Innovative deuteration strategies: Ionic liquid catalyzed synthesis of deuterated pharmaceuticals

Author(s)

Salvador, Marilia Vilela ; Scorsin, Leandro ; Gonsalves, Renan de Oliveira ; Venancio, Tiago ; dos Santos, Francisco P.

• Document type: Journal article
• Source: JOURNAL OF MOLECULAR LIQUIDS; v. 401, p. 8-pg., 2024-04-10.

Abstract

The 1- n butyl-2,3-dimethylimidazolium cation, when paired with the prolinate anion, serves as a highly effective catalyst for H/D exchange reactions of Active Pharmaceutical Ingredient (API) utilizing CDCl 3 as a deuterium source. Notably, this catalytic process occurs under mild conditions, eliminating the need of extreme pH or temperatures, or the employment of metals. In the specific case of flunitrazepam, we have successfully demonstrated the incorporation of deuterium (up to 95%) into the molecule's most acidic hydrogens. Nuclear Overhauser Effect (NOE) experiments provided evidence that the exchange depends on the interaction between Ionic Liquid (IL) and the substrate's exchange site. Kinetic experiments yielded saturation curves, revealing that the reaction reaches its maximum conversion in less than 10 h. Linearization of these curves have allowed us to observe the dependence of IL on deuteration, enabling the determination of the second -order rate constant. This observation further corroborates with the catalytic role of IL in facilitating the H/D exchange reaction with the compound. By varying the temperature, we systematically investigated activation parameters, including E a , A, Delta G double dagger , Delta H double dagger , and Delta S double dagger . In the final phase of our study, we have successfully scaled up the reaction, isolating the deuterated flunitrazepam with a remarkable yield of 89%. Stability and integrity of the compound were confirmed at the conclusion of the purification. (AU)

• FAPESP's process: 18/09145-5 - Characterization of supramolecular complexes by solution and solid state high resolution Nuclear Magnetic Resonance
• Grantee: Tiago Venancio
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/10246-0 - Nuclear magnetic resonance spectroscopy: from pulse sequences to structural assignments
• Grantee: Claudio Francisco Tormena
• Support Opportunities: Research Projects - Thematic Grants