a colorless oil. 1H NMR (300 MHz, CDCl3)
d 0.91–1.09 (m, 1H), 1.14–1.35 (m, 2H), 1.43 (s, 9H), 1.77–1.88
(m, 1H), 2.12–2.28 (m, 1H), 2.57–2.83 (m, 2H), 3.31 (dd, J = 9.5,
2.3 Hz, 1H), 3.98–4.18 (m, 2H), 7.01 (dd, J = 8.1, 2.1 Hz, 1H), 7.28
(d, J = 2.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 9.70 (d, J = 2.3 Hz, 1H).
MS: 272 [MÀBoc+H]+.
1.0 mL/min; detection, 220 nm; temperature, 30 °C). [a]
25 = +36.9
D
(c 0.9310, MeOH); 1H NMR (300 MHz, DMSO-d6) d (ppm): 0.57–
0.93 (1H, m), 0.94–1.14 (2H, m), 1.22–1.47 (12H, m), 1.69–1.84
(1H, m), 1.93–2.01 (1H, m), 2.70 (br s, 2H), 2.97–3.59 (4H, m),
3.67–4.01 (2H, m), 4.14 (1H, q, J = 6.4 Hz), 7.13–7.39 (6H, m)
7.43–7.69 (2H, m).
4.4.2. tert-Butyl 4-[(1S)-(3,4-dichlorophenyl)-2-hydroxyethyl]
piperidine-1-carboxylate 7
To a suspension of 9 (224 g, 440 mmol) in ethyl acetate
(2,250 mL) was added 0.2 M hydrochloric acid (2500 mL) at 5–
10 °C. After stirring for 30 min, the organic layer was separated
and aqueous layer was extracted with ethyl acetate (1200 mL).
The combined organic layer was washed with brine (1700 mL),
dried over anhydrous MgSO4, and concentrated under reduced
pressure to give (S)-8 as a colorless solid (171 g, quantitative,
99.9% ee).
4.3.2. tert-Butyl 4-[(1S)-(3,4-dichlorophenyl)-2-hydroxyethyl]
piperidine-1-carboxylate 7
The part of the solid (146 g, 376 mmol) was dissolved in THF
(1,020 mL) and to the solution was added a 1.1 M BF3ÁTHF complex
in THF (450 mL, 495 mmol) at 3–5 °C. After being stirred at room
temperature for 1 h, to the solution was added 30% aqueous citric
acid (470 mL) at 10–15 °C. The mixture was then concentrated
under reduced pressure and the residue was diluted with EtOAc
(1000 mL) and water (500 mL). The organic layer was separated
and washed with brine (1000 mL), dried over Mg2SO4, and concen-
trated under reduced pressure. The residue was purified by column
chromatography on silica gel (10–90% ethyl acetate in n-hexane) to
To tert-butyl 4-(1-(3,4-dichlorophenyl)-2-oxoethyl)piperidine-
1-carboxylate
5 (37 mg, 0.1 mmol), RuCl2{(R)-xylBINAP}{(R,R)-
DPEN}(1.1 mg, 1 mol %) in a glass autoclave was added a solution
of tert-BuOK (0.1 mL, 1.0 M in tert-BuOH) in 2-propanol (1.5 mL).
Hydrogen (1.0 MPa) was then introduced, and the reaction mixture
stirred at 50 °C. After 2 h, the enantiomeric excess (85%) and chem-
ical yield (73%) were determined by HPLC analysis using racemic 7
as the external standard. (CHIRALPAK AD-H, eluted with n-hex-
ane/2-propanol = 900/100 (v/v); flow rate, 1.0 mL/min; detection,
220 nm; room temperature).

942
M. Yamashita et al. / Tetrahedron: Asymmetry 26 (2015) 935–942
give 7 (138 g, 98%, 99.9% ee) as a colorless oil. Enantiomeric excess
was determined by HPLC analysis using racemic 7 as the external
standard. (CHIRALPAK AD, eluted with n-hexane/2-propa-
nol = 900/100 (v/v); flow rate, 1.0 mL/min; detection, 220 nm;
temperature, 40 °C). 1H NMR (400 MHz, CDCl3) d 1.00–1.36 (m,
4H), 1.43 (s, 9H), 1.67–1.90 (m, 2H), 2.50–2.76 (m, 3H), 3.78–3.94
(m, 2H), 3.95 (br s, 1H), 4.00–4.16 (m, 1H), 7.04 (dd, J = 2.2,
8.3 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H). MS:
318 [MÀtBu+H]+.
for 2 h and then at 5 °C for 2 h. The suspension was filtered and
the solid was washed with n-heptane (1000 mL) and dried under
reduced pressure to give 1 as colorless crystals (202 g, yield 96%,
purity 99.8% (HPLC area %), >99.9% ee. Enantiomeric excess was
determined by SFC analysis using racemic 1 as the external stan-
dard. (CHIRALPAK AD-H, eluted with CO2/MeOH/2-propa-
nol = 920/80/3 (v/v/v); flow rate, 2.35 mL/min; pressure, 150 bar;
detection, 220 nm; temperature, 30 °C). Chemical purity was
determined by HPLC analysis. (Imtact Cadenza C18, eluted with
(A) 50 mmol/L HClO4 aq (pH 2.5) (B) acetonitrile; flow rate,
1 mL/min; gradient program, 0 min: (B) 38%, 10 min: (B) 38%,
15 min: (B) 90%, 24.5 min: (B) 90%; detection, 220 nm; tempera-
4.4.3. tert-Butyl 4-[(1S)-(3,4-dichlorophenyl)-2-methoxyethyl]
piperidine-1-carboxylate 10
To a suspension of NaH (60% in oil, 18.4 g, 460 mmol) in DMF
(430 mL) was added a solution of tert-butyl 4-[(1S)-(3,4-dichloro-
ture, 40 °C). [a]
22 = +31.3 (c 0.5234, MeOH); 1H NMR (300 MHz,
D
DMSO-d6) d 1.10–1.31 (m, 1H), 1.31–1.52 (m, 2H), 1.73–1.99 (m,
2H), 2.63–2.87 (m, 3H), 3.00–3.29 (m, 5H), 3.51–3.67 (m, 2H),
7.24 (dd, J = 8.3 and 1.9 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.54–7.61
(m, 1H), 8.96 (br s, 2H). MS: 288 [M+H]+. Anal. Calcd for
phenyl)-2-hydroxyethyl]piperidine-1-carboxylate
7
(144 g,
384 mmol) and methyl iodide (109 g, 767 mmol) in DMF
(430 mL) at 0–10 °C. After being stirred at room temperature for
2 h, to the mixture was added water (500 mL) at 0–10 °C. After
being stirred for 30 min at 10 °C, the mixture was diluted with
water (1000 mL) and extracted by ethyl acetate (1500 mL). The
organic layer was separated and the aqueous layer was extracted
with ethyl acetate (750 mL). The combined organic layer was
washed successively with 10% aqueous citric acid (750 mL) and
brine (750 mL), dried over MgSO4, and concentrated under a
reduced pressure. The residue was recrystallized from toluene
(300 mL) and diisopropyl ether (150 mL). The collected crystals
were washed with diisopropyl ether (150 mL) and dried under
reduced pressure to give 10 (61 g, 41%). The mother liquid was
concentrated under reduced pressure and the residue was sus-
pended with tert-butyl methylether (150 mL) and filtered. The
solid was washed with a small amount of tert-butyl methylether
and dried under reduced pressure to give a 2nd crop of crystals
(52 g, 35%). The mother liquid was concentrated under reduced
pressure and the residue was purified by column chromatography
on silica gel (10–90% ethyl acetate in n-hexane) to give a 3rd crop
of crystals (17 g, 11%) (total yield 130 g, 87%). 1H NMR (400 MHz,
CDCl3) d 0.98–1.36 (m, 3H), 1.43 (s, 9H), 1.67–1.90 (m, 2H), 2.45–
2.76 (m, 3H), 3.28 (s, 3H), 3.52–3.67 (m, 2H), 4.01 (br s, 1H), 4.12
(br s, 1H), 7.02 (dd, J = 2.2 and 8.3 Hz, 1H), 7.28 (d, J = 2.2 Hz,
1H), 7.36 (d, J = 8.3 Hz, 1H). MS: 374 [MÀMe+H]+.
C14H20Cl3NO: C, 51.79; H, 6.21; N, 4.31. Found: C, 51.81; H, 6.32;
N, 4.23.
References
1. World Health Organization (WHO). Fact sheet No. 369: Depression, October,
2012. http://www.who.int/mediacentre/factsheets/fs369/en/index.html.
2. (a) Skolnick, P.; Popik, P.; Janowsky, A.; Beer, B.; Lippa, A. S. Life Sci. 2003, 73,
3175; (b) Skolnick, P.; Krieter, P.; Tizzano, J.; Basile, A.; Popik, P.; Czobor, P.;
Lippa, A. CNS Drug Rev. 2006, 12, 123; (c) Millan, M. J. Neurotherapeutics 2009, 6,
53; (d) Kulkarni, S. K.; Dhir, A. Expert Opin. Invest. Drugs 2009, 18, 767; (e)
Golembiowska, K.; Kowalska, M.; Bymaster, F. P. Synapse 2012, 66, 435.
3. Bhuniya, R.; Nanda, S. Tetrahedron Lett. 2012, 53, 1990.
4. Ishichi, Y.; Kimura, E.; Honda, E.; Yoshikawa, M.; Nakahata, T.; Terao, Y.; Suzuki,
A.; Kawai, T.; Arakawa, Y.; Ohta, H.; Kanzaki, N.; Nakagawa, H.; Terauchi, J.
Bioorg. Med. Chem. 2013, 21, 4600.
5. (a) Koskinen, A. M. P.; Klibanov, A. M. Enzymatic Reaction in Organic Media;
Blackie Academic
& Professional: Glasgow, 1996; (b) Bornscheuer, U. T.;
Kazlauskas, R. J. Hydrolases in Organic Synthesis: Regio- and Stereoselective
Biotransformations; Wiley-VCH: Weinheim, 1999.
6. Collins, A. N.; Sheldrake, G. N.; Crosby, J. Chirality in Industry; John Wiley & Sons
Ltd, 1992.
7. (a) Angoli, M.; Barilli, A.; Lesma, G.; Passarella, D.; Riva, S.; Silvani, A.; Danieli, B.
J. Org. Chem. 2003, 68, 9525; (b) Berti, F.; Forzato, C.; Nitti, P.; Pitacco, G.;
Valentin, E. Tetrahedron: Asymmetry 2005, 16, 1091; (c) Albrycht, M.;
Kiełbasinski, P.; Drabowicz, J.; Mikołajczyk, M.; Matsuda, T.; Harada, T.;
Nakamura, K. Tetrahedron: Asymmetry 2005, 16, 2015; (d) Isleyen, A.; Tanyeli,
C.; Dogan, Ö. Tetrahedron: Asymmetry 2006, 17, 1561.
8. (a) Zaks, A.; Klibanov, A. M. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 3192; (b) Zaks,
A.; Klibanov, A. M. J. Biol. Chem. 1988, 263, 8017; (c) Kitaguchi, H.; Itoh, I.; Ono,
M. Chem. Lett. 1990, 1203.
4.4.4. 4-[(1S)-1-(3,4-Dichlorophenyl)-2-methoxyethyl]piperidine
monohydrochloride 1
9. Yamano, T.; Kikumoto, F.; Yamamoto, S.; Miwa, K.; Kawada, M.; Ito, T.; Ikemoto,
T.; Tomimatsu, K.; Mizuno, Y. Chem. Lett. 2000, 448.
To a solution of tert-butyl 4-[(1S)-(3,4-dichlorophenyl)-2-meth-
oxyethyl]piperidine-1-carboxylate 10 (130 g, 336 mmol) in tert-butyl
methylether (650 mL) was added 4 M HCl/ethyl acetate solution
(910 mL) at 23 °C. After being stirred at room temperature for
3 h, to the resulting suspension was added n-heptane (1,040 mL).
The resulting suspension was stirred at room temperature for
1 h, and then stirred at 10 °C for 30 min, and filtered. The solid
was washed successively with tert-butyl methylether/n-heptane =
1/1 (1000 mL) and n-heptane (500 mL Â 2 times), and dried under
reduced pressure to give crude 1 as a colorless solid (101 g, yield
93%, purity 99.7% (HPLC area%)).
Crude 1 (210 g, 647 mmol, combined with the other crude 1)
was dissolved in 2-propanol (1800 mL) at 70 °C; to this solution
was added n-heptane (1000 mL) at 65 °C. After being stirred at
50 °C for 2 h, to the suspension was added n-heptane (900 mL) at
50 °C. The resulting suspension was stirred at room temperature
10. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New
York, 1993; (b) Burk, M. J. Acc. Chem. Res. 2000, 33, 363; (c) Noyori, R. Angew.
Chem., Int. Ed. 2002, 41, 2008; (d) Tang, W.; Zhang, X. Chem. Rev. 2003, 103,
3029; (e) Blaser, H. U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M.
Adv. Synth. Catal. 2003, 345, 103; (f) Lennon, I. C.; Moran, P. H. Curr. Opin. Drug
Discovery Dev. 2003, 6, 855; (g) Zhang, X. Tetrahedron: Asymmetry 2004, 15,
2099; (h) Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405; (i) de
Vries, J. G.; Elsevier, C. J. Handbook of Homogeneous Hydrogenation; Wiley-VCH:
Weinheim, 2007.
11. (a) Yamashita, M.; Yamano, T. Chem. Lett. 2009, 38, 100; (b) Yamashita, M.;
Negoro, N.; Yasuma, T.; Yamano, T. Bull. Chem. Soc. Jpn. doi: http://dx.doi.org/
10.1246/bcsj.20130324.
12. (a) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.; Katayama,
E.; England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1998, 37, 1703; (b)
Cobley, C. J.; Henscke, J. P. Adv. Synth. Catal. 2003, 345, 195.
13. Zhou, Z. T.; Xie, J. H.; Zhou, Q. L. Adv. Synth. Catal. 2009, 351, 363.
14. (a) Kinbara, K.; Sakai, K.; Hashimoto, Y.; Nohira, H.; Saigo, K. J. Chem. Soc., Perkin
Trans. 2 1996, 2615; (b) Saigo, K.; Kobayashi, Y. Chem. Rec. 2007, 7, 47; (c) Saigo,
K.; Sakai, K. Yuki gosei kagaku kyokaishi 2011, 69, 499.
15. Saigo, K.; Hashimoto, Y.; Kinbara, K.; Sudo, A. Chem. Sci. 1996, 108, 555.