Monitoring and Control of a Continuous Grignard Reaction for the Synthesis of an Active Pharmaceutical Ingredient Intermediate Using Inline NIR spectroscopy

Abstract

Inline near-infrared (NIR) spectroscopy has been used to monitor a continuous synthesis of an active pharmaceutical ingredient (API) intermediate by a Grignard alkylation reaction. The reaction between a ketone substrate and allylmagnesium chloride may form significant impurities with excess feeding of the Grignard reagent beyond the stoichiometric ratio. On the other hand, limiting this reagent would imply a loss in yield. Therefore, accurate dosing of the two reactants is essential. A feedforward−feedback control loop was conceived in order to maintain the reaction as closely as possible to the stoichiometric ratio, leading the path to full process automation. The feedback control loop relies on NIR transmission measurements performed in a flow cell where, in contrast to labor-intensive offline HPLC analytical methods, the whole reaction product can be scanned in real time without sample dilution. A robust PLS (projection to latent structures) model was developed with a satisfactory standard error of prediction, providing quantification of the ketone substrate in solutions with a high variability of the major solution componentthe alkoxide product. In addition, model performance supervision tools such as the spectral residuals or simple plots of pretreated spectra can assist in the identification of spectral outliers, which in this case could be related to Grignard reagent excess. If the sampling time of the NIR instrument is short enough, manipulating the inputs to the reactor may be used to obtain information about its dynamic behavior. This information is very useful for process control design, assessment of analytical tools and definition of sampling times. In this work, a systematic procedure for chemometric model building is followed, after which a discussion is made on some of the potential applications that can be found when exploiting the fast and rich information provided by NIR spectroscopy.

Continuous Hydrolysis and Liquid–Liquid Phase Separation of an Active Pharmaceutical Ingredient Intermediate Using a Miniscale Hydrophobic Membrane Separator

“…Continuous Grignard Alkylation Reactor. The alkylation reaction (Scheme 1, first line) was carried out in a filter reactor 39 coupled with a side-entry reactor 38 as shown in Figure 6. The filter reactor was a 1 L stirred vessel (Ace Glass Inc.) operated in fed-batch mode, since only about 1 L of product was desired for each experiment (although the setup is designed for continuous operation if desired).…”

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…7,72,73 Several different analytical systems were used successfully, such as in-line FT-IR (predominantly with Attenuated Total Reflectance (ATR) cells), [74][75][76][77][78][79][80] NIR, 81,82 Raman 83 and NMR spectroscopy, 84,85 as well as on-line MS 86,87 and HPLC. 88,89 However, everyday application of these approaches is hindered by the fact that off-line solutions are usually more convenient, since a wider toolbox (consisting of existing equipment) is available for the analysis of less demanding analytes (i.e.…”

Managing Hazardous Reactions and Compounds in Process Chemistry

“…An alternative is to use a halogen-metal exchange reaction where a preformed Grignard, such is isopropylmagnesium halide, reacts with an organic halide in an analogous manner seen for organolithium compounds when prepared from an organic halide. The formation of Grignard reagents in flow can be monitored conveniently by in-line IR (170,195). NMR has also been employed to monitor the reaction (196).…”