3-AMINO-ISONICOTINIC ACID ETHYL ESTER

Off-white powder or chunks solid

To an ethanol (20mL) solution of 3-aminolsonicotinoic acid (1.4g, 10 mmol), conc. sulfuric acid (2.94g, 30 mmol) was added and refluxed under heating for 20 hours. To an ethanol (20mL) solution of 3-aminolsonicotinoic acid (1.4g, 10 mmol), conc. sulfuric acid (2.94g, 30 mmol) was added and refluxed under heating for 20 hours. To an ethanol (20mL) solution of 3-aminolsonicotinoic acid (1.4g, 10 mmol), conc. sulfuric acid (2.94g, 30 mmol) was added and refluxed under heating for 20 hours. The reaction liquid was distilled under reduced pressure. Water was added to the obtained residue, which was made its pH to 8-9 with a 2N sodium hydroxide solution under ice-cooling. The precipitated solid was filtered and dried to give (j) Ethyl 3-aminoisonicotinate[00453] To an ice-cold suspension of 3-aminoisonicotinic acid (8 g, 58 mmol) in ethanol (36 mL) and toluene (36 mL) was added concentrated sulfuric acid (6.4 mL), and the mixture was stirred for 24 h. The solvents were removed under reduced pressure, the residue was dissolved in water, and the solution was adjusted to pH 8 with concentrated ammonium hydroxide to give 4.36 g (27.08 mmol, 1 eq.) of 1 -phenylpyrrolidin-2-one were dissolved in dichloromethane (35 mL) under argon and 4.15 g (2.5 mL, 27.08 mmol, 1 eq.) POCl3 is added. After stirring for 3 hours at room temperature, a solution of 5.00 g (30.09 mmol, 1.1 eq.) of ethyl 3-aminopyridine-4- carboxylate in dichloromethane (35 mL) was added over 5 minutes through a dripping top. The reaction mixture was refluxed for 16 hours. At the end of the reflux, the reaction mixture was cooled to room temperature and stirred with saturated NaHC03 solution to keep the aqueous phase alkaline (pH=8). The solution is added gently due to foaming. The organic phase is then dried over Na2S04, filtered and concentrated. 5.80 g of crude ethyl-3- { [(2E)-1 -phenylpyrrolidin- 2-ylidene] amino} pyridine-4-carboxylate (Compound la) is retained which is used without further purification. MTH+ =310.35A dry 4-neck 500-ml round-botomed flask was equipped with reflux cooler, thermometer, dripping top and gas inlet. 28.53 g (139 mmol, 1.05 eq.) of l-[(4- methoxyphenyl) methyl] pyrrolidin-2-one and 50 ml of dry chloroform are weighed in the flask. Slowly argon was introduced and phosphorus oxychloride (13 mL, 21.31 g, 139 mmol, 1.05 eq.) was added over 5 min from the dripping top. The reaction is slightly exothermic. Allow then to cool to room temperature and stir for three hours. Then, a solution of ethyl 3-amino- isonicotinate (22.00 g, 132 mmol, 1 eq.) in 50 mL of dry chloroform was added over 5 minutes. If the solution boils, the addition is slowed down to achieve slight boiling. After addition, the reaction mixture was further refluxed for 48 hours under an argon atmosphere. The reaction was monitored by thin layer chromatography. After 48 hours, the reaction mixture was cooled to room temperature and 220 ml of saturated Na2C03 3 solution (foaming) was added slowly with stirring. Then, another 150 ml of water was added and the phases were separated. The aqueous phase was washed twice with 100 ml of chloroform and the combined organic phases were extracted with water (100 ml) and dried over NS04. After filtration, it is concentrated and dissolved in 50 ml of ethyl-acetate. On a glass filter, 200 g of silica gel was wetted with ethyl acetate and through this a solution of the product was filtered. Wash with ethyl acetate until the product is detected in the filtrate by thin-layer chromatography. The combined solutions were then concentrated and the residue was dissolved in isopropyl acetate and dried over Na2S04. After filtration, it is concentrated in vacuo. Yield: 40.99 g (115 mmol, 88%). ESI-MS (M + H +) = 354. Rf = 0.55 running the same plate three times in ethyl acetate. -NMR d (500 MHz DMSO-^ T=300K): 1.20 (t , / = 7.0 Hz, 3H), 1.87 (m, 2H), 2.30 (t , / = 6.8 Hz, 2H), 3.26 (t, / = 6.8 Hz, 2H), 3.74(s, 3H), 4.21 (q , / = 7.0 Hz, 2H), 4.50 (s, 2H), 6.90 (m, /, = 8.5 Hz, 2H), 7.28 (m, /, = 8.5 Hz, 2H), 7.45 (d , / = 5.0 Hz, 1H), 8.16 (s, br, 1H), 8.21 (d, / = 5.0Hz, 1H). (0354) 13C-NMR d (126 MHz DMSO- T = 300K): 13.9, 19.1, 27.7, 46.2, 48.0, 55.0, 60.8, 113.7, 122.0, 129.2, 129.3, 130.1, 141.9, 145.9, 147.0, 157.5, 158.4, 162.1, 166.1.

Molecular Weight:166.18
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:166.074227566
Monoisotopic Mass:166.074227566
Topological Polar Surface Area:65.2
Heavy Atom Count:12
Complexity:161
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes