Optimization of the Synthesis Process for (S)-Oxetane-2- Methanamine

Abstract

(S)-Oxetane-2-methanamine serves as a key building block for small-molecule glucagon-like peptide-1 receptor agonists (GLP-
1RAs), which hold significant potential in the development of novel antidiabetic drugs. However, current synthetic routes often suffer from
lengthy procedures, high material costs, challenging purification steps, and the use of highly toxic reagents, rendering them unsuitable for
industrial-scale production. In this study, we innovatively replaced dibenzylamine with N-benzyl-?-methylbenzylamine as the amine-introducing reagent through systematic screening, leading to the development of an efficient, cost-effective, and scalable synthesis process for (S)-
oxetane-2-methanamine. Starting from inexpensive and readily available (S)-epichlorohydrin, and utilizing trimethylsulfoxonium iodide as the
ring-expansion reagent, the key intermediate was purified via recrystallization, effectively eliminating sulfide residues that could interfere with
the subsequent debenzylation step. This optimization significantly reduced the palladium-on-carbon (Pd/C) catalyst loading and shortened the
reaction time. The final product was obtained with a purity of 99.5% and an enantiomeric excess (ee) of 99.6%, providing a novel and practical approach for the development of GLP-1 receptor agonists.