Carbon Dioxide → 4-Chloro-5-cyclopropylpicolinic acid

Temperature

-15 °C

To a solution of N,N-Dimethylethanolamine (CAN 108-01-0, 1.89 g, 2.13 ml, 21.2 mmol) in dry Hexane (40 ml) under an argon atmosphere at −15° C. was slowly added BuLi 1.6M in Hexane (26.4 ml, 42.3 mmol). The reaction mixture was stirred at −15° C. for 15 minutes, then reaction mixture was cooled down to −78° C. followed by addition of a solution of 4-chloro-3-cyclopropylpyridine (Example 48a, 1.3 g, 8.46 mmol) in dry toluene (9 ml). The resulting reaction mixture was stirred at −78° C. for 1 hour. Addition of carbon dioxide (3.72 g, 84.6 mmol) (pellets from a dry ice dispenser) into the mixture. The reaction mixture was let to warm up to −15° C. and kept at −15° C. for 1 hour. The reaction was quenched by addition of water and stirred at r.t for 15 min. The reaction mixture was diluted with ethyl acetate, poured into a separatory funnel and extracted with 4.0M aqueous solution hydrochloric acid (21.2 ml, 84.6 mmol). The organic phase was collected and the aqueous was back-extracted twice with ethylacetate. All organic phases were combined, dried over sodium sulfate and evaporated down to dryness to give a yellow oil. The former oil was dissolved in diethylether which gave a white suspension. The suspension was kept at 0° C. for few hours. The precipitate was collected by filtration, dried under high vacuum to yield the title compound (886 mg, 53%) as a white solid. MS (ESI, m/z): 196.0 (M−H+).

1. customat −15° C.
2. customreaction mixture
3. temperaturewas cooled down to −78° C.
4. customThe resulting reaction mixture
5. stirringwas stirred at −78° C. for 1 hour
6. temperatureto warm up to −15° C.
7. waitkept at −15° C. for 1 hour
8. customThe reaction was quenched by addition of water
9. stirringstirred at r.t for 15 min
10. additionThe reaction mixture was diluted with ethyl acetate
11. additionpoured into a separatory funnel
12. customThe organic phase was collected
13. extractionthe aqueous was back-extracted twice with ethylacetate
14. dry with materialdried over sodium sulfate
15. customevaporated down to dryness
16. customto give a yellow oil
17. customgave a white suspension
18. waitThe suspension was kept at 0° C. for few hours
19. filtrationThe precipitate was collected by filtration
20. customdried under high vacuum

ORD record

ord-c3f1c280eb74404c9b13a6691e21103d

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09409866B2