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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;
Example 99[0344] [Formula 123] [0345] 1) In N,N-dimethylformamide (24 mL) was dissolved 5-bromo-3-chloropyridine-2- carboxylic acid (2.36 g), 1-hydroxybenzotriazole (2.2 g) and 3-ethyl-3-(3-dimethyl- aminopropyl)carbodiimide hydrochloride (2.87 g), Nu,Omicron-dimethylhydroxylamine hydrochloride (1.27 g) and triethylamine (1.95 mL) was added to the solution, and the resulting mixture was stirred at room temperature for 20 hours. Water was added to the obtained residue, extracted with ethyl acetate, and the organic layer was washed with water and then with a saturated brine. After drying the mixture over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain 5- bromo-3-chloro-N-methoxy-N-methylpyridine-2-carboxamide (2.67 g).MS (m/z): 279/281/283 [M+H]+
9.11 g
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 16h;Cooling with ice;
9.02 g of <strong>[1189513-51-6]5-bromo-3-chloropyridine-2-carboxylic acid</strong>, 9.10 g of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride, 4.11 g of N, O-dimethylhydroxylamine hydrochloride, To a mixture of 0.93 g of 4- (dimethylamino) pyridine and 100 mL of chloroform, 10.6 mL of triethylamine was added dropwise under ice cooling. After raising the temperature to room temperature and stirring for 16 hours, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography to obtain Intermediate 11 represented by the following formula9.11 g was obtained.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;
To a solution of Compound 1 (10 g) in methylene chloride (200 mL) were added oxalyl chloride (4.43 mL) andN,N-dimethylformamide (0.16 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours.The reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (50 mL),and this was added dropwise to a suspension of thiosemicarbazide (3.85 g) and pyridine (75 mL) under ice cooling over10 minutes. After dropwise addition, the mixture was stirred at room temperature for 2 hours and concentrated underreduced pressure. The residue was dissolved in a 2N aqueous sodium hydroxide solution (210 mL), and heated at refluxfor 16 hours. The reaction solution was ice cooled and neutralized with concentrated hydrochloric acid (35 mL). Thedeposit was collected by filtration and washed with water and methanol. The obtained solid was suspended and washedin diethyl ether (50 mL), collected by filtration and dried at 50 °C under reduced pressure to obtain Compound 2 (9.46g) as a beige solid.MS (m/z): 291/293/295 [M+H]+
To a 50-mL round-bottomed flask was added <strong>[1189513-51-6]5-bromo-3-chloropicolinic acid</strong> (1 g, 4.23 mmol) and di-tert-butyl dicarbonate (1.96 ml, 8.46 mmol) in THF (8.5 ml) followed by addition of 4-(dimethylamino)pyridine (0.052 g, 0.423 mmol). It was heated to 70° C. for 0.5 hr. It was quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic phase was washed by sat. aq. NaHCO3 and washed with brine and dried over MgSO4. The solution was filtered and concentrated to give the crude material as a yellow oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 15percent to 25percent to 35percent (40percent EtOAc in Heptane) in Heptane, to provide tert-butyl 5-bromo-3-chloropicolinate (1.15 g, 3.93 mmol, 93percent yield) as clear colorless oil. MS m/z=314.0/316.0 (M+Na)
With dmap; In tetrahydrofuran; at 60℃; for 3h;Cooling with ice;
Acid-19: 3-Chloro-5-difluoromethyl-pyridine-2-carboxylic acid; a) 5-Bromo-3-chloro-pyridine-2-carboxylic acid tert-butyl ester; To an ice cooled solution of 11.82 g (50 mmol) <strong>[1189513-51-6]5-bromo-3-chloro-pyridine-2-carboxylic acid</strong> (CAS 1189513-51-6) in 150 ml THF was added 61 1 mg (5 mmol) DMAP and 14.19 g (65 mmol) Boc20 and the reaction mixture was heated to 60 °C for 3 h. After cooling to 0 °C half saturated aq. sodium bicarbonate was added and the mixture extracted with EtOAc. The combined organic layers were washed with half saturated aq. NaCI, dried with Na2S04 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1 :1) to provide the title compound as colorless oil.HPLC: RtH8= 1.22 min; ESIMS [M-tBu]+ = 237.8;1H-NMR (600 MHz, DMSO-cfe): delta 8.73 (d, 1 H), 8.52 (d, 1 H), 1.55 (s, 9H).
With dmap; In tetrahydrofuran; at 20℃; for 48h;
To a solution of <strong>[1189513-51-6]5-bromo-3-chloropicolinic acid</strong> (5.0 g, 21 mmol) in THF (100 mL) at room temperature was added (Boc)20 (9.2 g, 42 mmol) followed by 4-dimethylaminopyridine (0.8 g, 6.3 mmol). The reaction was stirred for 2 days and poured into saturated aqueous NH4CI. The mixture was extracted with DCM. The combined organic layers were dried (MgS04), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (1 column volume of hexanes and then 0-20percent EtO Ac/hex) to provide the title compound Aa2.
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