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Compound 14B: methyl 3-bromo-2-chloroisonicotinate
To a stirred solution of 3-bromo-2-chloroisonicotinic acid 14A (1 g, 4.23 mmol) in MeOH (20 mL) at 0 °C under nitrogen was added 50C12 (2.0 mL, 27.4 mmol) drop-wise and the reaction mixture was allowed to stir at 80 °C for 5 h. The reaction mixture was evaporated under reduced pressure, basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 x 200 mL), the organic layer washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to get compound-14B (0.8 g, 3.19 mmol, 76 % yield) as a pale brown oil. LCMS: m/z = 252.2 [M+Hf’; ret. time 0.9 mm; condition B.
Step1: LDA (60 mL, 0.12 mol) was dripped into a solution of compound 81-1 (20 g, 0.1 mol) in THF (200 mL)at -78 C, the reaction mixture was stirred at -78C for 2h. The reaction mixture was poured into dry ice quickly. Thenthe mixture was stirred at room temperature for 30 min, and quenched with H2O in the end. The aqueous phase wasextracted with EtOAc. The combined organic phase was washed with brines, dried over sodium sulfate, and concentratedunder reduced pressure to deliver compound 81-2 (10 g, yield 43%) as white-off solid. MS ESI calcd for C6H3BrClNO2[M+H]+ 236, found 236.
With 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 16h;
81.3 Step 3
Step 3: CMPI (2.2 g, 8.9 mmol) was added into a solution of compound 81-2 (2.1 g, 8.9 mmol), compound 81-4(2.2 g, 8.9 mmol) and DIEA (2.3 g, 17.8 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at room temperaturefor 16h. The crude product was used for the next step directly. MS ESI calcd for C21H23BrClN3O2 [M+H]+ 464, found 464.
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; for 2h;
3.3A.3A.5
To a solution of 3-bromo-2-chloroisonicotinic acid (1, 3.0 g, 12.76 mmol) in dichloromethane (20 mL) is added N,N-dimethylformamide (0.09 mL, 1.27 mmol) at 0 °C followed by oxalyl chloride (1.7 mL, 19.14 mmol). Then the reaction mixture is stirred at -25 °C for 2 h. After completion, the reaction mixture is evaporated to dryness under reduced pressure. Crude reaction mixture is diluted with dichloromethane (10 mL) and poured into ice cold aqueous ammonia in a drop wise manner. Precipitated solid is filtered through sintered funnel and dried under vaccum to afford 3-bromo-2-chloroisonicotinamide (2).
With thionyl chloride In methanol at 0 - 80℃; for 12h;
232.1 Step 1: Methyl 3-bromo-2-chloroisonicotinate
To a solution of 3-bromo-2-chloroisonicotinic acid (400 mg, 1.69 mmol) in MeOH (10 mL) was added SOCl2 (1.31 g, 11.00 mmol) dropwise at 0 °C; then the mixture was stirred at 80 °C for 12 hrs. The reaction was concentrated to give a residue which was extracted with EtOAc (10 mL × 3) and saturated aqueous Na2CO3 (10 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to afford the title compound (390 mg, 92%) as a brown liquid, which was used without further purification. MS-ESI (m/z) calcd for C7H6BrClNO2 [M+H]+: 249.9/251.9. Found 249.8/251.9.
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