Nucleosidic Phosphoramidite Synthesis via Phosphitylation: Activator Selection and Process Development

Abstract

Nucleosidic phosphoramidites are key building blocks for the automated, solid supported syntheses of oligonucleotide-based drugs. A safe, industrially viable process for preparing nucleosidic phosphoramidites 5-Me-MOE-U and MOE-A has been developed and utilized on multikilogram scales. The optimization of this process is described in detail. Emphasis is placed on the search for activators to replace the hazardous 1H-tetrazole, the development of an extractive workup, and the advancement of a precipitation method to avoid both chromatographic purification and product foaming issues.