Application of Ring-Closing Metathesis Strategy to the Synthesis of Vaniprevir (MK-7009), a 20-Membered Macrocyclic HCV Protease Inhibitor

Abstract

Vaniprevir (MK-7009) bearing a 20-membered macrocycle and chiral components is a highly efficacious HCV protease inhibitor aiming for the treatment of chronic infection of hepatitis C virus. The efficient macrocyclization coupled with the assembling of key chiral components is of great challenge for the large-scale production of this structurally complex molecule. In this chapter, a convergent synthesis with a longest sequence of nine steps featuring highly efficient macrocyclization via ring-closing metathesis (RCM) along with the improvement in the syntheses of key components will be described. RCM for the construction of 20-membered macrocycle using low catalyst loading (0.2 mol%) and practically high concentration (0.13 M) was achieved by simultaneous and slow addition of ruthenium catalyst and the diene substrate. The strategy of using RCM in this costeffective synthesis sets a new paradigm for the synthesis of several other macrocyclic HCV protease inhibitors at Merck Research Laboratories.

Drug Syntheses Beyond the Rule of 5

“…[114] Over the years various improvementsi nt he synthesis of this small and complex chiral buildingb lock have been reported. [115][116][117][118][119] After the preparation of building blocks B1-B3, they wereefficiently assembled in seven steps by key amidation, Mitsunobu and metathesis reactions to give simeprevir (132,Scheme 20). [9,114] Initially, lactone carboxylic acid building block B2 (152)w as coupled to hexene amine 167 to provide amide 168,w hich was hydrolysed and coupled with amine building block B3 (166)t op rovide diamide 169.H ydroxylquinoline buildingb lock B1 (144)w as then incorporated by aM itsunobu reactionw ith alcohol 169 to give bis-terminal olefin 170.R ingclosing metathesis (RCM) using the Hoveyda-Grubbs first generation catalystafforded macrocycle 171 in 60 %yield.…”

“…[121] 3.6.2 Vaniprevir. Vaniprevir( 133)i smacrocyclisedi nadifferent manner than simeprevir (132), but was also synthesised from three buildingb locks, B1, B2 and B3 (Scheme 21). Synthesis of buildingb lock B1 (178)s tartedf rom 3-bromo-o-xylene (172), which was brominated by NBS to obtain bis-benzyl bro-mide 173.C yclisation with benzyl amine then provided bromoisoindolene 174,w hich underwentaStille coupling with vinyltributyltin to give benzylp rotected amine 175.Selective deprotection of the exocyclic benzylg roup in 175 under mild conditions by reaction with 1-chloroethyl chloroformate [122] gave amine 176.S ubsequentC DI-mediated coupling of 176 with protected hydroxyproline 177,f ollowed by Boc deprotection completed the synthesis of buildingb lock B1 (178).…”

“…To the best of our knowledge the synthesis of the macrocyclic moiety in simeprevir (132)h as only been reported using RCM with the Hoveyda-Grubbs first generation catalyst ( Figure 15). [9] However,m ultiple approaches for macrocyclisa-tion have been employed for synthesis of vaniprevir (133)a nd grazoprevir (135).…”

“…Each of the two different side chains in the non-symmetric ledipasvir (216)a re prepared by Figure 15. Overview of different macrocyclisationapproaches used for synthesizing simeprevir (132), vaniprevir (133), grazoprevir (135)and voxilaprevir (136). The 1-amino-cyclopropaneacylsulfonamideblock which is commontothe NS3/4A protease inhibitors is indicatedinr ed.…”

“…RifamycinB(31)a nd its semi-synthetic derivatives are 24-membered macrocyclest hat originate from the class of ansamycin natural products (Figure 5). They have high MWs (823-877 Da), > 10 HBAs and 5-6 hydrogen bond donors (HBDs) and are among the most structurally complex bRo5 drugs approved in the last three decades (SMCM [123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139]. Rifamycins are antibacteriala gents that are used to treat tuberculosis,a ided by their accumulation in the lungs and macrophages.…”