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Pd scavenging after a Suzuki-Miyaura Coupling using a GlaxoSmithKline Published Reaction

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A metal scavenging study was performed following the synthesis of a key synthetic intermediate obtained by the Suzuki-Miyaura coupling presented in scheme below. Various parameters were investigated including the efficiency of SiliaMetS in different formats, scavenging kinetics, intermediate recovery and purity.

 

Small-Scale Scavenging (Synthesis Scale ~ 5 g)

The table below shows the most efficient SiliaMetS Metal Scavenger products for the treatment of the reaction mixture after work-up in both bulk and fixed-bed mode bed (pre-packed SPE cartridges).

SiliaMetS Scavenging Efficiency & Intermediate Recovery Results (in %)
ScavengersBatch Reactor Mode (Bulk)Fixed-Bed Mode (SPE)Intermediate Recovery
5 equiv, 4 h, 22°C5 equiv, 4 h, 40°C6 mL / 1 g
SiliaMetS Thiol95> 9998> 99
SiliaMetS Thiourea83939998
SiliaMetS Cysteine849197> 99
SiliaMetS DMT97> 99> 9998
Initial Pd Concentration179 ppm in MTBE76 ppm in Toluene-

Scavenging Conclusion

Addition of 5 equivalents of SiliaMetS products for 4 h at the end of the reaction reduces the residual metal concentration to single-digit ppm.

Recovery & Purity Conclusion

Palladium was completely removed, while the organic compound was not sequestrated by SiliaMetS products. No impurities were released.

 

Larger Scale Scavenging (Synthesis Scale ~ 55 g)

SiliaMetS Metal Scavengers in pre-packed SiliaSep Flash Cartridges are a great alternative for metal removal at process development scale. These cartridges offer excellent scavenging efficiency as shown by the results in associated table. After the first run, almost all the palladium was captured. After three runs, less than 1 ppm remained in solution.

Experimental Conditions
Scavenger UsedSiliaMetS Thiol
Cartridge Size120 g
Nb. Equivalent25 equiv
Solution Volume1 L
Flow Rate40 mL/min

 

SiliaSep Scavenging Results (in %)
Run #Scavenging
197
299
3> 99
J. F. Toczko et al., Org. Proc. Res. Dev., 2008, 12, 896-899
Chemical Development, GlaxoSmithKline, North Carolina, United States

 

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