	US 12,116,345 B2
	Low-temperature continuous-flow preparation method of bedaquiline
Wanbin Zhang, Shanghai (CN); Yaohua Zhang, Shanghai (CN); Feng Gao, Shanghai (CN); Wei Yu, Shanghai (CN); Jing Li, Shanghai (CN); Ximing Jiang, Shanghai (CN); Zhenfeng Zhang, Shanghai (CN); Liang Wu, Shanghai (CN); Yuanlin Wang, Shanghai (CN); and Yujia Fu, Shanghai (CN)
Assigned to SHANGHAI JIAOTONG UNIVERSITY, Shanghai (CN); and SPH NO.1 BIOCHEMICAL & PHARMACEUTICAL CO., LTD., Shanghai (CN)
Filed by SHANGHAI JIAOTONG UNIVERSITY, Shanghai (CN); and SPH NO.1 BIOCHEMICAL & PHARMACEUTICAL CO., LTD., Shanghai (CN)
Filed on May 21, 2024, as Appl. No. 18/670,653.
Application 18/670,653 is a continuation of application No. PCT/CN2023/138097, filed on Dec. 12, 2023.
Claims priority of application No. 202310959686.6 (CN), filed on Aug. 1, 2023.
Prior Publication US 2024/0308963 A1, Sep. 19, 2024
Int. Cl. C07D 215/227 (2006.01); B01J 19/24 (2006.01)

CPC C07D 215/227 (2013.01) [B01J 19/2415 (2013.01); B01J 2219/00033 (2013.01)]

12 Claims

1. A continuous-flow preparation method of bedaquiline, comprising:

(a) subjecting a first feed liquid and a second feed liquid to a first continuous flow reaction for 30-600 seconds to obtain a first reaction mixture;

wherein the first feed liquid is a mixture of (1S,2R)-2-amino-1, 2-diphenylethanol, N-methylpiperazine, butyllithium, lithium chloride, and tetrahydrofuran; and the second feed liquid is a mixture of 6-bromo-3-benzyl-2-methoxyquinoline and tetrahydrofuran;

(b) subjecting the first reaction mixture and a third feed liquid to a second continuous flow reaction for 30-600 seconds to obtain a second reaction mixture;

wherein the third feed liquid is a mixture of 3-dimethylamino-1-naphthyl-1-acetone and tetrahydrofuran; and