The general procedure for the synthesis of 2-chloro-5-fluoronicotinic acid from 2,6-dichloro-5-fluoropyridine-3-carboxylic acid is as follows:
1. Synthesis of the intermediate 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine:
- Reagents and conditions:
i. Pd(OAc)2, PPh3, Et3N, HCOOH.
ii. 1) (COCl)2, CH2Cl2, catalytic amount of DMF; 2) NH3(g), Dioxane; iii.
iii. TFAA, Et3N, CH2Cl2, 0 °C.
H2NNH2-H2O, n-butanol, reflux. iv.
2. Synthesis of 2-chloro-5-fluoronicotinic acid (6):
- Degassed DMF (270 μL), 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) were added to a round-bottomed flask under N2 atmosphere.
- The mixture was stirred for 20 min and then HCOOH (3 eq, 28 mL, 714.3 mmol) was added.
- After 5 min, 2,6-dichloro-5-fluoronicotinic acid (50 g, 238.1 mmol) was added.
- The mixture was stirred at 50 °C and the progress of the reaction was monitored by 1H NMR analysis.
- When all ingredients were 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 diatomaceous earth pad and rinsed with water.
- The mixture was alkalized to pH 9 with 30% NaOH aqueous solution and then washed with EtOAc (2x).
- 12N HCl was added slowly to pH 1 and treated with a saturated solution of NaCl.
- The mixture was extracted with EtOAc (3x), the organic phases were combined, washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give 37 g (88% yield) of a beige solid, which could be used in the next step without further purification.
- 1H NMR (DMSO-d6, 300MHz): δ 8.16 (dd, 1H); 8.58 (d, 1H).
