Large-scale synthesis of high purity “Phos reagent” useful for oligonucleotide therapeutics

A large-scale, cost-effective, and environmentally clean synthesis of high purity 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphorodiamidite (Phos reagent) has been accomplished on a commercial scale. Treatment of PCl3 with diisopropylamine followed by 3-hydroxylpropionitrile furnished the Phos reagent in excellent yield. The 31P NMR of the Phos reagent prepared at large-scale show consistent purities >99% when several key factors are controlled. These controlling factors include sourcing high purity key raw materials, identification and elimination of critical impurities, stability and storage of Phos reagent.

Graphical abstractA cost-effective synthesis of high purity 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphorodiamidite (Phos Reagent) has been accomplished on a commercial scale. Two routes, which begin with PCl3, furnished high purity Phos Reagent with purities >99% when several key factors are controlled.Figure optionsDownload full-size imageDownload as PowerPoint slide