Synthesis Reference(s)
Journal of the American Chemical Society, 104, p. 1428, 1982
DOI: 10.1021/ja00369a049Organic Syntheses, Coll. Vol. 4, p. 532, 1963
Synthesis
General procedure for the synthesis of methyl 6-hydroxynicotinate from methanol and 6-hydroxynicotinic acid: first, 6-hydroxynicotinic acid (100 g, 719 mmol) was suspended in methanol (1 L). Subsequently, 18 M sulfuric acid (50 mL) was added and the reaction mixture was heated to reflux for 16 hours. Upon completion of the reaction, the reaction mixture was cooled and sodium bicarbonate powder (45 g) was slowly added to partially neutralize the acidity. Next, most of the methanol was evaporated under reduced pressure. Water (1 L) was added to the residue and the pH was adjusted to 7 by careful addition of sodium bicarbonate solution. the suspension was extracted with dichloromethane (4 x 200 mL), the organic phases were combined and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the resulting solid was dried in a vacuum oven at 50 °C for 1.5 h to give 83 g (75% yield) of methyl 6-hydroxynicotinate as a white solid. Mass spectrum (electrospray ionization): 154.2 (MH+, C7H7NO3). 1H NMR (300 MHz, CDCl3): δ 3.88 (s, 3H), 6.59 (dd, 1H), 8.02 (dd, 1H), 8.21 (m, 1H), 13.19 (bs, 1H).
References
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6679 - 6703
[2] Patent: WO2012/52444, 2012, A1. Location in patent: Page/Page column 12
[3] Chemistry - A European Journal, 2009, vol. 15, # 24, p. 5950 - 5955
[4] Patent: WO2009/106885, 2009, A1. Location in patent: Page/Page column 296
[5] Organic and Biomolecular Chemistry, 2010, vol. 8, # 15, p. 3534 - 3542
