Expeditious solution phase synthesis of fluoroquinolone antibacterial agents using polymer supported reagents

Tetrahedron Letters

Volumn 42, Issue 9, 2001, Pages 1645-1646

  Hilty, Peter ^a   Hubschwerlen, Christian ^a   Thomas, Andrew W ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFECTIVE AGENT; POLYMER; QUINOLINE DERIVED ANTIINFECTIVE AGENT; REAGENT;

ANALYTIC METHOD; ARTICLE; CHEMICAL REACTION; DRUG STRUCTURE; DRUG SYNTHESIS; REACTION ANALYSIS; STOICHIOMETRY;

EID: 0035951917     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(00)02340-6     Document Type: Article

References (9)

1. Parlow J.J. Tetrahedron Lett. 36:1995;1395-1396.
2. Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815-4195.
3. Previously two independent groups have reported the library synthesis of potential anti-infective agents. (a) Frank, K. E.; Jung, M.; Mitscher, L. A. Comb. Chem. High Throughput Screening 1998, 1, 73-87.
4. (b) MacDonald, A. A.; DeWitt, S. H.; Hogan, E. M.; Ramage, R. Tetrahedron Lett. 1996, 37, 4815-4818.
5. Domagala J.M., Heifetz C.L., Hutt M.P., Mich T.F., Nichols J.B., Solomon M., Worth D.F. J. Med. Chem. 31:1988;991-1001.
6. The resins 1a-d were commercially available and were purchased from Fluka.
7. Treatment of the resin with dilute HCl followed by washing with DCM resulted in an improved recovery of the product (overall yields approaching 90%) but unfortunately this was met with a reduction in the purity (69-81%) since the mixture included significant amounts of unreacted starting material. Increasing the reaction temperature resulted in no improvement in yield.
8. Typical experimental conditions: The Amberlite 900-Cl resin 1e was purchased from Fluka. For best results, prior to use, the resin was washed with consecutive portions of MeOH (×3), DCM (×3) and MeOH (×1) and dried overnight under vacuum. To a mixture of the trifluoroquinolone 2 (0.05 mmol) in acetonitrile (0.5 ml) was added the amine (1.0-4.0 equiv.) followed by the resin 1e (2.0 equiv.) and the resulting mixture heated at 60°C. Once the reaction was complete (30 min to 2 h, as judged by HPLC) the mixture was cooled to room temperature, filtered and evaporated to afford the product used directly for antibacterial testing.
9. 6) δ 14.51 (br s, 1H), 8.72 (s, 1H), 7.80 (d, J 9, 1H), 7.52-7.32 (m, 5H), 5.11 (br s, 2H), 4.31 (m, 1H), 4.22-3.21 (m, 6H), 1.33-1.24 (m, 4H); 2b δ 12.21 (br s, 1H), 8.81 (s, 1H), 7.96 (d, J 9, 1H), 6.87 (t, 1H), 6.64 (d, 1H), 6.45 (d, 1H), 5.50 (br s, 2H), 4.11 (m, 1H), 3.66 (dt, 2H), 3.31 (m, 4H), 2.82 (d, 2H), 1.43 (m, 4H); 2c δ 13.01 (br s, 1H), 8.74 (s, 1H), 7.94 (d, J 9, 1H), 7.43 (m, 5H), 4.23 (m, 1H), 3.94 (d, 1H), 3.74 (s, 3H), 3.33-2.94 (m, 4H), 2.13 (dt, 1H), 1.94 (dt, 1H), 1.66 (dt, 1H), 1.44 (m, 4H); 2d δ 11.05 (br s, 1H), 8.84 (s, 1H), 7.80 (d, J 9, 1H), 7.60 (m, 1H), 7.31 (d, 1H), 7.08 (t, 1H), 6.73 (dd, 1H), 4.43 (br s, 1H), 4.22 (m, 1H), 3.72 (s, 3H), 2.82-2.62 (m, 4H), 2.11-1.42 (m, 12H), 1.32 (m, 4H).