Yield: 11% ， 5%

Reaction Conditions:

with iodine;sodium carbonate;potassium iodide in water for 2 h;Heating / reflux;

Steps:

3
A solution OF 2-METHYL-4-NITROPYRIDINE-N-OXIDE (3.80 g, 24.6 mmol) in 100 ML of acetic acid was slowly heated with iron powder (6.89 g, 124 mmol) in a large flask (caution: the reaction becomes very exothermic upon turning brown). The resulting slurry was heated for 2 hours at 80 C. Excess acetic acid was removed IN VACUO, THE residue was taken up in 20% aqueous sodium hydroxide solution, and 100 mL of chloroform (CHC13) was added and the mixture filtered through CELITES FILTER aid. The aqueous phase was extracted with two 200 mL portions of chloroform. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product (2.2 g, 83% yield) was used without further purification. A solution OF KI (1. 96 g, 11. 9 mmol) and 12 (1.87 g, 7.36 mmol) in 10 ML of water was added to a REFLUXING solution of the 2-methylpyridin-4-ylamine (1.00 g, 9.25 mmol) and sodium carbonate (683 mg, 6.44 mmol) in 5 ML of water. The mixture was heated at reflux for 2 hours, cooled to room temperature, and treated with 20 mL of ethyl acetate (EtOAc). Phases were separated and the aqueous layer was extracted with three 20 ML portions of ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium thiosulfate (NA2S203) solution, dried over magnesium sulfate, and concentrated ILL vacuo. Flash chromatography (30% ethyl acetate in hexanes to 100% ethyl acetate, gradient) of the resulting residue yielded 4-amino-3-iodo-6-methylpyridine (first eluting: 226 mg, 11% yield) and 4- AMINO-3-IODO-2-METHYLPYRIDINE (second eluting : 116 mg; 5% yield).

References:

BOEHRINGER INGELHEIM PHARMACEUTICALS, INC. WO2005/30213, 2005, A1 Location in patent:Page/Page column 166