Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis

Abstract

Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores, resulting in considerable industrial and societal impacts; however, many hurdles persist that limit the number of sequential steps that can be achieved in such systems, including solvent and reagent incompatibility between individual steps, cumulated by-product formation, risk of clogging and mismatch of timescales between steps in a processing chain. To address these limitations, herein we report a strategy that merges solid-phase synthesis and continuous-flow operation, enabling push-button automated multistep syntheses of active pharmaceutical ingredients. We demonstrate our platform with a six-step synthesis of prexasertib in 65% isolated yield after 32 h of continuous execution. As there are no interactions between individual synthetic steps in the sequence, the established chemical recipe file was directly adopted or slightly modified for the synthesis of twenty-three prexasertib derivatives, enabling both automated early and late-stage diversification.

Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients

“…Liu et al , 33 demonstrated an end-to-end automated continuous flow synthesis of prexasertib 10 ; a compound that belongs to phenylpyrazoles class of compounds. It is an ATP checkpoint kinase inhibitor active against kinases 1 and 2 (CHK1 and CHK2).…”

“…It is an ATP checkpoint kinase inhibitor active against kinases 1 and 2 (CHK1 and CHK2). 33 Cole and coworkers 34 first demonstrated an eight-step batch synthesis procedure for prexasertib monolactate monohydrate (Fig. 2).…”

“…This procedure was then translated into continuous flow, a three stage semi-continuous cGMP process resulted in desired product at 85% yield and 1.99 kg per day throughput of prexasertib 10 . 34 In a recent example, Liu et al , 33 developed a six steps batch synthesis of prexasertib 10 starting from 2-chlorotrityl chloride 4 to afford 10 in 57% overall yield. Thereafter, the solid-phase synthesis (SPS) batch process was translated to continuous flow, which proved to be straight forward (Fig.…”

Continuous Flow Synthesis of Anticancer Drugs

“…The reported batch synthesis has several drawbacks such as high catalyst loadings, low yields, long reaction times, and the use of a potentially explosive coupling reagent (HATU) which would be a concern in a large-scale batch synthesis [74,45].…”

“…Additional studies towards automated access to prexasertib and various analogs have been reported recently by Liu et al outlining the exploitation of solid-phase assisted synthesis for these targets [74].…”