Reaction #417940

Reaction equation

phosphorous

phenol

4-nitrophenol

2-nitrophenol

2,4-dinitrophenol

→

phosphorous phenolate

Conditions

Procedure

The phosphorous chloridate Compound 100c reacts with an activated phenol such as 4-nitrophenol, 2-nitrophenol, and 2,4-dinitrophenol, in the presence of a suitable base to give a phosphorous phenolate Compound 100d that is stable for further purification. Compound 100d is then coupled with a Nucleoside; a solution of a Nucleoside in NMP (˜30 mL/mmol) is cooled to 0° C. using an ice bath. To this mixture, a solution of t-BuMgCl in THF (1.0 M, 1.5-2.5 eq. to the nucleoside) is added dropwise. A solution of Compound 100d (˜1.5 eq. to the nucleoside) in THF (˜15 mL/mmol) is then added dropwise to the reaction mixture. The resulting mixture is allowed to warm up to room temperature and stirred for 16 h. The solution is then quenched with H2O (˜30 mL/mmol) and purified via reverse phase HPLC (30-60% CH3CN in H2O). The product fractions are combined, concentrated under vacuum, and then further purified using flash silica gel chromatography (1-35% MeOH in CH2Cl2) to give a monophosphate prodrug Compound PD-A. The diasteromeric mixture of Compound 100d is optionally separated into two single stereoisomers Compound (S)-100d and Compound (R)-100d by crystallization or chromatography prior to coupling with the Nucleoside to afford a single stereoisomer Compound (S)-PD-A or Compound (R)-PD-A.

Source