Synthesis
(a) Synthesis of (E)-3-(6-aminopyridin-3-yl)acrylic acid: To an aqueous (600mL) solution of 2-amino-5-bromopyridine (25.92g, 0.15mol) was slowly added an aqueous solution of acrylic acid (23mL, 0.33mol) and sodium carbonate (Na2CO3, 55.64g, 0.53mol). Subsequently, palladium dichloride (PdCl2, 0.53 g, 0.003 mol) was added as a catalyst and the reaction mixture was heated to reflux. After 24 hours of reaction, it was cooled to room temperature and filtered to remove insoluble material. The filtrate was adjusted to pH 6 with aqueous hydrochloric acid, and water (0.5 L) was added to improve mixing, and stirring was continued for 1 hour. The pH was again adjusted to 6 and the precipitated solid product was collected by diafiltration. The solid was washed sequentially with water (2 × 0.5 L), cold anhydrous ethanol (EtOH, 100 mL) and ether (Et2O, 2 × 250 mL). Finally, the target product (E)-3-(6-amino-3-pyridinyl)acrylic acid (15.38 g, 62% yield) was obtained as a brown solid by drying at high temperature under high vacuum. The product was confirmed by 1H NMR (300 MHz, DMSO-d6) and mass spectrometry (MS): 1H NMR δ 8.11 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 8.7,2.0 Hz, 1H), 7.43 (d, J = 15.8 Hz, 1H), 6.53 (s, 2H), 6.45 (d, J = 8.7 Hz. 1H), 6.22 (d, J = 15.8 Hz, 1H); MS (ES) m/e 165 (M + H)+.
References
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 15, p. 3246 - 3256
[2] Patent: EP1226138, 2004, B1
[3] RSC Advances, 2018, vol. 8, # 42, p. 23698 - 23710
