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Erschienen in:
Development of a Manufacturing Process for the Formation of a Nucleoside Drug Candidate Kapitel lesen Erstes Kapitel lesen

2016 | OriginalPaper | Buchkapitel

Synthetic Routes to Sofosbuvir

verfasst von : Roland Barth, Christopher A. Rose, Olga Schöne

Erschienen in: Synthesis of Heterocycles in Contemporary Medicinal Chemistry

Verlag: Springer International Publishing

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Abstract

Due to its global pervasiveness and chronicity, the hepatitis C virus (HCV) is a major health problem that claims around half a million lives annually. In recent years, the pharmaceutical industry has witnessed a surge in the development of new therapies for the treatment of hepatitis C. One such drug, sofosbuvir, marketed by Gilead Sciences, was recently approved for clinical use in several countries. In combination with other antiviral agents, sofosbuvir has shown remarkable efficacy for a broad range of viral genotypes, along with high tolerability. The clinical success of sofosbuvir demands efficient approaches for the synthesis of this pharmaceutical. Marketed as a single isomer, sofosbuvir presents several interesting synthetic challenges, including fluorination chemistry, nucleotide synthesis, and regio- and stereoselective phosphoramidation. This review provides a brief pharmacological background of sofosbuvir including its mode of action, followed by an in-depth analysis of the current synthetic approaches to sofosbuvir and its close analogues.

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Fußnoten
1
Although it has been stated in some patent literature that deoxofluor can serve as a suitable fluorinating agent, no experimental evidence could be found.
 
2
Acetal protecting groups were found to be unstable under the reaction conditions.
 
3
Some mechanistic studies have been performed in the context of phosphate synthesis; see, for example, [68] Liu C-Y, Pawar VD, Kao J-Q, Chen C-T (2010) Adv. Synth. Catal. 352: 188–194, and references therein.
 
4
Other methods for the separation of impurities disclosed by development chemists of Pharmasset include: a) oiling out from crude sofosbuvir (11.6% overall chemical yield, single diastereomer (S P), purity >99%) and b) silica loading of crude sofosbuvir followed by successive washes with increasingly polar eluents and two final recrystallizations (~12 % overall chemical yield, single diastereomer (S P), purity > 99%).
 
5
While the patent application (example 3B) shows a structure number which is inconsistent with compound 153 and a IUPAC name which is inconsistent with 1, the experimental conditions (starting material dr and reaction scale) together with the scheme provided lead us to believe that 153 was employed to make 1 as drawn.
 
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Metadaten
Titel
Synthetic Routes to Sofosbuvir
verfasst von
Roland Barth
Christopher A. Rose
Olga Schöne
Copyright-Jahr
2016
Buch
Synthesis of Heterocycles in Contemporary Medicinal Chemistry

Print ISBN: 978-3-319-39915-7

Electronic ISBN: 978-3-319-39917-1

Copyright-Jahr: 2016

DOI
https://doi.org/10.1007/7081_2015_183

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