Methyl 6-aminonicotinate

Off-White Solid

General procedure: A mixture of 4-aminobenzoic acid (32-34, 5.0 mmol), thionyl chloride(1.487 g, 5.0 mmol), and MeOH (20.0 mL) was flushed with argon, and stirred at80°C for 12 hours. Remove reaction solvent by rota vapor. The reaction mixture wasneutralized with NaHCO3(sat) (20.0 mL) and extracted with ethyl acetate (100 mL ×3). The combined organic extracts were washed with brine, dried by Na2SO4, filtered, and evaporated, to get cmopound 35-37 (63-89percent) as a white solid.To a stirred solution of 6-amino-nicotinic acid (25 g, 181.1 mmol) in MeOH (200 mL) is added concentrated H2504 (7 mL) at 0 °C and the reaction mixture is heated at 80°C for overnight. The reaction mixture is cooled to room temperature and neutralized with saturated NaHCO3 solution (100 mL). The precipitated solid is filtered and dried under vacuum to give the title compound as a yellow solid (22 g, 8 1.5percent). LCMS mlz 153(M+H)tTo a stirred solution of 6-amino-nicotinic acid (25 g, 181.1 mmol) in MeOH (200 mL) is added concentrated HPREPARATION 1 [0198] A mixture of 6-aminonicotinic acid (4.0 g, 28.9 mmol), methanol (75 mL), and concentrated hydrochloric acid (4 mL) was heated under reflux for 16 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting solid was treated with water (20 mL) and enough sodium bicarbonate to adjust the pH to pH=8. The solution was then extracted with ethyl acetate (3.x.25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-aminonicotinic acid methyl ester (3.12 g, 71percent) as white foam: EI-HRMS m/e calcd for C7H8N2O2 (M+) 152.0586, found 152.0586. [0199] A solution of 2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (prepared as in Example 12, 300 mg, 0.79 mmol) in methylene chloride (6 mL) was treated with N, N-dimethylformamide (7 drops) and then cooled to 0° C. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.48 mL, 0.95 mmol). The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to 25° C., and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (6 mL) and was treated dropwise with a solution of 6-aminonicotinic acid methyl ester (252 mg, 1.67 mmol) in tetrahydrofuran (5 mL) and 2, 6-lutidine (0.48 mL, 3.95 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (100 mL) and extracted with methylene chloride (3.x.50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 7/3 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid methyl ester (227 mg, 55percent) as a white foam: EI-HRMS m/e calcd for C23H25F3N2O6S (M+H)+ 537.1277 found 537.1284.Scheme Al11 6A mixture of 6-aminonicotinic acid (1.0 equiv., 7.24 mmol, 1.00 g) and sulfuric acid (6.00 equiv., 65.16 mmol, 6.39 g) in methanol was refluxed for 24 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and then made alkaline by the addition of a saturated aqueous NaHCOMethyl-6-amineonicotinate 6-Amineonicotinic acid ( 1 .00 g, 7.246 mmol, 1 .00 eq) was dissolved in abs. MeOH (40 ml) and cooled to 0 °C. SOCI24.6 ml (3.4 equivalents) of 2.0M trimethylsilyldiazomethane in solution in cyclohexane are added to a solution of 2.0 g of 6-aminonicotinic acid in a chloroform/methanol (v/v: 10/30) mixture. The reaction medium is stirred at ambient temperature for 1 hour and is then hydrolysed with 100 μl of acetic acid and concentrated under reduced pressure. The crude product is triturated in a cyclohexane/ethyl acetate (1/2) mixture and filtered to produce 1.459 g of a yellow powder corresponding to the expected product. Yield: 66percent MS: MH+ 153

Used in ointments for treatment of psoriasis.

Molecular Weight:152.15
XLogP3:1.7
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