Preparation background and overview of 3-amino-5-fluoro-6-methoxypyridine
3-Amino-5-fluoro-6-methoxypyridine can be used as a pharmaceutical synthesis intermediate. If 3-amino-5-fluoro-6-methoxypyridine is inhaled, move the patient to fresh air; if skin contact occurs, remove contaminated clothing and rinse skin thoroughly with soap and water. If discomfort occurs , seek medical attention; if eye contact occurs, separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.
Preparation of 3-amino-5-fluoro-6-methoxypyridine
The preparation of 3-amino-5-fluoro-6-methoxypyridine is as follows:
Step 1: Using an explosion-proof shield and an alkaline scrubber, combine diphenylphosphoryl azide (376.91μL, 1.75mmol), tert-butyl alcohol (207 boric acid pinacol ester. 99uL, 2.19mmol) and tris Ethylamine (244 μL, 1.75 mmol) was added to the stirred solution. Fluoro-6-methoxy-pyridine-3-carboxylic acid (250 mg, 1.46 mmol) in toluene (4 mL). The resulting yellow reaction mixture was heated to 110° C. and stirred at the di-tert-butyl dicarbonate temperature for 3 hours. The reaction mixture was cooled to room temperature, then quenched by adding water (20 mL), and extracted with EtOAc (3 × 20 mL). The organic portion was collected, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by column chromatography (eluting with 0-50% EtOAc in heptane) to give the desired product N-(5-fluoro-6-methoxy-3-pyridinyl)carbamic acid tert-butyl ester ( 274 mg, 1.13 mmol, 77% yield) as colorless oil.
Step 2: Stir N-(5-fluoro-6-methoxy-3-pyridyl)carbamic acid tert-butyl ester (315 mg, 1.30 mmol) in trifluoroacetic acid (1.99 mL, 26.01 mmol) 2 Hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (100 mL) and 1 M HCl (100 mL) and extracted with EtOAc (50 mL). Add solid sodium carbonate to the aqueous layer until a neutral/slightly alkaline pH is obtained. The aqueous phase was then further extracted with EtOAc (3 × 50 mL), the organic portion was collected, passed through phase separation filter paper, and the solvent was concentrated in vacuo to give 3-amino-5-fluoro-6-methoxypyridine (91 mg, 0.64 mmol), 49% Yield), as dark red oil.
1HNMR (CDC, MHz) δ/ppm: 7.45 (1H, d, J = 2.5Hz), 6.85 (1H, dd, J = 11.3Hz, 2.5Hz), 3.97 (3H, s).
