Methanamine, N-methoxy-, hydrochloride (1:1) → 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide

Participants

Reaction Conditions

Reaction Steps

To a solution of 2-Amino-6-chloro-nicotinic acid (4.99g, 28.965 mmol, Example 2) in anhydrous N,N-dimethylformamide (50 mL) were added 1-hydroxybenzotriazole hydrate (6.21g, 40.57 mmol, Advanced ChemTech) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (15.38 g, 40.5648 mmol, Aldrich) at 0° C. A solution of N,O-dimethylhydroxylamine hydrochloride (306 mg, 3.15 mmol, Aldrich) in anhydrous N,N-dimethylformamide (15 mL) was treated with N,N-diisopropylethylamine (8.28 g, 64.1 mmol) and immediately added to the reaction which was stirred at 0° C. for ˜10 minutes then at room temperature for 4-5 hrs. The reaction was diluted with ethyl acetate (150 mL) and water (100 mL) and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water (3×) and saturated sodium chloride, dried and concentrated. The crude product was purified on silica gel with 90/10→70/30 of hexanes/ethyl acetate to give 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (4.72 g, 21.92 mmol, 75.7 % yield). HRMS, observed: 215.0463, Calcd for M+: 215.0462.

Provenance & Evidence