Wednesday, November 4, 2015

Process Wednesday: Synergistic effects from a combination of thiol/thiourea Silicycle products

Credit: Scheme and table taken from Wells et al.
I thought this OPRD ASAP [1] from a group at Janssen was pretty interesting, especially the notes about the effective combining of Silicycle-Thiol/Si-Thiolurea at removing 1400 ppm-1600 ppm palladium down to sub-10 ppm levels. The previous step was a tricky Suzuki with a cyclic boronic acid that seemingly required a reasonably high amount of palladium (see Scheme 9 above):
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


  1. one issue with Pd-catalyzed reactions like Suzuki is that you get residual Pd(II) complexes, and you often get also Pd(0) in the form of "soluble" Pd black - very fine colloids of nanoparticles that get through filters. Thiourea is probably good for getting rid of Pd(II) but for Pd(0) colloids you need a thiol + air oxidation.

    These are speculations, but I had my own problem with Pd colloids when hydrogenating ambiphilic polymers on Pearlman's catalyst. In my case, I was initially fightiong them by filtrations though activated charcoal or C-18 reverse phase, which was truly horrible on scale, before finding a better approach (saturate the solution with salt to bring about Oswald ripening, then follow with a filtration through PVDF 0.22 micron membrane)

  2. Dear Chemjobber, thanks for posting ! :)
    I'm Valerie, the Product Manager for our Metal and Organic Scavengers at SiliCycle.
    Over the years and our past experience with scavengers, it has been clear that combining multiple scavengers was a strong strategy for maximum chelating of undesired products. Combining multiple scavengers was even working stronger than using more equiv. of a single one. This is, not surprisingly, even more valid when multiple species are present in solution and to be get rid of.
    In fact, we've noticed this synergy no latter than last week in one of our R&D services for a pharmaceutical client.

    When there is a clear noticing that the scavenging level has plateaued, a strong move is really to mix the best two scavengers, which will often prove to be more effective than the usual other optimization approaches (temperature, time, etc.).
    From what I can see, while the authors didn’t discussed it, they’ve tried exactly what we would have suggested to in their case :)

    Don't hesitate to contact us if you wish to discuss this any further, we're always glad to discuss chemistry questions and comments :)

  3. anon electrochemistNovember 10, 2015 at 3:46 PM

    Milkshake is on point as usual, it's likely a bifunctional mechanism. I would nitpick that high salt conditions aggregate and precipitate nanoparticles (DLVO interaction) but that's not the same as Ostwald ripening, unless the anion is also corrosive like chloride is with Pd. Adding a trace of bromide into the salt mix will greatly accelerate the process, especially with the more difficult Au and Pt dispersions.