Dynamic Carbon Isotope Exchange of Pharmaceuticals with Labeled CO₂

Abstract

A copper-catalyzed procedure enabling dynamic carbon isotope exchange is described. Utilizing the universal precursor [ 14 C]CO 2 , this protocol allows to insert, in one single step, the desired carbon tag into carboxylic acids with no need of structural modifications. Reducing synthetic costs and limiting the generation of radioactive waste, this procedure will facilitate the access to carboxylic acids containing drugs and accelerate early 14 C-based ADME studies supporting drug development.

Direct Reversible Decarboxylation from Stable Organic Acids in Solution

“…The counter-cation of the carboxylate salt impacts carboxylate exchange reactivity ( Fig 2B). The carboxylic acid of 1 is not reactive, no 13 CO 2 exchange or protodecarboxylation was observed in DMF at + and Na + salts of 1 react more slowly, while transition metal salts (Zn 2+ or Cu 2+ ) are inert. The use of polar aprotic solvents is essential for the transformation, reactions conducted in THF, DCE, or water resulted in recovery of unlabeled 1.…”

“…An understanding of this phenomenon can be exploited to prepare isotopically labelled drug molecules and synthetic precursors in an operationally trivial manner. exchange when placed under an atmosphere of 13 CO 2 . In a reaction where approximately seven equivalents of 13 CO 2 is supplied (13 mL of CO 2 at ~1 atm, dissolved 13 CO 2 concentration of 0.25 M), equilibrium between 12 C and 13 C is achieved in 15 hours (Fig 2A, red trace).…”

“…exchange when placed under an atmosphere of 13 CO 2 . In a reaction where approximately seven equivalents of 13 CO 2 is supplied (13 mL of CO 2 at ~1 atm, dissolved 13 CO 2 concentration of 0.25 M), equilibrium between 12 C and 13 C is achieved in 15 hours (Fig 2A, red trace). Quantitative recovery of carboxylate 1 with 83% 13 C-enrichment was possible by acid/base extractive workup.…”

The Emergence of Carbon Isotope Exchange

“…Cantat, Audisio, [9] and co-workers also used [ 14 C]CO 2 gas as the isotope source for aC IE reaction on aromatic and heteroaromatic carboxylic acids (Figure 1c). They reported that aromatic carboxylates undergo thermal CO 2 extrusion in the presence of ac opper salt, which is followed by the reaction of the organometallic intermediates with labelled gas to yield the corresponding 14 C-labelled acids.T his CIE procedure was carried out on cesium salts of the carboxylic acids with 3equiv [ 14 C]CO 2 in only 2hours but at ah igh reaction temperature (150 8 8C).…”

Das aufkommende Konzept des Kohlenstoffisotopenaustauschs

“…Cantat, Audisio [9] und Mitarbeiter nutzten ebenfalls [ 14 C]CO 2 -Gas als Isotopenquelle füre ine CIE-Reaktion mit aromatischen und heteroaromatischen Carbonsäuren (Abbildung 1c). Sie berichteten, dass aromatische Carboxylate in Gegenwart eines Kupfersalzes eine thermische CO 2 -Extrusion eingehen, woraufhin die organometallischen Zwischenprodukte mit markiertem Gas zu den entsprechenden 14 Cmarkierten Säuren umgesetzt werden.…”