Kinetics Model for Designing Grignard Reactions in Batch or Flow Operations

Abstract

This paper describes the development of a "fit for use" model for a Grignard reaction, which was used to produce an intermediate compound during the manufacture of API for edivoxetine hydrochloride. The model includes three parameters, one (k SL a) of them representing the mass-transfer component and two others (k and E a ) representing the Arrhenius dependent rate constant. Several different experiments under various conditions were conducted to fit the parameters and test the model. The model achieves several goals, namely, ( 1) provides an understanding of the kinetics and mass transfer, useful for designing a batch or continuous process, (2) fits and predicts the mass and energy balance for laboratory data under different conditions of reactant stoichiometry or temperatures for process safety monitoring, (3) successfully predicts process dynamics at different scales of operation, from 0.25 to 1900 L to minimize uncertainty during scale-up, (4) presents a simple way to tune the model to predict dynamics using different magnesium supplies, and (5) develops a platform for quantifying the kinetics for similar Grignard reactions in the future. This model can serve as a powerful tool to help map out the design space and develop operation strategies for successfully running Grignard reactions in a batch or continuous mode to help pharmaceutical API development.

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 2: Enone Synthesis via a Barbier-Type Grignard Process

“…Here we propose a new mathematical model to describe the Grignard formation mechanism wherein the reaction occurs by diffusion of 2-BP to the surface of Mg particles. A model for similar chemistry in which Mg particles are assumed to diffuse from the magnesium surface to react with 2-BP has been previously reported . While this formulation can describe experimental observations, the extremely low solubility of solid Mg in tetrahydrofuran (THF) and 2-methyltetrahydrofuran (MeTHF) makes bulk diffusion of Mg an unlikely mechanism.…”

“…A model for similar chemistry in which Mg particles are assumed to diffuse from the magnesium surface to react with 2-BP has been previously reported. 20 While this formulation can describe experimental observations, the extremely low solubility of solid Mg in tetrahydrofuran (THF) and 2-methyltetrahydrofuran (MeTHF) makes bulk diffusion of Mg an unlikely mechanism. In the proposed mechanism, the time dependence of the bulk concentration of 2-BP (C 2BP ) is described by the mass transfer coefficient (k L ), the volumetric surface area available for diffusion of 2-BP to Mg particles (a), and the concentration of 2-BP at the surface of Mg particles (C 2BP * ):…”

“…Here we present a new kinetic model to describe the generation of the Grignard reagent from 2-bromopropene (2-BP) and magnesium. Others have modeled similar Grignard chemistry . The kinetic model assumes that the Grignard reaction occurs by diffusion of 2-BP from the bulk phase through a mass transfer boundary layer to react on the Mg surface.…”

“…Others have modeled similar Grignard chemistry. 20 The kinetic model assumes that the Grignard reaction occurs by diffusion of 2-BP from the bulk phase through a mass transfer boundary layer to react on the Mg surface. The model was fit to experimental data and used (1) to develop relationships between the Mg charging interval and reactor performance and (2) to determine the impact of process disturbances on the integrated process performance, including the conversion of morpholine amide 1 to enone 2, a critical in-process control.…”

Operation Strategy Development for Grignard Reaction in a Continuous Stirred Tank Reactor

“…The IR data was calibrated based on HPLC samples to determine the conversion rate and Compound D concentration as detailed elsewhere. 9 In order to maintained the 80−85% conversion, a Mg recharge of every 50 min was required as shown in Figure 2. The Compound D solution was added to the CSTR continuously to maintain a 30 min residence time and the operation volume of CSTR is controlled by the outlet tube position (see Settling Pipe Design section for details).…”