Scalable Protocol for Removing Triphenylphosphine Oxide from Reactions Using MgCl2 and Wet Milling

We report a scalable protocol for removing triphenylphosphine oxide (TPPO) from Mitsunobu coupling. In the protocol, solid MgCl₂ reacts with TPPO in solution, forming an insoluble solid complex that is easily removed from the reaction mixture by simple filtration. Our development work revealed that regeneration of the surface of the particles through grinding was key to exposing more MgCl₂, thereby increasing the rate of complexation of MgCl₂ with TPPO. As a result, we implemented wet milling to provide the shear necessary to grind the particles and to provide a more robust strategy for scale-up of the protocol. Introducing wet milling and MgCl₂ did not generate additional impurities in the studied reaction. Having established the protocol in development, we performed an appropriate scale-down reaction to determine the turnover number required to remove TPPO to a desired level at scale. Ultimately, we successfully demonstrated our wet milling protocol on a 14 kg scale of the Mitsunobu coupling, removing the TPPO in the crude mixture from 37.18 to 0.15 area % (HPLC) and to 0.6 wt % in the isolated product. Our protocol could be applied to other reactions in which TPPO is a byproduct, demonstrating its versatility and potentially expanding the scope of such reactions into later phases of pharmaceutical process development.