Practical Synthesis of a 6‑Triazolylazabicyclo[3.1.0]hexane

Abstract

We describe a practical, scalable synthesis of an advanced heterocyclic intermediate, (1<i>R</i>,5<i>S</i>,6<i>s</i>)-6-(4<i>H</i>-1,2,4-triazol-4-yl)-3-azabicyclo­[3.1.0]­hexane. A robust synthetic sequence based on a Kulinkovich–de Meijere pyrroline cyclopropanation followed by transamination of <i>N</i>,<i>N</i>′-dimethylformamide azine with the resultant amine was developed to supply >18 kg of the target triazolyl azabicycle with 98 wt % purity in its free base form. Reaction conditions and isolation methods for the key 1,2,4-triazole formation step were explored to minimize undesired reaction pathways and to increase the purity of the product. Additionally, at several stages different freebasing methods were implemented that addressed the high water solubility of the associated nitrogen-rich compounds