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To a flask containing THF (35 mL) was added LDA (1.0 M solution in hexane) (26.1 mL, 26.1 mmol) at -78 °C, then a solution of 2,3-difluoropyridine (2.5 g, 21.72 mmol) in THF (6 mL) was added dropwise at -78 °C. The reaction mixture turned into bright yellow suspension after addtion of pyridine. The resulting mixture was stirred at -78 °C for 1 h, then iodine (6.62 g, 26.1 mmol) was added in several batches at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. To the reaction mixture was added NH4CI solution and the reaction mixture was stirred for 10 min. The resulting mixture was extracted with ethyl acetate. The organic layer was separated and washed with saturated NaHCCb solution, dried over MgSCk The filtrate was concentrated in vacuo. The extract was purified via silica gel flash column chromatography, eluting with 0-15percent ethyl acetate in hexane to give Intermediate 21A (yellow solid, 3.3 g, 13.69 mmol, 63percent yield). LC-MS Anal. Calc'd for C5H2F2IN 240.92, found [M+H] 242.1. Tr = 0.82 min (Method A). NMR (499MHz, chloroform-d) delta 7.68 (dd, J=5.2, 0.9 Hz, 1H), 7.57 (dd, J=5.2, 3.5 Hz, 1H).
A mixture of 2,3-difiuoro-4-iodopyridine (from Ark Pharm, 3.0 g, 12 mmol) in acetic acid (30 mL) and water (15 mL) was heated to reflux overnight. Most of the solvent was removed by vacuum and the remaining was neutralized with aq. NaHCCb and extracted by EtOAc. The organic layers were combined, dried and concentrated. The white solid crude product obtained (2.5 g, 84%) was used directly in the next step without further purifications. LCMS calc. for C5H4FINO (M+H)+ m/z = 239.9; found, 240.0
71.4%
With acetic acid; In water;Reflux;
2,3-Difluoro-4-iodopyridine (300 mg, 1 .24 mmol) was suspended in acetic acid: water (2:1 , 15 mL). The mixture was heated to reflux and stirred at this temperature overnight. Reaction was concentrated to dryness, and triturated in water (10 mL) for 30 min. The solid was collected via filtration, washed with water (2x10 mL), and pentane (2x20 mL) and dried under vacuum to afford the title compound as a white solid (354 mg, 71.4%). LC-MS m/z 342.0 (M+1 ). 1H NMR (400 MHz, METHANOL-^) delta ppm 6.56 - 6.82 (m, 1 H) 6.83 - 7.18 (m, 1 H).
65.3%
With water; potassium hydroxide; In 1,4-dioxane; at 100℃;
[00495] To a solution of 2,3-Difluoro-4-iodopyridine (0.250 g, 1.04 mmol) in a mixture of water (1.04 mL, 1.04 mmol) and dioxane (0.10 mL) was added powdered KOH (0.116 g, 2.07 mmol) and heated to 100 °C overnight. The mixture was cooled to room temperature, at which time a white solid crashed out. Water (15 mL) and 3 mL glacial acetic acid were added and the reaction mixture was stirred for 30 min. The aqueous layer was extracted with 4:1 DCM:IPA (3 x10 mL), dried over Na2SO4, filtered and concentrated to afford 3-fluoro-4-iodopyridin-2(1H)-one (0.162 g, 0.678 mmol, 65.3 percent yield) as a white solid.
With potassium carbonate; In dimethyl sulfoxide; at 85℃; for 48h;Sealed vial;
To a 20 mL microwave vial (Biotage) was added 0.70 g (3.03 mmol) 3-[(4- methoxybenzyl)oxy]pyridin-4(lH)-one, 1.26 g (9,08 mmol) potassium carbonate, 1.10 g (4.54 mmol) <strong>[851386-34-0]2,3-difluoro-4-iodopyridine</strong> and 15 mL DMSO, A yellow suspension formed and the vial was sealed and heated at 85 °C for 48 h on a heat block. The suspension was cooled, diluted with ethyl acetate, and washed twice with 10 mL brine. The organic layer was dried over sodium sulfate, filtered, and evaporated onto silica gel. Purification by flash chromatography (silica gel 0-100percent hexanes/EtOAc gradient, followed by 10percent MeOH in EtOAc) afforded 3'-fluoro-4'-iodo- 3-[(4-methoxybenzyl)oxy]-4H-l,2'-bipyridin-4-one as a yellow solid. LCMS (M+H)+ 453,3.
1-(3-fluoro-4-iodopyridin-2-yl)-1H-pyrazole-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In methanol; water; ethyl acetate;
Step 1: 1-(3-Fluoro-4-iodopyridin-2-yl)-1H-pyrazole-3-amine (via A-1) A mixture of 3-aminopyrazole (0.50 g), <strong>[851386-34-0]2,3-difluoro-4-iodopyridine</strong> (1.45 g), potassium carbonate (3.3 g) and 10 ml anhydrous dimethyl sulphoxide was stirred at 85° C. for 48 hours. For work-up, 100 ml of water were added at room temperature and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and then concentrated completely and chromatographed on silica gel using an ethyl acetate/methanol gradient. This gave 705 mg of the title compound. HPLC-MS: log P=1.38; mass (m/z): 304.9 (M+H)+; 1H-NMR (DMSO-D6) 5.91 (m, 1H), 7.62 (m, 1H), 7.85 (m, 1H), 8.08 (m, 1H).
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