Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis

被引:22
作者
Arrington, Kenneth [1 ]
Barcan, Gregg A. [1 ]
Calandra, Nicholas A. [1 ]
Erickson, Greg A. [1 ]
Li, Ling [1 ]
Liu, Li [1 ]
Nilson, Mark G. [1 ]
Strambeanu, Iulia I. [1 ]
VanGelder, Kelsey F. [1 ]
Woodard, John L. [1 ]
Xie, Shiping [1 ]
Allen, C. Liana [1 ]
Kowalski, John A. [1 ]
Leitch, David C. [1 ]
机构
[1] GlaxoSmithKline, API Chem, King Of Prussia, PA 19406 USA
关键词
CROSS-COUPLING REACTION; C-H BORYLATION; POLYMERASE INHIBITOR; ARYL HALIDES; ARYLATION; MECHANISM; DISCOVERY; REAGENTS; CONVERSION; COMPLEXES;
D O I
10.1021/acs.joc.8b02269
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday SNAr arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methane-sulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated in situ using KPF6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh2 identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K2CO3/pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.
引用
收藏
页码:4680 / 4694
页数:15
相关论文
共 59 条
  • [1] [Anonymous], ANGEW CHEM INT ED
  • [2] Discovery of Daclatasvir, a Pan-Genotypic Hepatitis C Virus NS5A Replication Complex Inhibitor with Potent Clinical Effect
    Belema, Makonen
    Meanwell, Nicholas A.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (12) : 5057 - 5071
  • [3] Mechanism of the mild functionalization of arenes by diboron reagents catalyzed by iridium complexes. Intermediacy and chemistry of bipyridine-ligated iridium trisboryl complexes
    Boller, TM
    Murphy, JM
    Hapke, M
    Ishiyama, T
    Miyaura, N
    Hartwig, JF
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2005, 127 (41) : 14263 - 14278
  • [4] Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor G5K852A
    Bowman, Roy K.
    Bullock, Kae M.
    Copley, Royston C. B.
    Deschamps, Nicole M.
    McClure, Michael S.
    Powers, Jeremiah D.
    Wolters, Andy M.
    Wu, Lianming
    Xie, Shiping
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 2015, 80 (19) : 9610 - 9619
  • [5] Chong P. Y., 2013, Patent No. [WO 2013028371A1, 2013028371, WO2013028371A1]
  • [6] A decade advancement of transition metal-catalyzed borylation of aryl halides and sulfonates
    Chow, Wing Kin
    Yuen, On Ying
    Choy, Pui Ying
    So, Chau Ming
    Lau, Chak Po
    Wong, Wing Tak
    Kwong, Fuk Yee
    [J]. RSC ADVANCES, 2013, 3 (31): : 12518 - 12539
  • [7] Boron as a platform for new drug design
    Ciani, Laura
    Ristori, Sandra
    [J]. EXPERT OPINION ON DRUG DISCOVERY, 2012, 7 (11) : 1017 - 1027
  • [8] Discovery of MK-8742: An HCV NS5A Inhibitor with Broad Genotype Activity
    Coburn, Craig A.
    Meinke, Peter T.
    Chang, Wei
    Fandozzi, Christine M.
    Graham, Donald J.
    Hu, Bin
    Huang, Qian
    Kargman, Stacia
    Kozlowski, Joseph
    Liu, Rong
    McCauley, John A.
    Nomeir, Amin A.
    Soll, Richard M.
    Vacca, Joseph P.
    Wang, Dahai
    Wu, Hao
    Zhong, Bin
    Olsen, David B.
    Ludmerer, Steven W.
    [J]. CHEMMEDCHEM, 2013, 8 (12) : 1930 - 1940
  • [9] Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH-Rate Profiles, Autocatalysis, and Disproportionation
    Cox, Paul A.
    Leach, Andrew G.
    Campbell, Andrew D.
    Lloyd-Jones, Guy C.
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2016, 138 (29) : 9145 - 9157
  • [10] BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald-Hartwig Amination of (Hetero) aryl Chlorides
    Crawford, Sarah M.
    Lavery, Christopher B.
    Stradiotto, Mark
    [J]. CHEMISTRY-A EUROPEAN JOURNAL, 2013, 19 (49) : 16760 - 16771