The general procedure for the synthesis of 2,3-difluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine from 2,3-difluoro-5-chloropyridine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was as follows:
1. In a 60 L jacketed reactor, 36.0 L (15 v/v) of 2-methyltetrahydrofuran (2-MeTHF) was added and the solution was sprayed by nitrogen bubbling for 1 ± 0.5 hr.
2. 36.7 g of Pd2(dba)3, 75.6 g of X-Phos, 259 g of tetrabutylammonium bromide, and 7,397 g of tripotassium phosphate were added, and nitrogen bubbling was continued for 1 ± 0.5 hr.
3. 3.6 L (1.5 v/v) of nitrogen-injected water was slowly added to the reaction, keeping the internal temperature at 20 ± 5 °C.
4. 2412 g of 5-chloro-2,3-difluoropyridine was added, followed by 83.8 g (1.15 eq.) of 1-methylpyrazole-4-boronic acid pinacol ester, and after nitrogen purge for 1 ± 0.5 hr, the reaction was ramped up to 70 ± 5 °C for at least 4 hr until conversion was >99%.
5. Cool to 20±5°C, add 12.0L 20% w/v sodium bisulfite solution, stir for 30 minutes and separate the aqueous phase.
6. Add 12.0L 0.5M potassium fluoride solution, stir for 30 minutes and separate the aqueous phase.
7. Add 12.0L of 25% w/v sodium chloride solution, stir for 30 minutes and separate the aqueous phase.
8. distill the organic phase to no more than 0.3% water remaining, maintaining a volume of 36L (15 vol), cool to 20°C and transfer.
9. Concentrate to about 9 volumes, add heptane, adjust to 15% 2-MeTHF:heptane mixture, cool to 20±5°C and stir until product concentration is 7 mg/mL.
10. The solution was washed with 10% 2-MeTHF:heptane and filtered through a 25 μm polypropylene filter cloth to obtain the target product.
