An Efficient and Diastereoselective Synthesis of PSI-6130: A Clinically Efficacious Inhibitor of HCV NS5B Polymerase

Abstract

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.

New antiviral therapies for chronic hepatitis C

“…HCV SPRINT-1 study Naı¨ve treatment-naïve [27,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][93][94][95][96][97][98] assessed the safety and efficacy of boceprevir, an oral inhibitor of HCV-NS3 protease, plus pegIFN alpha-2b and ribavirin (Table 4). SVR was significantly increased in the 28-and 48-week boceprevir arms compared to pegIFN alpha-2b and RBV control.…”

“…The same as hepatitis B virus, human immunodeficiency virus, and herpes virus, HCV is thought to be a target of polymerase inhibitor. There are two classes: nucleoside inhibitors and non-nucleoside inhibitors (NNIs) [45]. These drugs reduce the efficiency of further RNA elongation.…”

Antiviral Nucleoside and Nucleotide Analogs: A Review

“…Modeling studies suggest that the 2`-C-methyl group of the incorporated nucleotide inhibitor might cause a steric conflict with the endogenous nucleotide substrate. 42 Therefore, Sofosbuvir and related 2`-C-methylated derivatives with a hydroxyl group or fluorine atom at the 2`-position act as potent chain terminators, such as PSI-6130, [43][44][45][46][47][48][49][50][51] Mercitabine, [52][53][54][55][56][57][58][59][60][61] …”

Sofosbuvir: The Discovery of a Curative Therapy for the Treatment of Hepatitis C Virus

“…We had successfully developed a homochiral synthesis of the uridine nucleoside PSI-6206 starting with d-glyceraldehyde (Figure 8.9) [38]. Consequently, after the preparation of the phosphoramidate prodrug, we were able to separate the diastereomers of PSI-7851 using chromatographic methods which gave the two compounds PSI-7976 17 and PSI-7977 1 (Figure 8.8a) [31].…”