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

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 enantiopure salt of TBZ, the active metabolite of the tardive dyskinesia drug valbenazine. Despite discovering an undesired racemic solid phase, inline racemization combined with careful control of crystallization conditions allowed for multigram quantities of enantiopure material to be harvested using our setup. Critically, this control was made possible by the use of PATs to observe and quantify the composition of both the solid and solution phases.

Real-Time Monitoring of Solid-Liquid Slurries: Optimized Synthesis of Tetrabenazine.

Solid-liquid slurries are vital and increasingly prevalent in the pharmaceutical and chemical industries. Despite the importance of these heterogeneous systems, process control and optimization are fundamentally hindered by a lack of compatible real-time analytical techniques. We present herein an online HPLC monitoring platform enabling access to real-time compositional information on slurries. We demonstrate the system by investigating the heterogeneous synthesis reaction of tetrabenazine. Furthermore, we integrated our online HPLC platform with the orthogonal monitoring techniques of a pH probe and a microscopic imaging probe to provide additional mechanistic insight. These combined insights enable the optimization of tetrabenazine synthesis in terms of reaction time, byproduct formation, and diastereomeric purity of the final product.

N-Oxide S-O chalcogen bonding in conjugated materials.

Non-covalent bonding interactions, such as chalcogen bonding, can have a substantial effect on the electronic and physical properties of conjugated polymers and is largely dependent on the strength of interaction. Functional groups that are traditionally used to instill chalcogen bonding such as alkoxy or fluorine substituents can demand challenging synthetic effort, as well as have drastic effects on the electronics of a π-system. The incorporation of a N-oxide functionality into bithiazole-containing materials, a synthetically simple transformation, has been entirely overlooked until now. A systematic analysis of the effects of N-oxidation on the electronic and physical properties of bithiazole-containing materials has been undertaken. N-Oxidation has been found to affect the electronic band gap through increase of the HOMO and lowering of the LUMO. Furthermore, exceptionally strong intramolecular S-O chalcogen bonding interactions in the bithiazole core contribute to rigidification of the conjugated system. Computational analysis of this system has shown this N-oxide chalcogen bonding interaction to be significantly stronger than other chalcogen bonding interactions commonly exploited in conjugated materials.