958002-33-0

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.

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].

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.

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[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