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SiliaMetS® - Metal Scavengers Case Studies

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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.

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Small-Scale Scavenging (Synthesis Scale ~ 5 g)

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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)

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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
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Metal Scavenging in Flow Chemistry (Preliminary Results)

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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

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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.

Ruthenium Scavenging with SiliaMetS

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Ruthenium-based catalysts are commonly used in organic synthesis, mainly in olefin metathesis reaction [ROM(P) and RCM]. Grubbs and Hoveyda-Grubbs catalysts are certainly the most popular ruthenium-based complexes in that field of applications. Complete ruthenium removal can be tedious using conventional methods.
SiliaMetS allow to reach the maximal tolerated concentration of the residual ruthenium. A ruthenium scavenging study was conducted and various parameters were investigated in order to learn more on their influence on the scavengers’ robustness as well as to establish the best experimental conditions.

Ruthenium Scavenging Results using SiliaMetS
SiliaMetS Grubbs 1st Gen. Grubbs 2nd Gen. Hoveyda-Grubbs 1st Gen. Hoveyda-Grubbs 2nd Gen.
Toluene1 DMF2 Toluene1 DMF2 Toluene1 DMF2 Toluene1 DMF2
SiliaMetS Thiol 90 % 96 % - 99 % 97 % 93 % - -
SiliaMetS Thiourea - 98 % - 96 % 97 % 98 % - -
SiliaMetS DMT 95 % 99 %2 > 99 % 99 %2 > 99 %2 98 %2 98 %2 99 %2
SiliaMetS Amine 95 % 97 % 92 % - - - - -
SiliaMetS Diamine 99 % 99 % 91 % 94 % > 99 % 98 % - 90%
SiliaMetS Triamine - 95 % - - 93 % 95 % - 95 %
SiliaMetS TAAcOH 93 % - - - - - - -
SiliaMetS TAAcONa 96 % - 96 % - 98 % - - -
Exp. Conditions: 1 8 eq. of SiliaMetS, 16 h, 80°C; 2 Only 4 eq. of SiliaMetS. Initial concentration: 500 ppm for all ruthenium-based catalysts.
Note: SiliaMetS Cysteine and Imidazole were not screen in this study (not launch at this moment). Only SiliaMetS results higher than 90% are presented in this table.

 

SiliaMetS vs Other Purification Methods

The use of SiliaMetS to remove ruthenium catalyst after ring-closing metathesis (RCM) reaction is the most effective purification method (over conventional ones). As demonstrated below, the main advantage is no product lost during the purification step.

case-study-other-purification

 

Scavenging Results for Various Purification Methods*
Scavenging Scavenger Filtration over packed bed of ...2 Flash Purification
SiliaMetS DMT1 Act. Carbon Celite Silica Manual SiliaSep Cart.
Ruthenium captation 93 % 73 % 24 % 58 % 70 % 73 %
1 Using 4 eq., 16h, 22°C. 2 Solution passed directly on a packed bed of various adsorbents, then washed with the same quantity of solvent.
*Quantitative yield obtained for each purification method (adjusted in function of the residual concentration of catalyst). No impurity generated in all cases using the different methods (determined by NMR).

 

Tin Scavenging with SiliaMetS

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Organotin compounds are versatile reagents commonly used in organic synthesis. The two main applications are in Stille couplings or in radical reactions. The removal of tin residues can often be an issue due to the well known high toxicity of this metal.
Traditional removal methods for this particular type of impurity are treatment with an aqueous solution of KF, NH4OH or NaOH, or with bases such as DBU. However, the efficiency of these methods can vary and may be inapplicable for particular compounds.
SiliaMetS Cysteine & TAAcONa can be used as an efficient method to remove tin residues from organic mixtures as demonstrated by the exemples below.

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Tin Scavenging using SiliaMetS Cysteine (TAAcONa)
Reactions Inital
Concentration
SiliaMetS Cysteine SiliaMetS TAAcONa
4 eq., 4 h, 22°C [2 treatments] 8 eq., 4 h, 22°C 4 eq., 4 h, 22°C [2 treatments] 8 eq., 4 h, 22°C 4 eq., 16 h, 22°C
Stille coupling #11 3 385 ppm 99 % 64 % 96 % 62 % -
Stille coupling #21 981 ppm 90 % 66 % 66 % 50 % -
Radical Reduction 4 090 ppm 92 % 88 % 90 % 90 % 90 %
1Pd residues were completely removed after only one treatment with SiliaMetS Cysteine.

 

Osmium Scavenging with SiliaMetS

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Osmium products are very useful in organic synthesis. One of the most common product is osmium tetroxide (OsO4), which is a very reliable and powerful reagent for the cis-dihydroxylation of alkenes. However, osmium compounds, in particular OsO4, are highly poisonous, even at low exposure levels, and must be handled with appropriate precautions. Therefore, it is desirable to efficiently remove residual osmium from products of interest.
A scavenging study on three organic reactions involving osmium reactants were performed. The metal scavenging efficiency of SiliaMetS is highlighted in the table on the following page.

case-study-osmium-scavenging

Osmium Scavenging using SiliaMetS
SiliaMetS Dihydroxylation Sharpless Dihydroxylation Lemieux-Johnson Oxidation
4 eq., 4 h, 22°C 8 eq., 4 h, 22°C 8 eq., 16 h, 22°C 8 eq., 4 h, 22°C 8 eq., 16 h, 22°C
SiliaMetS Thiol 87 % > 98 % > 98 % 87 % 92 %
SiliaMetS Cysteine 89 % > 98 % > 98 % 87 % 91 %
SiliaMetS DMT 92 % 97 % > 98 % 87 % 91 %
SiliaMetS Imidazole 87 % > 98 % > 98 % 89 % 91 %
Initial Os Concentration: 132 ppm in EtOAc 25 ppm in EtOAc 21 ppm in EtOAc
Note: > 98 % of scavenging means < 0.5 ppm of osmium.

 

Multiple Metal Scavenging with SiliaMetS

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SiliaMetS can be used to remove multiple metals in the same reaction with excellent efficiency. The Negishi coupling presented below was performed and SiliaMetS was used to remove simultaneously residual zinc, palladium and iron present after the reaction.

negishi-coupling

Multiple Removal Scavenging Results
SiliaMetS Palladium Iron Zinc
SiliaMetS Cysteine 95 % > 99 % 98 %
SiliaMetS DMT 83 % 93 % 99 %
SiliaMetS Imidazole 84 % 91 % 97 %
SiliaMetS TAAcONa 97 % > 99 % > 99 %
Initial Concentration: 188 ppm in THF 110 ppm in THF 6 ppm in THF
Conditions: 4 eq. of SiliaMetS (according to palladium), 4 h, 22°C.

 

Leaching & Stability Studies

Metal Scavengers Calculation