The Synthesis Of Bedaquiline And Recovery Of Its Inactive Stereoisomers And The Synthesis Of Its Derivatives

This thesis mainly involves the synthesis of bedaquiline and recovery of its inactive stereoisomers and the synthesis of its derivatives.Bedaquiline (trade name Sirturo), which inhibits the proton pump of M. tuberculosis’s ATP synthase, was developed by Johnson&Johnson and represented the first drug with a novel structure and mechanism for pulmonary MDR-TB in over40years. The current preparation process of bedaquiline requires the separation of active bedaquiline from a mixture of four isomers. Since Bedaquiline containing two chiral centers, so theoretically separation can only get25%of the products. Clearly, the other three undesired stereoisomers will inevitably lead to a huge waste of starting materials. In this thesis, a new method for the asymmetric synthesis of bedaquiline was studied, due to its special structure, this work don’t be completed. In the process of racemization reaction of inactive isomers, elimination of the hydroxyl group is different to our expected result, but we also found an interesting phenomenon, these inactive isomers of bedaquiline could be transformed to materials. Meanwhile, methodological research was studied to investigate the effects of solvents, alkalis, temperature, substrate structure and other factors on the reaction. By optimizing the reaction conditions, the total yield was reached90%. Besides, a series of diaryl quinoline compounds was synthesised and employed in this reaction for explaining the mechanism of C-C bond cleavage. In this studies, we discovered a classes of C-C bond cleavage reaction in aryl-substituted ethanol compounds, and we initially described its mechanism. Finally, we took bedaquiline as the lead compound, combined structure-activity relationships of DARQ compounds, to design and synthesis of a series of representative compounds. We also hope that these compounds will have excellent antibacterial activity.