Formic Acid → 2-Chloro-5-fluoronicotinic acid

Temperature

0 °C

To a round-bottomed flask under a N2 atmosphere were added degassed DMF (270 mL), Pd(OAc)2 (0.05 eq, 2.7 g, 11.9 mmol), PPh3 (0.1 eq, 6.2 g, 23.8 mmol) and degassed Et3N (6 eq, 200 mL, 1428.6 mmol). The mixture was stirred 20 minutes then HCOOH (3 eq, 28 mL, 714.3 mmol) was added followed after 5 minutes by 2,6-dichloro-5-fluoronicotinic acid (50 g, 238.1 mmol) and the mixture was stirred at 50° C. The reaction was followed by analysis (1H NMR) of a worked-up aliquot. When all starting material was consumed (24 h), the mixture was cooled to 0° C. and water (500 mL) was added. After 20 minutes, The mixture was filtered through a pad of Celite that was rinsed with water. The mixture was basified to pH 9 with 30% aq. NaOH and washed with EtOAc (2×). HCl (12 N) was added slowly to pH 1 and the solution was saturated with NaCl. The mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give 37 g (88%) of a beige solid used in the next step without further purification.

1. additionTo a round-bottomed flask under a N2 atmosphere were added
2. stirringthe mixture was stirred at 50° C
3. customWhen all starting material was consumed (24 h)
4. additionwater (500 mL) was added
5. waitAfter 20 minutes
6. filtrationThe mixture was filtered through a pad of Celite that
7. washwas rinsed with water
8. washwashed with EtOAc (2×)
9. additionHCl (12 N) was added slowly to pH 1
10. extractionThe mixture was extracted with EtOAc (3×)
11. washThe combined organic extracts were washed with brine
12. dry with materialdried (Na2SO4)
13. concentrationconcentrated under reduced pressure

ORD record

ord-4e7cbf82797a4cd780ca454158877810

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08426425B2