Process Development and Scale-Up of (S)-tert-Butyl(6-oxopiperdin-3-yl)carbamate

doi:10.6023/cjoc202406006

Chinese Journal of Organic Chemistry ›› 2025, Vol. 45 ›› Issue (1): 220-226.DOI: 10.6023/cjoc202406006 Previous Articles Next Articles

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(S)-(6-氧代哌啶-3-基)氨基甲酸叔丁酯的工艺开发与放大

李永胜^a, 唐小雯^a, 李旭^b^,^*(), 杨鹏^a^,^*()

a 郑州大学河南先进技术研究院郑州 450001
b 河南省科学院化学研究所有限公司郑州 450002

收稿日期:2024-06-06 修回日期:2024-08-16 发布日期:2024-09-26
基金资助:
国家自然科学基金(22101268); 河南省自然科学基金面上项目(242300420180); 河南省自然科学基金面上项目(242300420193); 河南省重点研发与推广专项(科技攻关)项目(242102230180); 河南省科学院基本科研费(230603001)

Process Development and Scale-Up of (S)-tert-Butyl(6-oxopiperdin-3-yl)carbamate

Yongsheng Li^a, Xiaowen Tang^a, Xu Li^b(), Peng Yang^a()

a Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001
b Institute of Chemistry Co. Ltd, Henan Academy of Sciences, Zhengzhou 450002

Received:2024-06-06 Revised:2024-08-16 Published:2024-09-26
Contact: *E-mail: yangpeng_imb@zzu.edu.cn; lixu8928753@163.com
Supported by:
National Natural Science Foundation of China(22101268); Henan Provincial Natural Science Foundation General Project(242300420180); Henan Provincial Natural Science Foundation General Project(242300420193); Henan Provincial Key R&D and Promotion Special (Science and Technology Tackling) Project(242102230180); Basic Research Fund of Henan Academy of Sciences China(230603001)

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Abstract

An efficient four-step synthesis methodology has been devised for the synthesis of the high-value chiral pharmaceutical building block (S)-tert-butyl(6-oxopiperdin-3-yl)carbamate (1). Commencing with L-pyroglutaminol, p-tosyl (p-Ts) was innovatively employed as the activating and leaving group for the hydroxyl moiety, thereby replacing the methylsulfonyl (Ms) group. Meanwhile, dibenzylamine was successfully substituted for sodium azide as the amine source. This effectively circumventing the utilization of difficult-to-obtain controlled reagents like MsCl and the highly toxic and explosive NaN₃. The synthesis process of 1 has been comprehensively optimized, resulting in an impressive total yield of 67% at the hundred-gram scale, while maintaining a purity of 99.4% for the target product. The reagents employed throughout the synthesis route are readily available and cost-effective. The synthesis route is concise and efficient, and the purification method is simple and user-friendly, laying a robust foundation for potential industrial-scale production.

Key words: amino-piperidone, pharmaceutical intermediate, process optimization, organic synthesis

Cite this article

Yongsheng Li, Xiaowen Tang, Xu Li, Peng Yang. Process Development and Scale-Up of (S)-tert-Butyl(6-oxopiperdin-3-yl)carbamate[J]. Chinese Journal of Organic Chemistry, 2025, 45(1): 220-226.

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Fig. & Tab. 6

References 30

[1]	Vitaku, E. V.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257.
[2]	Abdelshaheed, M. M.; Fawzy, I. M.; El-Subbagh, H. I.; Youssef, K. M. Future J. Pharm. Sci. 2021, 7, 188.
[3]	Chen, Q.-S.; Li, J.-Q.; Zhang, Q.-W. Pharm. Fronts 2023, 5, e1.
[4]	Frolov, N.; Vereshchagin, A. N. Int. J. Mol. Sci. 2023, 24, 2937.
[5]	Dowarah, J.; Singh, V. P. Bioorg. Med. Chem. 2020, 28, 115263.
[6]	Goel, P.; Alam, O.; Naim, M. J.; Nawaz, F.; Iqbal, M.; Alam, M. I. Eur. J. Med. Chem. 2018, 157, 480.
[7]	Rkash, R.; Asati, V.; Kashaw, S. K.; Agarwal, S.; Parwani, D.; Bhattacharya, S.; Mallick, C. Mini-Rev. Med. Chem. 2021, 21, 362.
[8]	Sun, W.; Liao, A.; Lei, L.; Tang, X.; Wang, Y.; Wu, J. Chin. Chem. Lett. 2025, 36, 109855.
[9]	Marineau, J. J.; Hamman, K. B.; Hu, S.; Alnemy, S.; Mihalich, J.; Kabro, A.; Whitmore, K. M.; Winter, D. K.; Roy, S.; Ciblat, S.; Ke, N.; Savinainen, A.; Wilsily, A.; Malojcic, G.; Zahler, R.; Schmidt, D.; Bradley, M. J.; Waters, N. J.; Chuaqui, C. J. Med. Chem. 2022, 65, 1458.
[10]	Johannessen, L.; Henry, S.; Sawant, P.; D’lppolito, A.; Ke, N.; Lefkowitz, A.; Eaton, M.; Dworakowski, W.; Rosario, M.; Hodgson, G. Blood 2021, 138, 1205.
[11]	Blair, H. A. Drugs 2023, 83, 1315.
[12]	Liu, J.; Solan, R.; Wolk, R.; Plotka, A.; O'Gorman, M. T.; Winton, J. A.; Kaplan, J.; Purohit, V. S. Br. J. Clin. Pharmacol. 2023, 89, 2208.
[13]	Zhang, Z.; Wallace, M. B.; Feng, J.; Stafford, J. A.; Skene, R. J.; Shi, L.; Lee, B.; Aertgeerts, K.; Jennings, A.; Rongda, A.; Xu, R.; Kassel, D. B.; Kaldor, S. W.; Navre, M.; Webb, D. R.; Gwaltney II, S. L. J. Med. Chem. 2011, 54, 510.
[14]	Grimshaw, C. E.; Jennings, A.; Kamran, R.; Ueno, H.; Nishigaki, N.; Kossaka, T.; Tani, A.; Sano, H.; Kinugawa, Y.; Koumura, E.; Shi, L.; Takeuchi, K. PloS One 2016, 11, e0157509.
[15]	Feng, J.; Zhang, Z.; Wallace, M. B.; Stafford, J. A.; Kaldor, S. W.; Kassel, D. B.; Navre, M.; Shi, L.; Skene, R. J.; Asakawa, T.; Takeuchi, K.; Xu, R.; Webb, D. R.; Gwaltney, S. L. J. Med. Chem. 2007, 50, 2297.
[16]	Fujita, H.; Taniai, H.; Murayama, H.; Ohshiro, H.; Hayashi, H.; Sato, S.; Kikuchi, N.; Komatsu, T.; Komatsu, K.; Komatsu, K.; Narita, T.; Yamada, Y. Endocr. J. 2014, 61, 159.
[17]	Panday, S. K.; Langlois, N. Tetrahedron Lett. 1995, 36, 8205.
[18]	Langlois, N.; Van Bac, N.; Dahuron, N.; Delcroix, J.-M.; Deyine, A.; Griffart-Bruned, D.; Chiaroni, A.; Riche, C. Tetrahedron 1995, 51, 3571.
[19]	Langlois, N. Tetrahedron Lett. 2002, 43, 9531.
[20]	Masse, J.; Langlois, N. Heterocycles 2009, 77, 417.
[21]	Thomas, A.; Bhavar, P. K.; Lingam, V. S. P. R.; Joshi, N. K. WO 2004/022536, 2004.
[22]	Albers, R.; Ayala, L.; Clareen, S. S.; Delgado Mederos, M. M.; Hilgraf, R.; Hedge, S.; Hughes, K.; Kois, A.; Plantevin-Krenitsky, V.; Mccarrick, M.; Nadolny, L.; Palanki, M.; Sahasrabudhe, K.; Sapienza, J.; Satoh, Y.; Sloss, M.; Sudbeck, E.; Wright, J. WO 2006/076595, 2006.
[23]	Do, S.; Hu, H.; Kolesnikov, A.; Tsui, V. H.; Wang, X. WO 2014/001377, 2014.
[24]	Marineau, J. J.; Chuaqui, C.; Ciblat, S.; Kabro, A.; Piras, H.; Whitmore, K. M.; Lund, K.-L. WO 2019/143719, 2019.
[25]	Marineau, J. J.; Chuaqui, C. WO 2020/093011, 2020.
[26]	Li, L.; Zhang, Y. CN 104098563, 2014.
[27]	Huang, S.-B.; Nelson, J. S.; Weller, D. D. J. Org. Chem. 1991, 56, 6007.
[28]	Ghosh, A. K.; Leshchenko-Yashchuk, S.; Anderson, D. D.; Bal- dridge, A.; Noetzel, M.; Miller, H. B.; Tie, Y.; Wang, Y.-F.; Koh, Y.; Weber, I. T.; Mitsuya, H. J. Med. Chem. 2009, 52, 3902.
[29]	Langlois, N. Org. Lett. 2002, 4, 185.
[30]	Tan, H.; Reed, M.; Gahm, K. H.; King, T.; Seran, M. D.; Bostick, T.; Luu, V.; Semin, D.; Cheetham, J.; Larsen, R.; Martinelli, M.; Reider, P. Org. Process Res. Dev. 2008, 12, 58.

Entry	Base	Solvent	Temp.^b/℃	Dibenzyamine/equiv.	Base/equiv.	Yield^c/%
1	Et₃N	CH₃CN	85	1.1	1.0	24
2	i-Pr₂NEt	CH₃CN	85	1.1	1.0	20
3	DBU	CH₃CN	85	1.1	1.0	10
4	K₂CO₃	CH₃CN	85	1.1	1.0	89
5	Cs₂CO₃	CH₃CN	85	1.1	1.0	93
6	None	CH₃CN	85	1.1	1.0	Trace
7	K₂CO₃	THF	85	1.1	1.0	60
8	K₂CO₃	DMF	85	1.1	1.0	50
9	K₂CO₃	DMSO	85	1.1	1.0	49
10	K₂CO₃	1,4-Dioxane	85	1.1	1.0	86
11	K₂CO₃	CH₃CN	75	1.1	1.0	86
12	K₂CO₃	CH₃CN	65	1.1	1.0	74
13	K₂CO₃	CH₃CN	85	1.05	1.0	86
14	K₂CO₃	CH₃CN	85	1.05	0.8	85

Entry	Base	Solvent	Temp.^b/℃	Dibenzyamine/equiv.	Base/equiv.	Yield^c/%
1	Et₃N	CH₃CN	85	1.1	1.0	24
2	i-Pr₂NEt	CH₃CN	85	1.1	1.0	20
3	DBU	CH₃CN	85	1.1	1.0	10
4	K₂CO₃	CH₃CN	85	1.1	1.0	89
5	Cs₂CO₃	CH₃CN	85	1.1	1.0	93
6	None	CH₃CN	85	1.1	1.0	Trace
7	K₂CO₃	THF	85	1.1	1.0	60
8	K₂CO₃	DMF	85	1.1	1.0	50
9	K₂CO₃	DMSO	85	1.1	1.0	49
10	K₂CO₃	1,4-Dioxane	85	1.1	1.0	86
11	K₂CO₃	CH₃CN	75	1.1	1.0	86
12	K₂CO₃	CH₃CN	65	1.1	1.0	74
13	K₂CO₃	CH₃CN	85	1.05	1.0	86
14	K₂CO₃	CH₃CN	85	1.05	0.8	85

Entry	Conditions	Result^a
1^b	Pd/C^c (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h	1/10 (1/12, 85%)
2^b	Pd/C (1.3 mol%), H₂ (101 kPa), K₂CO₃ (0.03 equiv.), MeOH, 22 ℃, 48 h	11 (80%), 12 (10%)
3^b	Pd/C (1.3 mol%), H₂ (101 kPa), NaHCO₃ (1.0 equiv.), MeOH, 22 ℃, 48 h	1/10 (3.7/1, 88%)
4^d	Pd/C (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (89%)
5^d	Pd(OH)₂/C^e (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (75%)
6^d	Pt/C^f (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (24%)

Entry	Conditions	Result^a
1^b	Pd/C^c (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h	1/10 (1/12, 85%)
2^b	Pd/C (1.3 mol%), H₂ (101 kPa), K₂CO₃ (0.03 equiv.), MeOH, 22 ℃, 48 h	11 (80%), 12 (10%)
3^b	Pd/C (1.3 mol%), H₂ (101 kPa), NaHCO₃ (1.0 equiv.), MeOH, 22 ℃, 48 h	1/10 (3.7/1, 88%)
4^d	Pd/C (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (89%)
5^d	Pd(OH)₂/C^e (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (75%)
6^d	Pt/C^f (1.3 mol%), H₂ (101 kPa), MeOH, 22 ℃, 48 h; then K₂CO₃ (0.03 equiv.), 2 h	1 (24%)

Entry	Conditions	Yield^a/%	Purity^b/%
1	i-PrOH/petroleum ether (V∶V=1∶3, 5 mL), 22 ℃, 12 h	88	99.4
2	MeOt-Bu/petroleum ether (V∶V=1∶3, 5 mL), 22 ℃, 12 h	97	90.1
3	EtOAc/petroleum ether (V∶V=1∶3, 5 mL), 22 ℃, 12 h	96	93.7
4	EtOAc/petroleum ether (V∶V=1∶2, 5 mL), 22 ℃, 12 h	95	96.1
5	EtOAc/petroleum ether (V∶V=1∶1, 5 mL), 22 ℃, 12 h	94	96.7
6	EtOAc/petroleum ether (V∶V=1∶1, 7 mL), 22 ℃, 12 h	94	99.2
7	EtOAc/petroleum ether (V∶V=1∶1, 10 mL), 22 ℃, 12 h	94	99.8
8	EtOAc/petroleum ether (V∶V=1∶1, 10 mL), 0 ℃, 12 h	95	99.3
9	EtOAc/petroleum ether (V∶V=1∶1, 10 mL), 40 ℃, 12 h	94	99.8

(S)-(6-氧代哌啶-3-基)氨基甲酸叔丁酯的工艺开发与放大

Process Development and Scale-Up of (S)-tert-Butyl(6-oxopiperdin-3-yl)carbamate

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