Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline**

Abstract

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation‐addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi‐lab reproducibility led to optimized reaction conditions that feature an unusual base‐salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.

Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Antituberculosis Drug Bedaquiline

“…The effect of temperature on the BA reaction with nonchiral bases has been previously reported . It was observed in those studies that carrying out the reaction at temperatures higher than −78 °C strongly favored the retro-addition of the lithium alkoxide 10 , leading the reaction equilibrium to favor 1a and 2 (Scheme , Equilibrium B).…”

“…At a 25 and 75 g scale of quinoline 1 , BDQ ( 3 ) was achieved in a 64% assay yield (entries 4 and 5, Table ), the highest yield reported for BA reaction to date. This represents a remarkable increase in the BDQ ( 3 ) yield, more than 50% compared to our previously reported nonasymmetric approach (26–33% assay yield of 3 ) …”

“…The M4ALL has recently reported a significant improvement in the overall yield of this coupling step . It was proven that higher conversion could be achieved by replacing LDA with less hindered or stronger lithium amide bases obtained from pyrrolidine, morpholine, or N -methylpiperazine (Scheme b).…”

“…The effect of temperature on the BA reaction with nonchiral bases has been previously reported. 12 It was observed in those studies that carrying out the reaction at temperatures higher than −78 °C strongly favored the retro-addition of the lithium alkoxide 10, leading the reaction equilibrium to favor 1a and 2 (Scheme 6, Equilibrium B). Although the 1,2-addition reaction is reversible, once the temperature is increased, other undesired side reactions begin to occur, further driving the reaction equilibrium away from the addition adduct 10, even if attempts are made to restore the reaction temperature to −78 °C.…”

“…Given the thermodynamics at play in the BA reaction, we turned our attention to the effect of reaction time on the equilibria as we had explored in our previous work. 12 For the nonchiral approach using lithium pyrrolidide, lithiation time did not seem to have a significant impact on the reaction outcome and no major side reactions were observed at lower temperatures. Deprotonation of 1 is usually very fast (<15 min), and when lithiation was monitored for 90 min, the mass balance was always higher than 95% for all time points.…”