| Identification | Back Directory | [Name]
Beclabuvir | [CAS]
958002-33-0 | [Synonyms]
Beclabuvir
Beclabuvir(BMS-791325)
(1aR,12bS)-8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide
Cycloprop[d]indolo[2,1-a][2]benzazepine-9-carboxamide, 12-cyclohexyl-N-[(dimethylamino)sulfonyl]-4b,5,5a,6-tetrahydro-3-methoxy-5a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-, (4bS,5aR)- | [Molecular Formula]
C36H45N5O5S | [MDL Number]
MFCD28515320 | [MOL File]
958002-33-0.mol | [Molecular Weight]
659.84 |
| Chemical Properties | Back Directory | [density ]
1.45±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMSO:30.0(Max Conc. mg/mL);45.46(Max Conc. mM) | [form ]
Solid | [pka]
4.44±0.40(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Description]
Beclabuvir is a non-nucleoside,
nonstructural protein 5B (NS5B) polymerase inhibitor
approved in Japan as part of a fixed-dose combination product
for the treatment of hepatitis C virus (HCV). Upon
administration and after intracellular uptake, the drug binds
to the allosteric, noncatalytic “Thumb 1” site of NS5B resulting
in a decreased rate of viral RNA synthesis and replication.4
Beclabuvir is combined with asunaprevir and declatasvir (both
approved in 2014) and was discovered and developed by
Bristol-Myers Squibb. | [Uses]
Beclabuvir is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, and inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 with IC50 of < 28 nM[1][2]. | [Synthesis]
The syntheses of asunaprevir and declatasvir were described
in an earlier review article.Condensation of
indole-6-carboxylic acid (1) with cyclohexanone under basic
conditions gave acid 2 in quantitative yield. Hydrogenation of
the double bond in 2 using Pearlman?ˉs catalyst was followed by
esterification to give ester 3 in high yield. Bromination of the
indole at the 2-position was accomplished with pyridinium
tribromide, and this was followed by saponification to provide
acid 4. Treatment of 4 with carbonyldiimidazole (CDI)
followed by N,N- dimethylsulfamide and 1, 8 -
diazabicyclo[5.4.0]undec-7-ene (DBU) gave compound 5 in
74% yield. Suzuki coupling of 5 with commercial boronic acid 6
provided intermediate 7, which converted to hemiaminal 8
upon continued heating in 61% yield. Compound 8 was then
treated with methyl 2-(dimethoxyphosphoryl)acrylate (9) to
affect a tandem conjugate addition and Horner?Wadsworth?
Emmons (HWE) olefination to give ester 10. Alternatively, the
Suzuki coupling reaction of 5 with 6 could be stopped at
intermediate 7, which could be treated with 9 to promote the tandem conjugate addition/HWE to give 10. Corey?-Chaykovsky cyclopropanation of 10 using sodium hydride
and trimethylsulfoxonium iodide followed by chiral separation
provided cyclopropane 11 in good yield and >99% enantiomeric
excess (ee). Saponification of the methyl ester of 11
followed by coupling with 3-methyl-3,8-diazabicyclo[3.2.1]-
octane dihydrochloride (12) gave beclabuvir (I) in high yield.
 | [in vivo]
The combination of beclabuvir with asunaprevir and daclatasvir achieves very high rates of viral eradication (about 90%) in patients infected with HCV genotype 1, which is the most common genotype worldwide[1]. | [storage]
Store at -20°C | [References]
[1] Gentile I, et al. Beclabuvir for the treatment of hepatitis C. Expert Opin Investig Drugs. 2015;24(8):1111-21 DOI:10.1517/13543784.2015.1059820
[2] Tatum H, et al. A randomized, placebo-controlled study of the NS5B inhibitor beclabuvir with peginterferon/ribavirin for HCV genotype 1. J Viral Hepat. 2015 Aug;22(8):658-64. DOI:10.1111/jvh.12372 |
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