Hydrochloric Acid → 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Temperature

15 °C

To a mixture of 2,3-dimethylbutane-2,3-diol (25.0 kg, 211.6 mol) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24, 55.0 kg, 206.7 mol) in 1,2-dichloroethane (750 kg) was slowly added a solution of HCl in MTBE (25.0 kg, 20-30% of HCl) at 0-5° C. The resulting reaction mixture was then stirred at 10-20° C. for 3-5 hours. After the selective deprotection reaction was complete as monitored by HPLC (1: below 1%), the reaction mixture was degassed and refilled with nitrogen before being cooled to −15° C. The cooled reaction mixture was then added triethylamine (TEA, 30.0 kg, 296.5 mol) to adjust pH to 7-8. The mixture was then gradually warmed to ambient temperature before being treated with water (150 kg). The two phases were separated and the organic layer was washed with brine (60 kg) and dried over sodium sulfate (Na2SO4). The drying reagent, sodium sulfate (Na2SO4), was removed by filtration and the resulting solution was concentrated under reduced pressure at 40-50° C. to a thick oil. The residue was warmed to 60-70° C. and diluted with petroleum ether (100 kg) at the same temperature. The resulting mixture was then gradually cooled to ambient temperature and subsequently to −5° C. and stirred at the same temperature for 3 hours. The solids was collected by centrifugation and dried at 50-60° C. under vacuum to afford the crude desired product (1, 33.75 kg, 40.11 kg theoretical, 84.1%). The crude desired product was then suspended in 1,2-dichloroethane (30 kg) and the resulting mixture was heated to reflux until a clear solution was formed. To the hot solution was then added petroleum ether (150 kg) at the same temperature. The resulting mixture was then gradually cooled to ambient temperature and subsequently to −5° C. and stirred and the same temperature for 3 hours. The solids were collected by centrifugation and dried under vacuum at 50-60° C. to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 31.0 kg, 40.11 kg theoretical, 77.3%) as an off-white solid, which is identical in every comparable aspect to the material synthesized by the synthetic method as described above in Example 5.

1. customThe resulting reaction mixture
2. customAfter the selective deprotection reaction
3. customthe reaction mixture was degassed
4. additionrefilled with nitrogen
5. temperaturebefore being cooled to −15° C
6. customThe cooled reaction mixture
7. temperatureThe mixture was then gradually warmed to ambient temperature
8. customThe two phases were separated
9. washthe organic layer was washed with brine (60 kg)
10. dry with materialdried over sodium sulfate (Na2SO4)
11. customThe drying reagent, sodium sulfate (Na2SO4), was removed by filtration
12. concentrationthe resulting solution was concentrated under reduced pressure at 40-50° C. to a thick oil
13. temperatureThe residue was warmed to 60-70° C.
14. additiondiluted with petroleum ether (100 kg) at the same temperature
15. temperatureThe resulting mixture was then gradually cooled to ambient temperature and subsequently to −5° C.
16. stirringstirred at the same temperature for 3 hours
17. customThe solids was collected by centrifugation
18. customdried at 50-60° C. under vacuum
19. customto afford the crude desired product (1, 33.75 kg, 40.11 kg theoretical, 84.1%)
20. temperaturethe resulting mixture was heated
21. temperatureto reflux until a clear solution
22. customwas formed
23. temperatureThe resulting mixture was then gradually cooled to ambient temperature and subsequently to −5° C.
24. stirringstirred
25. waitthe same temperature for 3 hours
26. customThe solids were collected by centrifugation
27. customdried under vacuum at 50-60° C.

ORD record

ord-2f4c9494561343cc85d55569f38ef8f3

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09221845B2