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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.

case-study-gsk

 

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.

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
case-study-siliasep

 

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]
Triphenylphosphine [PPh3]
Tri(o-tolyl)phosphine [P(otol)3]
Tri(o-tolyl)phosphine [P(otol)3]
Tri-n-butylphosphine [PnBu3]
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]
dppf
1,3-bis (diphenylphosphino) propane [dppp]
dppp
(+/-) BINAP
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.

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  1. SiliaMetS Thiol (SH) (R51030B)

    SiliaMetS Thiol (SH) (R51030B)

    Our most versatile and robust metal scavenger for a variety of metals under a wide range of conditions.
  2. SiliaMetS Thiourea (THU) (R69530B)

    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. It works particularly well in organic solvents. It can also be used to scavenge Ag, Pt, Ru, Rh and Hg. Once complexed with a transition metal, it has been reported as being an effective catalyst.
  3. SiliaMetS DMT (Dimercaptotriazine) (R79030B)

    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 (i.e. Pd(dppf)Cl2).
  4. SiliaMetS Cysteine (CYS) (R80530B)

    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.

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