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Synthesis 2006(15): 2563-2567  
DOI: 10.1055/s-2006-942472
PAPER
© Georg Thieme Verlag Stuttgart · New York

Practical Synthesis of 2-(2-Isopropylaminothiazol-4-yl)-7-methoxy-1H-quinolin-4-one: Key Intermediate for the Synthesis of Potent HCV NS3 Protease Inhibitor BILN 2061

Rogelio P. Frutos*a, Nizar Haddada, Ioannis N. Houpisa,, Michael Johnsona,, Lana L. Smith-Keenana, Victor Fuchsa, Nathan K. Yeea, Vittorio Farinaa, Anne-Marie Faucher*b, Christian Brochub, Bruno Hachéb, Jean-Simon Duceppeb, Pierre Beaulieub
a Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./P.O. Box 368, Ridgefield, CT 06877 0368, USA
Fax: +1(203)8374681; e-Mail: rfrutos@rdg.boehringer-ingelheim.com;
b Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard St., Laval, Québec, H7S 2G5, Canada
Further Information

Publication History

Received 7 March 2006
Publication Date:
04 July 2006 (online)

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Abstract

Herein we describe the development of an efficient, safe and practical process for the synthesis of 7-methoxy-2-(2-amino-4-thiazolyl)quinoline. Our new process allowed for a more convergent approach and eliminates the use of potentially dangerous reagents such as diazomethane used in the previous discovery approach.

Key words

BILN2061 - protease inhibitor - hepatitis C virus - Sugasawa­ - quinolone

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1

Present Address: Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.

2

Present Address: Battelle, 505 King Avenue, Columbus, Ohio 43201, USA.

14

The yield was determined by a quantitative HPLC assay.

15

2-Isopropylamino-7-methoxy-4-methylene-4,9-dihydro-3-thia-1,9-diazabenz[f]azulen-10-one (11): 1H NMR (400 MHz, DMSO-d 6): δ = 1.14 (d, J = 6.4 H, 6 H), 3.72 (s, 3 H), 3.70-3.85 (m, 1 H), 5.30 (s, 1 H), 5.34 (s, 1 H), 6.70-6.75 (m, 2 H), 6.75 (d, J = 2.4 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.74 (d, J = 7.5 Hz, 1 H), 10.0 (s, 1 H). 13C NMR (100 MHz, DMSO-d 6): δ = 22.7, 46.3, 55.7, 106.4, 110.6, 116.8, 123.1, 130.1, 131.5, 137.0, 139.6, 160.2, 161.4, 163.9.

17

A manuscript describing the complete assembly of BILN 2061 using 3 is in preparation and will be published in due course.