3-Pyridinecarboxylic acid, 5-amino-, methyl ester

Off-white solid

To a stirred solution of 5-amino-nicotinic acid (10.0 g, 72.5 mmol) in methanol (100 mL) was added SOCl5-Aminonicotinic acid (1g, .7.2mmmol) was suspended in methanol (100ml) and thionyl chloride (4.22ml, 57.9mmol) added dropwise at OOver 30 minutes hydrogen chloride gas was bubbled through dry methanol (60 [ML)] cooled to [0-5 C.] Then 5-amino-3-pyridinecarboxylic acid (i. e. the product of Step B) (6.0 g, 43 mmol) was added, and the reaction mixture was heated at [75 C] for 3 h. The reaction mixture was concentrated, the residue was poured into cold water (30 mL), and the pH of the resulting mixture was increased to 4-5 by adding sodium bicarbonate. The mixture was then extracted with ethyl acetate, and the ethyl acetate extract was washed with water and brine, and then dried [(NA2SO4)] and concentrated. The residue was triturated with ethyl acetate-petroleum ether to yield the title compound (4.2 g, 63percent yield).5-Amino-nicotinic acid methyl ester (5.7g, 30.2mmol) was dissolved in THF (150ml) and LiAIH4 (1 M in THF solution 133ml, 133mmol) added slowly at O0C. The reaction mixture was stirred at room temperature for 21 h. The reaction mixture was quenched and acidified to pH 3 using dilute HCI, and basified (pH 8) using solid Na2CO3. Solvents were removed under reduced pressure. The residue was filtered through silica gel using 20percent MeOH/DCM yielding the product 3.8g, (100percent) with LCMS purity 97percent, m/z 125 [M++H]+, by ELSMethyl 5-aminonicotinate (250 mg, 1.643 mmol) was dissolved in THF (20 mL) at 0 °C. LAH (6.57 mL, 6.57 mmol, 1 M in THF) was added dropwise to the solution over 2 minutes. The reaction mixture was then allowed to warm to room temperature and stirred at room temperature for 1.5 hours. The reaction mixture was then quenched water256 at 0 °C (lmL), followed by addition of 1M NaOH (2mL) and an additional 4 mL of water. The quenched reaction mixture was stirred for 10 minutes at room temperature then magnesium sulfate was added. The mixture was filtered through celite and the filtrate was concentrated to yield the intermediate alcohol. This cmde alcoholintermediate was reacted according to Procedure Ito yield Intermediate 1-119 (251 mg, 1.05 mmol, 65percent yield) after silica chromatography. LC-MS: Method H, MS (ESI) m/z:239.2 (M+H)tTo a stirred solution of 5-amino-nicotinic acid (10.0 g, 72.5 mmol) in methanol (100 mL) was added SOCl2 (10.4 g, 86.9 mmol) dropwise at 0C. The mixture was allowed warm to room temperature and then refluxed for 16 hours. The mixture was cooled, concentrated in vacuum and the residue was diluted with water (200 mL). The mixture was neutralized with aqueous NaHC03 solution to pH = 7. The aqueous mixture was extracted with DCM (100 mL x2). The combined organic layers were washed with brine (100 mL x2), dried over anhydrous Na2S04, filtered and the filtrate was concentrated in vacuum to dryness to give 9.5 g (yield: 86%) of 5-Aminonicotinic acid (1g, .7.2mmmol) was suspended in methanol (100ml) and thionyl chloride (4.22ml, 57.9mmol) added dropwise at O0C. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated to dryness and the resultant yellow oil was re-dissolved in methanol/ether (1:1) and afforded yellow crystals (HCI salt) which were collected by filtration, yield 1.2g (85%). LCMS purity 91%, m/z 153 [M++H]+, 3-(4-(2, 4, 4-trimethylpentan-2-yl)phenoxy)propanoic acid (1.0 equiv) and 4-Fluoroaniline (444 mg, 4.00 mmol, 1.00 equiv) was dissolved in DCM (15 mL) and treated with a solution of oxone (4.92 g, 8.00 mmol, 2.00 equiv) in water (50 mL). The biphasic mixture was vigorously stirred until thin layer chromatography indicated complete consumption of the starting material. The watery phase was discarded and the organic phase washed with an aq. HCl-solution (1 M, 3 × 10 mL) and water (3 × 10 mL), then dried over MgSO4. The solution was concentrated to a volume of 5 mL under reduced pressure and added to a solution of 9 (609 mg, 4.00 mmol, 1.00 equiv) in acetic acid (20 mL). The reaction mixture was stirred at 60 C for two weeks, cooled to room temperature, poured onto ice cooled sat. aq. NaHCO3-solution and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with water (3 × 50 mL), sat. aq. NaCl solution (30 mL) and dired overMgSO4. The solvent was evaporated under reduced pressure and the residue purified by silica gel column chromatography (cyclohexane/EtOAc 3:1). The product was obtained as orange solid (431 mg, 1.67 mmol, 42%): Rf= 0.52 (cyclohexane/EtOAc 3:1); mp: 103.6 C; 1H NMR, H, H-COSY (400 MHz, DMSO-d6) delta (ppm) 9.34 (d, J = 2.3 Hz, 1H), 9.22 (d, J= 2.0 Hz, 1H), 8.50 (pseudo-t, J= 2.2 Hz, 1H), 8.09-8.01 (m, 2H), 7.52-7.44 (m, 2H), 3.95 (s, 3H); 13C NMR, DEPT135, HSQC, HMBC (75.5 MHz, DMSO-d6) delta (ppm) 164.5, 164.4 (d, J= 251.8 Hz), 151.8, 150.3, 148.5 (d, J = 2.8 Hz), 146.7, 126.4 (d, J= 6.7 Hz), 125.4 (d, J= 9.5 Hz), 116.6 (d, J = 23.2 Hz), 52.7; IR (ATR) nu (cm-1): 3081, 1713, 1583, 1496, 1286, 1222, 1092, 1000, 843, 498.

Molecular Weight:152.15
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