Dielectrically controlled resolution (DCR) of 3-aminopiperidine via diastereomeric salt formation with N-tosyl-(S)-phenylalanine

Article abstract of DOI:10.1016/j.tetasy.2012.02.002

A useful key intermediate for the dipeptidyl peptidase-4 (DPP-4) inhibitor, 3-aminopiperidine 1, was successfully resolved with an enantiomerically pure resolving agent, N-tosyl-(S)-phenylalanine 2, to give both stereoisomers (R)-1 and (S)-1 as a less-sol

Full text of DOI:10.1016/j.tetasy.2012.02.002

Tetrahedron: Asymmetry 23 (2012) 221–224
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Dielectrically controlled resolution (DCR) of 3-aminopiperidine via
diastereomeric salt formation with N-tosyl-(S)-phenylalanine
a,
⇑
b
c
a
Rumiko Sakurai , Kenichi Sakai , Koichi Kodama , Masanori Yamaura
a
Faculty of Pharmacy, Iwaki Meisei University, Iwaki, Fukushima 970-8551, Japan
Technology Development Division, Toray Fine Chemicals Co., Ltd, Nagoya, Aichi 455-8502, Japan
Department of Applied Chemistry, Saitama University, Sakura-ku, Saitama 338-8570, Japan
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A useful key intermediate for the dipeptidyl peptidase-4 (DPP-4) inhibitor, 3-aminopiperidine 1, was suc-
cessfully resolved with an enantiomerically pure resolving agent, N-tosyl-(S)-phenylalanine 2, to give
both stereoisomers (R)-1 and (S)-1 as a less-soluble diastereomeric salt with (S)-2, via a dielectrically con-
trolled resolution (DCR) phenomenon.
Received 21 December 2011
Accepted 31 December 2011
Available online 13 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1
. Introduction
Resolutionviadiastereomericsaltformationis widely knownasa
2. Results and discussion
2.1. Optimum resolving agent for (RS)-1
reliable method to obtain various enantiopure compounds, espe-
cially in the industrial-scale production of key intermediates for
pharmaceuticals. It has numerous advantages when compared to
other methods such as easy scale-up from the laboratory scale, no
special equipment needed, and lower impurities through the crys-
tallization process. In fact, more than half of the chiral pharmaceuti-
Resolving agents for the resolution of (RS)-1 were chosen from
the former DCR examples, multi-functional acids such as N-tosyl-
(S)-phenylalanine 2, (R,R)-tartaric acid 5, and (S)-mandelic acid 7.
The molar ratio of the resolving agent was selected from 1.0 to
2.0 equiv based on the acid–base stoichiometry. Alcoholic solvents
were used and their volumes were determined by the respective
solubility of the solutes (a mixture of racemate and resolving
agent) at 50 °C. Our results are listed in Table 1.
As shown in Table 1, resolving agent (S)-7 gave no crystals at all
from methanol and 2-propanol; the molar ratio of the resolving
agent (1.0–2.0 equiv) was not effective in giving salt crystals.
Resolving agent (R)-2-methoxy-2-phenylacetic acid 9 gave salt
crystals containing (R)-1 from methanol, ethanol, and 2-propanol,
but diastereomeric excesses were not high enough. In contrast,
the resolving agent (S)-2 gave much higher diastereomeric excesses
(approximately 90%) when methanol or ethanol was used as a sol-
vent. The configurations of these salt crystals were opposite; (R)-1
and (S)-1 were obtained as the less-soluble salt from methanol
and from ethanol, respectively. When methanol was used as the
solvent, a higher molar ratio of (S)-2 caused a decrease in the diaste-
reomeric excesses of the deposited (R)-salt crystals. On the other
hand, ethanol and 2-propanol gave (S)-salt crystals. Based on the
elemental and water contents analyses, salt deposits containing
1
cal intermediates on a market have been produced by this method.
(
R)-3-Aminopiperidine 1 is known as a useful key molecule for a
2,3
dipeptidyl peptidase-4 (DPP-4) inhibitor and a protein kinase
inhibitor. However, the resolution of (RS)-1 via diastereomeric salt
4
formation has not been reported so far. With regards to the resolu-
tion of (RS)-1, we found that N-tosyl-(S)-phenylalanine 2 is not
only a useful resolving agent but also that the resolution can be
controlled by a dielectrically controlled resolution (DCR) phenom-
enon to give both stereoisomers, (R)-1 and (S)-1, as a less-soluble
diastereomeric salt with (S)-2.
Until now, the DCR phenomenon has been observed in the res-
5
6
7
8
olution of mono-amino compounds such as 3, 4, 6, and 8 as
starting racemates coupled with multi-functional homochiral acids
such as tartaric acid 5, mandelic acid 7, or phenylalanine derivative
2
(Fig. 1). Herein, the resolution of a di-amino compound is the first
example that shows the DCR phenomenon. We also report the res-
olution of (RS)-1 via diastereomeric salt formation and that the
DCR phenomenon is observed (Fig. 2).9
2
(R)-1 and (S)-1 were (R)-1/2(S)-2/H O and (S)-1/2(S)-2, respec-
tively. These results show that (R)-1 and (S)-1 need a stoichiometric
resolving agent in order to crystallize the respective less-soluble
diastereomeric salt. Moreover, (R)-1 requires water molecules to
crystallize a less-soluble salt crystal. These results indicate that
(R)-1 and (S)-1 have quite different molecular recognition mecha-
nisms for crystallizing the respective salt crystal.
⇑
Corresponding author.
E-mail address: rsakurai@iwakimu.ac.jp (R. Sakurai).
0
957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.02.002

2
22
R. Sakurai et al. / Tetrahedron: Asymmetry 23 (2012) 221–224
O
OH
COOH
Ts
H
N
NH2
HOOC
HN
COOH
HN
OH
OH
(
RS)-3
(S)-2
(RS)-4
(R,R)-5
OH
COOH
NH2
COOH
NH2
(RS)-6
(S)-7
(RS)-8
(S)-7
Figure 1. Resolution systems showing the DCR phenomenon.
NH2
NH2
NH2
(
S)-2
(S)-2
2
(S)-2
H2O
2 (S)-2
N
H
MeOH
N
H
EtOH
N
H
(
R)-1
(RS)-1
(S)-1
COOH
Ts
HN
(S)-2
Figure 2. Dielectrically controlled resolution of (RS)-1 with (S)-2.
Table 1
Resolution of (RS)-1 with various resolving agents
Entry
Resolving
agenta
Molar ratio
(equiv)
Solvent
Solvent volume
versus (RS)-1 (w/w)
Yieldb (%)
de (%)
Resolution
efficiency (E)
Absolute configuration
of 1
c
1
2
3
4
5
6
7
8
9
(S)-7
1.0
2.0
1.0
1.5
MeOH
2-PrOH
MeOH
2-PrOH
MeOH
2-PrOH
MeOH
EtOH
MeOH
MeOH
EtOH
2-PrOH
MeOH
MeOH
1
1
2
10
2
6
8
8
2
6
Not crystallized
Not crystallized
Not crystallized
Oil obtained
6
35
32
43
(R)-9
74
20
66
70
9
14
42
60
(R)
(R)
(R)
(R)
2.0
1.0
Oil obtained
10
11
12
13
14
(S)-2
22
27
33
46
86
91
89
51
63
14
40
48
34
58
24
(R)
(S)
(S)
(R)
(R)
30
30
20
20
1.5
2.0
a
b
c
Resolving agent: (S)-2, N-tosyl-(S)-phenylalanine; (S)-7, (S)-mandelic acid; (R)-9, (R)-2-methoxy-2-phenylacetic acid.
Yield: calculated based on (RS)-1.
Resolution efficiency (E) = yield (%) ꢀ 2 ꢀ diastereomeric purity (% de)/100.
2
.2. DCR phenomenon on the resolution of (RS)-1 with (S)-2
In addition, 92% ethanol is also useful for (R)-1. This suggests that
the configuration of the salt crystal can be controlled by the solvent
combination of ethanol and water.
In order to determine the applicable range of the DCR phenom-
enon for the resolution of (RS)-1 with (S)-2, various dielectric con-
stants ( ) of alcoholic solvents were examined. The results are
listed in Table 2 and are shown in Figure 3. We found that the
DCR phenomenon was dramatic: dielectric constant 5 27 gave
S)-1/2(S)-2 while = 28 gave (R)-1/2(S)-2/H O. These data reveal
that methanol is useful for (R)-1 while ethanol is useful for (S)-1.
e
3
. Conclusion
-Aminopiperadine 1, a useful key intermediate for a DPP-4
e
3
(
e
2
inhibitor, was successfully resolved with an enantiomerically pure
resolving agent, N-tosyl-(S)-phenylalanine 2. Moreover, we found

R. Sakurai et al. / Tetrahedron: Asymmetry 23 (2012) 221–224
223
Table 2
a
Resolution of (RS)-1 with (S)-2 in alcoholic solvents
Entry Solvent (w/w) Dielectric constantb
(e
)
Solvent volume versus (RS)-1 (w/w) Yield (%) de (%) Resolution efficiency (E) Absolute configuration of 1
1
2
3
4
5
6
7
8
2-PrOH
EtOH
18
24
26
27
28
33
38
47
30
30
33
33
22
6
33
27
22
26
16
22
11
11
51
89
93
88
94
91
82
46
34
48
41
46
30
40
18
10
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
96% EtOH
95% EtOH
92% EtOH
MeOH
90% MeOH
70% MeOH
4
4
a
Resolving agent (S)-2/(RS)-1 = 1.0 (molar ratio).
Dielectric constant (e) of a mixed solvent is indicated as a weighted average value calculated from those of pure solvents.
b
1
00
3
in CH CN (0.5 mL) was added to the solution. The mixture was al-
lowed to stand for 15 min at room temperature, after which N-
acylation proceeded to yield N-acyl 1. To the solution were added
8
6
4
2
0
0
0
0
0
2
.0% phosphoric acid solution (0.1 mL) and CH
then the insolubles were removed by filtration. The filtrate (5
was injected into the HPLC. Analytical conditions for the HPLC
were as follows; eluent: 0.03% NH aq solution (acidified with ace-
tic acid to pH 4.9) + methanol (50/50), 1.0 mL/min, 40 °C, detected
at 254 nm, injection sample 5 L. Retention times: the (S)-enantio-
mer 39.4 min, the (R)-enantiomer 42.5 min. The sample for diaste-
3
CN (2.5 mL), and
lL)
3
l
-
-
-
-
20
40
60
80
reomeric excess analysis by HPLC was treated with
injection.
L-PTAN prior to
-
100
4.3. Resolution procedure
1
0
20
30
40
50
Dielectric constant (ε)
4.3.1. Preparation of the (S)-1/2(S)-2 salt
A typical experimental procedure involving the preparation of
Figure 3. Configuration change with the solvent dielectric constant.
(S)-1/2(S)-2 salt is as follows (Table 1, entry 11): to a 300 mL flask,
free diamine (RS)-1 (3.0 g, 30.0 mmol) and ethanol (90 g) were
added. The solution was stirred, and then (S)-2 (9.6 g, 30.0 mmol)
was added at room temperature, and heated up to approximately
that this resolution of di-amine 1 with (S)-2 was the first example
of a DCR phenomenon. This result suggests that the DCR phenom-
enon might be observed in other types of compounds, not only in
mono-amino compounds.
6
0 °C to give a clear solution. The mixture was gradually cooled
to 37 °C, kept for 2 h at 36–38 °C (corresponding to the crystalliza-
tion temperature), and then gradually cooled again to 20 °C. After
aging the suspension at the same temperature for 2 h, the crystals
were filtered off and washed twice with ethanol (8 mL in total) to
yield wet salt crystals, which were dried at 60 °C for 3 h to afford
the crude (S)-1/2(S)-2 salt (6.0 g, 8.12 mmol, yield 27%, 89% de, E
4
4
. Experimental
.1. General
4
8%).
The crude salt was recrystallized from ethanol. To a 500 mL
(
RS)-3-Aminopiperidine 1 (containing 1.7% of water) and N-to-
syl-(S)-phenylalanine 2 (>99.5% ee) were made by Yamakawa
Chemical Industry Co., Ltd (Tokyo). H NMR spectra were recorded
on a JEOL ECA-500 spectrometer in CD OD. IR spectra were mea-
3
sured on a SHIMADZU FTIR-8400S spectrometer using KBr pellets.
Optical rotations were measured on a JASCO P-1010 polarimeter.
High-performance liquid chromatography was performed by a JAS-
CO Intelligent HPLC system equipped with UV-2075 detector.
Melting points were determined with a Yanaco MP-S3 instrument
and are uncorrected.
flask, (S)-1/2(S)-2 salt (5.0 g, 6.77 mmol) and ethanol (230 g) were
added. The suspension was stirred, then heated up to approxi-
mately 72 °C to give a clear solution. The solution was then gradu-
ally cooled, seeded (2 mg) at 71 °C, kept for 2 h at 62–64 °C
1
(
corresponding to the crystallization temperature), and then
cooled again to 20 °C. After leaving the suspension at this temper-
ature overnight, the crystals were filtered off and washed twice
with ethanol (8 mL in total) to give wet salt crystals, which were
dried at 60 °C for 3 h to afford pure (S)-1/2(S)-2 salt (4.4 g, yield
8
8%, 96% de). Analytical data for the recrystallized salt are as fol-
2
5
4
.2. Determination of diastereomeric excess of 1 in the salt
lows. (S)-1/2(S)-2: ½
aꢁ
¼ ꢂ7:0 (c 0.01, MeOH/H O = 1/1); 96% de;
D
2
ꢂ1
Mp 193.0–195.0 °C; IR (KBr) cm : 3449, 3211, 3185, 1655, 1551,
1
The diastereomeric excess (de%) of the salt was based on the
1524, 1390, 1323, 1162; H NMR (CD OD, 500 MHz): d 7.55–7.53
3
enantiomeric excess (ee%) of 1 liberated from the salt. The enantio-
meric excess of 1 was determined by HPLC using an Inertsil ODS-2
(4H, m), 7.22 (4H, d, J = 8.0 Hz), 7.18–7.12 (10H, m), 3.82 (2H, dd,
J = 7.5, 5.0 Hz), 3.36 (1H, dd, J = 12.0, 4.0 Hz), 3.30–3.26 (1H, m),
3.15 (1H, dt, J = 13.0, 4.0 Hz), 3.01 (2H, dd, J = 13.5, 5.0 Hz), 2.86–
2.81 (1H, m), 2.84 (2H, dd, J = 13.5, 7.5 Hz), 2.81 (1H, dd, J = 12.0,
10.0 Hz), 2.09–2.03 (1H, m), 1.94 (1H, dquit, J = 15.0, 4.0 Hz), 1.70
(1H, dtt, J = 15.0, 11.0, 4.0 Hz), 1.55 (1H, dtd, J = 13.0, 11.0,
4.0 Hz); Anal. Calcd for C37H46N O S (FW 738.91): C, 60.14; H,
column (GL Science, 5
the enantiomeric excess determined by HPLC analysis was as fol-
low: (R)-1/2(S)-2/H 80 mg [(0.106 mmol), containing (R)-1
10 mg)] was placed in a vial to which 1 M NaOH aq (0.6 mL) and
lm, 4.6 ꢀ 150 mm). Sample preparation for
2
O
(
CH
3
CN (5 mL) were added. The solution (0.1 mL) was transferred
-tartaric acid anhydride ( -PTAN)
4
8 2
to a vial, and 0.8% di-p-toluoyl-
L
L
6.27; N, 7.58. Found C, 60.14; H, 6.13; N, 7.63.

2
24
R. Sakurai et al. / Tetrahedron: Asymmetry 23 (2012) 221–224
4
.3.2. Preparation of the (R)-1/2(S)-2/H
To a 50 mL flask, free diamine (RS)-1 (3.0 g, 30.0 mmol) and
methanol (18 g) were added. The solution was stirred, and (S)-2
9.6 g, 30.0 mmol) was added at room temperature, and then
2
O salt
1.70 (1H, dtt, J = 14.5, 11.0, 4.0 Hz), 1.55 (1H, dtd, J = 14.0, 11.0,
4.0 Hz); Water content (KF): calcd for 1.0 equiv: 2.38%. found:
2.38%. Anal. Calcd for C37H N O S (FW 756.93): C, 58.71; H,
48 4 9 2
6.39; N, 7.40. Found C, 58.77; H, 6.29; N, 7.39.
(
heated up to approximately 60 °C to give a clear solution. The mix-
ture was gradually cooled to 35 °C, kept for 2 h at 34–36 °C (corre-
sponding to the crystallization temperature), and then gradually
cooled again to 20 °C. After aging the suspension at this tempera-
ture for 2 h, crystals were filtered off and washed twice with meth-
anol (6 mL in total) to yield wet salt crystals, which were dried at
References
1
2
.
.
Rouhi, A. M. Chem. Eng. News, 2003, 46.
Alogliptin: (a) Deacon, C. F. Diabetes Obes. Metab. 2011, 13, 7–18; (b) Neumiller, J.
J. Clin. Ther. 2011, 33, 528–576; (c) Ghatak, S. B.; Patel, D. S.; Shanker, N.;
Srivastava, A.; Deshpande, S. S.; Panchal, S. J. Curr. Diab. Rev. 2010, 6, 410–421.
Linagliptin: (a) Prabavathy, N.; Vijayakumari, M.; Minil, M.; Sathiyaraj, U.;
Kavimani, S. Int. J. Pharm. Bio Sci. 2011, 2, 438–442; (b) Scott, L. J. Drugs 2011, 71,
3
.
6
2
0 °C for 3 h to afford the crude (R)-1/2(S)-2/H O salt (5.0 g,
6
.61 mmol, yield 22%, 91% de, E 40%).
6
11–624.
4. (a) Ciavarri, J. P.; Reddy, P. A.; Siddiqui, M. A.; Zhao, L. WO 2010088368 (2010).;
b) Ciavarri, J. P.; Reddy, P. A.; Siddiqui, M. A.; Zhao, L. US 20090175852 (2009).
(a) Sakai, K.; Sakurai, R.; Yuzawa, A.; Hirayama, N. Tetrahedron: Asymmetry 2003,
4, 3713–3718; (b) Sakai, K.; Sakurai, R.; Hirayama, N. Tetrahedron: Asymmetry
The crude salt can be recrystallized from methanol or 92% eth-
anol to afford pure (R)-1/2(S)-2/H O salt. The test results are fol-
(
2
5.
lows; from methanol: yield 83%, >99% de; from 92% ethanol:
yield 83%, >99% de. Analytical data for the recrystallized salt are
1
2004, 15, 1073–1076; (c) Sakai, K.; Sakurai, R.; Akimoto, T.; Hirayama, N. Org.
Biomol. Chem. 2005, 3, 360–365.
2
D
5
as follows. (R)-1/2(S)-2/H
1
1
2
O: ½
aꢁ
¼ ꢂ4:6 (c 0.01, MeOH/H
2
O = 1/
ꢂ1
6. Sakurai, R.; Yuzawa, A.; Sakai, K.; Hirayama, N. Crystal Growth Design 2006, 6,
606–1610.
); >99% de; Mp 175.5–177.0 °C; IR (KBr) cm : 3384, 3228,
1
656, 1569, 1411, 1386, 1306, 1160; 1H NMR (CD
3
OD, 500 MHz):
7.
Sakai, K.; Sakurai, R.; Nohira, H.; Tanaka, R.; Hirayama, N. Tetrahedron:
Asymmetry 2004, 15, 3495–3500.
d 7.55–7.53 (4H, m), 7.22 (4H, d, J = 8.0 Hz), 7.17–7.11 (10H, m),
8.
(a) Sakai, K.; Yokoyama, M.; Sakurai, R.; Hirayama, N. Tetrahedron: Asymmetry
3.82 (2H, dd, J = 7.5, 5.0 Hz), 3.35 (1H, dd, J = 12.5, 4.0 Hz), 3.28–
3.24 (1H, m), 3.15 (1H, dt, J = 12.5, 4.0 Hz), 3.01 (2H, dd, J = 13.5,
5.0 Hz), 2.87–2.80 (1H, m), 2.84 (2H, dd, J = 13.5, 7.5 Hz), 2.80
2
006, 17, 1541–1543; (b) Sakai, K.; Sakurai, R.; Hirayama, N. Tetrahedron:
Asymmetry 2006, 17, 1812–1816.
9. Sakurai, R.; Yuzawa, A.; Yamaura, M.; Sakai, K. Chirality 2010 (ISCD-22), PA-34,
2010) Sapporo.
(
(
1H, dd, J = 12.5, 9.5 Hz), 2.08–2.03 (1H, m), 1.97–1.90 (1H, m),