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Synthetic Routes to Sofosbuvir

Chapter
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 44)

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.

Keywords

Fluorination Hepatitis C virus Nucleoside synthesis Phosphoramidate synthesis Sofosbuvir 

Abbreviations

Ac

Acetyl

AcOH

Acetic acid

API

Active pharmaceutical ingredient

aq

Aqueous

Ar

Aryl

Bn

Benzyl

Boc

tert-Butoxycarbonyl

bp

Boiling point

Bu

Butyl

Bz

Benzoyl

Bz2O

Benzoic anhydride

CALB

Candida antarctica lipase B

cat

Catalyst, catalytic

Cbz

Benzyloxycarbonyl

conc

Concentrated

Cyt

Cytosine

CytBz

N 4-benzoylcytosine

DAA

Direct-acting antiviral

DABCO

1,4-Diazabicyclo[2.2.2]octane

DAST

(Diethylamino)sulfur trifluoride

DBU

1,8-Diazabicyclo [5.4.0]undec-7-ene

de

Diastereomer excess

DIBALH

Diisobutylaluminum hydride

DIPEA

N,N-Diisopropylethylamine

DMAP

4-(Dimethylamino)pyridine

DMF

Dimethylformamide

DMP

Dess–Martin periodinane

DMSO

Dimethyl sulfoxide

dr

Diastereomer ratio

equiv

Equivalent(s)

Et

Ethyl

EWG

Electron withdrawing group

FDA

Food and Drug Administration (U.S.A.)

GC

Gas chromatography

h

Hour(s)

HATU

1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

HCV

Hepatitis C virus

HMDS

1,1,1,3,3,3-Hexamethyldisilazane

HPLC

High-performance (pressure) liquid chromatography

IPC

In-process control

i-Pr

isopropyl

LC

Liquid chromatography

LDA

Lithium diisopropylamide

LG

Leaving group

M

Molar

m-CPBA

m-Chloroperoxybenzoic acid

Me

Methyl

mol

Mole(s)

MOM

Methoxymethyl

MS

Mass spectrometry

Ms

Methanesulfonyl (mesyl)

NCS

N-chlorosuccinimide

NMI

N-methylimidazole

NMP

N-methyl-2-pyrrolidone

Nph

Naphthyl

Nu

Nucleophile

Nuc

Nucleoside

PCC

Pyridinium chlorochromate

PDC

Pyridinium dichromate

PEG-INF

Pegylated interferon α

Ph

Phenyl

Piv

Pivaloyl

PLG

Potential leaving group

PMB

4-Methoxyphenyl

PPA

Poly(phosphoric acid)

PPTS

Pyridinium p-toluenesulfonate

Pr

Propyl

py

Pyridine

quant

Quantitative

rac

Racemic

RBV

Ribavirin

RdRp

RNA-dependent RNA polymerase

Red-Al

Sodium bis(2-methoxyethoxy)aluminumhydride

RNA

Ribonucleic acid

RP

Reverse phase

rt

Room temperature

SFC

Supercritical fluid chromatography

TASF

Tris(dimethylamino)sulfonium difluorotrimethylsilicate

TBAF

Tetrabutylammonium fluoride

TBDMS, TBS

tert-Butyldimethylsilyl

TBDMSCl

tert-Butyldimethylsilyl chloride

TBDPS

tert-Butyldiphenylsilyl

TBDPSCl

tert-Butyl(chloro)diphenylsilane

TBSOTf

tert-Butyldimethylsilyl trifluoromethanesulfonate

TCA

Trichloroacetyl

t-Bu

tert-Butyl

TEA

Triethylamine

TEMPO

(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl, free radical

Tf

Trifluoromethanesulfonyl (triflyl)

TFA

Trifluoroacetic acid

TFAA

Trifluoroacetic anhydride

THF

Tetrahydrofuran

THP

Tetrahydropyran-2-yl

TIPDS

1,1,3,3-Tetraisopropyldisiloxane- 1,3-diyl

TIPDSCl2

1,3-Dichloro-tetraisopropyldisiloxane

TMP

2,2,6,6-Tetramethylpiperidine

TMS

Trimethylsilyl

Tol

4-Methylphenyl

XTalFluor E

(Diethylamino) difluorosulfonium tetrafluoroborate

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Sandoz Development Center Austria, Sandoz GmbHLangkampfenAustria
  2. 2.Sandoz Development Center Austria, Sandoz GmbHKundlAustria

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