669008-26-8Relevant articles and documents
Development of a Large-Scale Route to Glecaprevir: Synthesis of the Side Chain and Final Assembly
Abrahamson, Michael J.,Chemburkar, Sanjay,Chen, Shuang,Cink, Russell D.,Ding, Chen,Engstrom, Kenneth M.,Henry, Rodger,Hill, David R.,Kielbus, Angelica B.,Lukin, Kirill A.,Mei, Jianzhang,Nere, Nandkishor K.,Pelc, Matthew J.,Reddy, Rajarathnam E.,Towne, Timothy B.,Zhang, Hongqiang
, p. 1393 - 1404 (2020/10/15)
The preceding article described the development of the large-scale synthetic route to macrocycle 3 of glecaprevir (1), a potent HCV protease inhibitor. This article describes the development of the synthesis of the difluoromethyl-substituted cyclopropyl amino acid 4, its conversion to the fully elaborated side chain, amino sulfonamide 2, and the subsequent final coupling to form glecaprevir. The synthesis of amino acid 4 consists of four key transformations: (a) formation of the difluoromethyl-substituted cyclopropane ring of (±)-diester 15 via Knoevenagel condensation and Corey-Chaykovsky cyclopropanation, (b) diastereoselective hydrolysis of (±)-diester 15 to yield (±)-monoacid 14a-b, (c) conversion of (±)-monoacid 14a-b to (±)-amino ester 10 via a Curtius rearrangement, and (d) resolution of (±)-amino ester 10 followed by saponification to give the desired (1R,2R)-amino acid 4. The large-scale synthetic route to amino acid 4 was successfully used to produce the fully elaborated side chain 2 and ultimately the amount of glecaprevir required to support the late-stage clinical development.
Hepatitis C virus inhibitors
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Page/Page column 617, (2017/01/23)
Hepatitis C virus inhibitors having the general formula (I) are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
P2-quinazolinones and bis-macrocycles as new templates for next-generation hepatitis C virus NS3/4a protease inhibitors: Discovery of MK-2748 and MK-6325
Rudd, Michael T.,Butcher, John W.,Nguyen, Kevin T.,McIntyre, Charles J.,Romano, Joseph J.,Gilbert, Kevin F.,Bush, Kimberly J.,Liverton, Nigel J.,Holloway, M. Katharine,Harper, Steven,Ferrara, Marco,Difilippo, Marcello,Summa, Vincenzo,Swestock, John,Fritzen, Jeff,Carroll, Steven S.,Burlein, Christine,Dimuzio, Jillian M.,Gates, Adam,Graham, Donald J.,Huang, Qian,McClain, Stephanie,McHale, Carolyn,Stahlhut, Mark W.,Black, Stuart,Chase, Robert,Soriano, Aileen,Fandozzi, Christine M.,Taylor, Anne,Trainor, Nicole,Olsen, David B.,Coleman, Paul J.,Ludmerer, Steven W.,McCauley, John A.
supporting information, p. 727 - 735 (2015/04/14)
With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.
