Mechanism-Based Solution to the ProTide Synthesis Problem: Selective Access to Sofosbuvir, Acelarin, and INX-08189

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• ProTides are crucial prodrugs enhancing drug bioavailability.
• Current synthesis methods for ProTides can be complex and require multiple steps.
• Efficient synthesis of 5 -phosphoramidate monoesters is key for developing new therapeutics.

Purpose of the Study:

• To develop a general and efficient method for synthesizing pronucleotide (ProTide) 5 -phosphoramidate monoesters.
• To demonstrate the utility of this method for pharmaceutically relevant compounds.

Main Methods:

• Utilized dimethylaluminum chloride for highly stereoselective 5 -phosphorylation.
• Developed a strategy that bypasses the need for 3 -protection groups.
• Applied the methodology to synthesize various marketed and investigational drugs.

Main Results:

• Achieved excellent yields of target ProTides.
• The method proved general and efficient for a range of compounds.
• Successfully synthesized pharmaceutically relevant ProTides without 3 -protection.

Conclusions:

• The reported method offers a significant advancement in ProTide synthesis.
• This efficient and stereoselective approach facilitates the development of novel prodrugs.
• The methodology is applicable to the synthesis of important pharmaceutical agents.