SiliCycle’s SiliaMetS Metal Scavengers are functionalized silica gels designed to react and bind excess metal complexes. In recent years, the time pressure associated with quickly bringing candidate drugs to market has increased the number of transition metal-catalyzed reactions being transferred from lead optimization to early scale-up. The removal of post-reactions metal residues has become a major issue in the pharmaceutical industry. Purification of APIs from residual metal catalyst by traditional methods (chromatography, activated carbon, distillation, etc.) often leads to problems such as high costs, time loss, low efficiency, and reduced API yields. To overcome these limitations, SiliCycle has developed SiliaMetS Metal Scavengers, a range of products that have significantly changed how chemists can purify APIs.
|Product||Description / Typical Application|
|SiliaBond Amine (WAX) nec (R52130B)||SiliaBond Amine (Si-NH2) is an effective scavenger of acid chlorides, sulfonyl chlorides, isocyanates and other electrophiles. Si-NH2 has been shown to be effective metal scavenger and catalyst for Knoevenagel reactions. SiliaBond Amine is also used in chromatography as normal phase sorbent.|
|SiliaMetS Thiol (SH) (R51030B)||Our most versatile and robust metal scavenger for a variety of metals under a wide range of conditions.|
|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).|
|SiliaBond Amine (WAX) (R52030B)||SiliaBond Amine (Si-NH2) is an effective scavenger of acid chlorides, sulfonyl chlorides, isocyanates and other electrophiles. Si-NH2 has been shown to be effective metal scavenger and catalyst for Knoevenagel reactions. SiliaBond Amine is also used in chromatography as normal phase sorbent.|
|SiliaMetS Diamine (R49030B)||A proven scavenger for metals and electrophiles. It scavenges acids, acid chlorides, anhydrides, aldehydes, isocyanates, and chloroformates as well as Pb, Ni, and Cd.|
|SiliaMetS Triamine (R48030B)||Effective for scavenging metals such as Pb, Co, Ru and Pd. Our screening studies have shown it to be the preferred scavenger for Pb. It can also be used as a scavenger for acid chlorides, isocyanates and other electrophiles.|
|SiliaMetS AMPA (R85130B)||SiliaMetS AMPA is an aminomethylphosphonic acid ligand known for its excellent metal-bonding properties. It is particularly efficient to remove Aluminium, Antimony, Nickel, Lanthanides, and also very effective for Cobalt, Iron, Manganese and Zinc scavenging from reaction intermediates or final APIs.|
|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.|
|SiliaMetS DEAM (R54430B)||SiliaMetS DEAM is a versatile scavenger designed to remove trace metal or boronic acids from reaction intermediates or final APIs.|
|SiliaMetS DOTA (R91030B)||SiliaMetS DOTA is a silica-supported tetracarboxylic acid and its various conjugate bases. DOTA molecule is a well-adopted complexing agent. Linked to various metals, so formed-complexes are used as contrast agents in cancer treatments or other medical applications.|
|SiliaMetS Imidazole (IMI) (R79230B)||SiliaMetS Imidazole (Si-IMI) is a versatile metal scavenger for a variety of metals including Cd, Co, Cu, Fe, Ni, Pd, and Rh under a wide range of conditions and the preferred metal scavenger for iron catalysts. It can also be used as an amine base in systems that are generally sensitive to basic conditions compared to other SiliaMetS supported bases.|
|SiliaMetS TAAcOH nec (R69030B)||SiliaMetS TAAcOH (SiliaMetS Triaminetetraacetic Acid) is a silica bound metal scavenger for Pd(0), Ni(0) and Cu. It is the supported version of EDTA in its free form. It is an effective scavenger for metals in low or zero oxidation states, which includes many of the most synthetically useful catalysts such as tetrakis-(triphenylphosphine)palladium(0)|
|SiliaMetS TAAcONa nec (R69230B)||SiliaMetS TAAcONa or (or SiliaMetS Triaminetetraacetate, sodium salt) is a silica bound metal scavenger for Pd(II), Ni(II) and Cu. It is the supported version of EDTA in its sodium salt form. It is an effective scavenger for metals in higher oxidation state, 2+ or higher.|
|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.|
|SiliaBond Tosic Acid (SCX) (R60530B)||SiliaBond Tosic Acid (SiliaBond SCX, Si-TsOH) is a versatile bound strong acid with a pka <<1. It is widely used for the scavenging of amines and other basic functionalities, including weakly basic anilines, borohydrides, and metals such as Ni and Ag. It can also be used as an acid catalyst for organic reactions. Si-TsOH can serve as an alternative method to quench reactions instead of aqueous or organic soluble acids.|
In addition, several kits (5-100g product) are available:
- SiliaMetS Metal Scavengers Kit (K30730B) includes Cysteine ; DMT ; Imidazole ; TAAcOH ; TAAcONa ; Thiol ; Thiourea ; Triamine
- SiliaMetS Palladium Metal Scavengers Kit (K34630B) includes DMT ; Diamine ; Thiol ; Thiourea ; Imidazole ; Triamine
- SiliaMetS Novel Scavengers Kit (K34530B) includes AMPA ; DEAM ; DOTA ; DMT ; Guanidine ; Thiol
- SiliaMetS Tin Metal Scavenger Kit (K34730B) includes Carbonate ; Cysteine ; DEAM ; DMT ; TAAcOH ; TAAcONa ; Thiol ; Thiourea
The following selection table helps in selecting the most efficient scavenger for a specific metal and application. However, since some parameters may affect the efficiency of the scavenging, we highly recommend performing a preliminary screening experiment using the scavengers kit. In the table + denotes ‘good’ and ++ denotes ‘best’ scavenger.
|MetS Thiol||++||+||++||+||++||+||++||+||++||+||+||MetS Thiol|
|MetS DMT||+||+||+||+||++||++||++||++||++||++||++||+||++||+||MetS DMT|
|Bond Amine||++||+||++||+||+||+||+||++||++||++||+||+||Bond Amine|
|MetS AMPA||++||++||+||+||+||++||++||+||++||++||+||MetS AMPA|
|MetS Cysteine||+||++||+||+||+||++||++||+||+||++||+||+||+||++||++||+||++||+||MetS Cysteine|
|MetS DEAM||++||++||+||++||++||++||MetS DEAM|
|MetS Diamine||+||+||++||+||+||+||++||+||+||++||++||+||+||+||+||++||++||MetS Diamine|
|MetS DOTA||++||+||++||+||++||+||++||+||+||+||++||++||MetS DOTA|
|MetS Imidazole||++||++||+||++||++||++||++||++||++||++||+||+||++||++||MetS Imidazole|
|MetS TAAcOH||++||++||+||+||+||++||++||++||++||++||+||+||++||++||++||MetS TAAcOH|
|MetS TAAcOMa||++||++||+||++||++||++||++||++||++||++||++||++||+||+||+||++||+||++||+||MetS TAAcOMa|
|MetS Thiourea||+||+||+||+||++||+||++||+||+||MetS Thiourea|
|Bond Tosic Acid||+||+||+||+||+||++||+||++||+||Bond Tosic Acid|
|MetS Triamine||+||+||+||++||+||+||+||+||+||+||++||++||+||+||+||+||++||++||MetS Triamine|
To get an effective metal removal, the amount of SiliaMetS Metal Scavenger used is very important. You can determine by two different ways how much scavenger will be needed;
- from the residual concentration (more accurate method)
- from the amount of metal catalyst used (when the residual metal concentration is unknown)
1. From residual metal concentration (ppm)
Knowing the palladium (Pd) level in 800 g of material is 500 ppm, (the oxidation state does not affect the calculation).
- Loading of the scavenger (SiliaMetS Thiol): 1.2 mmol/g
- Metal molecular weight: Ex. Pd = 106.42 g/mol
- Amount of product to be treated containing the Pd: Ex. 800 g
- Residual concentration of metal: Ex. 500 ppm of Pd
Determine the amount of palladium to be scavenged
Calculate the amount of scavenger (SiliaMetS Thiol) to use (1 equivalent)
To scavenge 400 mg of palladium, 3.13 g of SiliaMetS Thiol is needed if using only one equivalent. However, it is highly recommend trying a minimum of 4 equivalents at first. In this case, the amount of SiliaMetS Thiol will be 4 times higher (4 x 3.13 g = 12.40 g).
Sometimes, the metal residual concentration is unknown. In such a case, the amount (g) of palladium to be scavenged can be replaced by the amount of metal catalyst used for the reaction.
2. From amount of metal catalyst used
- Amount of metal catalyst used: Ex. 10 g of Pd(PPh3)4
- Metal catalyst molecular weight: Pd(PPh3)4 = 1155.56 g/mol
Determine the amount of palladium to be scavenged
The amount of SiliaMetS Thiol to be used can then be determined as stated above (see point 2. above). In this particular case, one equivalent of SiliaMetS Thiol corresponds to 7.20 g.
Screening in Batch Reactor Mode (Bulk)
To select the best scavenger for initial screening experiments, do the following steps for each SiliaMetS Metal Scavengers included in the kit. Use 4-8 molar equivalents of each SiliaMetS in respect to the residual metal concentration.
- Dissolve the crude product to be treated in a suitable solvent (or use directly the crude reaction mixture) and prepare vials containing the same solution volume.
- Directly, add to these vials the amount needed for each SiliaMetS included in the kit. Note: no pre-wetting of the SiliaMetS is required. See Calculation of the amount of SiliaMetS to use.
- For initial tests, stir the solution for at least one hour at room temperature.
- Scavenging progress can be followed by normal analytical techniques. The scavenging progress can be estimated by looking at the color of the solution as demonstrated in the figure. When the scavenging is almost completed, the solution is less colored and SiliaMetS becomes colored. In some occasional cases, if all the samples are still coloured, let them react for a longer time and/or add more equivalents of the SiliaMetS and/or increase the temperature of the reaction.
- At the end of the scavenging, filter off the SiliaMetS using a fritted funnel or filtration device.
- Wash the SiliaMetS with additional solvent for total recovery of the API (or compound of interest) and concentrate the solution under vacuum.
- Analyze the residual metal concentration of each vial to identify the most efficient SiliaMetS Metal Scavenger.
Note: you can choose more than one scavenger.
- If you are satisfied with the scavenging efficiency of the best SiliaMetS, direct scale-up is possible. Otherwise, scavenging optimization can be done with SiliaMetS identified in #7 (see next section).
Screening with SiliaMetS Fixed Bed Mode (SPE or Flash Cartridges)
SiliaMetS fixed bed formats are a great alternative for metal removal and are directly scalable. Initial screening investigations can be done using SiliaPrep 2g/6mL SPE cartridges.
- Condition the cartridge with 3-4 cartridge volume using the same solvent as the solution to be treated.
- Add to the top of the cartridge the solution containing the API and the metal and let it pass through the cartridge under gravity
Note: if needed, a slight positive pressure on the top of the cartridge or a light vacuum can be applied to speed up the flow rate.
- As shown by the picture on the right, a dark coloured band will be observed on the top of the silica bed most of the time.
- If the residual solution is still coloured, multiple passes through the same cartridge can be done.
- Once the scavenging is completed, wash the cartridge using at least 3 column volumes of solvent to insure total API (or compound of interest) recovery. Note: in some particular cases, additional washing may be required.