2-Trifluoromethyl-4-Chloropyridine

A mixture of B8.1 (2.0 g, 12.3 mmol) in POClPreparation of 4-Chloro-2-trifluoromethyl-pyridine In a 25 ml round bottom flask equipped with a reflux condenser, magnetic stirrer and a inert gas supply 1.63 g (10.0 mmol) 4-Hydroxy-2-trifiuoromethyl-pyridine was treated with 4.9 ml cyclohexane and 0.077 ml DMF, at room temperature 2.19 ml (25.0 mmol) oxalyl chloride was added, the mixture was heated to reflux for 3 hours, cooled to room temperature, slowly (gas evolution) 18 ml water was added dropwise, the mixture was extracted with 18 ml MTBE, the separated organic layer was washed with 1M NaHCOs and the separated organic layer was dried with anhydrous NaTo a stirred solution of 2-(trifluoromethyl)pyridin-4-ol (9.4 g) in 50 mL cyclohexane and a drop of DMF, oxalyl dichloride (2.6 equiv.) was added dropwise over a period of 5 minutes at 25°C. After addition, the reaction mixture was heated to 80°C for 3 hours. The reaction mixture was cooled to room temperature and 50 mL of water were added dropwise. The aqueous phase was exteacted with 3x 100 mL TBME. The combined TBME layers were washed with 70 ml of a saturated aqueous solution of sodium bicarbonate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain 4-chloro-2-(trifluoromethyl)pyridine (12-A) as a yellow liquid (7.31 g). LCMS (method 5): 192 (M+HTo a stirring solution of NaH (60% dispersion in mineral oil, 46 mg, .1.19 mmol) was added portionwise to a stirred solution of l-Boc-4-hydroxypiperidine (CAS: 109384-19-2; 200 mg, 0.99 mmol) in DMF (3 mL) in a sealed tube and under N2 at 0 C. The reaction mixture was stirred at 0 C for 30 min and a solution of The solution of Intermediate 32 (1 10 g, 330.33 mmol), Under an atmosphere of nitrogen, palladium (II) chloride (117 mg, 0.66 mmol), triphenylphosphine (347 mg, 0.76 mmol) was added to a solution of 4-chloro-2- (trifluoromethyl) pyridine (6.01 g, 33.1 mmol) in triethylamine , 1.3 mmol), copper iodide (I) (189 mg, 0.99 mmol), , And trimethylsilylacetylene (3.90 g, 39.7 mmol) was added dropwise under ice cooling. After completion of the dropwise addition, The mixture was stirred at 80 C. for 8 hours and filtered through Celite.After concentrating the filtrate under reduced pressure, aqueous ammonia (30 mL) and water were added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After removing the white precipitate by filtration, concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1: 15) to give the title compound as an orange oil (1 , 12 g, yield 13.9%).

Molecular Weight:181.54
XLogP3:2.4
Hydrogen Bond Acceptor Count:4
Exact Mass:180.9906113
Monoisotopic Mass:180.9906113
Topological Polar Surface Area:12.9
Heavy Atom Count:11
Complexity:136
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes