Synthesis of 4-Halogenated 3-Fluoro-6-methoxyquinolines: Key Building Blocks for the Synthesis of Antibiotics

Thomas Flagstad; Mette T. Petersen; Daniel M. Hinnerfeldt; Michael Givskov; Thomas E. Nielsen

doi:10.1055/s-0034-1378554

Synthesis, Table of Contents

Synthesis 2014; 46(23): 3263-3267
DOI: 10.1055/s-0034-1378554

paper

Synthesis of 4-Halogenated 3-Fluoro-6-methoxyquinolines: Key Building Blocks for the Synthesis of Antibiotics

Authors

Thomas Flagstad

^aDepartment of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark Fax: + 45(4593)3968 Email: ten@kemi.dtu.dk
Mette T. Petersen

^aDepartment of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark Fax: + 45(4593)3968 Email: ten@kemi.dtu.dk
Daniel M. Hinnerfeldt

^aDepartment of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark Fax: + 45(4593)3968 Email: ten@kemi.dtu.dk
Michael Givskov

^bDepartment of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark

^cSingapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551, Singapore
Thomas E. Nielsen*

^aDepartment of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark Fax: + 45(4593)3968 Email: ten@kemi.dtu.dk

^cSingapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551, Singapore

Abstract

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Abstract

A practical and scalable 4-step route is presented for the synthesis of 4-bromo-3-fluoro-6-methoxyoquinoline and 3-fluoro-4-iodo-6-methoxyoquinoline from readily available 2,4-dichloro-3-fluoroquinoline with an overall yield of 81–85%. Halogenated quinoline building blocks have found much use in antimicrobial drug discovery, and the method reported here would be useful for the synthesis of these compounds.

Key words

antibiotic - quinolone - fluorine - heterocycle - regioselectivity

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References

References

For selected reviews on fluoroquinolones, see:

1a Appelbaum PC, Hunter PA. Int. J. Antimicrob. Agents 2000; 16: 5
1b Just PM. Pharmacotherapy 1993; 13: 4S
1c Hooper DC, Wolfson JS. N. Engl. J. Med. 1991; 324: 384

For selected articles on fluoroquinolines, see:

2a Horchler CL, McCauley JP, Hall JE, Snyder DH, Moore WC, Hudzik TJ, Chapdelaine MJ. Bioorg. Med. Chem. 2007; 15: 939
2b Hoeglund IP. J, Silver S, Engstroem MT, Salo H, Tauber A, Kyyroenen H.-K, Saarenketo P, Hoffren A.-M, Kokko K, Pohjanoksa K, Sallinen J, Savola J.-M, Wurster S, Kallatsa OA. J. Med. Chem. 2006; 49: 6351
2c Takahashi K, Kamiya M, Sengoku Y, Kohda K, Kawazoe Y. Chem. Pharm. Bull. 1988; 36: 4630
2d Kato T, Hakura A, Mizutani T, Saeki K. Mutat. Res. 2000; 465: 173

3 Stein GE. Clin. Infect. Dis. 1996; 23 (Suppl. 1): S19
4 Black MT, Stachyra T, Platel D, Girard A.-M, Claudon M, Bruneau J.-M, Miossec C. Antimicrob. Agents Chemother. 2008; 52: 3339
5 Surivet J.-P, Zumbrunn C, Rueedi G, Hubschwerlen C, Bur D, Bruyère T, Locher H, Ritz D, Keck W, Seiler P, Kohl C, Gauvin J.-C, Mirre A, Kaegi V, Dos Santos M, Gaertner M, Delers J, Enderlin-Paput M, Boehme M. J. Med. Chem. 2013; 56: 7396
6 Novexel Discontinues Development of NXL 101 . Novexel Press Release; Paris: 2008. June 3
7 For a recent review, see: Mayer C, Janin YL. Chem. Rev. 2014; 114: 2313

8a Bigot A, Mignani S, Ronan B, Tabart M, Viviani F. US Patent Appl. US 20050032800 A1, 2005 ; Chem. Abstr. 2005, 142, 219160
8b Miller WH, Pendrak I, Seefeld MA. Patent PCT Int. Appl. WO 2006002047 A2, 2006 ; Chem. Abstr. 2006, 144, 108362
8c Miller WH, Rouse MB, Seefeld MA. Patent PCT Int. Appl. WO 2006014580 A1, 2006 ; Chem. Abstr. 2006, 144, 212789
8d Miller WH, Rouse MB, Seefeld MA. Patent PCT Int. Appl. WO 2006081289 A2, 2006 ; Chem. Abstr. 2006, 145, 188914
8e Daines RA, Price AT. Patent PCT Int. Appl. WO 2007016610 A2, 2007 ; Chem. Abstr. 2007, 146, 229364
8f Baque F, Carry J.-C, El-Ahmad Y, Evers M, Hubert P, Malleron J.-L, Mignani S, Pantel G, Tabart M, Viviani F. Patent PCT Int. Appl. WO 2002040474 A2 2002, 2002 ; Chem. Abstr. 2002, 136, 386033
8g Fukuda Y, Kaelin DE. Jr, Singh SB. Patent PCT Int. Appl. WO 2013003383 A1, 2013 ; Chem. Abstr. 2013, 158, 158577.

9 Li B, Zhang Z, Mangano M. Org. Process Res. Dev. 2008; 12: 1273
10 Inspired by the selective Sonogashira coupling in the 2-position of 2,4-dichloroquinolines: Reddy EA, Islam A, Mukkanti K, Bandameedi V, Bhowmik DR, Pal M. Beilstein J. Org. Chem. 2009; 5: 32
11 The desired intermediate, 4-chloro-3-fluoro-6-methoxy-quinoline (7), has also been preparred by fluorination of 4-chloro-6-methoxyquinoline in 31% yield (0.4 g), see ref. 8c
12 Farhanullah Kim SY, Yoon EJ, Choi EC, Kim S, Kang T, Samrin F, Puri S, Lee J. Bioorg. Med. Chem. 2006; 14: 7154

13a Rowlett RJ, Lutz RE. J. Am. Chem. Soc. 1946; 68: 1288
13b Ohashi T, Oguro Y, Tanaka T, Shiokawa Z, Shibata S, Sato Y, Yamakawa H, Hattori H, Yamamoto Y, Kondo S, Miyamoto M, Tojo H, Baba A, Sasaki S. Bioorg. Med. Chem. 2012; 20: 5496

14 Wolf C, Tumambac GE, Villalbos CN. Synlett 2003; 1801
15 A reviewer noted that this transformation might require flame-dried NaI. However, in our hands the reaction proceeded in 95% yield using NaI from the shelf.

Supplementary Material

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