Removal of Palladium from Organic Reaction Mixtures by Trimercaptotriazine

Abstract

In an effort to remove residual palladium from a drug candidate prepared by palladium-catalyzed indolization, many treatments were examined. The most effective treatment was to precipitate palladium from solution using 2,4,6-trimercapto-s-triazine (TMT), which reduced palladium levels from 600−650 ppm to 20−60 ppm in an isolated indole intermediate. Subsequent crystallizations routinely afforded active pharmaceutical ingredient with <1 ppm of palladium. TMT treatment should prove useful to reduce the concentration of residual palladium in other reactions.

The Art of Meeting Palladium Specifications in Active Pharmaceutical Ingredients Produced by Pd‐Catalyzed Reactions

“…[10] This treatment resulted in insoluble complexes of TMT and Pd which could be filtered out of the product solution. [11] The original synthesis called for the drug substance to be prepared by a palladiumcatalyzed indolization.…”

A High‐Throughput Methodology for Screening Solution‐Based Chelating Agents for Efficient Palladium Removal

“…Since this approach had been successful with various, closely related intermediates, initial work was focused on the use of insoluble scavenger materials to remove the metal from a solution of the API. One of the most effective commercially available treatments is thiolcontaining reagents on solid supports [2]. Therefore, our first attempt utilized in-house prepared 10% wt./wt.…”

“…These approaches can be divided into two main categories (Scheme 2): (A) solid phase and precipitation treatments (API in solution) and (B) extraction treatments (API in the precipitate) [2,3]. Although approach A is normally the most common, it did not work in a practical way for our example, and therefore, a comprehensive screen of chelating agents was carried out to explore the unusual alternative B.…”

Use of polymer-supported phenyltin for the creation of aryl–aryl or aryl–heteroaryl bonds via Stille cross-coupling reactions

“…Indeed, 119 Sn MAS-NMR experiments revealed that the regeneration of 2 was incomplete in cycles 3, 4 and 5 and presumably due to a partial removal of the palladium residues along the cycles. On the other hand, we were delighted to see that treatment of polymer 5 with a THF solution of 2,4,6-trimercapto-s-triazine (L 2 ) [60,61], followed by a reaction with 2 equiv. of PhMgBr allowed both the regeneration and recycling of polymer 2 at least 4 times (Fig.…”