Synthesis of 2,2,2-trifluoro-N-[3-(4-fluorophenyl)-6-benzoylimidazo[1,2-b]pyridazine-2-yl]acetamide by TFAA Mediated Amide Cyclization ; Imidazo[1,2-b]pyridazineSyntheticPage 246 (2006)
A contribution from the Dr. Asit K. Chakraborti Medicinal Chemistry Group, NIPER
1)Preparation of 2-[3-benzoyl-6-(tolune-4-sulfonylimino)6H-pyridazin-1-yl]-2-(4-fluorophenyl)acetamide:- p-tolylsulfonyl chloride (s. d. fine), Pyridine (Qualigens), Hunig's base (Aldrich), 2-aryl acetic acid (Aldrich), NBS (Aldrich), DMF (Qualigens). 2)Preparation of 2,2,2-trifluoro-N-[3-(4-fluorophenyl)-6-benzoylimidazo[1,2-b]pyridazine-2-yl]acetamide:- Trifluoro acetic anhydride (Aldrich), Dichloromethane (Qualigens)
To a solution of 2-[3-benzoyl-6-(tolune-4-sulfonylimino)6H-pyridazin-1-yl]-2-(4-fluorophenyl)acetamide (7.22 g, 14.32, 1 equiv.) in 50 ml anhydrous dichloromethane in a flame- dried two neck round-bottomed flask under an nitrogen atmosphere, cooled to 0ºC in an ice bath. Trifluoroacetic anhydride (3.85 ml, 18.33 mmol, 1.3 equiv.) was added over a period of 30 minute at 0ºC. The reaction mixture was vigorously stirred (for 3h at 0ºC ) until a clear solution was obtained. The solvents were removed, and residue was taken up in ethyl acetate, washed with sodium bicarbonate (2 x 20 mL) and saturated NaCl (2 x 20 mL), and dried over anhydrous sodium sulfate. Ethyl acetate was removed in vaccuo, and the residue was crystalized from ethyl acetate to yield 4.42 g (72 %)of 2,2,2-trifluoro-N-[3-(4-fluorophenyl)-6-benzoylimidazo[1,2-b]pyridazine-2-yl]acetamide.
It is imperative to maintain cooled temperature (0ºC) and inert (N2) atmosphere throughout the course of reaction. Trifluoro acetic anhydride quantity, purity and reaction condition is an important key for this synthesis.
mp-277ºC; 1H NMR (300 MHz, DMSO) 11.94 (bs, 1H, NHCOCF3), 8.32 (d, J=9.0, 1H, Het), 8.16 (dd, J=7.0, J=1.8, 2H, Ar), 7.92 (d, J=9.6, 1H, Het), 7.80 (dd, J=8.5, J=5.7, 2H, Ar), 7.69 (dd, J=7.0, J=1.8, 2H, Ar), 7.56 (t, J=7.2, 2H, Ar),7.33 (t, J = 8.9, 1 H, Ar); MS m/z 428 (M+).
Hamdouchi, C.; Sanchez-Martinez, C.; Gruber, J.; del Prado, M.; Lopez, J.; Rubio, A.; Heinz, B. A. J. Med. Chem.; 2003; 46(20); 4333-4341
Kate F. Byth, Nicola Cooper, Janet D. Culshaw, David W. Heaton, Sandra E. Oakes, Claire A. Minshull, Richard A. Norman, Richard A. Pauptit, Julie A. Tucker, Jason Breed et al. Bioorganic & Medicinal Chemistry Letters, Volume 14, Issue 9, 3 May 2004, Pages 2249-2252
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