A new preparation process to afuresertib, a pan-AKT inhibitor under clinical development

Afuresertib is one of the only two AKT inhibitors currently undergoing critical clinical development. The current preparations for afuresertib are limited to suboptimal overall yields and the use of hazardous chemical reagents, thereby emphasizing the need for a novel preparation method for bulk synthesis. This study provides a novel synthesis process for afuresertib that is characterized by environmentally friendly reaction conditions and improved overall yield. In this process, the starting material 4-bromothiophene-2-carboxaldehyde (17) was subjected to four reactions of chlorination, Suzuki coupling, secondary chlorination and oxidation to give the 2-thiophencarboxylic acid intermediate (5). While intermediate 10 was synthesized via four reactions including reduction, Boc protection, substitution reaction and deprotection using (S)-2-amino-3-(3-fluorophenyl)propanoic acid (6) as the starting material. Finally, the final product afuresertib in 99.6% purity by chiral HPLC analysis was prepared by condensation and deprotection reactions through the key intermediates 5 and 10. In particular, the use of highly corrosive reagent bromine is circumvented by substituting the starting material from 5-chlorothiophene-2-carboxylic acid to 4-bromothiophene-2-carbaldehyde. Moreover, explosive reagents such as borane and anhydrous hydrazine are replaced by mild reagents sodium borohydride and hydrazine hydrate, respectively. The overall yield has significantly increased from 18 to 37% from the literature to the present and streamlined the route from 11 to 10 steps. Meanwhile, the condition of Mitsunobu reaction of were optimized to increase the yield from 54 to 84%. The new route demonstrates high repeatability at 10 g scale and is better suitable for afuresertib preparation for the ongoing clinical trials.

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