2-Pyridinecarboxylic acid, 3-amino-, methyl ester

(Step 1) (1070) To a solution of 3-aminopyridine-2-carboxylic acid (20 g, 144.9 mmol) in methanol (300 mL) was added conc. sulfuric acid (5.4 mL), and the mixture was heated under reflux for 5 days. The reaction mixture was concentrated under reduced pressure, water was added thereto, and sodium carbonate was added thereto until the complete of foaming. The mixture was extracted with dichloromethane (x3), the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give methyl 3-aminopyridine-2-carboxylate (17.0 g, 77percent) as a pale yellow solid. A solution of 3-aminopyridine-2-carboxylic acid(Bioorg. Med Chem. 2001, 9, 2061) (1.0 g, 7.25 mmol) andH2SO4 (2.75 ml) in methanol (15 ml) was heated at 80 oC for 7 days. The reaction was cooled and the methanol removed by evaporation. The residue was poured into water (ca. 30 ml) and solid sodium carbonate was added until effervescence ceased(pH ~7). The mixture was extracted with dichloromethane (4 x 50 ml) and the combined organic fractions dried over MgS04 and concentrated to give the title compound as a beige solid (0. 84 g, 76 percent). 1H NMR (360 MHz, CDCl3) 8 8.07(1H, dd, J4. 2, 1. 4), 7.22(1H, dd, J8. 4, 4. 2), 7.05(1H, dd, J8. 4, 1. 4), 5.73 (2H, brs), 3.98 (3H, s).Mlz (ES+) 153 (M+H+).To a suspension of 3-aminopicolinic acid (100 g, 724 mmol, 1.0 eq.) in dry MeOH (1.5 L) was added conc.H3-Aminopyridine-2-carboxylic acid (10.0 g, 72.5 mmol) was dissolved in methanol (100 ml). After cooling to 0° C., concentrated hydrochloric acid (25 ml) was added dropwise thereto, and the reaction solution was stirred at 85° C. for 12 hours. After the solvent was removed under reduced pressure, water and sodium hydrogen carbonate (10 g) were added to the obtained residue, followed by stirring and extraction with ethyl acetate (80 ml×4). The extraction liquids were combined, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure. The residue was stirred in petroleum ether/ ethyl acetate=8:1, and the obtained solid was filtered and dried under reduced pressure to obtain the title compound (4.50 g, 41percent). [1164] Synthesis of (+/-)-9- [acetyl -(3 , 5-bis-trifluoi'omethylbenzyl)amino] -2-bromo-6, 7 , 8 , 9- tetrahydro-pyrido[3, 2-b]azepine-5-carboxylic acid'isopropyl ester; Step 1;. Preparation of 3-amino-pyridine-2-carboxylic acid methyl ester; Add dropwise a solution of trimethylsilyl diazomethane (2.0 M in toluene, 7.24 mL, 14.48 mmol) to a solution of 3-amino-pyridine-2-carboxylic acid (1.0 g, 7.24 mmol) in ethyl acetate (5 mL) and methanol (5 mL) at room temperature. After the addition is complete, remove the solvent under reduced pressure. Suspend the residue in water (5 mL), add a saturated solution of sodium bicarbonate, and extract with ethyl acetate. Separate the organic layer, dry over sodium sulfate, and filter. Remove the solvent under reduced pressure to afford the title compound (590 mg, 54percent). MS (ES+): 153 (M+H).In an inert three-necked flask under argon, 5.00 g (31.02 mmol, 1 eq.) of l-phenylpyrrolidin-2- one was dissolved in 35 ml of dry dichloromethane. A dripping top, a reflux condenser and a CaCl2 tube were placed on the flask. A solution of trifluoromethanesulfonic anhydride (5.2 mL, 8.75 g, 31.02 mmol, 1 eq) in 10 mL of dry dichloromethane was added dropwise over 2 min. The temperature rises until the solution boils slightly. Allow to cool to room temperature and stir for three hours. Then, a suspension of 5.19 g (34.12 mmol, 1.1 eq.) of 3-aminopyridine-2-carboxylic acid-methyl ester in 35 ml of dry dichloromethane is carefully added through a large diameter funnel. The apparatus was re -inerted with argon and the reaction mixture was stirred at reflux temperature for 24 hours. To the cooled reaction mixture was slowly added 60 mL of saturated Na2C03 solution while stirring. After separation of the phases, the aqueous phase was extracted with dichloromethane (2x40 mL). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was used without further purification. Yield: 10.12 g of black oil, solidified on standing.

Molecular Weight:152.15
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:152.058577502
Monoisotopic Mass:152.058577502
Topological Polar Surface Area:65.2
Heavy Atom Count:11
Complexity:149
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes