Enhancing Reaction Understanding with Online NMR Reaction Monitoring – Application to Chemical Route Development0 pages

Enhancing Reaction Understanding with Online NMR Reaction
Monitoring – Application to Chemical Route Development
Anna L. Dunn1,3, Anna Codina2, David A. Foley3, Mark T. Zell3
Author Information: 1Department of Chemistry, University of Wisconsin, 2Bruker UK Limited, 3Analytical Research and Development, Pfizer

The quantitative nature of nuclear magnetic resonance (NMR)
and the fact that it is structurally rich and non-intrusive makes
the technique extremely powerful for the identification and
characterisation of reaction intermediates, providing insights
into the reaction mechanisms and kinetics of chemical
reactions.
While many chemical transformations have been analysed in
standard NMR tubes over the years, physical and chemical
restrictions limit the types of reactions to which this form of
NMR reaction monitoring is applicable. The lack of control
over parameters such as mixing, temperature and pressure
can have significant effects on the rate of a reaction. It has
been demonstrated that the use of online reaction monitoring
circumvents these limitations1.
In this work, we demonstrate the complementarity of NMR
and infrared (IR) spectroscopy and show the use of NMR to
improve the understanding and robustness of the synthesis
of an active pharmaceutical ingredient (API) precursor.

Results and Discussion
The reaction of 3-methylhexanoic acid (I) with Meldrum’s
acid (II) and pivaloyl chloride (III) to form the Meldrum’s acid
adduct (IV) is the first step of a telescoped reaction for the
formation of an API2. The study of this first step by traditional
process analytical technology techniques such as LC-UV or
GC-MS was not feasible due to the reagents, intermediates
and products lacking strong chromophores and readily
decomposing with temperature.
Figure 1