Rethinking Dipolar Aprotic Solvents in Medicinal Chemistry: Practical Applications of Cyrene

The increasing demand for sustainable practices in pharmaceutical research has accelerated the identification of safer and greener alternatives to conventional organic solvents. Cyrene™, a bio-based dipolar aprotic solvent derived from cellulose, has emerged as a promising alternative to widely used solvents such as DMF and NMP, due to its low toxicity, biodegradability, and favorable physicochemical profile.1 In this contribution, we present our systematic investigation of Cyrene™ in a range of synthetic transformations relevant to medicinal chemistry, including nucleophilic aromatic substitutions,2 amidation reactions, and synthesis of key nitrogen-containing functional groups, such as triazoles3 and sulfonamides. Targeted optimization of reaction parameters enabled the efficient preparation of small libraries of compounds for each reaction class, generally affording high yields and good purity under operationally straightforward conditions. Selected compounds were evaluated for their biological activity against different targets,4 demonstrating the compatibility of Cyrene-based protocols with early-stage drug discovery workflows. Overall, these results position Cyrene™ as a viable alternative to traditional dipolar aprotic solvents, offering a concrete contribution toward greener medicinal chemistry practices. 1 Kong, D. et al., 2022, Sustain. Chem. Pharm., 25, 100591 2 Citarella A. et al., 2024, Eur.J.Org.Chem, 27, e202301305 3 Citarella A. et al., 2025, ChemSusChem, e202402538 4 Citarella A. et al., 2024, ACS Med. Chem. Lett., 15, 9, 1474–1481