Scalable Multigram Syntheses of Antimalarial 4(1H)‐Quinolones ELQ‐300 and P4Q‐391

Abstract

Antimalarial compounds ELQ‐300 and P4Q‐391 are highly potent against the blood and the liver stages of the Plasmodium parasite and also possess potent transmission‐blocking activity. Gram amounts of these two compounds were required for extensive assessment of in vivo efficacy, pharmacokinetics, and safety. Several deficiencies existed in the original synthetic routes of ELQ‐300 and P4Q‐391 including reliance on toxic heavy‐metal reagents, harsh reaction conditions, and several low‐yielding steps. Herein, we report the development of two alternative syntheses, which are reliable, high yielding, scalable, and have the potential to become a route of choice at process scale.

New Scalable Synthetic Routes to ELQ-300, ELQ-316, and Other Antiparasitic Quinolones

“…This approach would avoid the use of copper in the synthetic sequence, as iodine­(III) mediates the formation of the diaryl ether C–O bond. A similar strategy has been used in previous syntheses of ELQ-300 with symmetrical diaryliodonium salts. , In our case, we considered the use of an unsymmetrical diaryliodonium salt in which a relatively inexpensive aryl auxiliary replaces half of the desired aryl group, which would otherwise go to the waste stream, in the coupling with an appropriate phenol. Aryl­(TMP)­iodonium salts (TMP = 2,4,6-trimethoxyphenyl) were a logical choice given their established chemoselective aryl transfer, scalable synthesis, and use in C–O coupling, and the low cost of the auxiliary precursor, 1,3,5-trimethoxybenzene.…”

“…Recently, the synthesis of 3-diaryl ether 4(1H)-quinolones via substituted β-keto esters has been revisited. 28,29 However, these routes were not shown to be amenable to industrial-scale production. Our optimized approach, presented here, is relatively short (five reaction steps), does not require palladium, involves no chromatographic separation, and avoids high vacuum distillation.…”

“…As part of our effort to establish a synthetic route to sythesize ELQ-300 which would be amenable to industrial-scale preparation, we returned to Andersag’s original method by which 3-substituted 4­(1 H )-quinolones were prepared from substituted β-keto esters using the Conrad–Limpach reaction as the final step. Recently, the synthesis of 3-diaryl ether 4­(1 H )-quinolones via substituted β-keto esters has been revisited. , However, these routes were not shown to be amenable to industrial-scale production. Our optimized approach, presented here, is relatively short (five reaction steps), does not require palladium, involves no chromatographic separation, and avoids high vacuum distillation.…”