Enantioselective synthesis of (−)-tetrabenazine via continuous crystallization-induced diastereomer transformation

Abstract

A multi-well continuous CIDT approach with inline racemization of the solution phase is presented. Using two in-house built PATs and a flow reactor, we were able to successfully crystallize an...

Keeping an “eye” on the experiment: computer vision for real-time monitoring and control

“…This workflow is a critical intermediate step in the synthesis of Valbenazine drug, 51 and follows a crystallization-induced asymmetric transformation (CIAT) to convert racemic TBZ to the desired enantiomer, which is isolated as the pure (–)TBZ(–)CSA salt. 52 Advancing the synthesis requires charging a reactor with isolated crystals, suspension in a mixture of DCM and water while charging sodium hydroxide to neutralize the acid, then recovery of the free amine from the organic layer, as shown in Fig. 6c.…”

Rapid deracemization through solvent cycling: proof-of-concept using a racemizable conglomerate clopidogrel precursor

“…¶ 19 In addition, we foresee that solvent cycling processes can readily be scaled-up in conventional equipment, adapted in a continuous fashion, and implemented for the practical production of enantiopure molecules. 13,20,21 Many types of stimuli can be exploited for crystallizationinduced deracemizations; oscillating electrochemical potentials, alternating pressures or pH, photo-switchable reactions, and electromagnetic oscillations are just some of the many ways to induce continuous or alternating crystal growth and dissolution. Also, our results show the importance of cyclic physical chemical processes in synthesizing chiral molecules for practical purposes as well as in origin of life scenarios.…”

“…19 19 In addition, we foresee that solvent cycling processes can readily be scaled-up in conventional equipment, adapted in a continuous fashion, and implemented for the practical production of enantiopure molecules. 13,20,21…”

Guided optimization of a crystallization-induced diastereomer transformation to access a key navoximod intermediate

“…14 We then applied this tool to study and optimize the continuous controlled crystallization of a different API precursor using online chiral HPLC to monitor enantiomer concentrations. 15 Additionally, we demonstrated the utility of using real-time turbidity measurements to profile crystallization events and assist in solid-phase interrogation. As such, we sought to apply the same tools to the CIDT of ( S )- 1 to understand the reaction and investigate potential improvements.…”