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Pre aration 86A: 3-Fluoro-4-iodopicolinonitrile[00297] To a solution of diisopropylamine (2.80 ml, 19.66 mmol) in THF (Volume: 201 ml) cooled to -78 C was added n-butyllithium (7.86 ml, 19.66 mmol) dropwise. The dry ice/acetone bath was replaced with an ice water bath and reaction mixture was stirred at 0 C for 25 min, and then re-cooled to -78 C. In a separate flask, a solution of 3- fluoropicolinonitrile (1.5 g, 12.29 mmol) in THF (50 mL) was cooled to -78 C, and then LDA (130 mL, 1.0 equiv) was added. The solution turned dark red. After 35 min, iodine (3.43 g, 13.51 mmol) was added rapidly. The reaction mixture was stirred for 45 min, then quenched with H20. Layers were separated and the aqueous phase extracted with CH2CI2 (2X). Organics combined, dried over Na2S04, filtered, and concentrated to afford a brown residue. The crude material was dissolved in a minimal amount of CH2CI2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-20% EtOAc in hexanes over 23 min, tr = 18 min) gave the title compound (1.7 g, 6.79 mmol, 55.2% yield) as a brown solid.
31.5%
[0088] Preparation 1 : 7-iodo-lH-pyrazolo[4,3-b]pyridine [0089] Diisopropylamine (50.9 mL, 360 mmol) was added to THF (1600 mL), and the mixture was cooled to 0 C in an ice bath and then n-butyllithium (137.6 ml, 2.5 M in hexane) was added drop wise at 0 C, and stirred for another 30 minutes. The mixture was then cooled to -78 C, and a solution of 2-cyano-3-fluoropyridine (40 g, 328 mmol) in 300 mL of THF was added. After 25 minutes, a solution of I2 (83.2 g, 328 mmol) in THF (80mL) was added and the reaction was stirred for 40 minutes at -78 C. The reaction was removed from the cooling bath and quenched with 400 mL sodium thiosulfate solution (10% aq.) followed by water (400 mL). The reaction mixture was diluted with ether (400 mL), and the layers were separated. The organic layer were washed with brine, dried over sodium sulfate, filtered and concentrated to a brown solid. The solid was purified with silica column chromatography eluted with 95:5 hexanes: ethyl acetate to give 3-fluoro-4- iodopicolinonitrile (25.6 g, 31.5 % yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.25 - 8.26 (m, 1 H) 8.35 (t, J=5.05 Hz, 1 H). MS [M+H] found 249.0.
A solution of LDA (40.9 mmol, prepared from 11.4 mL of diisopropylamine and 16.4 mL of 2.5 M n-butyl lithium in hexanes) in 200 mL THE at-78C was treated with 2-cyano-3-fluoropyridine (5.0 g, 40.9 mmol) in 50 mL of THF drop-wise. After 10 minutes a solution of iodine (10.4 g, 40.9 mmol) in 10 mL of THF was added. After 30 minutes the reaction was quenched with 40 mL of water followed by workup with aqueous sodium thiosulfate. The mixture was diluted with ether, washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-20% ethyl acetate in hexanes to provide 3-fluoro-4-iodopyridine-2- carbonitrile that gave proton NMR spectra consistent with theory
With n-butyllithium; diisopropylamine; In tetrahydrofuran; water; ethyl acetate;
To a cold (0 C.) solution of diisopropylamine (4.84 mL, 32 mmol) in THF (82.3 mL) was added n-butyllithium (12.8 mL, 2.5 M in hexanes, 32 mmol) dropwise. The resultant solution was stirred at 0 C. for 15 minutes to give a 0.32 M stock solution of LDA. To a cold (-78 C.) solution of LDA (74 mL, 0.32 M in THF, 23.7 mmol) in THF (50 mL) was added 3-fluoro-2-pyridinecarbonitrile (2.4 g, 19.7 mmol) (Sakamoto et. al. Chem. Pharm. Bull. 1985, 33, 565) as a solution in THF (20 mL). After 15 minutes, a solution of I2 (5.49 g, 21.6 mmol) in THF (20 mL) was added rapidly and the resultant suspension was stirred for 20 minutes at -78 C. The reaction mixture was quenched by the addition of water and warmed to ambient temperature. Ethyl acetate was added and the organic layer was washed successively with sodium thiosulfate, and brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulphate. Filtration and concentration followed by purification by silica gel chromatography provided 3-fluoro-4-iodo-2-pyridinecarbonitrile (3.6 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.14 (d, J=4.8 Hz, 1H), 7.98 (t, J=4.8 Hz, 1H).
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