Reaktionsgleichung
[P:1].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-])=O.[N+]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])([O-])=O.[N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O>>[C:2]1([O-:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P+3:1].[C:15]1([O-:18])[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1.[C:23]1([O-:28])[CH:24]=[CH:25][CH:26]=[CH:27][CH:22]=1Komponenten
Versuchsvorschrift
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.
Quellen und Nachweise
- ORD-Eintrag
- ord-1e97bdd6e2d84f58b9af90d2846b4f11
- Quelldatensatz
- uspto-grants-2014_11
- Patentnummer
- US08877733B2
Verknüpfte Notizen
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