In 2009, Amgen published a chapter in “Catalysis of Organic Reactions” related to the used of scavengers for the removal of palladium in small to multi-kilogram production scale. In their study, they evaluated various parameters such as the scavenging efficiency, the influence of the scavenger loading and the loss of product to adsorption (recovery). The study was made on a palladium catalyzed sulfonamide coupling and scavenger screening was performed at both room temperature and 65°C using 31 different scavengers.
Amgen Scavenger Screening Results
Condition: 20 mg of each scavenger (20% wt) in 2 mL HPLC vial that contains 1 mL of crude reaction mixture containing 100 mg of product. Each vial was sealed and agitated overnight. Initial palladium concentration was 423 ppm.
The BEST scavenger identified during their study was the SiliaMetS Thiourea providing the lowest Pd content (residual palladium concentration: 3 % or < 14 ppm) without product sequestration. They mentioned that SiliaMetS Thiourea was used extensively in early process development work.
1Catalysis of Organic Reactions, Chapter 5. Application of Scavengers for the Removal of Palladium in Small Lot Manufacturing
Allgeier & al., Amgen Inc., Thousand Oaks (California)
Cost Comparison for Most Efficient Scavengers (≥ 80%)
In pilot-plant scale, the best compromise between the cost per ppm removed and the scavenging efficiency is crucial. The histogram at right shows a cost comparison on best scavengers identified.
Results highlighted by the graph reduced the number of options to only 4 candidates for further evaluation: in pole position the SiliaMetS Thiourea , and then the TMT, TMT-Na3, and the Smopex 234.
Top 4 scavengers overview
A screening validation was conducted on 1 g scale purification (10 mL of solution) with 20% w/w of each top 4 scavengers at 65°C overnight. After filtration, residual metal concentration was analyzed by ICP-MS as well as product recovery by HPLC (see table below). SiliaMetS Thiourea was chosen for the large scale purification. See Amgen’s paper for further details.
|Screening Validation Results on Top 4 Scavengers
||Residual Metal Concentration (ppm)
|Screening Exp. in Solution
||Validation Exp. in Solution
||Validation Exp. in Solid Product1
||Best performance but also most expensive.
||Fine in suspension, filterability concerns on scale.
||Favorable cost but product recovery not satisfied.
||Very basic compounds (not good with base sensitive groups). Low recovery.
||3 577 ppm
|Note: 1 Solid product refers to dividing the metal concentration in ppm by the amount of product in the test (1g).
“Scavengers offer a practical and expedient option for removing Pd from process streams to ensure quality of organic products... The screening protocol involves treatment of a candidate process stream with 20 % w/w scavenger on product at both room temperature and 65°C followed by analysis of Pd and product adsorption. High-temperature treatment increased the efficiency of Pd removal... Evaluation of process costs is key to identifying Pd removal solutions. While scavengers add cost to a process, their use is often justified by the speed to production in early phase development.”
||Ryberg, P., Organic Process Research & Development, 12 (2008) p.540
||Process Chemistry, AstraZeneca PR&D, Sweden.
In 2008, AstraZeneca published a paper in witch they removed palladium impurities in a large-scale process. The workup method that was found to work the best was a treatment with SiliaMetS Thiol (25 % w/w or ~1.4 kg) at 50°C to purify more than 6.7 kg. Final residual palladium concentration was as low as 1-2 ppm
||Dorow, R.L. & all, Organic Process Research & Development, 10 (2006) p.493
||Pfizer Global Research and Development, Kalamazoo, Michigan (USA).
In 2006, Pfizer published a paper in witch they removed palladium & copper impurities in a 20 kg pilot plant scale. They made two subsequent treatments using SiliaMetS Thiol (20 % + 7 % w/w) at room temperature for 12 hours. After scavenging with SiliaMetS Thiol, the desired product was obtained with a yield of 76 % and was containing only 17 ppm Pd and 1 ppm Cu. An alternative method was also tried using 80 % w/w of Deloxan THP (Degussa AG) overnight followed by basification with Na2CO3. Residual metal concentration with this method was higher compared to the one withSiliaMetS and the yield was lower (about 60-70 %).SiliaMetS allows lower residual metal concentration & higher yield in less manipulations!
||Ravn, M.M. & all, P., Organic Process Research & Development, 14 (2010) p.417
||Global Pharmaceutical R&D, Process Research & Development and Discovery, Abbott Laboratories, Chicago, Illinois (USA).
In 2010, Abbott Laboratories published a paper in witch they removed palladium and iron impurities using SiliaMetS Thiol (50 % w/w relative to 1). Thus, palladium and iron levels were respectively 6 ppm and 66 ppm. Take a look at Abbott’s publication for more details.
||Houpis I.N. & all, Organic Process Research & Development, 13 (2009) p.598
||Johnson & Johnson PRD, API Development, Belgium, and Solvias A.G., Synthesis and Catalysis, Switzerland.
In 2009, J&J in collaboration with Solvias published a paper in witch they developed a mild Sonogashira reaction using various metal catalysts. Treatment with SiliaMetS Thiol removed simultanously Pd, Cu & Al. Residual concentrations were respectively < 50, 10, and 3 ppm, in the isolated product 3. Take a look at J&J’s publication for more details.
Note: copper comes from a previous synthesis step.