4-Chloropyridine-2-carboxylic acid tert-butyl ester

To a solution of t-butanol (25 mL), pyridine (20 mL) and 1, 2-dichloroethane (80 mL) at -40° C., was added a solution of 4-chloropicolinyl chloride (9.0 g, 51.1 mmol) in dichloroethane (60 mL). 4-chloropicolinic acid (10.5 g, 66.64 mmol) was suspended in thionyl chloride (40 mL), and the mixture was heated to 80° C. and refluxed. N, N-dimethylformamide (0.2 mL) was added dropwise, and the mixture was refluxed for 2 hours. The excess of thionyl chloride was removed under reduced pressure to give the pale yellow acyl chloride, followed by addition of dichloromethane (60 mL). The resulted solution was added into a mixed solution of tert-butanol (25 mL), pyridine (20 mL) and dichloromethane (80 mL) at -40° C. The reraction mixture was heated to 50° C. and stirred for 16 hours. The solvents were removed under reduced pressure and ethyl acetate (150 mL) was added. The resulted mixture was washed with saturated brine (50 mL*2) and a sodium hydroxide solution (1 N, 50 mL*2), and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under the reduced pressure. The residue was dried under vacuum to give the title compound (11.1 g, purity 95percent, yield 78percent) as a pale yellow solid. A solution of 4-chloro-pyridine-2-carbonyl chloride (150 g, 0.857 mol) in DCM (750 ml) was slowly added to a solution of 2-methyl-propan-2-ol (158.8 g, 2.14 mol) and DMAP (21 g, 0.171 mol) in DCM (750 mL) and pyridine (750 mL). The resultant mixture was stirred at 30 °C overnight. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography to give A- chloro-pyridine-2-carboxylic acid t-butyl ester (90 g, 49percent yield) as a yellow solid. [0176] 4-chloropicolinic acid (10.5 g, 66.64 mmol) was suspended in thionyl chloride (40 mL). The resulted mixture was heated to 80° C. and refluxed. N, N-dimethyl formamide (0.2 mL) was dropwise added, and the resulted mixture was refluxed for 2 h. Thionyl chloride was removed under reduced pressure to give light yellow acyl chloride. The residue was dissolved in dichloromethane (60 mL). At −40° C., the dichloromethane solution prepared above was added dropwise to a mixed solution of tert-butanol (25 mL), pyridine (20 mL) and dichloromethane (80 mL). The reaction solution was heated to 50° C. and stirred for 16 h. The solvent was removed under reduced pressure, and to the residue was added ethyl acetate (150 mL). The resulted mixture was washed with saturated brine (50 mL×2) and a solution of sodium hydroxide (1 N, 50 mL×2), and then separated. The organic phase was dried over anhydrous sodium sulfate. The solvent in the organic phase was removed under reduced pressure. The residue was dried in vacuum to give the title compound (11.1 g, purity 95percent, yield 78percent) as a light yellow solid. [0177] To 100 mL of THF was added 18 gm (240 mmol) of tert-butanol, while the solution was cooled into an ice-water bath, 30 mL (84 mmol) of 2.8 M nBuLi hexane solution was added slowly, and solution was warmed up to room temperature and 6.0 g (35.9 mmol) of methyl 4-chloropicolinate, which was prepared according to the procedure (Organic Process and Development, 2002, 6, p 777-781). The resulting mixture was stirred overnight and 100 mL of ethyl acetate was added. The mixture was washed once with brine solution and organic layer was dried over NaDMF (40 ml), 4-amino-3-fluoro-phenol (5.8 g, 45.8 mmol), potassium t-butoxide (5.35 g, 47.7 mmol) were sequentially added to a 100 ml single-necked flask. After stirring for 30 minutes,

Molecular Weight:213.66
XLogP3:2.7
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:213.0556563
Monoisotopic Mass:213.0556563
Topological Polar Surface Area:39.2
Heavy Atom Count:14
Complexity:213
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes