SiliaMetS - A GlaxoSmithKline Case Study¹

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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 below. Various parameters were investigated like the efficiency of SiliaMetS in different formats, scavenging kinetic, intermediate recevory and purity.

Small-Scale Scavenging (Synthesis Scale ~ 5 g)

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 mode bed (pre-packed SPE cartridges).

Scavenging Conclusion

Addition of only 5 equivalents of SiliaBond products for 4 hours 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 without adding any impurities.

¹Org. Proc. Res. & Dev., 2008, 12, p. 896

Larger Scale Scavenging (Synthesis Scale ~ 55 g)

SiliaMetS Metal Scavenger in pre-packed SiliaSep Flash Cartridge is a great alternative for metal removal for process development scale. These cartridges offer excellent scavenging efficiency as shown by results in the following table and time-saving for the chemist. After the first run, almost all the palladium is capted. After three times, less than 1 ppm remained in solution.

SiliaSep Scavenging Results Run# Scavenging 1 97 % 2 99 % 3 > 99 % Initial Pd Concentration: 700 ppm in AcOEt Experimental Conditions: Cartridge Size: 120 g of SiliaMetS Thiol Nb. Equivalent of SiliaMetS Thiol: 25 eq. Solution Volume: 1 liter Flow Rate: 40 mL / min

Metal Scavenging in Flow Chemistry (Preliminary Results)

Flow chemistry is a relatively new technique that is gaining in popularity for large scale manufacturing because of the small investment needed to be able to produce large quantities in a short time. SiliaMetS Metal Scavenger can also be used in flow chemistry to scavenge metal. Crude reaction mixture was purified using a Syrris ASIA^® Flow Chemistry System.

Variation of Phosphorous Ligand Nature & Scavenging

Even for the same metal, a variation in the scavenging efficiency can be observed depending on the nature of the products present inside the solution to be treated. For example, the steric hindrance of the catalyst and the electronic effects of the phosphorous ligands, are factors influencing the removal of the metal. The same suzuki coupling shown on page xx was performed using different phosporous ligands; three monodentate and three bidentate ligands. For comparison purposes, scavenging screening was done by using the same two sets of conditions. No optimization was done to increase SiliaMetS performance. By experience, using longer reaction time or higher temperature will allow for better results.

SiliaMetS Scavenging Results with Monodentate Ligands
SiliaMetS	Triphenylphosphine [PPh3]		Tri(o-tolyl)phosphine [P(otol)3]		Tri-n-butylphosphine [PnBu3]
	4 eq., 4 h, 22°C	4 eq., 4 h, 60°C	4 eq., 4 h, 22°C	4 eq., 4 h, 60°C	4 eq., 4 h, 22°C	4 eq., 4 h, 60°C
SiliaMetS Thiol	70 %	97 %	87 %	96 %	26 %	85 %
SiliaMetS Thiourea	55 %	86 %	54 %	82 %	18 %	41 %
SiliaMetS Cysteine	69 %	76 %	77 %	90 %	17 %	44 %
SiliaMetS DMT	95 %	97 %	95 %	> 99 %	36 %	87 %
Initial Pd Concentration:	27 ppm in EtOAc		84 ppm in EtOAc		90 ppm in EtOAc

SiliaMetS Scavenging Results with Bidentate Ligands
SiliaMetS	1,1’-bis (diphenylphosphino) ferrocene [dppf]		1,3-bis (diphenylphosphino) propane [dppp]		(+/-) BINAP
	4 eq., 4 h, 22°C	4 eq., 4 h, 60°C	4 eq., 4 h, 22°C	4 eq., 4 h, 60°C	4 eq., 4 h, 22°C	4 eq., 4 h, 60°C
SiliaMetS Thiol	50 %	69 %	75 %	90 %	31 %	56 %
SiliaMetS Thiourea	3 %	23 %	40 %	60 %	33 %	21 %
SiliaMetS Cysteine	29 %	36 %	47 %	55 %	19 %	29 %
SiliaMetS DMT	14 %	22 %	95 %	98 %	41 %	64 %
Initial Pd Concentration:	63 ppm in EtOAc		93 ppm in EtOAc		16 ppm in EtOAc

Scavenging Conclusion

In all cases, SiliaMetS DMT and Thiol remain the better scavengers throughout the study, even though there is a variation in the nature of the ligand.