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Description 1 (3. 55 g,25. 7 mmol),H2SO4 (2. 5 ml) and methanol(50 ml) were heated at 80 C for 3 days. The methanol was evaporated, the residue diluted with water(75 ml) and heated to 80 C. Solid sodium carbonate was added until effervescence ceased. The mixture was cooled and extracted with dichloromethane (2 x 100 ml). The combined organic layers were dried overMgS04 and concentrated to give the title compound as a beige solid (2.36 g,60 percent). 'H NMR (500 MHz, DMSO) 5 8.24 (1H, s), 7.74 (1H, d, J5. 3), 7.46 (1H, d, J5.2), 6.67 (2H, brs), 3.83 (3H, s). M/z (ES+) 153 (M+H+).
With thionyl chloride; for 72h;Heating / reflux;
A mixture of 3-amino-isonicotinic acid (613 mg, 4.44 mmol), methanol (15 mL) and thionyl chloride (0.7 mL, 8.88 mmol) was stirred at reflux for 3 days. The volatiles were <n="64"/>removed under reduced pressure and the residue stirred with diethylether (20 mL) and saturated solution of sodium hydrogenocarbonate (40 mL). The phases were separated and the aqueous phase extracted with diethylether (2x20 mL). The combined organic phases were dried over sodium sulfate and evaporated to dryness affording 400 mg of the title compound.IH-NMR (400 MHz), delta (ppm, DMSO-J6): 8.26 (s, IH), 7.76 (d, J=5.2 Hz, IH), 7.48 (d,J=5.2 Hz, IH), 6.69 (bs, 2H), 3.85 (s, 3H).
With thionyl chloride; In methanol; diethyl ether;
EXAMPLE 1A 3-aminoisonicotinic acid, methyl ester A suspension of 3-aminoisonicotinic acid (13.81 g, 100 mmol, prepared using the procedure described in Crum J. D.; Fuchsman, C. H. J. Heterocyclic Chem., 1966, 3, 252) in methanol (250 mL) was treated with thionyl chloride (14.7 mL, 200 mmol) and heated to reflux for 3 days. The yellow solution was concentrated to dryness to provide a yellow solid. This solid was suspended in 200 mL of ethyl ether and treated with 400 mL of saturated, aqueous NaHCO3 and the biphasic solution was stirred until all of the solids were dissolved. The layers were separated and the aqueous phase was extracted with 2 additional portions of ethyl ether. The combined organic phases were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the title compound as a light yellow solid. MS (DCI/NH3) m/z 153 (M+H)+.
In methanol; diethyl ether; toluene; at 20℃; for 2h;
Step 6: Preparation of 3-aminoisonicotinic acid methyl ester; 3-Aminoisonicotinic acid (400 mg) was suspended in methanol(6 mL) and toluene (18 mL) was added. A solution of (trimethylsilyl) diazomethane (2.0 M in diethyl ether, 1.88 mL) was added slowly to the suspension. Within 5 to 10 minutes after addition, the suspension turned into a solution. After 2 hours stirring at room temperature, the reaction mixture was quenched with water and extracted 3x with ethyl acetate. The combined organic layer was washed with 2N hydrochloric acid, saturated bicarbonate solution and brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica gel 60, hexane/ethyl acetate = 1:2, Rf = 0.40) to afford 340 mg of the title compound of the formulaas a white solid.1H-NMR (CDCl3, TMS) delta (ppm) : 3.91 (3H, s), 5.65 (2H, br s), 7.59 (IH, d, J = 5 Hz), 7.93 (IH, d, J = 5 Hz), 8.19 (IH, s) .
methyl 3-(2-ethoxybenzamido)isonicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
Example 165 [0573] methyl 3-aminoisonicotinate (200 mg, 1.31 mmol) in dichloromethane (25.0 mL) and triethylamine (0.550 mL, 3.94 mmol) was treated at 0 C. with <strong>[42926-52-3]2-ethoxybenzoyl chloride</strong> (243 mg, 1.31 mmol). The reaction mixture was stirred at 0 C. for 2 h and at room temperature for 2 h. The reaction mixture was concentrated and purified via silica gel chromatography using a gradient of 0-100% of EtOAc in hexanes to give 45 mg (11%) of the title product as a white solid which was used directly in the next reaction without further purification.
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