Hydrochloric Acid → 6-Acetamido-4-(trifluoromethyl)pyridin-3-ylboronic acid

Temperature

2 °C

To a suspension of Lithium amide (5.6 g, 233.2 mmol) in 140 ml THF was added at room temperature 2-propanol (1.3 g, 21.2 mmol). The reaction mixture was cooled to IT=2° C. A solution of B2 (60.0 g, 212 mmol) in 280 ml THF was added while keeping the temperature at IT 2° C. The reaction mixture was stirred at IT=2° C. for 90 min. THF (240 ml) was added and solvent (˜380 ml) was removed by distillation. THF (360 ml) was added and solvent (˜380 ml) was removed by distillation. THF (200 ml) was added and the reaction mixture was cooled to IT=−85° C. A solution (76 ml, 190 mmol) nBuLi, 2.5 M in hexane was added at −85° C. followed by addition of a solution of triisopropylborate (31.9 g, 170 mmol) in THF (17 ml). A solution (17.3 ml, 43.3 mmol) n BuLi, 2.5 M in hexane was added at −85° C. followed by addition of a solution of triisopropylborate (23.9 g, 127 mmol) in THF (13 ml). The reaction mixture was allowed to warm to RT and was stirred over night at RT. Water (15.3 g) and HCl in 2-propanol, 5-6 M (36.7 g) was added at RT. Isopropylacetate (480 ml) was added and solvent was removed by distillation until a volume of ˜360 ml was obtained. Isopropylacetate (480 ml) was added and solvent was removed by distillation until a volume of ˜360 ml was obtained. Isopropylacetate (480 ml) was added and the mixture was cooled to IT=0° C. Water (480 g) was added and by addition of 1N NaOH the pH was adjusted at IT=0° C. to pH 11. The precipitate was removed by filtration. The aquoeus layer was separated at IT=0° C. Water was added and the aquoeus layer was separated at IT=0° C. The combined aquoues layers were cooled to IT=0° C. and the pH was adjusted by addition of 1 N HCl to pH 3. The precipitate was collected and the dried at 30° C./40-45 mbar until constant weight was obtained. 48.9 g (93%) 6-acetamido-4-(trifluoromethyl)pyridin-3-ylboronic acid B3 were obtained.

1. customat IT 2° C
2. customsolvent (˜380 ml) was removed by distillation
3. additionTHF (360 ml) was added
4. customsolvent (˜380 ml) was removed by distillation
5. additionTHF (200 ml) was added
6. temperaturethe reaction mixture was cooled to IT=−85° C
7. temperatureto warm to RT
8. stirringwas stirred over night at RT
9. customsolvent was removed by distillation until a volume of ˜360 ml
10. customwas obtained
11. customsolvent was removed by distillation until a volume of ˜360 ml
12. customwas obtained
13. temperaturethe mixture was cooled to IT=0° C
14. customwas adjusted at IT=0° C. to pH 11
15. customThe precipitate was removed by filtration
16. customThe aquoeus layer was separated at IT=0° C
17. additionWater was added
18. customthe aquoeus layer was separated at IT=0° C
19. temperatureThe combined aquoues layers were cooled to IT=0° C.
20. additionthe pH was adjusted by addition of 1 N HCl to pH 3
21. customThe precipitate was collected
22. customthe dried at 30° C./40-45 mbar until constant weight
23. customwas obtained

ORD record

ord-8960f59fb45e415ba184c84f00e85bb9

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09359326B2