(414e) Development a Workup for Removing Triphenylphosphine Oxide from a Mitsunobu Coupling | AIChE

(414e) Development a Workup for Removing Triphenylphosphine Oxide from a Mitsunobu Coupling


Development a Workup for Removing Triphenylphosphine Oxide from a Mitsunobu Coupling

Eric G. Moschetta, Benoit Cardinal-David, and Moiz Diwan

AbbVie, Inc. Process R&D 1401 Sheridan Road North Chicago, IL 60064, USA

Triphenylphosphine is a common and useful reagent in many organic reactions, such as the Wittig reduction, the Mitsunobu coupling, and the Staudinger reaction, among others. Additionally, triphenylphosphine is used often as a stoichiometric reagent in these reactions, resulting in a stoichiometric amount of triphenylphosphine oxide, the main byproduct of such reactions. Triphenylphosphine oxide (TPPO) is notoriously difficult to remove from reaction mixtures, especially at such large concentrations. Chromatography works to purify reactions in the laboratory, but is impractical for the larger scales required to manufacture drug substance. Extraction is not a viable option, either. TPPO is poorly water soluble and would lead to a solvent inefficient process (nonpolar solvents are common media for Mitsunobu couplings). Process chemists in pharmaceutical development often avoid implementing reactions where TPPO will be a byproduct because of the challenges associated with removing it from the reaction mixture. Bypassing such reactions limits the synthetic tools available for API process development and may lead to the implementation of longer synthetic routes, thereby creating more wasteful processes and requiring more time and effort to develop the process. As such, developing a scalable workup to remove TPPO from such reactions presents a valuable opportunity for pharmaceutical process development to enable reactions where triphenylphosphine is used as a stoichiometric reagent.

This presentation describes the development of a procedure to remove TPPO by reacting it with solid magnesium chloride. This protocol was developed on a Mitsunobu coupling in toluene. Magnesium chloride and the resulting magnesium chloride-TPPO complex are virtually insoluble in toluene, creating an intrinsic biphasic system. This presentation will detail the key features of the solid-liquid reaction and the factors that control the rate of reaction as observed with on-line IR spectroscopy. The rate of reaction was observed to be very fast upon addition of solid magnesium chloride, with a sharp decrease in the rate of reaction seconds after addition. Based on this observation, it was hypothesized that employing a surface regenerating technique to expose fresh magnesium chloride for reaction with TPPO would increase the rate of reaction. Including surface regeneration significantly increased the rate of reaction compared to conditions without. The protocol was then implemented on a model Mitsunobu coupling to demonstrate that the workup had no impact on the impurity profile and could effectively remove TPPO from the reaction mixture.

Eric Moschetta, Benoit Cardinal-David, and Moiz Diwan are employees of AbbVie and may own AbbVie stock. AbbVie sponsored and funded the study; contributed to the design; participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final publication.