Yield: 97%

Reaction Conditions:

Stage #1:3-bromo-5-methylpyridin-2-amine with hydrogen bromide in water
Stage #2: with bromine in water at 0 - 5; for 0.166667 h;
Stage #3: with sodium hydroxide;sodium nitritemore than 3 stages;

Steps:

32.5
In a 30-ml three-necked flask, 2-amino-3-bromo-5- methylpyridine (187 mg, 1.00 mmol) ) was charged, 48% aqueous hydrogen bromide solution (1 ml) was added and 2-amino-3- bromo-5-methylpyridine was dissolved. Then, the mixture was ice-cooled, and bromine (154 μl, 3.00 mmol) was slowly added dropwise thereto at the internal temperature of 2 to 5°C. The mixture was stirred at the same temperature for 10 minutes. To this solution, sodium nitrite (174 mg, 2.5 mmol) /water (500 μl) solution was added dropwise at the same temperature, and the mixture was stirred for 1 hour. Sodium hydroxide (377 mg, 9.4 mmol) /water (2 ml) was slowly added dropwise thereto. The mixture was stirred at room temperature for 1 hour. The solution was poured into a separating funnel. The organic layer was separated by extraction using ethyl acetate (10 ml) and water (10 ml), and the aqueous layer was further extracted with ethyl acetate (10 ml) . The organic layers were combined, washed with a 5% aqueous sodium sulfite solution (5 ml) and saturated brine (10 ml), and then dried over sodium sulfate. The solvent was distilled away under reduced pressure, to yield the title compound (244 mg, 0.97 mmol) as a yellow solid (yield 97%)¹H-NMR (CDCl₃, TMS, 300 MHz) δ (ppm) : 2.30 (s, 3H), 7.73 (d, IH, J = 1.5 Hz) , 8.14 (d, IH, J = 1.2 Hz) . ¹³C-NMR (CDCl₃, TMS, 300 MHz) δ (ppm): 17.41, 123.16, 134.13, 140.39, 142.29, 148.57.High resolution mass spectrometry (C₆H₅Br₂N)Theoretical value: [M⁺] 248.8789Measured value: [M⁺] 248.8786 Melting point: 54.2°C

References:

TAKEDA PHARMACEUTICAL COMPANY LIMITED WO2008/16184, 2008, A1 Location in patent:Page/Page column 187-188