2-Fluoro-5-(trifluoromethyl)pyridine

Colorless liquid

1, to 1L three-necked flask was added KF46.20g (0.80mol), 500 mL of N, N-dimethylacetamide, warmed to 125 ° C., Stir for 30 minutes, Connected to the distillation unit, Micro-vacuum distillation, collecting fractions, tracking three bottles of water content, water <500ppm, stop distillation, stand-by. In a 200 mL autoclave, 46.0 g (0.2 mol) of the first product 2-chloro-5-trichloromethylpyridine was added, on a good kettle cover, filling nitrogen 10.0MPa to maintain the pressure 5h, the reactor leak. After confirming that the kettle does not leak, empty the kettle pressure.And then the reactor was placed in an ice-salt bath for cooling. When the temperature of the kettle dropped below -5 ° C, the reactor was filled with 40.0 g (~ 2.0 mol) of anhydrous HF and the reaction was heated to 180 , the insulation reaction 12h.After completion of the reaction, the temperature was lowered to 25 ° C, and the inside of the autoclave was replaced with nitrogen for half an hour (the replaced gas was neutralized and absorbed in a 10percent aqueous solution of sodium hydroxide.)Adding the 20percent sodium hydroxide solution to the reaction solution to adjust the pH to 7 to 8, washing the mixture three times, collecting the organic phase, adding anhydrous sodium sulfate or anhydrous sodium carbonate to the organic phase for 6 hours, filtering out the solid, 2-Fluoro-5-trifluoromethylpyridine crude.(3) The crude 2-fluoro-5-trifluoromethylpyridine was put into a distillation column under reduced pressure and the boiling point was collected at 40 to 45 ° C / 11 mmHg to obtain 2-fluoro-5-trifluoromethylpyridine product 28.55g, analysis of the product measured in the 2-fluoro-5-trifluoromethyl pyridine content of 98.77percent (GC), weighing the amount of distillation and kettle residue weight, and do gas chromatography, calculated 2 - The results of the fluorination of 5-trifluoromethylpyridine were: conversion rate: 96.33percent; selectivity: 91.17percent; yield: 85.45percent.A mixture of 3-fluoro-4-nitrophenol (Compound 34, 2.1 g), a crude product of Compound 5 (Reference example 1) (2.0 g), diisopropylethylamine (8.0 mL), and NMP (25 mL) was stirred at 110 C. for 4 hours. To the reaction solution were added cesium carbonate (6.4 g) and A mixture of 4-amino-3-nitrophenol (Compound 19, 200 mg), cesium carbonate (458 mg), To a solution of the compound of Reference example 31 (50 mg) in NMP (1 mL) were added A mixture of Example 112B (65 mg, 0.190 mmol), A mixture of tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1 .1 ]heptane-2-carboxylate (p14, 150 mg, 0.66 mmol), General procedure: To a stirred suspension of NaH 60% w/w (1.3 eq) in dry DMF (-30 vol), the desired alcohol intermediate (p78-82 as reported on the table, 1 eq) was added at RT. After 30', the corresponding aryl fluoride (1.1 eq) was added and the reaction mixture was stirred at room temperature for 2 hrs. The reaction was quenched adding iced water and the mixture was extracted with dichloromethane. Combined organics were dried and concentrated. The crude was purified by FC on silica gel and/or NH column (eluting mixture Cy/AcOEt) and/or C18 cartridge (eluent from water + 0.1 % formic acid / MeCN + 0.1 % formic acid) and/or preparative HPLC to afford the title compound.A mixed solution of compound 61-a (1.6 g, 4.34 mmol),