Preparation of 2-amino-4-methylpyridine-5-carboxylic acid_Industrial additives

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