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Dielectrically controlled resolution (DCR) of 3-aminopiperidine via diastereomeric salt formation with N-tosyl-(S)-phenylalanine
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 Rumiko Sakurai a,⇑, Kenichi Sakai b, Koichi Kodama c, Masanori Yamaura a 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 c Department of Applied Chemistry, Saitama University, Sakura-ku, Saitama 338-8570, Japan b
a r t i c l e
i n f o
Article history: Received 21 December 2011 Accepted 31 December 2011 Available online 13 March 2012
a b s t r a c t 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-soluble diastereomeric salt with (S)-2, via a dielectrically controlled resolution (DCR) phenomenon. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Resolution via diastereomeric salt formation is widely known as a reliable method to obtain various enantiopure compounds, especially 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 crystallization process. In fact, more than half of the chiral pharmaceutical intermediates on a market have been produced by this method.1 (R)-3-Aminopiperidine 1 is known as a useful key molecule for a dipeptidyl peptidase-4 (DPP-4) inhibitor2,3 and a protein kinase inhibitor.4 However, the resolution of (RS)-1 via diastereomeric salt formation has not been reported so far. With regards to the resolution 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) phenomenon 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 resolution of mono-amino compounds such as 3,5 4,6 6,7 and 88 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 resolution of (RS)-1 via diastereomeric salt formation and that the DCR phenomenon is observed (Fig. 2).9
2.1. Optimum resolving agent for (RS)-1
⇑ Corresponding author. E-mail address: [email protected] (R. Sakurai). 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2012.02.002
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 solvent. 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 diastereomeric 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 (R)-1 and (S)-1 were (R)-1/2(S)-2/H2O and (S)-1/2(S)-2, respectively. 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 mechanisms for crystallizing the respective salt crystal.
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R. Sakurai et al. / Tetrahedron: Asymmetry 23 (2012) 221–224
O
COOH
NH2
HN
HN
(RS)-3
OH
H N
HOOC
Ts
COOH OH
(S)-2
(RS)-4
(R,R)-5
OH
OH NH2
COOH
COOH
NH2 (RS)-6
(S)-7
(RS)-8
(S)-7
Figure 1. Resolution systems showing the DCR phenomenon.
NH2 2 (S)-2
N H
H2O
NH2
(S)-2 MeOH
(R)-1
N H
NH2
(S)-2 EtOH
2 (S)-2
N H (S)-1
(RS)-1 COOH HN
Ts
(S)-2 Figure 2. Dielectrically controlled resolution of (RS)-1 with (S)-2.
Table 1 Resolution of (RS)-1 with various resolving agents
a b c
Entry
Resolving agenta
Molar ratio (equiv)
Solvent
Solvent volume versus (RS)-1 (w/w)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
(S)-7
1.0
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 30 30 20 20
2.0 (R)-9
1.0 1.5
(S)-2
2.0 1.0
1.5 2.0
Yieldb (%) Not crystallized Not crystallized Not crystallized Oil obtained 6 35 32 43 Oil obtained 22 27 33 46 86
de (%)
Resolution efficiencyc (E)
Absolute configuration of 1
74 20 66 70
9 14 42 60
(R) (R) (R) (R)
91 89 51 63 14
40 48 34 58 24
(R) (S) (S) (R) (R)
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 order to determine the applicable range of the DCR phenomenon for the resolution of (RS)-1 with (S)-2, various dielectric constants (e) 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 e 5 27 gave (S)-1/2(S)-2 while e = 28 gave (R)-1/2(S)-2/H2O. These data reveal that methanol is useful for (R)-1 while ethanol is useful for (S)-1.
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. 3. Conclusion 3-Aminopiperadine 1, a useful key intermediate for a DPP-4 inhibitor, was successfully resolved with an enantiomerically pure resolving agent, N-tosyl-(S)-phenylalanine 2. Moreover, we found
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R. Sakurai et al. / Tetrahedron: Asymmetry 23 (2012) 221–224 Table 2 Resolution of (RS)-1 with (S)-2 in alcoholic solventsa
a b
Entry
Solvent (w/w)
1 2 3 4 5 6 7 8
2-PrOH EtOH 96% EtOH 95% EtOH 92% EtOH MeOH 90% MeOH 70% MeOH
Dielectric constantb (e)
Solvent volume versus (RS)-1 (w/w)
18 24 26 27 28 33 38 47
30 30 33 33 22 6 4 4
Yield (%)
de (%)
33 27 22 26 16 22 11 11
51 89 93 88 94 91 82 46
Resolution efficiency (E)
Absolute configuration of 1
34 48 41 46 30 40 18 10
(S) (S) (S) (S) (R) (R) (R) (R)
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.
in CH3CN (0.5 mL) was added to the solution. The mixture was allowed to stand for 15 min at room temperature, after which Nacylation proceeded to yield N-acyl 1. To the solution were added 2.0% phosphoric acid solution (0.1 mL) and CH3CN (2.5 mL), and then the insolubles were removed by filtration. The filtrate (5 lL) was injected into the HPLC. Analytical conditions for the HPLC were as follows; eluent: 0.03% NH3 aq solution (acidified with acetic acid to pH 4.9) + methanol (50/50), 1.0 mL/min, 40 °C, detected at 254 nm, injection sample 5 lL. Retention times: the (S)-enantiomer 39.4 min, the (R)-enantiomer 42.5 min. The sample for diastereomeric excess analysis by HPLC was treated with L-PTAN prior to injection.
100
Diastereomeric excess (% de) (R )-form (S )-form
80 60 40 20 0 -20 -40 -60 -80
4.3. Resolution procedure
-100 10
20
30
40
50
Dielectric constant (ε) Figure 3. Configuration change with the solvent dielectric constant.
that this resolution of di-amine 1 with (S)-2 was the first example of a DCR phenomenon. This result suggests that the DCR phenomenon might be observed in other types of compounds, not only in mono-amino compounds. 4. Experimental 4.1. General (RS)-3-Aminopiperidine 1 (containing 1.7% of water) and N-tosyl-(S)-phenylalanine 2 (>99.5% ee) were made by Yamakawa Chemical Industry Co., Ltd (Tokyo). 1H NMR spectra were recorded on a JEOL ECA-500 spectrometer in CD3OD. IR spectra were measured 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 JASCO Intelligent HPLC system equipped with UV-2075 detector. Melting points were determined with a Yanaco MP-S3 instrument and are uncorrected. 4.2. Determination of diastereomeric excess of 1 in the salt The diastereomeric excess (de%) of the salt was based on the enantiomeric excess (ee%) of 1 liberated from the salt. The enantiomeric excess of 1 was determined by HPLC using an Inertsil ODS-2 column (GL Science, 5 lm, 4.6 150 mm). Sample preparation for the enantiomeric excess determined by HPLC analysis was as follow: (R)-1/2(S)-2/H2O 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 CH3CN (5 mL) were added. The solution (0.1 mL) was transferred to a vial, and 0.8% di-p-toluoyl-L-tartaric acid anhydride (L-PTAN)
4.3.1. Preparation of the (S)-1/2(S)-2 salt A typical experimental procedure involving the preparation of (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 60 °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 crystallization 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 48%). The crude salt was recrystallized from ethanol. To a 500 mL 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 approximately 72 °C to give a clear solution. The solution was then gradually cooled, seeded (2 mg) at 71 °C, kept for 2 h at 62–64 °C (corresponding to the crystallization temperature), and then cooled again to 20 °C. After leaving the suspension at this temperature 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 88%, 96% de). Analytical data for the recrystallized salt are as follows. (S)-1/2(S)-2: ½a25 D ¼ 7:0 (c 0.01, MeOH/H2O = 1/1); 96% de; Mp 193.0–195.0 °C; IR (KBr) cm1: 3449, 3211, 3185, 1655, 1551, 1524, 1390, 1323, 1162; 1H NMR (CD3OD, 500 MHz): d 7.55–7.53 (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 C37H46N4O8S2 (FW 738.91): C, 60.14; H, 6.27; N, 7.58. Found C, 60.14; H, 6.13; N, 7.63.
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R. Sakurai et al. / Tetrahedron: Asymmetry 23 (2012) 221–224
4.3.2. Preparation of the (R)-1/2(S)-2/H2O salt 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 heated up to approximately 60 °C to give a clear solution. The mixture was gradually cooled to 35 °C, kept for 2 h at 34–36 °C (corresponding to the crystallization temperature), and then gradually cooled again to 20 °C. After aging the suspension at this temperature for 2 h, crystals were filtered off and washed twice with methanol (6 mL in total) to yield wet salt crystals, which were dried at 60 °C for 3 h to afford the crude (R)-1/2(S)-2/H2O salt (5.0 g, 6.61 mmol, yield 22%, 91% de, E 40%). The crude salt can be recrystallized from methanol or 92% ethanol to afford pure (R)-1/2(S)-2/H2O salt. The test results are follows; from methanol: yield 83%, >99% de; from 92% ethanol: yield 83%, >99% de. Analytical data for the recrystallized salt are as follows. (R)-1/2(S)-2/H2O: ½a25 D ¼ 4:6 (c 0.01, MeOH/H2O = 1/ 1); >99% de; Mp 175.5–177.0 °C; IR (KBr) cm1: 3384, 3228, 1656, 1569, 1411, 1386, 1306, 1160; 1H NMR (CD3OD, 500 MHz): d 7.55–7.53 (4H, m), 7.22 (4H, d, J = 8.0 Hz), 7.17–7.11 (10H, m), 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 (1H, dd, J = 12.5, 9.5 Hz), 2.08–2.03 (1H, m), 1.97–1.90 (1H, m),
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 C37H48N4O9S2 (FW 756.93): C, 58.71; H, 6.39; N, 7.40. Found C, 58.77; H, 6.29; N, 7.39. References 1. Rouhi, A. M. Chem. Eng. News, 2003, 46. 2. 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. 3. 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, 611–624. 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). 5. (a) Sakai, K.; Sakurai, R.; Yuzawa, A.; Hirayama, N. Tetrahedron: Asymmetry 2003, 14, 3713–3718; (b) Sakai, K.; Sakurai, R.; Hirayama, N. Tetrahedron: Asymmetry 2004, 15, 1073–1076; (c) Sakai, K.; Sakurai, R.; Akimoto, T.; Hirayama, N. Org. Biomol. Chem. 2005, 3, 360–365. 6. Sakurai, R.; Yuzawa, A.; Sakai, K.; Hirayama, N. Crystal Growth Design 2006, 6, 1606–1610. 7. Sakai, K.; Sakurai, R.; Nohira, H.; Tanaka, R.; Hirayama, N. Tetrahedron: Asymmetry 2004, 15, 3495–3500. 8. (a) Sakai, K.; Yokoyama, M.; Sakurai, R.; Hirayama, N. Tetrahedron: Asymmetry 2006, 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.
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 Rumiko Sakurai a,⇑, Kenichi Sakai b, Koichi Kodama c, Masanori Yamaura a 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 c Department of Applied Chemistry, Saitama University, Sakura-ku, Saitama 338-8570, Japan b
a r t i c l e
i n f o
Article history: Received 21 December 2011 Accepted 31 December 2011 Available online 13 March 2012
a b s t r a c t 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-soluble diastereomeric salt with (S)-2, via a dielectrically controlled resolution (DCR) phenomenon. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Resolution via diastereomeric salt formation is widely known as a reliable method to obtain various enantiopure compounds, especially 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 crystallization process. In fact, more than half of the chiral pharmaceutical intermediates on a market have been produced by this method.1 (R)-3-Aminopiperidine 1 is known as a useful key molecule for a dipeptidyl peptidase-4 (DPP-4) inhibitor2,3 and a protein kinase inhibitor.4 However, the resolution of (RS)-1 via diastereomeric salt formation has not been reported so far. With regards to the resolution 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) phenomenon 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 resolution of mono-amino compounds such as 3,5 4,6 6,7 and 88 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 resolution of (RS)-1 via diastereomeric salt formation and that the DCR phenomenon is observed (Fig. 2).9
2.1. Optimum resolving agent for (RS)-1
⇑ Corresponding author. E-mail address: [email protected] (R. Sakurai). 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2012.02.002
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 solvent. 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 diastereomeric 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 (R)-1 and (S)-1 were (R)-1/2(S)-2/H2O and (S)-1/2(S)-2, respectively. 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 mechanisms for crystallizing the respective salt crystal.
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R. Sakurai et al. / Tetrahedron: Asymmetry 23 (2012) 221–224
O
COOH
NH2
HN
HN
(RS)-3
OH
H N
HOOC
Ts
COOH OH
(S)-2
(RS)-4
(R,R)-5
OH
OH NH2
COOH
COOH
NH2 (RS)-6
(S)-7
(RS)-8
(S)-7
Figure 1. Resolution systems showing the DCR phenomenon.
NH2 2 (S)-2
N H
H2O
NH2
(S)-2 MeOH
(R)-1
N H
NH2
(S)-2 EtOH
2 (S)-2
N H (S)-1
(RS)-1 COOH HN
Ts
(S)-2 Figure 2. Dielectrically controlled resolution of (RS)-1 with (S)-2.
Table 1 Resolution of (RS)-1 with various resolving agents
a b c
Entry
Resolving agenta
Molar ratio (equiv)
Solvent
Solvent volume versus (RS)-1 (w/w)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
(S)-7
1.0
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 30 30 20 20
2.0 (R)-9
1.0 1.5
(S)-2
2.0 1.0
1.5 2.0
Yieldb (%) Not crystallized Not crystallized Not crystallized Oil obtained 6 35 32 43 Oil obtained 22 27 33 46 86
de (%)
Resolution efficiencyc (E)
Absolute configuration of 1
74 20 66 70
9 14 42 60
(R) (R) (R) (R)
91 89 51 63 14
40 48 34 58 24
(R) (S) (S) (R) (R)
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 order to determine the applicable range of the DCR phenomenon for the resolution of (RS)-1 with (S)-2, various dielectric constants (e) 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 e 5 27 gave (S)-1/2(S)-2 while e = 28 gave (R)-1/2(S)-2/H2O. These data reveal that methanol is useful for (R)-1 while ethanol is useful for (S)-1.
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. 3. Conclusion 3-Aminopiperadine 1, a useful key intermediate for a DPP-4 inhibitor, was successfully resolved with an enantiomerically pure resolving agent, N-tosyl-(S)-phenylalanine 2. Moreover, we found
223
R. Sakurai et al. / Tetrahedron: Asymmetry 23 (2012) 221–224 Table 2 Resolution of (RS)-1 with (S)-2 in alcoholic solventsa
a b
Entry
Solvent (w/w)
1 2 3 4 5 6 7 8
2-PrOH EtOH 96% EtOH 95% EtOH 92% EtOH MeOH 90% MeOH 70% MeOH
Dielectric constantb (e)
Solvent volume versus (RS)-1 (w/w)
18 24 26 27 28 33 38 47
30 30 33 33 22 6 4 4
Yield (%)
de (%)
33 27 22 26 16 22 11 11
51 89 93 88 94 91 82 46
Resolution efficiency (E)
Absolute configuration of 1
34 48 41 46 30 40 18 10
(S) (S) (S) (S) (R) (R) (R) (R)
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.
in CH3CN (0.5 mL) was added to the solution. The mixture was allowed to stand for 15 min at room temperature, after which Nacylation proceeded to yield N-acyl 1. To the solution were added 2.0% phosphoric acid solution (0.1 mL) and CH3CN (2.5 mL), and then the insolubles were removed by filtration. The filtrate (5 lL) was injected into the HPLC. Analytical conditions for the HPLC were as follows; eluent: 0.03% NH3 aq solution (acidified with acetic acid to pH 4.9) + methanol (50/50), 1.0 mL/min, 40 °C, detected at 254 nm, injection sample 5 lL. Retention times: the (S)-enantiomer 39.4 min, the (R)-enantiomer 42.5 min. The sample for diastereomeric excess analysis by HPLC was treated with L-PTAN prior to injection.
100
Diastereomeric excess (% de) (R )-form (S )-form
80 60 40 20 0 -20 -40 -60 -80
4.3. Resolution procedure
-100 10
20
30
40
50
Dielectric constant (ε) Figure 3. Configuration change with the solvent dielectric constant.
that this resolution of di-amine 1 with (S)-2 was the first example of a DCR phenomenon. This result suggests that the DCR phenomenon might be observed in other types of compounds, not only in mono-amino compounds. 4. Experimental 4.1. General (RS)-3-Aminopiperidine 1 (containing 1.7% of water) and N-tosyl-(S)-phenylalanine 2 (>99.5% ee) were made by Yamakawa Chemical Industry Co., Ltd (Tokyo). 1H NMR spectra were recorded on a JEOL ECA-500 spectrometer in CD3OD. IR spectra were measured 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 JASCO Intelligent HPLC system equipped with UV-2075 detector. Melting points were determined with a Yanaco MP-S3 instrument and are uncorrected. 4.2. Determination of diastereomeric excess of 1 in the salt The diastereomeric excess (de%) of the salt was based on the enantiomeric excess (ee%) of 1 liberated from the salt. The enantiomeric excess of 1 was determined by HPLC using an Inertsil ODS-2 column (GL Science, 5 lm, 4.6 150 mm). Sample preparation for the enantiomeric excess determined by HPLC analysis was as follow: (R)-1/2(S)-2/H2O 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 CH3CN (5 mL) were added. The solution (0.1 mL) was transferred to a vial, and 0.8% di-p-toluoyl-L-tartaric acid anhydride (L-PTAN)
4.3.1. Preparation of the (S)-1/2(S)-2 salt A typical experimental procedure involving the preparation of (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 60 °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 crystallization 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 48%). The crude salt was recrystallized from ethanol. To a 500 mL 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 approximately 72 °C to give a clear solution. The solution was then gradually cooled, seeded (2 mg) at 71 °C, kept for 2 h at 62–64 °C (corresponding to the crystallization temperature), and then cooled again to 20 °C. After leaving the suspension at this temperature 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 88%, 96% de). Analytical data for the recrystallized salt are as follows. (S)-1/2(S)-2: ½a25 D ¼ 7:0 (c 0.01, MeOH/H2O = 1/1); 96% de; Mp 193.0–195.0 °C; IR (KBr) cm1: 3449, 3211, 3185, 1655, 1551, 1524, 1390, 1323, 1162; 1H NMR (CD3OD, 500 MHz): d 7.55–7.53 (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 C37H46N4O8S2 (FW 738.91): C, 60.14; H, 6.27; N, 7.58. Found C, 60.14; H, 6.13; N, 7.63.
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4.3.2. Preparation of the (R)-1/2(S)-2/H2O salt 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 heated up to approximately 60 °C to give a clear solution. The mixture was gradually cooled to 35 °C, kept for 2 h at 34–36 °C (corresponding to the crystallization temperature), and then gradually cooled again to 20 °C. After aging the suspension at this temperature for 2 h, crystals were filtered off and washed twice with methanol (6 mL in total) to yield wet salt crystals, which were dried at 60 °C for 3 h to afford the crude (R)-1/2(S)-2/H2O salt (5.0 g, 6.61 mmol, yield 22%, 91% de, E 40%). The crude salt can be recrystallized from methanol or 92% ethanol to afford pure (R)-1/2(S)-2/H2O salt. The test results are follows; from methanol: yield 83%, >99% de; from 92% ethanol: yield 83%, >99% de. Analytical data for the recrystallized salt are as follows. (R)-1/2(S)-2/H2O: ½a25 D ¼ 4:6 (c 0.01, MeOH/H2O = 1/ 1); >99% de; Mp 175.5–177.0 °C; IR (KBr) cm1: 3384, 3228, 1656, 1569, 1411, 1386, 1306, 1160; 1H NMR (CD3OD, 500 MHz): d 7.55–7.53 (4H, m), 7.22 (4H, d, J = 8.0 Hz), 7.17–7.11 (10H, m), 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 (1H, dd, J = 12.5, 9.5 Hz), 2.08–2.03 (1H, m), 1.97–1.90 (1H, m),
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 C37H48N4O9S2 (FW 756.93): C, 58.71; H, 6.39; N, 7.40. Found C, 58.77; H, 6.29; N, 7.39. References 1. Rouhi, A. M. Chem. Eng. News, 2003, 46. 2. 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. 3. 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, 611–624. 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). 5. (a) Sakai, K.; Sakurai, R.; Yuzawa, A.; Hirayama, N. Tetrahedron: Asymmetry 2003, 14, 3713–3718; (b) Sakai, K.; Sakurai, R.; Hirayama, N. Tetrahedron: Asymmetry 2004, 15, 1073–1076; (c) Sakai, K.; Sakurai, R.; Akimoto, T.; Hirayama, N. Org. Biomol. Chem. 2005, 3, 360–365. 6. Sakurai, R.; Yuzawa, A.; Sakai, K.; Hirayama, N. Crystal Growth Design 2006, 6, 1606–1610. 7. Sakai, K.; Sakurai, R.; Nohira, H.; Tanaka, R.; Hirayama, N. Tetrahedron: Asymmetry 2004, 15, 3495–3500. 8. (a) Sakai, K.; Yokoyama, M.; Sakurai, R.; Hirayama, N. Tetrahedron: Asymmetry 2006, 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.