title: Synthesis of diastereomerically pure nucleotide phosphoramidates.
abstract: Prodrugs of therapeutic nucleoside monophosphates masked as phosphoramidate derivatives have become an increasingly important class of antiviral drugs in pharmaceutical research for delivering nucleotides in vitro and in vivo. Conventionally, phosphoramidate derivatives are prepared as a mixture of two diastereomers. We report a class of stable phosphoramidating reagents containing an amino acid ester and two phenolic groups, one unsubstituted and the other with electron-withdrawing substituents. The reagents can be isolated as single diastereomers and reacted with the 5'-hydroxyl group of nucleosides through selective nucleophilic displacement of the substituted phenol to prepare single diastereomer phosphoramidate products. This method has been used to prepare the HCV clinical candidate PSI-7977 in high yield and high diastereomeric purity.
authors.affiliation: Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540, United States. bruce.ross@pharmasset.com
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Ross
authors.forename: P Ganapati
authors.initials: PG
authors.lastname: Reddy
authors.forename: Hai-Ren
authors.initials: HR
authors.lastname: Zhang
authors.forename: Suguna
authors.initials: S
authors.lastname: Rachakonda
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sofia
mesh_terms: D000577:Amides / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004583:Electrons; D004952:Esters / Q000737:chemistry; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009705:Nucleosides / Q000737:chemistry; D009711:Nucleotides / Q000737:chemistry; D010636:Phenols / Q000737:chemistry; D010756:Phosphoric Acids / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology; D000069474:Sofosbuvir; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D000596:Amino Acids; D000998:Antiviral Agents; D004952:Esters; D009705:Nucleosides; D009711:Nucleotides; D010636:Phenols; D010756:Phosphoric Acids; D011355:Prodrugs; D014764:Viral Proteins; C011067:phosphoramidic acid; D014542:Uridine Monophosphate; D012321:DNA-Directed RNA Polymerases; D000069474:Sofosbuvir