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

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

References

• 3a Lamarre D. Anderson PC. Bailey M. Beaulieu P. Bolger G. Bonneau P. Boes M. Cameron DR. Cartier M. Cordingley MG. Faucher A.-M. Goudreau N. Kawai SH. Kukolj G. Lagace L. LaPlante SR. Narjes H. Poupart M.-A. Rancourt J. Sentjens RE. St. George R. Simoneau B. Steinmann G. Thibeault D. Tsantrizos YS. Weldon SM. Yong C.-L. Llinàs-Brunet M. Nature (London)  2003,  426:  186 
• 3b Llinàs-Brunet M. Bailey M. Bolger G. Brochu C. Faucher A.-M. Ferland J.-M. Garneau M. Ghiro E. Gorys V. Grand-Maître C. Halmos T. Lapeyre-Paquette N. Liard F. Poirier M. Rhéaume M. Tsantrizos YS. Lamarre D. J. Med. Chem.  2004,  47:  1605 
• 4 Faucher A.-M. Bailey MD. Beaulieu PL. Brochu Duceppe J.-S.. Ferland J.-M. Ghiro E. Gorys V. Halmos T. Kawai SH. Poirier M. Simoneau B. Tsantrizos YS. Llinàs-Brunet M. Org. Lett.  2004,  6:  2901 
• 5 For an alternative approach to 3 via a carbonylative Sonogashira coupling-cyclization see: Haddad N. Tan J. Farina V. J. Org. Chem. submitted for publication
• For additional examples of similar cyclizations to prepare quinolones, see:
• 6a Combs DW. Reed MS. Klaubert DH. Synth. Commun.  1992,  22:  323 
• 6b Li L. Wang H.-K. Kuo S.-C. Wu T.-S. Lednicer D. Lin CM. Hamel E. Lee K.-H. J. Med. Chem.  1994,  37:  1126 
• 6c Fuerstner A. Hupperts A. Ptock A. Janssen E. J. Org. Chem.  1994,  59:  5215 
• 6d Li L. Wang H.-K. Kuo S.-C. Wu T.-S. Mauger A. Lin CM. Hamel E. Lee K.-H. J. Med. Chem.  1994,  37:  3400 
• 6e Mahboobi S. Pongratz H. Synth. Commun.  1999,  29:  1645 
• 6f Traxler P. Green J. Mett H. Séquin U. Furet P. J. Med. Chem.  1999,  6:  1018 
• 6g Takami H. Kishibayashi N. Ishii A. Kumazawa T. Bioorg. Med. Chem.  1998,  6:  2441 
• 6h Haesslein J.-L. Baholet I. Fortin M. Iltis A. Khider J. Periers AM. Pierre C. Vevert J.-P. Bioorg. Med. Chem. Lett.  2000,  10:  1487 
• 6i Beney C. Hadjeri M. Mariotte A.-M. Boumendjel A. Tetrahedron Lett.  2000,  41:  7037 
• 6j Niedzinski EJ. Lashley MR. Nantz MH. Heterocycles  2001,  55:  623 
• For additional examples of thiazoles prepared from 3-bromopyruvic acid in a similar fashion, see:
• 7a Kelly TR. Echavarren A. Chandrakumar NS. Koeksal Y. Tetrahedron Lett.  1984,  25:  2127 
• 7b Bailey N. Dean AW. Judd DB. Middlemiss D. Storer R. Watson SP. Bioorg. Med. Chem. Lett.  1996,  6:  1409 
• 8 Brown FJ. Bernstein PR. Cronk LA. Dosset DL. Hebbel KC. Maduskuie TP. Shapiro HS. Vacek EP. Yee YK. Willard AK. Krell RD. Snyder DW. J. Med. Chem.  1989,  32:  807 
• Water-soluble side-products from the reaction mixture were not isolated, but most likely a major side-product was 4-amino-2-hydroxyacetophenone. For leading references on the related formation of 4-acetamido-2-hydroxyaceto-phenone by Friedel-Crafts acylation/demethylation of 4-acetamido-2-methoxyacetophenone and similar reactions, see:
• 9a Gibson CS. Levin B. J. Chem. Soc.  1931,  2388 
• 9b Chen FC. Chang CT. J. Chem. Soc.  1958,  146 
• 9c Cignarella G. Barlocco D. Curzu MM. Pinna GA. Cazzulani P. Cassin M. Lumachi B. Eur. J. Med. Chem.  1990,  25:  749 
• 10a Sugasawa T. Toyoda T. Adachi M. Sasakura K. J. Am. Chem. Soc.  1978,  78:  4842 
• 10b Douglas AW. Abramson NL. Houpis IN. Karady S. Molina A. Xavier LC. Yasuda N. Tetrahedron Lett.  1994,  35:  6807 
• 11 For recent mechanistic studies and industrial application of the Sugasawa reaction, see: Prasad K. Lee GT. Chaudhary A. Girgis MJ. Streemke JW. Repič O. Org. Process Res. Dev.  2003,  7:  723 
• 12 Sugasawa T. Adachi M. Sasakura K. Kitagawa A. J. Org. Chem.  1979,  44:  578 
• 13 Houpis IN. Molina A. Douglas AW. Xavier L. Lynch J. Volante RP. Reider PJ. Tetrahedron Lett.  1994,  35:  6811 
• 16 Up to 50% of 11 was formed when the reaction was carried out at 50 °C. Electrophilic reaction of 2-aminothiazoles at C-5 is well precedented. In this case, it may be promoted by ionization of the C-2 isopropylamino group, although usually strong bases like sodium amide have been employed to obtain deprotonation at such amino groups. See: Heterocyclic Compounds   Weissberger A. Taylor EC. Wiley; New York: 1979. 

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.