2-Chloro-5-fluoronicotinonitrile

2-Chloro-5-fluoro-3-pyridinecarboxamide (18 g, 102 mmol) was suspended in CH2Cb (500 mL), and then Et3N (31 mL, 220 mmol) was added at 0°C. Trifluoroacetic anhydride (TFAA) (16 mL, 110mmol) was added dropwise to the reaction mixture at 0°C. The white carboxamide startingmaterial disappeared after 20 min at 0°C, indicating the completion of the reaction. The reaction mixture was stirred at ooc for 1 h. The reaction mixture was diluted with CH2Cl2 , and then washed with satd. NaHC03(aq). The organic layer was washed with brine, dried over MgS04, filtered and the filtrate was concentrated to a brown residue. The residue was purified by column chromatography (8percent-20percent EtOAc/hexanes; 330g column). Collectedfractions were combined and concentrated to give the desired product as a white solid (15g, 96percent yield). MS (m/z) 157 (M+H+). 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.68 (dd, 1H), 8.83 (d, 1 H).2-chloro-5-fluoro-3-pyridinecarboxamide (18 g, 102 mmol) was suspended in DCM (500 mL), and then triethylamine (31 mL, 220 mmol) was added at 0°C. Trifluoroacetic anhydride (TFAA) (16 mL, 110 mmol) was added dropwise to the reaction mixture at 0 °C. At 0°C, the white formazan amine starting material disappeared after 20 minutes and it showed complete reaction. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM and then washed with saturated NaHCO 3 (aq). The organic layer was washed with brine, dried over MgSO4, filtered and the filtrate was concentrated to a brown residue. The residue was purified on an Isco Combiflash (8percent-20percent EtOAc/hexane; 330 g column). The collected fractions were combined and concentrated to give the desired product as a white solid (15 g, 96percent yield).Step 2. 2-chloro-5-fluoro-3-pyridinecarbonitrile: 2-Chloro-5-fluoro-3-pyridinecarboxamide (18 g, 102 mmol) was suspended in DCM (500 mL), and then triethylamine (31 mL, 220 mmol) was added at 0 °C. Trifluoroacetic anhydride (TFAA) (16 mL, 110 mmol) was added dropwise to the reaction mixture at 0 °C. The white carboxamide starting material disappeared after 20 minutes at 0 °C, indicating the completion of the reaction. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with DCM, and then washed with saturated NaHCO2-chloro-5-fluoro-3-pyridinecarbonitrile 2-Chloro-5-fluoro-3-pyridinecarboxamide (18 g, 102 mmol)Suspended in DCM (500 mL), And then triethylamine (31 mL, 220 mmol) was added at 0 °C.Trifluoroacetic anhydride (TFAA) (16 mL, 110 mmol) was added dropwise to the reaction mixture at 0 °C.After 20 minutes at 0°C, the white formazan amine disappeared.It shows that the reaction is complete. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM andAnd then washed with saturated NaHCO3 (aq).The organic layer was washed with brine and dried over MgSO4.Filter and concentrate the filtrate to a brown residue.The residue was purified on an Isco Combiflash (8percent-20percent EtOAc/hexane; 330 g column). The collected fractions were combined and concentrated to give the desired product as a white solid (15 g, 96percent yield).To an oven-dried, 250-mL, round-bottomed flask containing a magnetic stir bar were added 2-chloro-5-fluoro-nicotinic acid (4.39 g, 25.0 mmol) and anhydrous toluene (50 mL). Thionyl chloride (5.95 g, 3.65 mL, 50 mmol) was added, and a reflux condenser with N2-inlet was attached. A heating mantle was applied and the solution was heated to reflux for 2 hours. After cooling to room temperature, the solvent/volatiles were removed by rotary evaporator to give a golden oil. The crude acid chloride was added to a cold (0 C) solution of ammonium hydroxide, and a white precipitate formed. The precipitate was collected by vacuum flitration on a glass frit and air dried. To an oven-dried, 250 mL, round-bottomed flask were added the crude 2-chloro-5- fluoronicotinamide (1.05 g, 6.00 mmol) from above, anhydrous dichloromethane (25 mL), and triethylamine (2.12 g, 2.92 mL, 21.0 mmol). The flask was sealed with a septum and cooled to 0 C in an ice bath. Neat trifluoroacetic anhydride (1.89 g, 1.25 mL, 9.00 mmol) was added slowly via syringe and the resulting solution was stirred at 0 C for 30 minutes then allowed to warm to room temperature over 1 hour. Water (20 mL) was added, and the mixture was transferred to a separatory funnel. The mixture was extracted with dichloromethane (3 x 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a golden oil. The product was purified by flash chromatography (silica gel: 10percent ethyl acetate, 90percent hexanes - product Rf 0.3) to give 862 mg (92percent) of the title compound as a pale yellow solid. 'H NMR (CDC13) 5 8.66 (dd, J = 7.8, 3.0 Hz, 1H), 8.82 (d, J = 2.7 Hz, 1H).Example 3A2-Chloro-5-fluornicotinonitrileA suspension of 46.2 g (264.66 mmol) of 2-chloro-5-fluoronicotinamide in dichloromethane (783 ml) was admixed with 81.2 ml (582.25 mmol) of triethylamine and cooled to 0°C. Then, with stirring, 41.12 ml (291.13 mmol) of trifluoroacetic anhydride were added slowly dropwise and the mixture was stirred at 0°C for 1.5 h. The reaction solution was subsequently washed twice with saturated aqueous sodium hydrogen carbon solution (391 ml each time), dried and concentrated under reduced pressure. Yield: 42.1 g (90percent of theory).Example 3AExample 4A 2-Chloro-5-fluoronicotinonitrile Example 4A Example 21A Example 3A 81.2 ml (582.25 mmol) of triethylamine were added to a suspension of 46.2 g (264.66 mmol) of 2-chloro-5-fluo- ronicotinamide in dichloromethane (783 ml), and the mixture was cooledto 0°C. With stirring, 41.12 ml (291.13 mmol) of trifluoroacetic anhydride were then slowly added dropwise, and the mixture was stirred at 0° C. for another 1.5 h. The reaction solution was then washed twice with saturated aqueous sodium bicarbonate solution (391 ml each), dried and concentrated under reduced pressure.10418] Yield: 42.1 g (90percent of theory).10419] ‘H NMR (400 MHz, DMSO-d5): ö=8.66 (dd, 1H), 8.82 (d, 1H).To a stirred solution of 2-chloro-54luoropyridine-3-carboxamide (60 g, 0.34 moD and Et3N (105.6 mL ) in DCM (400 mL) was added TFAA (60 mL) drop wise at 0 00 and resulting reaction mixture was stirred at 0 °C for 1.5 h . The reaction was quenched with saturated aqueous N..a HCO3 solution and extracted with DCM (400 mL x 3). The combined organiclayers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude title compound (55 g, 87percent yield) as a brown solid. MS: 157.1 [M+H].A suspension of crude compound 3a (65 g, 372.4 mmol) and EtA suspension of crude compound 3 (65 g, 372.4 mmol) and Et3N (114 mL, 819.2 mmol) in DCM (700 mL) was cooled to 0A suspension of crude compound 3 (65 g, 372.4 mmol) and EtA suspension of crude compound 3 (65 g, 372.4 mmol) and Et3N (114 mL, 819.2 mmol) in DCM (700 mL) was cooled to 02-Chloro-5-fluoronicotinonitrile (4)[00147] A suspension of crude compound 3 (65 g, 372.4 mmol) and Et3N (114 mL, 819.2 mmol) in DCM (700 mL) was cooled to 0Weigh 2-chloro-5-fluoronicotinamide (6.4 g, 37 mmol) in a 500 ml flask.Trichloromethane (100 mL) and phosphorus oxychloride (24.0 mL, 264 mmol) were added thereto.The temperature was raised to 80 ° C for 8 hours.Cool to room temperature and quench the reaction by adding saturated sodium bicarbonate solution (100 mL).Extracted with dichloromethane (50 mL x 3), combined organic phases, The organic layer was washed with a saturated aqueous solution of sodium hydrogen sulfate (50 mL) and brine (30 mL)Filtration and purification, the residue was purified by silica gel column chromatography (EtOAc /EtOAcA white solid (3.80 g, 66.0percent) was obtained.A solution of 2-chloro-5-fluoronicotinamide (350 mg, 2 mmol) and 2, 4, 6-trichloro-1, 3, 5-triazine (220 mg, 1.2 mmol) in DMF (1 mL) was stirred at room temperature. Formation of 2-chloro-5-fluoropyridine-3-carbonitrile (131a)To a suspension of 2-chloro-5-fiuoropyridine-3-carboxamide, 130a, (29.8 g, 170.4 mmol) in dichloromethane (327 mL) was added triethylamine (52.3 mL, 374.9 mmol). This mixture was cooled down to 0 °C. Trifluoroacetic anhydride (26.1 mL, 187.4 mmol) was added slowly over period of 15 min. The mixture was stirred at 0 °C for 90 min. The mixture was diluted into dichloromethane (300 mL) and the resulting organic phase was washed with aqueous saturated NaHCC'3 solution (300 mL) and brine (300 mL). The organic layer was dried over Na81.2 ml (582.25 mmol) of triethylamine were added to a suspension of 46.2 g (264.66 mmol) of 2-chloro-5-fluoronicotinamide in dichloromethane (783 ml), and the mixture was cooled to 0° C. Then, with stirring, 41.12 ml (291.13 mmol) of trifluoroacetic anhydride were added slowly dropwise, and the mixture was stirred at 0° C. for 1.5 h. To a solution of hydroxylamine hydrochloride (0.410 g, 5.902 mmol) in H

Molecular Weight:156.54
XLogP3:1.6
Hydrogen Bond Acceptor Count:3
Exact Mass:155.9890539
Monoisotopic Mass:155.9890539
Topological Polar Surface Area:36.7
Heavy Atom Count:10
Complexity:164
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes