A highly efficient, asymmetric synthesis of benzothiadiazine-substituted tetramic acids: Potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase

Organic Letters

Volumn 7, Issue 24, 2005, Pages 5521-5524

  Fitch, Duke M ^a   Evans, Karen A ^a   Chai, Deping ^a   Duffy, Kevin J ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 PYRROLIDONE DERIVATIVE; ANTIVIRUS AGENT; BENZOTHIADIAZINE DERIVATIVE; RNA DIRECTED RNA POLYMERASE; TETRAMIC ACID;

ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; COMBINATORIAL CHEMISTRY; CYCLIZATION; DRUG ANTAGONISM; DRUG EFFECT; ENZYMOLOGY; HEPATITIS C VIRUS; SYNTHESIS;

ANTIVIRAL AGENTS; BENZOTHIADIAZINES; COMBINATORIAL CHEMISTRY TECHNIQUES; CYCLIZATION; HEPACIVIRUS; MOLECULAR STRUCTURE; PYRROLIDINONES; RNA REPLICASE;

EID: 28844459948     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol052371w     Document Type: Article

References (26)

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15. Acid 4 was prepared by hydrolysis (see Supporting Information for details) of the known ethyl ester: Kovalenko, S. N.; Chernykh, V. P.; Shkarlat, A. E.; Ukrainets, I. V.; Gridasov, V. I.; Rudnev, S. A. Chem. Heterocycl. Compd. (Engl. Transl.) 1998, 34, 791-795.
16. r (R) = 25.9 min). Analysis of a sample of 6a stored for > 1 month at ambient temperature showed no sign of racemization.
17. 50 values. See refs 6 and 7 for details.
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21. Details of the solid-phase approach will be reported in a separate publication: Evans, K. A.; Chai, D.; Graybill, T. L.; Sarisky, R. T.; Lin-Goerke, J.; Johnson, V. K.; Burton, G.; Rivero, R. A. Manuscript in preparation.
22. For certain analogues, a subsequent deprotection step was required. See ref 16 and Supporting Information for details.
23. Cyclization was generally complete after 1.5 h at ambient temperature.
24. Details of the optimization of the benzothiadiazine portion of inhibitor 1 will be reported in due course.
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26. Cyclization was incomplete after stirring overnight at ambient temperature with an 18% yield of the uncyclized intermediate obtained in addition to the desire product 13.