|Credit: Scheme and table taken from Wells et al.|
The results presented in Table 2 showed that Si-Thiourea was, in general, most effective at reducing the amount of Pd from product 1a; Si-Thiol was about 5 times less effective, whereas all others were ineffective at changing the residual palladium.
It was interesting to find that Si-Thiourea was effective even at room temperature, reducing the residual Pd to 34 ppm, which was within specification for the initial scale-up campaign. However, an unexpected result was found by the synergistic effect of a combination of two Silicycle products, Si-Thiol and Si-Thiourea, when used in concert in EtOAc/MeOH at about 55 °C for 1−2 h, which was not apparent from the screening array. (emphasis CJ's) Their use in combination at 1:1 w/w (total 35−40% by weight relative to compound 1a) proved to be effective at removing residual Pd and decolorizing the product and consistently provided white to off-white solid product with less than 10 ppm of Pd.The authors don't discuss why there was synergy. Anyone have an idea?
1. Wells, K.M.*; Mehrman, S.J.; Abdel-Magid, A.F; Ferraro, C.; Scott, L.; Zhong, H.M.; Teleha, C.A.; Ballentine, S.; Li, X.; Russell, R.K.; Spink, J.M.; Diamond, C.; Youells, S.; Zhang, Y.; Tsay, F.-R.; Cesco-Cancia, S.; Manzo, S.M.; Beauchamp, D.A. "Synthesis of Mavatrep: A Potent Antagonist of Transient Receptor Potential Vanilloid-1." Org. Process Res. Dev., Article ASAP DOI: 10.1021/acs.oprd.5b00271