The Impact of Solvent Quality on the Heck Reaction: Detection of Hydroperoxide in 1-Methyl-2-pyrrolidinone (NMP)

Unexpected failures of a Heck reaction in the lab led to the detection of 5-hydroperoxy-1-methyl-2-pyrrolidinone (NMP-5-OOH) in the cosolvent 1-methyl-2-pyrrolidinone (NMP). This hydroperoxide, formed by autoxidation in the presence of air, oxidized the ligand tri(o-tolyl)phosphine (P(o-tol)3) to tri(o-tolyl)phosphine oxide (O═P(o-tol)3) and ultimately slowed down the Heck reaction. Because of this finding, control strategies were implemented for NMP quality and air exclusion during manufacturing campaigns, which ensured delivery of metric tons of compound 2 en route to Ronacaleret Hydrochloride used in clinical studies. Similar detrimental impact of NMP-5-OOH to the ligand-free Heck reaction was also demonstrated.