Enantioselective Organocatalysis in Microreactors: Continuous Flow Synthesis of a (S)-Pregabalin Precursor and (S)-Warfarin

Abstract

Continuous flow processes have recently emerged as a powerful technology for performing chemical transformations since they ensure some advantages over traditional batch procedures. In this work, the use of commercially available and affordable PEEK (Polyetheretherketone) and PTFE (Polytetrafluoroethylene) HPLC (High Performance Liquid Chromatography) tubing as microreactors was exploited to perform organic reactions under continuous flow conditions, as an alternative to the commercial traditional glass microreactors. The wide availability of tubing with different sizes allowed quickly running small-scale preliminary screenings, in order to optimize the reaction parameters, and then to realize under the best experimental conditions a reaction scale up for preparative purposes. The gram production of some Active Pharmaceutical Ingredients (APIs) such as (S)-Pregabalin and (S)-Warfarin was accomplished in short reaction time with high enantioselectivity, in an experimentally very simple procedure.

Green Asymmetric Organocatalysis

“…Puglisi et al. demonstrated the possibility of using HPLC connections (polytetrafluoroethylene (PTFE) tubing with a total volume of 500 μL), instead of traditional glass microreactors, to perform organocatalyzed reactions in flow . The same thiourea ( C36 ) catalyzed the gram‐scale synthesis of ( S )‐pregabalin intermediate 41 (Scheme ).…”

Process modelling, simulation and technoeconomic optimisation for continuous pharmaceutical manufacturing of (S)-warfarin

“…This paper presents the systematic evaluation of six candidate separation solvents for the continuous liquid-liquid extraction (LLE) of (S)-warfarin following the experimentally demonstrated continuous flow synthesis (Porta et al, 2015). Comparison of minimum total costs via nonlinear optimisation with LLE solvent feed rate and tank residence time as decision variables establish promising candidate LLE solvents for the CPM of (S)-warfarin.…”

“…Gerogiorgis (S)-Warfarin is an anticoagulant API, commonly known as Coumadin ® , commonly used for the treatment of deep vein thrombosis and pulmonary embolism (Porter, 2015). The continuous flow synthesis of (S)-warfarin features a single reaction and subsequent liquid-liquid extraction (LLE) process (Porta et al, 2015). Comparison of different conceptual separation process alternatives is essential for establishing cost-effective, materially efficient designs for upstream CPM configurations.…”

Design Space Identification and Visualization for Continuous Pharmaceutical Manufacturing

“…The CPM flowsheet for warfarin is shown in Figure 14 [68]. The continuous synthesis of (S)-warfarin was demonstrated by Porta et al (2015), featuring the nucleophilic addition of 4-hydroxy-coumarin to benzalacetone in the presence of TFA and a chiral amine catalyst in 1,4-dioxane [67]. Upon addition of the candidate LLE solvent, the process forms an organic (product) phase containing recovered API and an aqueous (waste) phase.…”