Preparation background and overview of 2-amino-4-methylpyridine-5-carboxylic acid
2-Amino-4-methylpyridine-5-carboxylic acid is a pharmaceutical intermediate that can be obtained by heating and hydrolyzing 6-amino-4-methylnicotinonitrile under acid or alkali conditions.
[Di-tert-butyl dicarbonate label: title] Preparation
Preparation report of 2-amino-4-methylpyridine-5-carboxylic acid 1.
Step 1, preparation of 6-amino-4-methylnicotinonitrile
Copper(II) cyanide (2.87 g, 32 mmol) was added to a solution of 2-amino-5-bromo-4-methylpyridine (3.0 g, 16.0 mmol) in DMA (12 ml) and the reaction was Stir at 170°C for 24 hours under argon atmosphere. After cooling to room temperature, the reaction mixture was added to a solution of ethylenediamine (60 ml) in water (240 ml) and stirred for 15 minutes. The mixture was then diluted with EtOAc, washed with water and NaCl solution, dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex:EtOAc 4:1 to 1:9 for 40 min; Hex:EtOAc 1:9 for 10 min) and then crystallized from DCM (MeOH)/diethyl ether/hexane, 1.73 g (81%) of the title compound were obtained as pale yellow crystals. [1H-NMR (DMSO, 600 MHz) 8.23 (s, 1H), 6.91 (s, 2H), 6.35 (s, 1H), 2.25 (s, 3H); LCMS RtD = 1.959 min; [M+H]+ = 134.0]
Step 2, preparation of 2-amino-4-methylpyridine-5-carboxylic acid
6-Amino-4-methylnicotinonitrile (1.7g, 12.8mmol) was suspended in 4N sodium hydroxide solution and stirred at 100°C for 5h to obtain a clear solution. The reaction mixture was cooled in an ice bath and acidified by adding 4N hydrochloric acid. Filter the precipitate and wash with a little water. The residue was dissolved in MeOH, the solvent was evaporated under reduced pressure and the product was dried under high vacuum to give the title compound 1.74 g (90%) as a colorless solid. [1H-NMR (DMSO, 600 MHz) 12.17 (s, 1H), 8.45 (s, 1H), 6.56 (2H), 6.23 (s, 1H), 2.38 (s, 3H) ; LCMS RtD = 1.910 min; [M+H]+ = 153.0].
Preparation report 2 of 2-amino-4-methylpyridine-5-carboxylic acid,
Sodium carbonate
2-amino-4-methylpyridine-5-carboxylic acid can also be produced by heating 6-amino-4-methylnicotinonitrile in hydrochloric acid for 24 hours.
References
[1] From PCT Int. Appl., 2011073316, 23 Jun 2011
[2] From European Journal of Medicinal Chemistry, 84, 404-416; 2014
