Dimethylacetamide → 2-Cyano-6-methoxyisonicotinic acid

Temperature

95 °C

Into an oven-dried microwave vial was added ethyl 2-chloro-6-methoxyisonicotinate (0.6 g, 2.78 mmol), zinc cyanide (392 mg, 3.34 mmol), zinc dust (36.4 mg, 0.2 mmol) and N,N-dimethylacetamide (10 mL). The vial was capped, evacuated, and filled with nitrogen. This process was repeated 3 times. Then the cap of the vial was removed and bis(tri-t-butylphosphine)palladium(0) (142 mg, 0.278 mmol) was added. The vial was capped again, evacuated, and filled with nitrogen (3×). The reaction mixture was heated to 95° C. and left stirring for 18 h. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through Celite. The filtrate was poured into a saturated aqueous solution of sodium bicarbonate (100 mL). Then the mixture was extracted with ethyl acetate (50 mL×3). The combined organics were washed with a saturated aqueous solution of ammonium chloride, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified via flash chromatography to afford 2-cyano-6-methoxyisonicotinic acid (260 mg, 45.3%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 3H), 4.01 (s, 3H), 4.43 (s, 2H), 7.53 (s, 1H), 7.82 (s, 1H).

1. customThe vial was capped
2. customevacuated
3. additionfilled with nitrogen
4. customThen the cap of the vial
5. customwas removed
6. customThe vial was capped again
7. customevacuated
8. additionfilled with nitrogen (3×)
9. waitleft
10. additionThe reaction mixture was diluted with ethyl acetate (100 mL)
11. filtrationfiltered through Celite
12. additionThe filtrate was poured into a saturated aqueous solution of sodium bicarbonate (100 mL)
13. extractionThen the mixture was extracted with ethyl acetate (50 mL×3)
14. washThe combined organics were washed with a saturated aqueous solution of ammonium chloride
15. washwashed with brine
16. dry with materialdried over sodium sulfate
17. customThe solvent was removed under reduced pressure
18. customthe residue was purified via flash chromatography

ORD record

ord-b1ab5088b4ec430cbd7238b196b4230e

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296745B2