|Credit: Harris et al., Org. Process. Res. Dev.|
The workup of the Saegusa reaction involved the addition of triethylamine to reduce any residual palladium(II) to palladium(0) which then precipitated and was removed by filtration through Celite. This reduction to palladium(0) was not 100% efficient and the residual palladium(II) in solution caused oiling during attempts to crystallise product 4. Replacing triethylamine with aqueous potassium formate in the workup gave a more efficient reduction of palladium resulting in large particles of palladium(0) that were removable by simple filtration (<80 ppm Pd by ICP). The efficient removal of palladium allowed the development of a crystallisation of phenol 4 from MeTHF with heptane as the antisolvent. The optimised process was carried out in the pilot plant to prepare 11 kg of phenol 4 in 42% yield from compound 8 with a further 2 kg product remaining in the liquors.
The potassium formate workup not only avoided the requirement for chromatography but also allowed the efficient recovery of palladium from the process. Of the 10.5 kg Pd metal used, 10.3 kg was recovered and sold back to Johnson Matthey for a profit of £62.5 K as a result of the doubling of the price of palladium during the campaign. However, due to the volatility of palladium prices an alternative route avoiding stoichiometric Pd(OAc)2 was desired prior to further scale-up.It's interesting that the authors note that palladium (II) was interfering with the crystallization of the product; I think that's the first I've heard of that (not that my own knowledge of the issue is comprehensive.)
I'm amused that the authors note the profit, but $100,000 is nothing to laugh at. (I wonder what Johnson Matthey's revenue streams look like -- how much do they make by essentially performing precious metal arbitrage?)
1. Harris, R.M.; Andrews, B.I.; Clark, S.; Cooke, J.W.B.; Gray, J.C.S.; Ng, S.Q.Q. "The Fit For Purpose Development of S1P1 Receptor Agonist GSK2263167 Using a Robinson Annulation and Saegusa Oxidation to Access an Advanced Phenol Intermediate." Org. Process Res. Dev. 2013, 17, 1239−1246. dx.doi.org/10.1021/op400162p