Metal and Organic Scavenging

Summary: In the case that scavenging is incomplete or if you wish to increase scavenging efficiency, optimization steps can be undertaken as described in this Application Note. Various parameters can be changed one at a time or simultaneously to improve removal efficiency and this document is intended as a guide to improve your scavenging process.

Summary: The use of solid supported scavengers has become a common method for post-synthesis purification. It’s a known fact that the polystyrene backbone greatly influences the behavior of the scavenger in terms of solvent compatibility and reaction rate. On the other hand, silica-bound scavengers have the advantage of a rigid, non-swelling backbone which eliminates kinetic issues and the need to choose a compatible solvent. Additionally, silica-bound scavengers are easier to handle and weigh due to the absence of static.

Summary: SiliaMetS Metal Scavengers were developed to eliminate post-reaction purification issues with metallic residues. While generally used in organic solvents, due to recent environmental laws and concerns, green chemistry in aqueous media has gained popularity. Metal Scavengers have been shown to be effective in aqueous environments, a key opportunity for greening chemical processes. This Application Note demonstrates the chemical stability of SiliaMetS DMT and Thiol in water.

Summary: Rhodium can be found as an impurity after being used as a catalyst in many reactions for the manufacturing of active pharmaceutical ingredients (API). In this Application Note, residual rhodium is removed, via a combination of SiliaMetS Scavengers, from a cyclisation step in the synthesis of (S)-4,6-Difluoro-5-(4-(tetrahydro-2H-pyran-2-yl)-phenyl)-1H-indole-3-carboxylic Acid, a potential API.

Summary: Although metal catalysts greatly facilitate many synthetic reactions, once the desired product is obtained, the residual metal must be removed. Chromatography and scavenging are two ways to remove such impurities. This Application Note offers a comparison of these two different techniques to remove left over metals, herein rhodium, from a cycloisomerization catalytic reaction, and includes a comparison of metal scavengers from different manufacturers.

Summary: When the creation of Potentially Genotoxic Impurities (PGI) cannot be avoided, purification techniques can be used to remove them from the final products. PGI have a carcinogenic character that induce genetic mutations and / or chromosomal rearrangements. Some PGI are regulated under the guidelines by the International Conference on Harmonization (ICH). This Application Note investigates the selective scavenging of two such PGI, namely benzyl bromide and aniline, using model reactions.

Summary: For the synthesis of Active Pharmaceutical Ingredients (API), rhodium is one of the catalysts of choice. According to the International Council for Harmonization (ICH) guidelines, leftover metallic and elemental impurities should be reduced below a certain amount from the final products. This Application Note details different options to minimize residual rhodium contamination in a crude product: silica gel chromatography, activated carbon, metal scavengers and radial flow cartridges (E-PAK).

Summary: The Sandmeyer reaction is a versatile synthesis tool that consists of the substitution of an aromatic amino group with a wide range of substituents. A common substitution is bromination using a copper(I) salt. In this Application Note, SiliCycle’s R&D team looked at the bromination of a thiadiazole before its coupling to an aromatic group and the removal of copper with SiliaCarb activated carbons and SiliaMetS metal scavengers prior to the next step involving a Suzuki cross coupling.

Summary: Triphenylphosphine (TPP) is a reagent frequently used in organic synthesis. This compound has the property of being easily oxidized to generate the Triphenylphosphine oxide (TPPO), and this characteristic is often exploited in organic chemistry in various reactions. However, TPP and TPPO are quite difficult to remove using traditional chromatography methods, which is why the SiliaBond organic scavengers become an interesting alternative for their removal from reaction media.

Summary: SiliaBond Carbonate (Si-CO3) is the silica bound equivalent of Tetramethylammonium Carbonate. This sorbent can be used as a general base to quench a reaction, to freebase amines from their ammonium salt form as well as to scavenge acids and acidic phenols. This Application Note explores some of these applications in more detail.

Summary: Among the most popular reactions in organic chemistry for carbon-carbon (C-C) bond formation, the Suzuki-Miyaura cross coupling reaction allows the production of various compounds for the pharmaceutical, chemical, drug, agrochemical, and polymer industries. With the new ICH-Q3D guidelines on concentration limits for the residues of metal catalysts, SiliCycle’s chemists compared the efficiency of various metal scavengers in removing traces of one of the most popular Suzuki catalyst, Pd(PPh3)4. All screenings were performed using the MiniBlock apparatus to determine which scavengers were the most successful in removing traces of leftover palladium-catalyst. The main objective was to demonstrate a direct and straightforward transfer to the E-PAK technology.

Summary: In recent years, the removal of post-reaction residues has become a major issue in the pharmaceutical industry. For several years, SiliCycle has offered SiliaMetS metal scavengers allowing customers to achieve this goal. SiliCycle now offers a new proprietary technology called E-PAK to purify API from residual metals. Tests were conducted to measure the efficiency of the E-PAK technology with SiliaMetS and activated carbon to remove Pd(Ph3)4 from a Suzuki coupling reaction. Screening tests in bulk were performed in a multi-reaction apparatus to select the best sorbents. In this Application Note, we demonstrate the direct and straightforward transfer from bulk to E-PAK for the removal of palladium.

Summary: In recent years, the new ICH-Q3D guidelines on concentration limits for the residues of metal catalysts have forced the pharmaceutical industry to search for new solutions to remove them. To help reach this goal, SiliCycle developed a new proprietary technology called E-PAK. The present study demonstrates the efficiency of activated carbons and SiliaMetS metal scavengers to remove rhodium residues both in bulk and with the E-PAK cartridge.

Summary: Catalytic hydrogenation of double bonds is one of the most common and studied reactions in chemistry. Some of the most complex hydrogenations involve the creation of a chiral center from an alkene. In the early 70’s, Crabtree and co-workers developed an iridium based catalyst for the asymmetric hydrogenations of mono-, di-, tri-, and tetrasubstituted alkenes with high enantioselectivity. Since its first report, several iterations of Crabtree’s catalyst have been synthesized with different ligands. This catalyst is now used in various industrial processes and one of the challenges is to be able to remove the iridium after the reaction. In this Application Note, the scavenging efficiency of activated carbons and of the SiliaMetS portfolio, as well as their use in E-PAK cartridges for the removal of iridium is showcased.

Summary: Since its first reports in the late 1960’s, cross-coupling methods have become one of the most ubiquitous reactions for the synthesis of drug candidates. In fact, its discovery has been so groundbreaking that those involved were awarded the 2010 Nobel prize in chemistry. Among the seminal discoveries of Heck and Mizoroki in the early 1970’s,3 the works of Corriu and Kumada showcased Ni as a catalyst for a Grignard based cross-coupling reaction with aryl and alkenyl halides. In this Application Note, a nickel‑based Kumada-Corriu coupling reaction was followed by the scavenging of nickel. The efficiency of activated carbons and SiliaMetS metal scavengers, as well as their use with the E-PAK technology for the capture of nickel is demonstrated.

Summary: The following study demonstrates the efficiency of E-PAK activated carbon cartridges to remove chlorophyll and other impurities from a biomass sample. Cannabis was herein chosen as the model sample.

The variables analyzed after a pre-purification step were:

• Recovery of cannabinoids (CBD);
• The signal level of the chlorophyll by UV-visible spectroscopy (qualitative test);
• The saturation of the E-PAK cartridge.

Summary: Among the numerous types of cross-coupling reactions, the Sonogashira coupling of aryl halides with terminal alkynes stands out for its use in the synthesis of complex molecules, such as eneyne-based natural products. This Application Note showcases the ease of scalability of the E-PAK technology with a Pd purification from a Sonogashira reaction for the synthesis of a halogenated TMS protected ethynyl aniline.

Summary: With the increasing use of metathesis in the pharmaceutical industry, the removal of the metal catalyst has become a focus. One of the most popular metals as a catalyst is ruthenium, due to being air stable, highly active and versatile for all types of metathesis. To investigate the efficiency of the SiliaCarb activated carbons and SiliaMetS metal scavengers at removing ruthenium, a ring-closing metathesis was performed using the 3rd generation Grubbs catalysts on a functionalized diene. This Application Note details the screening of the bulk SiliaCarband SiliaMetS as well as the experimental conditions to be transferred to E-PAK.