Uses
2-Hydroxy-4-methylpyridine is an intermediate used to prepare oxobenzopyrancarboxylate derivatives as inhibitors of serine proteases and human leukocyte elastase. It is also used in the synthesis of (indanylamino)(pyridinyloxy)pyrazines and analogs as corticotropin releasing factor type-1 receptor antagonists.
Synthesis
The general procedure for the synthesis of 2-hydroxy-4-methylpyridine from 2-amino-4-methylpyridine was as follows: the synthesis of intermediate V-a (4-methylpyridin-2-ol) was carried out with reference to the method reported by Adger et al. in J. Chem. Soc. Perkin Trans. 1, 1988, p2791-2796. Concentrated HCl was added to a 1 L flask containing water (240 mL) and subsequently cooled to 0°C. 2-Amino-4-methylpyridine (30 g, 277 mmol) was added all at once, followed by a dropwise addition of a solution of NaNO2 (20.6 g, 299 mmol) in water (40 mL) over a period of 1 h, ensuring that the internal temperature did not exceed 5 °C. The reaction was carried out at 0 °C by stirring the reaction mixture. The reaction mixture was stirred at 0 °C for 1 h and then heated to 95 °C, held for 15 min and subsequently cooled to room temperature. The pH was adjusted to 6-7 with 50% NaOH aqueous solution (note exothermic) and extracted with EtOAc (4 x 120 mL) while hot. The organic phases were combined, dried with MgSO4, filtered and the solvent evaporated to give a beige crystalline solid intermediate V-a (24.5 g, 81% yield).1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 7.23 (d, J = 6.7 Hz, 1H), 6.10 (s, 1H), 6.00 (dd, J = 6.7, 1.2 Hz, 1H). 1.2 Hz, 1H), 2.10 (s, 3H).
References
[1] Patent: WO2013/14170, 2013, A1. Location in patent: Page/Page column 77-78
[2] Chemische Berichte, 1924, vol. 57, p. 794
[3] Organic Syntheses, 2002, vol. 78, p. 51 - 51
