Investigation of a Flow Step Clogging Incident: A Precautionary Note on the Use of THF in Commercial-Scale Continuous Process

Abstract

Despite the many benefits that flow chemistry brings in the context of commercial manufacturing, a major issue for such continuous processing can be the clogging of flow equipment. In the case of verubecestat (MK-8931), the development of a flow chemistry process for the Mannich step greatly increased the reaction yield and the purity of the isolated product. However, in one of the plant-scale solvent runs in advance of process validation, an unforeseen and isolated clogging incident occurred. Herein, we report the methodical troubleshooting leading to the location of the clog, the structural elucidation of the solids, and eventual root cause analysis. The culprit was eventually tied to poly­(THF), which was present in extremely low levels in a specific lot of THF solvent used. An interesting observation with regards to the deposition of solids in the filter cartridge and static mixer element with respect to solvent flow led us to speculate that the precipitation of the solids is caused by a phenomenon known as hydrodynamic cavitation.

Bromine–Lithium Exchange on a gem-Dibromoalkene, Part 2: Comparative Performance of Flow Micromixers

“…With hexane as the common solvent (and i -PrOH used as a protic quench to keep the reaction mixture homogeneous), the system immediately clogged whatever the angle of micromixer, probably because of LiBr precipitation. Preparing a solution of n -BuLi in THF proved to be very challenging, as THF solutions of n -BuLi are prone to rapid degradation at room temperature. , …”

“…Preparing a solution of n-BuLi in THF proved to be very challenging, as THF solutions of n-BuLi are prone to rapid degradation at room temperature. 15,16 The equilibrium hypothesis, on the other hand, was ruled out by dedicated experiments: a microflow setup was implemented with fixed flow rate (Q 1+n-BuLi = 9 mL/min) and micromixer (θ = 90°, ID = 500 μm), and only the length of the reactor tube was modified (with fixed ID = 500 μm) (Scheme 3). With L = 3 cm (t R = 40 ms), 6 cm (t R = 80 ms), or 9 cm (t R = 120 ms), full conversion into 2 was observed with almost no evolution of the E/Z ratio over time.…”

“…In the worst case laminar regime and bad mixing would force THF and BuLi in THF proved very challenging, as THF solutions of n-BuLi are prone to rapid degradation at room temperature. 15,16 The equilibrium hypothesis, on the other hand, was ruled out by dedicated experiments: a microflow set-up was implemented with fixed flow rate Q (1+n-BuLi) (9 mL/min) and micromixer ( = 90 °, ID = 500 m), and only the length of the reactor tube was modified (with fixed ID = 500 m; Scheme 3).…”

Overcoming the Hurdles and Challenges Associated with Developing Continuous Industrial Processes

“…An example was recently reported by researchers at Merck during a scale‐up campaign towards Verubecestat (Scheme 12). [ 23 ] When developing the synthesis of a key intermediate it was found that flow processing provided a 20 % increase in yield for a Mannich reaction between a chiral Ellman sulfinyl ketimine ( 37 ) and a methyl sulfonamide anion ( 38 ) due to the suppression of unproductive proton transfer as observed in batch mode. Flow processing was thereby employed in both the deprotonation step (using n ‐HexLi, 2.3 m , THF, –20 °C) and the subsequent Mannich reaction.…”

What Elements Contribute to a High-Quality Continuous Processing Submission for OPR&D?

“…In most continuous reactor types, small-dimension tubing or fittings are locations where plugging or fouling will occur unless care is taken to filter feed solutions and ensure that every component of the system is fully in solution during all phases of the process. Even if the chemistry seems clean and homogeneity is established, solid materials can gradually coat the walls of flow reactors over time, such as polymeric species in solvents or metal plating from homogeneous catalysts . Fouling events often take many reactor turnovers to become manifest.…”