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Synthetic Routes to Sofosbuvir

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Synthesis of Heterocycles in Contemporary Medicinal Chemistry

Part of the book series: Topics in Heterocyclic Chemistry ((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.

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Notes

  1. 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. 2.

    Acetal protecting groups were found to be unstable under the reaction conditions.

  3. 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. 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. 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.

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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Authors and Affiliations

  1. Sandoz Development Center Austria, Sandoz GmbH, Biochemiestr. 10, 6336, Langkampfen, Austria

    Roland Barth & Olga Schöne

  2. Sandoz Development Center Austria, Sandoz GmbH, Biochemiestr. 10, 6250, Kundl, Austria

    Christopher A. Rose

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  1. Roland Barth
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  2. Christopher A. Rose
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  3. Olga Schöne
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Correspondence to Olga Schöne .

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  1. Head Prototype Analytics, Sandoz Development Center Slovenia, Lek Pharmaceuticals d.d., Ljubljana, Slovenia

    Zdenko ÄŒasar

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Barth, R., Rose, C.A., Schöne, O. (2015). Synthetic Routes to Sofosbuvir. In: Časar, Z. (eds) Synthesis of Heterocycles in Contemporary Medicinal Chemistry. Topics in Heterocyclic Chemistry, vol 44. Springer, Cham. https://doi.org/10.1007/7081_2015_183

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