2-Hydroxyisonicotinic acid

White powder

2-Hydroxyisonicotinic acid methyl ester (57a). A mixture of 2- hydroxyisonicotinic acid (0.28 g, 2.0 mmol, 1 equiv.) and a catalytic amount of concentrated H2SO4 (1 drop) in methanol (8 ml_) was refluxed overnight. Evaporation of solvent gave crude product, which was purified by flash chromatography (EtOAc/MeOH 1 :1 ) giving 0.25 g (82 %) of the product as white solid. 1H NMR (CHCI3, 500.1 MHz) 13.00 (bs, 1 H), 7.44 (d, J = 6.7 Hz, 1 H), 7.21 (s, 1 H), 6.79 (d, J = 6.7 Hz, 1 H), 3.93 (s, 3H) ppm.Methyl 2 -hydroxy isonicotinate. To a solution of Methyl 2-hydroxyisonicotinate. To a solution of methyl 2-hydroxyisonicotinate (1.4 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 40mmol) at 0C. The mixture was stirred for 12 hours. The solvent was evaporated in vacuum. To the residue a saturated sodium bicarbonate aqueous solution was added and the mixture was extracted with acetic ether (100 mL x 3). The organic phase was dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuum to give methyl 2-hydroxyisonicotinate (1.2 g, 78%).1H NMR (300 MHz, CD3OD): delta 7.52 (d, J = 6.9 Hz, 1H), 7.07 (s, 1H), 6.79 (dd, J =6.9 Hz, J= 1.8 Hz, 1H), 3.91 (s, 3H).Methyl 2-hydroxyisonicotinate. To a solution of methyl 2-hydroxyisonicotinate (1.4 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 40 mmol) at 0C. The reaction was then mixed for 12 h. The solvent was evaporated in vacuo. The residue was diluted with aq. saturated sodium bicarbonate solution and extracted with EtOAc (3X). The organic phase was dried over Na2SO4, filtered and concentrated to afford methyl 2-hydroxyisonicotinate (1.2 g, 78%).1H NMR (300 MHz, CD3OD) delta 7.52 (d, J= 6.9 Hz, 1H), 7.07 (s, 1H), 6.79 (dd, J=6.9, 1.8 Hz, 1H), 3.91 (s, 3H).Methyl 2-hydroxyisonicotinate To a solution of To a solution of methyl 2-hydroxyisonicotinate (1.4 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 40 mmol) at 0 C. The mixture was stirred for 12 hours. The solvent was evaporated in vacuum. To the residue a saturated sodium bicarbonate aqueous solution was added and the mixture was extracted with acetic ether (100 mL×3). The organic phase was dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuum to give methyl 2-hydroxyisonicotinate (1.2 g, 78%). 1H NMR (300 MHz, CD3OD): delta 7.52 (d, J=6.9 Hz, 1H), 7.07 (s, 1H), 6.79 (dd, J=6.9 Hz, J=1.8 Hz, 1H), 3.91 (s, 3H).General procedure: 4-Hydroxypicolinic acid 3 (348 mg, 2.5 mmol) was added to methanol (25 mL), and then concentrated sulfuric acid (0.2 mL). The mixture was refluxed for 20 h, then the solvent was evaporated under vacuum. The residue was neutralized with saturated aqueous sodium bicarbonate solution, extracted with DCM/MeOH (10/1, 5×30 mL), dried over anhydrous Na2SO4, concentrated under vacuum to give compound 4 (196 mg, 51%) as a white solid. 1H NMR (400 MHz, Methanol-d4) delta 7.92 (d, J = 7.0 Hz, 1H), 7.14 (s, 1H), 6.63 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H). MS (ESI) m/z = 154.1 ([M+H]+). To a solution of compound 4 (77 mg, 0.5mmol) in DMF (2 mL) was added potassium carbonate (104 mg, 0.75 mmol), then 1, 4-dibromobutane (325 mg, 1.5 mmol) at 0C. The mixture was stirred at room temperature for 3 h, and then partitioned between water (30 mL) and ethyl acetate (EA, 30 mL). The organic phase was washed with water (3×30 mL), saturated brine (30 mL), dried over anhydrous Na2SO4, concentrated under vacuum, purified by column chromatography using DCM : MeOH (100:1) as eluent to give 5 (95 mg, 66%) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) delta 8.51 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.22 (dd, J = 5.7, 2.6 Hz, 1H), 4.19 (t, J = 6.2 Hz, 2H), 3.62 (t, J = 6.5 Hz, 2H), 1.98 (p, J = 6.7 Hz, 2H), 1.92 - 1.83 (m, 2H). MS (ESI) m/z = 288.2 ([M+H]+). Corresponding arylpiperazine (arylpiperidine) (0.24 mmol), 5 (90 mg, 0.31 mmol), potassium carbonate (83 mg, 0.6mmol) and potassium iodide (40 mg, 0.24 mmol) were added to acetonitrile (5 mL). The reaction mixture was refluxed overnight, cooled to room temperature, partitioned between EA and water. The organic layer was dried over anhydrous Na2SO4, concentrated under vacuum to give 6a-6e which was used directly in the next step without further purification.2-Hydroxyisonicotinic acid (4.2g, 30.2 mmol) was dissolved in MeOH (200 ml) , then H2SO4(0.2mL, 3.75 mmol) was added to the solution and the resulting solution was stirred at 100 for 48 h. Then the solution was concentrated under reduced pressure, and the crude product was used without future purification. MS (ESI) Calc' dfor (C7H7NO3) [M+H]+, 154.1 found 154.1To a suspension of

Molecular Weight:139.11
XLogP3:-0.5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:139.026943022
Monoisotopic Mass:139.026943022
Topological Polar Surface Area:66.4
Heavy Atom Count:10
Complexity:239
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes