贝达喹啉类抗结核药物的合成进展★

doi:10.6023/cjoc202505017

有机化学 ›› 2025, Vol. 45 ›› Issue (9): 3113-3127.DOI: 10.6023/cjoc202505017 上一篇下一篇

综述与进展

贝达喹啉类抗结核药物的合成进展^★

高峰^a^,^b, 张万斌^a^,^*()

^a 上海交通大学化学化工学院上海市手性药物分子工程重点实验室变革性分子前沿科学中心上海 200240
^b 郑州上海交大产业技术研究院郑州 450018

收稿日期:2025-05-13 修回日期:2025-06-07 发布日期:2025-06-30
基金资助:
国家重点研发计划(2023YFA1506400); 上海市科技重大专项; 上海市青年科技启明星计划(24QB2705200); 国家自然科学基金(22361132533); 比尔及梅琳达·盖茨基金会(INV-008413)

Advances in Bedaquiline-Based Antitubercular Drug Synthesis^★

Feng Gao^a^,^b, Wanbin Zhang^a^,^*()

^a Frontiers Science Center for Transformative Molecules, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240
^b Zhengzhou Industrial Technology Research Institute of Shanghai Jiao Tong University, Zhengzhou 450018

Received:2025-05-13 Revised:2025-06-07 Published:2025-06-30
Contact: *E-mail: wanbin@sjtu.edu.cn
About author:
^★ Academic Papers of the 27^th Annual Meeting of the China Association for Science and Technology.
Supported by:
National Key R&D Program of China(2023YFA1506400); Shanghai Municipal Science and Technology Major Project; Shanghai Rising-Star Program(24QB2705200); National Natural Science Foundation of China(22361132533); Bill and Melinda Gates Foundation(INV-008413)

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摘要/Abstract

肺结核是严重的全球性公共卫生问题, 尤其是耐药结核病的流行, 使得传统治疗方案面临巨大挑战. 贝达喹啉作为一类新型抗结核药物, 为耐药结核病的治疗提供了重要选择. 然而, 该分子连续三取代和四取代的手性中心的构建对合成工艺提出了较高要求. 因此, 开发高效、绿色的不对称合成工艺成为研究热点. 综述了贝达喹啉类药物的合成工艺进展, 重点探讨了双金属协同催化策略等关键技术路径. 此外, 连续流合成技术作为一种新兴工艺, 因其高效、安全及易于放大等优势, 在制备贝达喹啉工艺中展现出巨大潜力. 未来, 结合新型催化体系、绿色化学及智能化生产技术的开发, 贝达喹啉类药物的合成工艺将朝着更高效环保的方向发展, 为抗结核药物的规模化生产提供重要支持.

关键词: 贝达喹啉, 抗结核药物, 不对称合成, 连续流技术

Tuberculosis remains a significant global public health concern, particularly due to the increasing prevalence of drug-resistant tuberculosis, which poses substantial challenges to traditional treatment strategies. Bedaquiline, a novel class of anti-tuberculosis drug, offers a critical alternative for managing drug-resistant tuberculosis. However, the synthesis of this compound is one of the greatest challenges in synthetic chemistry due to its contiguous tertiary and tetrasubstituted chiral centers, necessitating advanced synthetic methodologies. Consequently, the advancement of efficient and environmentally sustainable asymmetric synthesis technologies has emerged as a key research priority. This review summarizes the synthetic pathways of bedaquiline, with an emphasis on pivotal technological approaches such as bimetallic catalysis. Furthermore, continuous flow technology, owing to its inherent advantages of efficiency, safety, and scalability, demonstrates considerable promise in the production of bedaquiline. Looking ahead, the integration of innovative catalytic systems, green chemistry principles, and intelligent manufacturing technologies will likely drive the evolution of bedaquiline synthesis toward greater efficiency and environmental compatibility, thereby facilitating large-scale production of anti-tuberculosis medications.

Key words: bedaquiline, anti-tuberculosis-specific drug, asymmetric synthesis, continuous flow

引用此文

高峰, 张万斌. 贝达喹啉类抗结核药物的合成进展^★[J]. 有机化学, 2025, 45(9): 3113-3127.

Feng Gao, Wanbin Zhang. Advances in Bedaquiline-Based Antitubercular Drug Synthesis^★[J]. Chinese Journal of Organic Chemistry, 2025, 45(9): 3113-3127.

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图/表 23

图式1. 贝达喹啉及其立体异构体

Scheme 1. Bedaquiline and its stereoisomers

图式2. 贝达喹啉的工业合成路线

Scheme 2. Industrial synthesis of BDQ

图式3. 通过不饱和酮合成贝达喹啉

Scheme 3. Synthesis of BDQ via unsaturated ketone

图式4. 通过格氏试剂合成贝达喹啉

Scheme 4. Synthesis of BDQ via Grignard reagent

图式5. 通过硼酸衍生物合成贝达喹啉

Scheme 5. Synthesis of BDQ via boronic acid derivatives

图式6. Shibasaki不对称合成贝达喹啉

Scheme 6. Shibasaki’s enantioselective synthesis of BDQ

图式7. Chandrasekhar不对称合成贝达喹啉

Scheme 7. Chandrasekhar’s enantioselective synthesis of BDQ

图式8. 采用手性邻氨基醇锂不对称合成贝达喹啉

Scheme 8. Asymmetric synthesis of BDQ using lithium alkoxides

图式9. 手性邻氨基锂不对称合成贝达喹啉

Scheme 9. Asymmetric synthesis of BDQ using lithium amides

图式10. Li/Li协同活化不对称合成贝达喹啉

Scheme 10. Asymmetric synthesis of BDQ using Li/Li synergistic activation

图式11. 用于模拟收率的简化模型及计算结果

Scheme 11. Simplified model for the simulation of yield and the calculated results

图1. (a)中间体RS-a4(左)和RS-b7(右)的AIM分析; (b)中间体SS-b2 (左)和RS-b7(右)的三明治模型

Figure 1. (a) Result of atom in molecule (AIM) analysis of RS-a4 (left) and RS-b7 (right); (b) Three-layer model and details of SS-b2 (left) and three-layer model and the details of RS-b7 (right) Portions of molecules in the different layers are marked with blue, red, or green, while other parts outside the layer are black (color online)

图2. 手性脯氨酸配体

Figure 2. Chiral proline ligands

图式12. 采用手性胺基锂33提升非对映选择性

Scheme 12. Use of chiral lithium amide of 33 to promote stereoselectivity toward BDQ

图式13. 舒达吡啶的合成工艺

Scheme 13. Synthesis of sudapyridine

图式14. Li/Li双金属协同体系不对称合成TBAJ-876

Scheme 14. Asymmetric synthesis of TBAJ-876 using Li/Li bimetallic synergistic system

图3. Li/Li双金属协同体系不对称合成TBAJ-876

Figure 3. Asymmetric synthesis of TBAJ-876 using Li/Li bimetallic synergistic system

图式15. Li/Li双金属协同体系不对称合成TBAJ-587

Scheme 15. Asymmetric synthesis of TBAJ-587 using Li/Li bimetallic synergistic system

图4. Li/Li双金属协同体系不对称合成TBAJ-587

Figure 4. Asymmetric synthesis of TBAJ-587 using Li/Li bimetallic synergistic system

图式16. 利用连续流反应优化贝达喹啉的实验室合成

Scheme 16. Optimization of laboratory synthesis of bedaquiline via continuous flow

图5. 利用连续流技术合成贝达喹啉

Figure 5. Continuous flow process for the synthesis of bedaquiline

图6. 连续流工艺不对称合成贝达喹啉

Figure 6. Asymmetric synthesis of bedaquiline using continuous flow

图7. 连续流技术不对称合成TBAJ-876

Figure 7. Asymmetric synthesis of TBAJ-876 using continuous flow

参考文献 35

[1]	WHO Global Tuberculosis Report 2024, Geneva, 2024,
[2]	Dheda, K.; Mirzayev, F.; Cirillo, D. M.; Udwadia, Z.; Dooley, K. E.; Chang, K.-C.; Omar, S. V.; Reuter, A.; Perumal, T.; Horsburgh, C. R.; Murray, M.; Lange, C. Nat. Rev. Dis. Primers 2024, 10, 22.
[3]	Berida, T.; Lindsley, W. C. J. Med. Chem. 2024, 67, 21633.
[4]	Andries, K.; Verhasselt, P.; Guillemont, J.; Göhlmann, W. H. H.; Neefs, J.-M.; Winkler, H.; Gestel, Van, J.; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; Chaffoy, Huitric, E.; Hoffner, S.; Cam- bau, E.; Truffot-Pernot, C.; Lounis, N.; Jarlier, V. Science 2005, 307, 223. doi: 10.1126/science.1106753 pmid: 15591164
[5]	(a) Mahajan, R. Int. J. Appl. Basic Med. Res. 2013, 3, 1. doi: 10.4103/2229-516X.112228 pmid: 24259600
	(b) Chahine, E. B.; Karaoui, L. R.; Mansour, H. Ann. Pharmacother. 2014, 48, 107. doi: 10.1177/1060028013504087 pmid: 24259600
[6]	Guillemont, J.; Meyer, C.; Poncelet, A.; Bourdrez, X.; Andries, K. Future Med. Chem. 2011, 3, 1345. doi: 10.4155/fmc.11.79 pmid: 21879841
[7]	(a) Christoffers, J.; Baro, A. Quaternary Stereocentres: Challenges and Solutions for Organic Synthesis, Wiley-VCH, Weinheim, 2005, p. 1. pmid: 27284169
	(b) Beletskaya, I. P.; Nájera, C.; Yus, M. Chem. Rev. 2018, 118, 5080. doi: 10.1021/acs.chemrev.7b00561 pmid: 27284169
	(c) Tomita, D.; Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946. pmid: 27284169
	(d) Quasdor, K. W.; Overman, L. E. Nature 2014, 516, 181. pmid: 27284169
	(e) Yang, Y.; Perry, I. B.; Lu, G., Liu, P.; Buchwald, S. L. Science 2016, 353, 144. doi: 10.1126/science.aaf7720 pmid: 27284169
[8]	Andries, K.; Gestel, J. V. EP 1527050B1, 2004.
[9]	Janssen Pharmaceutica N. V. WO 2006125769A1, 2005.
[10]	Li, J.; Liu, Y.; Bing, S.CN 105085395, 2015.
[11]	Weng, M.; Wang, Z.CN 105175329, 2015.
[12]	(a) Lin, G.; Yang, F.; Han, J.; Geng, Y.; Hao, Y.; Ma, G.; Yan, M.; Pan, H.CN 105198808, 2014.
	(b) Feng, W.; Kong, D.CN 105017147, 2014.
[13]	Zheng, G.; Wang, Y.; Zhang, W.; Wang, Z.; Wang, Z.; Kurt, M.; Hu, K.; Pei, R.; Zhang, F.CN 111747975, 2020.
[14]	Saga, Y.; Motoki, R.; Makino, S.; Shimizu, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem Soc. 2010, 132, 7905. doi: 10.1021/ja103183r
[15]	Chandrasekhar, S.; Babu, G. S. K.; Mohapatra, D. K. Eur. J. Org. Chem. 2011, 2011, 2057.
[16]	Zhao, X.; Huang, Y.; Zheng, Z.; Lin, Y.; Chen, Z.CN 106866525, 2017.
[17]	Lubanyana, H.; Arvidsson, P. I.; Govender, T.; Kruger, G. H.; Naicker, T. ACS Omega 2020, 5, 3607.
[18]	Huo, X.; He, R.; Zhang, X.; Zhang, W. J. Am. Chem. Soc. 2016, 138, 11093.
[19]	Wu, Y.; Huo, X.; Zhang, W. Chem.-Eur. J. 2020, 26, 4895.
[20]	Huo, X.; Li, G.; Wang, X.; Zhang, W. Angew. Chem., nt. Ed. 2022, 61, e202210086.
[21]	Li, P.; Zheng, E.; Li, G.; Luo, Y.; Huo, X.; Ma, S.; Zhang, W. Science 2024, 385, 972.
[22]	Chen, J.; Zhang, Z.; Li, B.; Li, F.; Wang, Y.; Zhao, M.; Gridnev, D. I.; Imamoto, T.; Zhang, W. Nat. Commun. 2018, 9, 5000.
[23]	Hu, Y.; Zhang, Z.; Zhang, J.; Liu, Y.; Gridnev, D. I.; Zhang, W. Angew. Chem., nt. Ed. 2019, 58, 15767.
[24]	Chen, J.; Wei, H.; Gridnev, D. I.; Zhang, W. Angew. Chem., Int. Ed. 2025, 64, e202425589.
[25]	Gao, F.; Li, J.; Ahmad, T.; Luo, Y.; Zhang, Z.; Yuan, Q.; Huo, X.; Song, T.; Zhang, W. Sci. China Chem. 2022, 65, 1968.
[26]	Liu, W.; Lu, X.; Wang, X.; Bao, H.; Ling, R.; Tao, R.CN 117603137, 2023.
[27]	Robey, M. S. J.; Maity, S.; Aleshire, L. S.; Ghosh, A.; Yadaw, K. A.; Roy, S.; Mear, J. S.; Jamison, F. T.; Sirasani, G.; Senanayake, H. C.; Stringham, W. R.; Gupton, B. F.; Donsbach, O. K.; Nelson, C. R.; Shanahan, S. C. Org. Process Res. Dev. 2023, 27, 2146.
[28]	(a) Sarathy, J. P.; Ragunathan, P.; Shin, J.; Cooper, B. C.; Upton, M. A.; Grüber, G.; Dickd, T. Antimicrob. Agents Chemother. 2019, 63, e01191.
	(b) Yao, R.; Wang, B.; Fu, L.; Li, L.; You, K.; Li, Y.-G.; Lu, Y. Microbiol. Spectrum 2022, 10, e02477.
	(c) Calvert, B. M.; Furkert, P. D.; Cooper, B. C.; Brimble, A. M. Bioorg. Med. Chem. Lett. 2020, 30, 127172.
	(d) Choi, J. P.; Conole, D.; Sutherland, S. H.; Blaser, A.; Tong, S. T. A.; Cooper, B. C.; Upton, M. A.; Palmer, D. B.; Denny, A. W. Molecules 2020, 25, 1423.
[29]	(a) Huang, Z.; Ding, Z. Tang, D.; Wang, Y.; Li, Z.CN 108473428, 2017.
	(b) Huang, Z.; Luo, W.; Xu, D.; Guo, F.; Yang, M.; Zhu, Y.; Shen, L.; Chen, S.; Tang, D.; Li, L.; Li, Y.; Wang, B.; Franzblau, S.; Ding, C. Bioorg. Med. Chem. Lett. 2022, 71, 128824.
[30]	Li, J.; Gao, F.; Ahmad, T.; Luo, Y.; Zhang, Z.; Yuan, Q.; Zhang, W. Chin. J. Chem. 2023, 41, 1319.
[31]	Ahmad, T.; Gao, F.; Li, J.; Zhang, Z.; Song, T.; Yuan, Q.; Zhang, W. J. Org. Chem. 2023, 88, 7601.
[32]	Mear, S.; Lucas, T.; Ahlqvist, G.; Robey, J.; Dietz, J.-P.; Khairnar, P.; Maity, S.; Williams, C.; Snead, D.; Nelson, R.; Opatz, T.; Jamison, T. Chem.-Eur. J. 2022, 28, e202201311.
[33]	Pei, G.; Wang, C.; Su, R.; Wu, C.; Sun, T.; Yuan, Q. Cent. South Pharm. 2022, 20, 2490.
[34]	(a) Zhang, Y.; Zhang, W.; Yu, W.; Gao, F.; Jiang, X.; Li, J.; Wu, L.; Zhang, Z.; Fu, Y.; Wang, Y.CN 220696701, 2023.
	(b) Zhang, W.; Zhang, Y.; Gao, F.; Yu, W.; Li, J.; Jiang, X.; Zhang, Z.; Wu, L.; Wang, Y.; Fu, Y.CN 105017147, 2014.
[35]	Gao, F.; Li, J.; Zhang, G.; Gu, W.; Zhang, Z.; Liu, Z.; Zhang, W. Org. Process Res. Dev. 2024, 28, 1869.

贝达喹啉类抗结核药物的合成进展^★

Advances in Bedaquiline-Based Antitubercular Drug Synthesis^★

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贝达喹啉类抗结核药物的合成进展★

Advances in Bedaquiline-Based Antitubercular Drug Synthesis★

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贝达喹啉类抗结核药物的合成进展^★

Advances in Bedaquiline-Based Antitubercular Drug Synthesis^★