The Synthesis of Warfarin Using a Reconfigurable‐Reactor Platform Integrated to a Multiple‐Variable Optimization Tool

Abstract

Optimization of the asymmetric synthesis of warfarin, an important anticoagulant, has been evaluated using a reconfigurable reaction platform capable of performing batch, continuous flow, and plug‐flow synthesis. Further, this platform has been integrated with a novel, multidimensional, multiple variable analysis tool that can evaluate multiple critical quality attributes (CQA), percent conversion and enantiomeric excess in this case, from a single injection that is repeatedly recycled in a closed loop of chromatography columns, a detector and a heart‐cut valve. Further, the new, integrated analysis system also facilitates validation of each QA, providing a high‐level of confidence in analytical measurements, which are obtained without operator intervention.

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and Sustainable Fine‐Chemical Manufacturing

“…Thestability (or alack thereof) of analytes under pH values that can range from extremely acidic (pH % 1) to extremely basic (pH % 12) Arecently published report describes amultidimensional LC technology that uses at least two LC columns connected to au niquely designed heart-cut valve (V3) and ac ommercial column selector valve (V2) to recirculate an analyte of interest (Figure 31). [23] Ak ey innovation of V3 is the semicircular flow paths etched into the rotor that allow analytes to be isolated in the heart-cutting loops and iteratively analyzed until all attributes of am ulti-attribute continuous process have been assessed from asingle analytical injection. Asingle injection at valve V1 is recycled through LC columns multiple times until all aspects of the analysis are judged complete.In at ypical run, the analyte of interest is passed twice through each LC column.…”

“…Such separation techniques were considered to be a low‐throughput offline technology until the emergence of ultraperformance liquid chromatography (UPLC) in 2004 [21] . The advancement of liquid chromatography, especially with the commercialization of two‐dimensional liquid chromatography techniques, allowed chemists to find creative ways of repurposing analytes through more than one chromatographic medium from a single injection, and to rapidly optimize and monitor multiple quality attributes for CM processes [22–24] …”

“…[21] Thea dvancement of liquid chromatography,e specially with the commercialization of two-dimensional liquid chromatography techniques,allowed chemists to find creative ways of repurposing analytes through more than one chromatographic medium from asingle injection, and to rapidly optimize and monitor multiple quality attributes for CM processes. [22][23][24] Process chemists and quality control (QC) analysts routinely conduct process checks during batch manufacturing. Their experience and expertise in designing and validating analytical methods are two key factors that make the production sustainable,a nd nonstop for days at at ime in some cases.I nterestingly,asubstantial knowledge gap exists when the mode of manufacturing transitions from batch to flow,since there is no similar depth of experience with in-flow process checks from which to draw upon.…”

Continuous Flow Intensification for the Synthesis of High-Purity Warfarin

“…The third flow synthesis was reported within the context of a platform designed to optimize asymmetric reactions. 31 DPEN was selected as the asymmetric catalyst and acetic acid as a cocatalyst, and a conversion of 21% and enantioselectivity of 99% were obtained, but no yield was reported. 31 The development of a practical, high-yielding, and highthroughput continuous flow synthesis at competitive costs remains a challenge.…”

Advanced Real-Time Process Analytics for Multistep Synthesis in Continuous Flow

“…2 As the chemical industries move towards increased digitization in development and manufacturing, establishing data-rich multistep synthesis is of prime importance. 3 Process analytical technology (PAT) 4 now plays an increasingly central role in continuous flow processing, 5 enabling real-time reaction monitoring for a range of applications, such as self-optimization, 6 reaction kinetic analysis, 7 dynamic experimentation, 8 online chiral analysis 9 and process control. 10 Furthermore, there is clear support from regulatory agencies within the pharmaceutical industry for the incorporation of PAT in continuous manufacturing processes to ensure a high standard of safety and product quality.…”