Advances in Bedaquiline-Based Antitubercular Drug Synthesis★

doi:10.6023/cjoc202505017

Chinese Journal of Organic Chemistry ›› 2025, Vol. 45 ›› Issue (9): 3113-3127.DOI: 10.6023/cjoc202505017 Previous Articles Next Articles

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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)

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

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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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Fig. & Tab. 23

Scheme 1. Bedaquiline and its stereoisomers

Scheme 2. Industrial synthesis of BDQ

Scheme 3. Synthesis of BDQ via unsaturated ketone

Scheme 4. Synthesis of BDQ via Grignard reagent

Scheme 5. Synthesis of BDQ via boronic acid derivatives

Scheme 6. Shibasaki’s enantioselective synthesis of BDQ

Scheme 7. Chandrasekhar’s enantioselective synthesis of BDQ

Scheme 8. Asymmetric synthesis of BDQ using lithium alkoxides

Scheme 9. Asymmetric synthesis of BDQ using lithium amides

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

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

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)

Figure 2. Chiral proline ligands

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

Scheme 13. Synthesis of sudapyridine

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

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

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

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

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

Figure 5. Continuous flow process for the synthesis of bedaquiline

Figure 6. Asymmetric synthesis of bedaquiline using continuous flow

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

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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★

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Abstract

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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^★