Development and practical synthesis of a triple reuptake inhibitor, (1 R,2 S)-SIPI 5357

Article abstract of DOI:10.1021/op300258w

A new chromatography-free synthetic route to triple reuptake inhibitor (1R,2S)-SIPI 5357 was developed and demonstrated on a 300-g scale. The key feature of this route is an asymmetric induction reaction, where the (2S,3S)-aminoketone 6 was highly stereoselectively reduced to (1R,2S,3S)-amino alcohol 7. After hydrogenation, chlorination, and cyclization, (1R,2S)-SIPI 5357 was prepared in 33% overall yield via seven steps from α-bromo ketone 3.

Full text of DOI:10.1021/op300258w

Article
pubs.acs.org/OPRD
Development and Practical Synthesis of a Triple Reuptake Inhibitor,
(1R,2S)‑SIPI 5357
Yong-Yong Zheng, Peng Xie, Long-Xuan Xing, Jing-Yu Wang, and Jian-Qi Li*
Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai Engineering
Research Center of Pharmaceutical Process, 1111 North Zhongshan No.1 Road, Shanghai 200437, P.R. of China
ABSTRACT: A new chromatography-free synthetic route to triple reuptake inhibitor (1R,2S)-SIPI 5357 was developed and
demonstrated on a 300-g scale. The key feature of this route is an asymmetric induction reaction, where the (2S,3S)-aminoketone
6 was highly stereoselectively reduced to (1R,2S,3S)-amino alcohol 7. After hydrogenation, chlorination, and cyclization, (1R,2S)-
SIPI 5357 was prepared in 33% overall yield via seven steps from α-bromo ketone 3.
product (2S,3S)-isomer 6 can be readily obtained by
recrystallization, and subsequently reduced to (1R,2S,3S)-
amino alcohol 7 with high stereoselectivity.
INTRODUCTION
■
Depression has received considerable attention in the last
decades. Notoriously, it is involved in people’s thought, feeling
and behavior, which can eventually lead to suicide.1 Recently, it
has been reported that triple reuptake inhibitors (TRIs, the
reuptake inhibits of serotonin (5-HT), noradrenalin (NA), and
dopaminergic (DA)) are promising chemical entities for the
treatment of depression.2−6 TRIs have been hypothesized to
have a more rapid onset of activity and better efficacy over
current antidepressants.7 In our previous studies on such triple
acting compounds,8,9 we disclosed a series of novel and potent
arylalkanol-piperazine TRI candidates such as (1R,2S)-SIPI
5357 (Scheme 1).10 To prepare sufficient quantity of this TRI
candidate for further preclinical pharmacology and safety
studies, a practical synthesis is highly desired with improved
overall yield and suitable pilot plant scale preparation.
The initial synthetic route to (1R,2S)-SIPI 5357 is outline in
Scheme 1.10 The major drawback of this synthetic sequence
was the requirement of column separation and isolation in the
last two steps. Specifically, a column chromatographic
separation of 40% low yield, and a subsequent chiral HPLC
isolation of about 30% yield. These two problematic steps
limited itself from large-scale production of (1R,2S)-SIPI 5357.
Herein we report an alternative scale-up synthesis of (1R,2S)-
SIPI 5357 in high yield without any column separation.
It was also found that under existing reaction conditions the
N-debenzylation of alcohol 7 produced a more favorable
dechlorination product 10 instead of the proposed key
intermediate 8. Further investigation into the reaction
conditions, such as temperature, pressure, and time with
common catalysts (Pd/C and Pd(OH)2) and reagents
(HCO2H, HCO2NH4 and H2) confirmed that 10 was the
preferred product under all conditions studied (Table 1).
Therefore, the working process (Scheme 2) was adjusted and
the final process route (Scheme 3) was established for the scale-
up preparation of (1R,2S)-SIPI 5357.
As shown in Scheme 3, (1R,2S,3S)-amino alcohol 7 was
hydrogenated using 10% Pd/C at 60 °C to give the key
intermediate β-amino alcohol 10 in good yield (95%). 10 was
then reacted with CDI to obtain 1,3-oxazolidin-2-one 11.
Subsequently, the chlorine substitution of 11 yielded
compound 12. The (1R,2S)-amino alcohol 8 can be furnished
by basic hydrolysis to remove the oxazolidinone group. Finally,
the coupling of (1R,2S)-amino alcohol 8 with N-benzyl-N,N-
bis(2-chloroethyl)amine 9 gave the desired product (1R,2S)-
SIPI 5357.
The chlorination of 11 was further studied for the large-scale
preparation even though the ortho chlorination of 2-
methoxynaphthalene derivatives are well-known reactions.12−16
As shown in Table 2, a number of chlorination reagents were
explored. Specifically, by using Cl2 as a chlorinating reagent, the
starting material 11 was completely consumed but only
afforded the desired chlorine-substituted compound 12 in
51% isolated yield after 15 h (entry 1). By lowering the
temperature to 10 °C and shortening reaction time to 5 h, the
isolated yield of 12 decreased to 38% (entry 2), and by using
other chlorination reagents, such as HCl/H2O2, NCS, and
Ca(ClO)2/AcOH, low yields of 12 were observed (entries 3−
5). Eventually a system of NaClO/H+ was developed with
RESULTS AND DISCUSSION
■
It is recognized that the initial synthetic route involved an early
preparation of diastereomeric alcohol 5. This synthesis began
with a SN2 reaction between α-bromo ketone 3 and 1-
benzylpiperazine, and subsequent reduction of piperazine-
ketone 4 by sodium borohydride. To improve the synthesis
and develop a chromatography-free synthetic route, an
asymmetric induction route has been considered (Schemes 2
and 3) and extensively investigated in this study.
The working process was proposed in Scheme 2: (S)-(−)-1-
phenylethylamine was introduced into compound 3 by well-
documented11 nucleophilic displacement with (S)-(−)-1-
phenylethylamine, yielding a mixture of diastereomers amino-
ketone. The HPLC analysis revealed the ratio of resulting
(2S,3S)-isomer/(2R,3S)-isomer was 3/1. Therefore the SN2
Received: September 14, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/op300258w | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
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Scheme 1. Initial Synthesis of (1R,2S)-SIPI 5357
Scheme 2. Working Process for the Synthesis of (1R,2S)-SIPI 5357
satisfactory yields (entries 6−9), which was further optimised
for scale-up preparation of 12 in a good yield (entry 10).
In addition, the coupling of (1R,2S)-amino alcohol 8 and N-
benzyl-N,N-bis(2-chloroethyl)amine (9) was explored in this
study for optimal coupling conditions (Table 3). Under base-
free conditions (entries 1−3), (1R,2S)-SIPI 5357 was obtained
asymmetric induction reaction where (2S,3S)-aminoketone 6
can be highly stereoselectively reduced to (1R,2S,3S)-amino
alcohol 7. In addition, we have demonstrated the optimal
conditions for the chlorination of 11 and the coupling of
compounds 8 and 9.
in poor yields (35−55%), and similar yields were achieved in
EXPERIMENTAL SECTION
■
the presence of an inorganic base such as K2CO3 and NaHCO3
Nuclear magnetic resonance (NMR) spectra were recorded on
a Varian INOVA-400 spectrometer with TMS as an internal
standard. Chemical shifts (δ values) and coupling constants (J
values) are given in ppm and Hz, respectively. ESI mass spectra
were performed on an Agilent 6210 TOF spectrometer.
Elemental analyses were performed on an MOD-1106
instrument and are consistent with theoretical values within
0.3%. Uncorrected melting points were determined on an
electrothermal melting point apparatus. Optical rotations were
measured with an Autopol V Plus polarimeter. Solvents and
reagents were used without any pretreatment. Reaction
progress and chemical purity were evaluated by HPLC analysis
(entries 4−5). In contrast, by switching from inorganic to
organic bases (TEA and DIEA), the desired product can be
afforded in good yields (69−76%) (entries 6−7), which was
further optimised from 76% to 87% by increasing the molar
ratio of 9/8 from 1.1 to 1.3 (entries 8−9).
CONCLUSION
■
In conclusion, we have developed an efficient and scalable
seven-step process for the preparation of (1R,2S)-SIPI 5357
and improved the overall yield from 8% to 33% (from α-bromo
ketone 3). We have achieved this by successfully introducing an
B
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Scheme 3. Final process route for the synthesis of (1R,2S)-SIPI 5357
Table 1. N-Debenzylation of 7 under different reaction conditions
a
a
a
entry
catalyst
regent
H2
temp (°C)
pressure (MPa)
time (h)
7 (area %)
8 (area %)
10 (area %)
1
2
3
4
5
6
7
8
9
10% Pd/C
10% Pd/C
5% Pd/C
60
60
30
30
60
60
60
30
30
0.5
0.3
0.1
0.1
0.1
0.1
0.5
0.1
0.1
6
4
4
2
4
2
4
4
2
0
0.2
0.5
7.9
0
0.1
0.5
1.5
4.5
1.3
2.2
0.5
6.4
11.2
99.9
99.3
98.0
87.6
98.7
97.8
99.5
90.1
76.2
H2
H2
5% Pd/C
H2
10% Pd/C
5% Pd/C
HCO2H
HCO2NH4
H2
0
20% Pd(OH)2
10% Pd(OH)2
10% Pd(OH)2
0
H2
3.5
12.6
H2
a
Determined by HPLC analysis.
using a Waters symmetry column, C18 (5 μm, 250 mm × 4.6
mm); with a mobile phase A (MeOH + 0.05% TFA) and B
(0.3% TEA), 88:12 v/v; detection at 230 nm; flow: 1.0 mL/
min; temp 25 °C. Chiral purity was evaluated by HPLC analysis
using a Daicel 100 OJ-H chiral column (5 μm, 250 mm × 4.6
mm) with isocratic mobile phase N-hexane/isopropanol/
diethylamine, 80:20:0.1 v/v/v; and detection at 230 nm;
flow: 1.0 mL/min; and temp 30 °C.
1-(5-Chloro-6-methoxynaphthalen-2-yl)hexan-1-one
(2). To a stirred solution of 1-chloro-2-methoxynaphthalene
(1) (800 g, 4.2 mol) in dichloromethane (4 L) was added
anhydrous aluminum chloride (665 g, 5 mol) portion-wise at
room temperature. The reaction mixture was stirred at the same
temperature for 1 h. After cooling to 0−5 °C, a solution of
hexanoyl chloride (617 g, 4.6 mol) in dichloromethane (500
mL) was added dropwise, and then the mixture was stirred at
room temperature for 10 h. The reaction was completed as
determined by thin layer chromatography (TLC) with EtOAc/
hexane (1:15, v/v). The reaction mixture was poured slowly
onto ice water (3 L); after the mixture stirred for 2 h, the
organic layer was washed with water (1 L) and brine (1 L),
dried over anhydrous sodium sulfate, filtered, and concentrated
at reduced pressure (∼30 mmHg). The light-yellow solid was
crystallised from 95% aqueous ethanol (1 L) to afford 967 g of
the product 1-(5-chloro-6-methoxynaphthalen-2-yl)hexan-1-
1
one (2) as a white solid (80% yield). Mp 89−90 °C; H
NMR (400 Hz, CDCl3) δ 8.48 (s, 1H), 8.25−8.22 (d, J = 12
Hz, 1H), 8.14−8.11 (dd, J1 = 4 Hz, J2 = 12 Hz, 1H), 7.90−7.88
(d, J = 8 Hz, 1H),7.34−7.31 (dd, J1 = 4 Hz, J2 = 12 Hz, 1H),
4.05 (s, 3H), 3.97−3.93 (t, J = 8 Hz, 2H), 1.73−1.51 (m, 4H),
1.48−1.34 (m, 2H), 0.95−0.91 (t, J = 8 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 198.5, 155.2, 134.0, 130.4, 128.4, 125.6,
124.1, 122.6, 116.5, 113.6, 56.6, 40.3, 32.5, 26.6, 21.3, 13.8; MS
m/z 291 [M + H]+.
2-Bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)-
hexan-1-one (3). To a stirred solution of 2 (900 g, 3.1 mol) in
AcOEt/CH2Cl2 (2 L/2 L) was added CuBr2 (830 g, 3.7 mol).
The reaction mixture was slowly heated to reflux, and the
refluxing was continued for 4 h. After the mixture was cooled to
room temperature and filtered, the solvent was removed under
C
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125.8, 124.1, 122.9, 116.7, 114.0, 56.8, 47.5, 33.3, 29.7, 22.4,
14.0; MS m/z 370 [M + H]+.
Table 2. Chlorination conditions of 11
(S)-1-(5-Chloro-6-methoxynaphthalen-2-yl)-2-(((S)-1-
phenylethyl)amino)hexan-1-one (6). To a stirred solution
of (S)-(−)-1-phenylethylamine (375 g, 3.1 mol) and Et3N (390
g, 3.9 mol) in ethanol (5 L) was added 3 (950 g, 2.6 mol) at
room temperature. The mixture was heated to reflux for 15 h
and cooled to room temperature. The solution was
concentrated under reduced pressure (∼30 mmHg) to give a
light-yellow oil. AcOEt (4 L) was added to the residue, and the
mixture was heated to reflux for 30 min, then cooled to room
temperature, stirred for 3 h, and filtered. The filter cake was
dried under vacuum to afford the desired (2S,3S)-isomer 6 as a
white solid (686 g, 65% yield) with 99.0% purity and 98.2% ee.
[α]25D −72.1 (MeOH, c 1.0); mp 210−212 °C; 1H NMR (400
Hz, DMSO-d6) δ 10.53 (br, 1H), 9.36 (s, 1H), 8.79 (s, 1H),
8.20−7.96 (m, 2H), 7.72−7.60 (m, 3H), 7.21 (m, 3H), 5.47
(m, 1H), 4.42 (m, 1H), 4.06 (s, 3H), 2.12 (m, 2H), 1.76 (m,
3H), 1.16−1.04 (m, 4H), 0.70 (m, 3H); 13C NMR (100.6
MHz, DMSO-d6) δ 195.3, 155.6, 137.2, 134.0, 132.4, 131.4,
130.2, 129.3, 129.2, 128.9, 128.1, 125.7, 123.7, 115.7, 115.3,
59.9, 58.4, 57.4, 30.8, 36.4, 22.4, 19.5, 14.0; MS m/z 410 [M +
H]+.
scale
(11)
temp time yield
a
entry
(g)
reagent
solvent
CHCl3
(°C)
(h)
(%)
1
2
3
4
5
1
1
1
1
1
Cl2
Cl2
20
10
60
50
0
15
5
51
38
58
48
33
CHCl3
MeOH
CH3CN
HCl/H2O2
NCS
12
5
Ca(ClO)2/
AcOH
10/10 (v/v)
acetone/H2O
4
6
7
1
1
NaClO/HCl 2/1 (v/v)
CH2Cl2/H2O
0
0
5
5
68
78
NaClO/
NaCl/
H2SO4
2/1 (v/v)
CH2Cl2/H2O
8
9
1
1
NaClO/HCl 2/1 (v/v)
CH2Cl2/H2O
20
20
3
2
75
88
NaClO/
NaCl/
H2SO4
2/1 (v/v)
CH2Cl2/H2O
(1R,2S)-1-(5-Chloro-6-methoxynaphthalen-2-yl)-2-
(((S)-1-phenylethyl)amino)hexan-1-ol (7). The (2S,3S)-
aminoketone 6 (650 g, 1.6 mol) was dissolved in EtOH (4
L) and cooled below 10 °C. To this stirred solution was added
NaBH4 (30 g, 0.8 mol) portionwise over a period of 30 min.
After the final addition of NaBH4, the mixture was allowed to
stir at 25 °C for 30 min. The resulting solution was quenched
into 3 N hydrochloric acid (300 mL) to crystallise. The mixture
was heated to reflux for 30 min, then cooled to room
temperature and filtered. The filter cake was washed with EtOH
(300 mL), dried under vacuum to afford the (1R,2S,3S)-amino
alcohol 7 as a white solid (555 g, 85% yield) with 99.2% purity
10
50
NaClO/
NaCl/
H2SO4
2/1 (v/v)
CH2Cl2/H2O
20
2
89
a
Isolated yield.
reduced pressure (∼30 mmHg). The crude residue was washed
with water (500 mL), and then the light-yellow solid was
crystallised from ethanol (1 L) to afford 970 g of 2-bromo-1-(5-
chloro-6-methoxynaphthalen-2-yl) hexan-1-one (3) as a white
solid (85% yield). Mp 106−108 °C; 1H NMR (400 Hz,
CDCl3) δ 8.49 (s, 1H), 8.26−8.23 (d, J = 12 Hz, 1H), 8.13−
8.10 (dd, J1 = 4 Hz, J2 = 12 Hz, 1H), 7.90−7.88 (d, J = 8 Hz,
1H),7.36−7.28 (dd, J1 = 12 Hz, J2 = 20 Hz, 1H), 5.30−5.27 (t,
J = 8 Hz, 1H), 4.06 (s, 3H), 2.32−2.14 (m, 2H), 1.69−1.51 (m,
2H), 1.49−1.34 (m, 2H), 0.97−0.94 (t, J = 8 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 192.7, 154.8, 133.4, 130.1, 128.1,
and 98.6% ee. [α]25 −22.6 (MeOH, c 1.0); mp 189−191 °C;
D
1H NMR (400 Hz, DMSO-d6) δ 7.98−7.96 (d, J = 8 Hz, 1H),
7.94−7.96 (d, J = 8 Hz, 1H), 7.85−7.83 (d, J = 8 Hz, 2H), 7.78
(s, 1H), 7.55−7.43 (m, 4H), 7.24−7.22 (d, J = 8 Hz, 1H),
6.36−6.35 (d, J = 4 Hz, 1H), 5.30 (s, 1H), 4.58 (br, 1H), 3.42
(s, 1H), 2.96 (br, 1H), 1.76−1.75 (d, J = 4 Hz, 1H), 1.57−1.54
Table 3. Reagents and conditions for coupling 8 with 9
a
b
entry
9/8 ratio
base
none
solvent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
1.2:1
1.3:1
EtOH
75
115
75
10
8
35
42
55
45
58
69
76
87
86
none
BuOH
none
CH3CN
EtOH
12
5
K2CO3
NaHCO3
TEA
75
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
75
5
75
5
DIEA
DIEA
DIEA
75
5
75
5
75
5
a
b
Mole ratio. Isolated yield.
D
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1
(m, 2H), 0.95−0.88 (m, 2H), 0.86−0.81 (m, 1H), 0.64−0.57
(m, 1H), 0.48−0.44 (t, J = 8 Hz, 3H); 13C NMR (100.6 MHz,
DMSO-d6) δ 152.6, 140.9, 133.8, 103.8, 130.4, 129.2, 129.0,
128.8, 127.0, 125.2, 122.6, 115.2, 114.8, 70.2, 69.7, 60.3, 57.2,
51.5, 47.6, 29.7, 23.5, 22.5, 14.2; MS m/z 412 [M + H]+. Anal.
Calcd for C25H30ClNO2: C, 72.89; H, 7.34; N, 3.40. Found: C,
72.88; H, 7.28; N, 3.42.
−28.1 (CH2Cl2, c 1.0); H NMR (400 Hz, DMSO-d6) δ 8.41
(s, 1H), 8.24−8.22 (d, J = 8 Hz, 1H), 8.13−8.10 (dd, J1 = 4 Hz,
J2 = 8 Hz, 1H), 7.88−7.86 (d, J = 8 Hz, 1H),7.35−7.32 (dd, J1
= 4 Hz, J2 = 8 Hz, 1H), 6.30−6.29 (d, J = 4 Hz, 1H), 3.87 (s,
3H), 3.13 (m, 1H), 1.51−1.48 (m, 2H), 1.30−1.25 (m, 2H),
1.14−1.00 (m, 2H), 0.61−0.57 (t, J = 8 Hz, 3H); 13C NMR
(100.6 MHz, DMSO-d6) δ 165.6, 157.8, 136.9, 135.2, 131.2,
129.0, 127.7, 126.1, 120.2, 106.6, 72.1, 55.4, 54.9, 28.3, 25.8,
21.4, 13.7; MS m/z 334 [M + H]+; Anal. Calcd for
C18H20ClNO3: C, 64.77; H, 6.04; N, 4.20. Found: C, 64.69;
H, 6.07; N, 4.18.
(1R,2S)-2-Amino-1-(6-methoxynaphthalen-2-yl)-
hexan-1-ol (10). A 5 L hydrogenation reactor was charged
with Pd/C (10% Pd content, 10 g), EtOH (3 L) and
(1R,2S,3S)-amino alcohol 7 (500 g, 1.2 mol). The reactor was
pressurised with hydrogen (0.5 MPa) and then warmed to 60
°C for 6 h. The reaction mixture was filtered to remove catalyst,
and the solvent was concentrated under reduced pressure (∼30
mmHg) to give a light-yellow solid. The solid was added to
AcOEt (600 mL) and stirred for 1 h. After the mixture was
filtered, the filter cake was washed with AcOEt (500 mL) and
dried under vacuum to afford the β-amino alcohol 10 as a white
(1R,2S)-2-Amino-1-(5-chloro-6-methoxynaphthalen-
2-yl)hexan-1-ol (8). Chlorine substitute 12 (285 g, 0.85 mol)
was dissolved in MeOH (1 L). To this mixture was added 2 N
sodium hydroxide solution (640 mL). The reaction mixture was
heated to reflux for 5 h. MeOH was removed in vacuo, and
DCM (1 L) was added and stirred for 30 min. The organic
phase was separated and concentrated in vacuo (∼30 mmHg)
at 35 °C. The residue was crystallised from 90% aqueous
ethanol to afford 239 g of (1R,2S)-amino alcohol 8 as a white
solid (91% yield) with 99.6% purity and 99.1% ee. [α]25D −24.2
solid (315 g, 95% yield) with 99.5% purity and 99.0% ee. [α]25
−32.7 (MeOH, c 2.0); mp 152−154 °C; H NMR (400 Hz,
D
1
DMSO-d6) δ 7.85−7.76 (m, 3H), 7.49−7.47 (d, J = 8 Hz, 1H),
7.32 (s, 1H), 7.17−7.11 (dd, J1 = 4 Hz, J2 = 16 Hz, 1H), 6.17−
6.16 (d, J = 4 Hz, 1H), 5.20 (br, 1H), 3.87 (s, 3H), 3.35 (br,
2H), 3.12 (m, 1H), 1.50−1.47 (m, 2H), 1.39−1.30 (m, 2H),
1.15−1.02 (m, 2H), 0.71−0.67 (t, J = 8 Hz, 3H); 13C NMR
(100.6 MHz, DMSO-d6) δ 157.7, 136.7, 134.1, 129.8, 128.6,
127.1, 125.8, 125.1, 119.2, 106.3, 71.9, 56.4, 55.8, 27.6, 26.3,
22.3, 14.1; MS m/z 274 [M + H]+; Anal. Calcd for C17H23NO2:
C, 74.69; H, 8.48; N, 5.12. Found: C, 74.52; H, 8.43; N,5.07.
(4S,5R)-4-Butyl-5-(6-methoxynaphthalen-2-yl)-
oxazolidin-2-one (11). To a stirred solution of β-amino
alcohol 10 (300 g, 1.1 mol) and Et3N (166 g, 1.6 mol) in DCM
(2 L) was added N,N′-carbonyldiimidazole (267 g, 1.6 mol) at
room temperature. The reaction mixture was stirred for 12 h,
H2O (500 mL) was added, and the mixture stirred for 20 more
min. The organic phase was then washed with 10% hydro-
chloric acid (500 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated in reduced pressure (∼30 mmHg).
The residue was crystallised from AcOEt (800 mL) to afford
292 g of 1,3-oxazolidin-2-one 11 as a white solid (89% yield)
with 99.3% purity and 98.7% ee. [α]25D −27.8 (CH2Cl2, c 1.0);
1
(MeOH, c 2.0); mp 161−162 °C; H NMR (400 Hz, DMSO-
d6) δ 8.42 (s, 1H), 8.23−8.21 (d, J = 8 Hz, 1H), 8.12−8.10 (dd,
J1 = 4 Hz, J2 = 8 Hz, 1H), 7.89−7.87 (d, J = 8 Hz, 1H),7.34−
7.32 (dd, J1 = 4 Hz, J2 = 8 Hz, 1H), 6.18−6.17 (d, J = 4 Hz,
2H), 5.21 (br, 1H), 3.88 (s, 3H), 3.37 (br, 2H), 3.15 (m, 1H),
1.52−1.48 (m, 2H), 1.40−1.32 (m, 2H), 1.13−1.02 (m, 2H),
0.68−0.66 (t, J = 8 Hz, 3H); 13C NMR (100.6 MHz, DMSO-
d6) δ 158.9, 137.8, 135.3, 131.1, 128.9, 127.8, 126.2, 125.6,
119.8, 106.9, 71.8, 56.3, 55.9, 28.1, 26.5, 22.4, 14.0; MS m/z
308 [M + H]+; Anal. Calcd for C17H22ClNO2: C, 66.33; H,
7.20; N, 4.55. Found: C, 66.21; H, 7.23; N, 4.58.
(1R,2S)-2-(4-Benzylpiperazin-1-yl)-1-(5-chloro-6-me-
thoxynaphthalen-2-yl)hexan-1-ol ((1R,2S)-SIPI 5357). A
solution of (1R,2S)-amino alcohol 8 (230 g, 0.75 mol) and
Et3N (91 g, 0.9 mol) in acetonitrile (800 mL) was stirred at
room temperature, and then N-benzyl-N,N-bis(2-chloroethyl)-
amine 9 (207 g, 0.9 mol) was added. The reaction mixture was
heated to reflux and stirred for 8 h. The mixture was
concentrated in vacuo, and DCM (1 L) and water (500 mL)
were added and stirred vigorously for 30 min. The phases were
separated, and the organic layer was washed with brine (300
mL). The DCM was distilled, and the residue was crystallised
from AcOEt (500 mL) to afford 303 g of (1R,2S)-SIPI 5357 as
a white solid (87% yield) with 99.6% purity and 99.3% ee.
[α]25D −12.1 (MeOH, c 0.5); mp 218−220 °C; 1H NMR (400
Hz, DMSO-d6) δ 8.04−8.01(d, J = 12 Hz, 1H), 7.96−7.96 (d, J
= 8 Hz, 1H), 7.92 (s, 1H), 7.63−7.61 (d, J = 8 Hz, 1H), 7.54−
7.52 (d, J = 8 Hz, 1H), 7.47−7.46 (m, 2H), 7.41−7.34 (m, 3H),
5.22 (s, 1H), 3.98 (s, 3H), 3.93 (s, 2H), 3.10 (m, 4H), 2.97−
2.85 (m, 5H), 1.61−1.41 (m, 2H), 1.23−1.12 (m, 1H), 1.09−
0.97 (m, 2H), 0.89 (m, 1H), 0.62 (t, J = 8 Hz, 3H); 13C NMR
(100.6 MHz, DMSO-d6) δ 152.6, 140.9, 133.8, 130.8, 130.4,
129.2, 129.0, 128.8, 127.0, 125.2, 122.6, 115.2, 114.8, 70.2, 69.7,
60.3, 57.2, 51.5, 47.6, 29.7, 23.5, 22.5, 14.2; MS m/z 467 [M +
H]+; Anal. Calcd for C28H35ClN2O2: C, 72.01; H, 7.55; N, 6.00.
Found: C, 72.10; H, 7.53; N, 5.92.
1
mp 178−179 °C; H NMR (400 Hz, DMSO-d6) δ 8.53 (br,
1H), 7.83−7.76 (m, 3H), 7.50−7.48 (d, J = 8 Hz, 1H), 7.34 (s,
1H), 7.18−7.14 (dd, J1 = 4 Hz, J2 = 12 Hz, 1H), 6.32−6.31(d, J
= 4 Hz, 1H), 3.85 (s, 3H), 3.15 (m, 1H), 1.52−1.48 (m, 2H),
1.32−1.25 (m, 2H), 1.16−1.01 (m, 2H), 0.67−0.63 (t, J = 8
Hz, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 165.3, 157.8,
136.4, 134.0, 129.9, 128.3, 127.0, 125.9, 125.3, 119.1, 106.1,
73.1, 56.1, 55.2, 27.4, 26.0, 22.1, 13.8; MS m/z 300 [M + H]+;
Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found:
C, 72.19; H, 7.03; N, 4.61.
(4S,5R)-4-Butyl-5-(5-chloro-6-methoxynaphthalen-2-
yl)oxazolidin-2-one (12). 1,3-Oxazolidin-2-one 11 (290 g,
0.97 mol) was dissolved in DCM (1.5 L), and to this solution
were added sodium chloride (67 g, 1.2 mol) and 40% sulfuric
acid (280 mL). Then a solution of 11% sodium hypochlorite
(980 mL) was added dropwise over a period of 30 min at room
temperature. After this mixture stirred for 2 h, the organic
phase was separated, then washed with brine (1 L), and
concentrated in reduced pressure (∼30 mmHg) at 35 °C to
give a crude product. The crude residue was crystallised from
AcOEt (500 mL) to afford 287 g of chlorine substitute 12 as a
AUTHOR INFORMATION
■
Corresponding Author
*Telephone: +86 21 55514600. Fax: +86 21 65312830. E-mail:
white solid (89% yield) with 99.5% purity and 98.9% ee. [α]25
lijianqb@126.com.
D
E
dx.doi.org/10.1021/op300258w | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the financial support from the Chinese
National Science and Technology Major Project (Grant No.
2012ZX09103-101-038; 2012ZX09102101-008).
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dx.doi.org/10.1021/op300258w | Org. Process Res. Dev. XXXX, XXX, XXX−XXX