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).
SiliaMetS Scavenging Efficiency & Intermediate Results | ||||
SiliaMetS | Batch Reactor Mode (Bulk) | Fixed Mode (SPE) | Intermediate Recovery | |
5 eq., 4 h, 22°C | 5 eq., 4 h, 40°C | 6 mL / 1 g | ||
SiliaMetS Thiol | 95 % | > 99 % | 98 % | > 99 % |
SiliaMetS Thiourea | 83 % | 93 % | 99 % | 98 % |
SiliaMetS Cysteine | 84 % | 91 % | 97 % | > 99 % |
SiliaMetS DMT |
97 % | > 99 % | > 99% | 98 % |
Initial Pd Concentration: | 179 ppm in MTBE | 76 ppm in Toluene |
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.
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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.
SiliaMetS Thiol Scavenging Results in Flow Chemistry | ||||
Flow Rate | Solution Volume | Contact Time with SiliaMetS Thiol | Time Needed to Treat the Solution |
Scavenging Results |
1.50 mL/min | 100 mL | 16 min | 1h10 | 94.0 % |
1.00 mL/min | 100 mL | 24 min | 1h40 | 94.3 % |
0.75 mL/min | 50 mL | 32 min | 1h10 | 94.5 % |
0.50 mLmin | 50 mL | 48 min | 1h40 | 95.0 % |
Initial Pd Concentration: 547 ppm in EtOAc | Experimental Conditions: | Scavenger Used: SiliaMetS Thiol SiliaMetS Nb. Equivalent: 13.5 eq. Reactors: 2 x 12 mL Reactors in Series |
Total Solution Volume: 100 mL Purification Scale: 12.5g Temperature: 22°C |
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]![]() |
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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![]() |
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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.
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SiliaMetS Thiol (SH) Metal Scavenger (R51030B)
Our most versatile and robust metal scavenger for a variety of metals under a wide range of conditions. Best scavenger for: Ag, Hg, Os, Pd & Ru. Good scavenger for: Cu, Ir, Pb, Rh, Se & Sn. -
SiliaMetS Thiourea (THU) (R69530B)
SiliaMetS Thiourea (Si-THU) is a versatile metal scavenger for all forms of palladium, and is widely used in the pharmaceutical industry. Once complexed with a transition metal, it has also been reported as being an effective catalyst. Best scavenger for: Pd & Ru. Good scavenger for: Ag, Cu, Fe, Os, Rh, Sc & Sn. -
SiliaMetS DMT (Dimercaptotriazine) (R79030B)
SiliaMetS DMT is the silica - bound equivalent of 2,4,6 - trimercaptotriazine (trithiocyanuric acid, TMT). It is a versatile metal scavenger for a variety of metals and the preferred metal scavenger for ruthenium catalysts and hindered Pd complexes. Best scavenger for: As, Ir, Ni, Os, Pd, Pt, Rh, Ru & Se. Good scavenger for: Cd, Co, Cu, Fe, Sc & Zn. -
SiliaMetS Cysteine (CYS) (R80530B)
SiliaMetS Cysteine (Si-Cys) is the silica bound equivalent of the amino acid Cysteine. It is a versatile metal scavenger for a variety of metals including Pd, Sn, Ru, Pt, Cu, Rh, Cd and Sc under a wide range of conditions and the preferred metal scavenger for tin residues.