Реакция #58376

Уравнение реакции

2-Amino-6-chloro-nicotinic acid

1-hydroxybenzotriazole hydrate

O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

N,O-dimethylhydroxylamine hydrochloride

N,N-diisopropylethylamine

→

2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide

Выход 75.7%

Растворители

N,N-dimethylformamide

ethyl acetate

water

N,N-dimethylformamide

Условия реакции

Обработка

1. 1
   workup.ADDITIONimmediately added to the reaction which
2. 2
   workup.WAITat room temperature for 4-5 hrs
3. 3
   Экстракцияthe aqueous layer was extracted with ethyl acetate (3×150 mL)
4. 4
   ПромывкаThe combined organic layers were washed with water (3×) and saturated sodium chloride
5. 5
   Другоеdried
6. 6
   Концентрированиеconcentrated
7. 7
   ДругоеThe crude product was purified on silica gel with 90/10→70/30 of hexanes/ethyl acetate

Методика

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.

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