C-N Bond Formation by Consecutive Continuous-Flow Reductions towards A Medicinally Relevant Piperazine Derivative.

Zsolt Fülöp,István Greiner,Péter Bana,János Éles

doi:10.3390/molecules26072040

Zsolt Fülöp, István Greiner + Show 2 more

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https://doi.org/10.3390/molecules26072040

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Abstract

A new, continuous-flow consecutive reduction method was developed for the C-N bond formation in the synthesis of the key intermediate of the antipsychotic drug cariprazine. The two-step procedure consists of a DIBAL-H mediated selective ester reduction conducted in a novel, miniature alternating diameter reactor, followed by reductive amination using catalytic hydrogenation on 5% Pt/C. The connection of the optimized modules was accomplished using an at-line extraction to prevent precipitation of the aluminum salt byproducts.

Highlights

As a key driver of the current molecular industrial revolution [1], the modular nature of flow chemistry [2,3,4,5] facilitates the automated production of small molecules by enabling the construction of continuous-flow modules, which are responsible for the synthesis of certain structural elements [6,7,8]
Several successful approaches have been recently described within the field of central nervous system (CNS) drugs, including the integrated continuous-flow syntheses of flibanserin [22], ketamine [23], paroxetine [24], tramadol [25], or baclofen [26]
active pharmaceutical ingredients (APIs) [30], we aimed to explore the key C-N bond formation through the production of its tert-butoxycarbonyl protected intermediate (3)

Summary

Introduction

As a key driver of the current molecular industrial revolution [1], the modular nature of flow chemistry [2,3,4,5] facilitates the automated production of small molecules by enabling the construction of continuous-flow modules, which are responsible for the synthesis of certain structural elements [6,7,8] Integration of such modules leads to the development of end-to-end systems [9,10,11] capable of the continuous-flow preparation of active pharmaceutical ingredients (APIs) from simple compounds, with advanced safety features and straightforward scalability [12,13,14,15,16,17,18,19]. As a continuation of our efforts to develop a continuous-flow protocol for the synthesis of this

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