title: Kinetic Comparison of Trifluoroacetic Acid Cleavage Reactions of Resin-Bound Carbamates, Ureas, Secondary Amides, and Sulfonamides from Benzyl-, Benzhydryl-, and Indole-Based Linkers.
abstract: The kinetics of cleavage reactions of 16 resin-bound carbamates, ureas, secondary amides, and sulfonamides from four different acid labile linkers including benzyl, benzhydryl, and indole linkers has been investigated. The optimized cleavage conditions are generally milder than those commonly used and reported (e.g., 0.5% TFA as opposed to 5%). Among various linkers studied in this work, the indole linker has been found to be the most acid labile followed by the Rink linker. The rate of cleavage of compounds linked to the resin via various functional groups can be summarized as follows: sulfonamide >carbamate approximately urea > amide. This study shows that cleavages of 16 compounds from four different acid labile linkers have been optimized to much milder conditions in terms of TFA concentration and the reaction time. It also demonstrates that single bead FTIR is an effective tool for optimizing cleavage conditions.
authors.affiliation: Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, New Jersey 07901, and Texas Biotechnology Corporation, 7000 Fannin, Suite 1920, Houston, Texas 77030.
authors.initials: B
authors.lastname: Yan
authors.initials: N
authors.lastname: Nguyen
authors.initials: L
authors.lastname: Liu
authors.initials: G
authors.lastname: Holland
authors.initials: B
authors.lastname: Raju