An efficient and diastereoselective synthesis of PSI-6130: a clinically efficacious inhibitor of HCV NS5B polymerase.
R7128 is the prodrug of 2'-deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130), a potent and selective inhibitor of HCV NS5B polymerase. Currently, R7128 is in clinical trials for the treatment of HCV infection. To support clinical development efforts, we needed an efficient and scalable synthesis of PSI-6130. We describe an improved, diastereoselective synthetic route starting with protected d-glyceraldehyde. No chiral reagents or catalysts were used to produce the three new contiguous stereocenters. Introduction of fluorine at the C-2 tertiary carbon was accomplished in a highly regio- and stereoselective manner through nucleophilic substitution on a cyclic sulfate. Scale-limiting chromatographic purifications were eliminated through the use of crystalline intermediates.
Wang
Peiyuan
P
Pharmasset, Inc., 303A College Road E., Princeton, New Jersey 08540, USA.
Chun
Byoung-Kwon
BK
Rachakonda
Suguna
S
Du
Jinfa
J
Khan
Noshena
N
Shi
Junxing
J
Stec
Wojciech
W
Cleary
Darryl
D
Ross
Bruce S
BS
Sofia
Michael J
MJ
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D002625:Chemistry, Organic / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002845:Chromatography / Q000379:methods; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D005461:Fluorine / Q000737:chemistry; D005985:Glyceraldehyde / Q000737:chemistry; D006031:Glycosylation; D007783:Lactones; D008956:Models, Chemical; D010753:Phosphoranes / Q000737:chemistry; D013237:Stereoisomerism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D002244:Carbon; D003841:Deoxycytidine; D005461:Fluorine; D005985:Glyceraldehyde; D007783:Lactones; D010753:Phosphoranes; D017361:Viral Nonstructural Proteins; C504520:2'-deoxy-2'-fluoro-2'-C-methylcytidine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase