Synthesis
The general procedure for synthesizing 5-chloro-2-methoxynicotinic acid from 2-methoxynicotinic acid is as follows:
Example 1:
A. A 306 mg (0.002 mol) sample of 2-methoxynicotinic acid (product of Preparation A) was taken and added in a single addition to 20 mL of a well-stirred aqueous 5.25% sodium hypochlorite solution (Clorox). The resulting mixture (now in solution) was stirred for about 18 hours (i.e., overnight) at room temperature (about 20°C). Upon completion of the reaction, the reaction mixture was acidified with 10 mL of 1N hydrochloric acid and the resulting precipitate was subsequently extracted with chloroform. The organic extracts were combined, dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 195 mg (52% yield) of pure 5-chloro-2-methoxynicotinic acid with a melting point of 139-141 °C (melting points of 149-150 °C have been reported in the literature, based on D.E. Kuhla et al. in U.S. Patent No. 3,879,403). The pure product was further characterized by NMR data and mass spectrometry.
References
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 7, p. 1859 - 1865
[2] Synthetic Communications, 1989, vol. 19, # 9-10, p. 1505 - 1508
[3] Patent: US4980357, 1990, A
[4] Patent: US4716231, 1987, A
[5] Patent: EP306251, 1990, A3
