Silica metal scavengers

S - Silica metal scavenger Scheme 9.1 Metal scavenger process. 

The high-throughput purification in a discovery environment and the removal of transition metals using adsorption on or crystallization in the presence of activated carbon, glass-bead sponges, polymeric fibers, or silica-bound scavengers and the preparative isolation of radiolabeled compounds are out of the scope of this contribution. 

There are several players in this field who have developed silica and polymer based functionalized metal scavengers - SiliCycle, Polymer Labs, Reaxa and Aldrich are key players in the medicinal and process chemistry fields. ChemRoutes Corporation has carried out significant research effort in this field, commercialized by the above-mentioned players, and is now developing novel technologies in the metal scavenging area for the nanotechnology field. Examples of the chemistries commercialized by the various players are given below. 

Removing residual transition metals after reaction completion is a major task for many chemists in the pharmaceutical industry. The toxic nature of transition metals means their concentration has to be reduced to the single digit ppm level for the material to be used in vivo and in clinical work. Silicycle Inc. is a silica gel company who has commercialized several functionalized silica based metal scavengers for the purification of active pharmaceutical ingredients. Scheme 9.1 shows the process for using silica based metal scavengers. 

Silicycle offers a wide range of silica-based metal scavenger products (Figure 9.1 ) to simplify the purification step and remove various transition metals. These metal scavengers are based on functionalized silica designed to react and bind excess... 

Silica-based metal scavengers, such as pentaerythritol 2-mercaptoacetate ethyl sulfide and 3-mercaptopropyl ethyl sulfide, which have been developed by Phos-phonics are used to remove rhodium and iron across all oxidation states. These scavengers work well in virtually all solvents, including water, and are available in various particle sizes. 

There has recently been extensive development of selective scavenging systems. These include ion-exchange resins (beads), functionalised polymers[7] and functionalised silica. The scavengers can target the whole active catalyst, or just the metal or ligand components if desired. It is possible in some cases to remove the catalyst from the scavenger and recycle it directly. 

The reaction procedures reported in the hterature were relatively similar and therefore only a few examples will be shown for each type of protocol. However, the work-up procedures for the reactions differed between research groups. Typical work-up procedures for polymerizations in polar solvents involved precipitation in aqueous solution (neutral, acidic or basic) while reactions carried out in nonpolar solvents were precipitated in aqueous methanol solutions. The crude polymer was washed with various solvents (acetone, methylvinylketone (MVK), hexanes, dichloromethane), typically through Soxhlet extraction, to remove lower molecular weight materials. The polymer was then extracted in chloroform or o-dichlorobenzene and repredpitated in methanol. Often, the polymer was washed with a metal scavenger, such as ethylenediaminetetracetic acid disodium salt, to remove residual metals, and this can be done before or after removal of low molecular weight materials. Filtration of the chloroform solution through celite or silica gel has also been used for this purpose. 

Several specialized silica-based functionalized platinum scavengers such as N-acetyl-L-cysteine, 2-aminoethyl sulfide, 2-mercaptoethyl ethyl sulfide, 3-mercapto-propyl ethyl sulfide, pentaerythritol 2-mercaptoacetate ethyl sulfide and triamine ethyl sulfide amide, developed by Strem Chemicals, are also available. These scavengers are highly stable and available in pure forms, which successfully scavenge platinum metal ions in batch processes. 

Coupled with the fact that the proportion of trace metal contaminants detected within continuous flow reaction products is inherently low, due to reduced catalyst degradation, the use of a scavenger cartridge at the end of a reaction sequence represents a relatively long-term solution to this problem. Other examples of the use of solid-supported scavengers have been reported by Ley and co-workers [65], where in one example, two scavenger modules, comprising QuadraPure TU (126) and phosphane resin, were used in the synthesis of 1,4-disubstituted-l,2,3-triazoles [66], and by Watts and co-workers [67], where silica-supported copper sulfate was used for the removal of residual dithiol (ppb) in the synthesis of 1,3-dithiolanes and 1,3-dithianes. 

In recent years the Asahi Corporation has developed a benzene-to-cyclohexene process involving a liquid-liquid two-phase system (benzene-water) with a solid ruthenium catalyst dispersed in the aqueous phase. The low solubility of cyclohexene in water promotes rapid transfer towards the organic phase. An 80000 t annum plant using this process is in operation. Another way to scavenge the intermediate cyclohexene is to support the metal hydrogenation catalyst on an acidic carrier (e. g. silica-alumina). On such a bifunctional catalyst the cyclohexene enters catalytic alkylation of the benzene (present in excess) to yield cyclohexylbenzene [19], which can be converted, by oxidation and rearrangement reactions, into phenol and cyclohexanone. 

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