ethyl 3-hydroxypicolinate

ethyl 3-hydroxypicolinate Property

storage temp. 

Inert atmosphere,Room Temperature

Appearance

Light yellow to yellow Solid-Liquid Mixture

Safety

HS Code 

2933399990

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P321Specific treatment (see … on this label).

P332+P313IF SKIN irritation occurs: Get medical advice/attention.

P362Take off contaminated clothing and wash before reuse.

ethyl 3-hydroxypicolinate Chemical Properties,Usage,Production

Synthesis

GENERAL STEPS: To a 1 L dry round bottom flask was added 3-hydroxy-2-pyridinecarboxylic acid (25 g, 179.5 mmol), 400 mL of anhydrous ethanol, and 100 mL of toluene, followed by the slow addition of 10 mL of concentrated sulfuric acid. The reaction mixture was stirred at reflux for 72 hours at 95 °C. Upon completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to 1/4 of the original volume. 600 mL of ethyl acetate and 200 mL of water were used to dilute the concentrate, and the aqueous layer was separated and subjected to a secondary extraction with 200 mL of ethyl acetate. The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (3 x 200 mL), saturated saline (200 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to afford 21.9 g of ethyl 3-hydroxypyridine-2-carboxylate (73% yield), which was used directly in the subsequent reaction without purification. The above ester product (21.9 g, 131 mmol) was dissolved in pyridine, cooled to -40 °C, and trifluoromethanesulfonic anhydride (48 g, 170 mmol) was added slowly and dropwise. The reaction mixture was stirred at 0 °C for 30 min, then raised to room temperature and continued stirring for 30 min. At the end of the reaction, the reaction was quenched by adding 100 mL of water. The reaction mixture was extracted with ethyl acetate (3 x 200 mL), the organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (200 mL), water (200 mL), saturated saline (200 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give 39 g of the target product (99% yield), which was directly used in the next reaction without further purification.1H NMR (300 MHz, CD2Cl2) δ 8.73 (dd, 1H), 7.72 (dd, 1H), 7.62 (dd, 1H), 4.46 (q, 2H), 1.42 (t, 3H).

References

[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 665 - 668
[2] Patent: US2005/192294, 2005, A1. Location in patent: Page/Page column 20-21
[3] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4702 - 4713
[4] Patent: WO2005/42538, 2005, A1. Location in patent: Page/Page column 15; 16
[5] MedChemComm, 2015, vol. 6, # 10, p. 1767 - 1772