Ethyl isobutyrate → HCID 90011193, compound

To a freshly prepared solution of lithium diisopropyl amide (prepared by the addition of n-butyl lithium (12.27 mL, 19.63 mmol) to a solution of diisopropylamine (2.80 mL, 19.63 mmol) in THF (20 mL)) at −78° C., was drop-wise added a solution of ethyl isobutyrate (2.21 mL, 16.36 mmol) in THF (10 mL). The resulting mixture was stirred at the same temperature for 1 h and then the above prepared solution of 1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbonyl chloride (5.80 g, 16.36 mmol) in THF (20 mL) was drop-wise added. The resulting mixture was stirred at −78° C. for 30 min, then gradually warmed to room temperature over 1 h and then stirred for another 1 h at room temperature. The reaction was cooled to 0° C. and then quenched with saturated ammonium chloride solution (20 mL) and then diluted with ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (10% ethyl acetate in hexanes as eluent) to afford 2.50 g (35%) of the title compound as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.58 (d, J=2.0 Hz, 1H), 8.02 (dd, J=2.0 & 8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 4.11 (q, J=7.0 Hz, 2H), 1.60 (s, 3H), 1.58 (s, 3H), 1.04 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 434, 436 [(MH)+Br79,81].

1. stirringThe resulting mixture was stirred at −78° C. for 30 min
2. stirringstirred for another 1 h at room temperature
3. temperatureThe reaction was cooled to 0° C.
4. customquenched with saturated ammonium chloride solution (20 mL)
5. additiondiluted with ethyl acetate (100 mL)
6. customThe layers were separated
7. extractionthe aqueous layer was extracted with ethyl acetate (2×50 mL)
8. washThe combined organic layers were washed with brine (50 mL)
9. dry with materialdried (Na2SO4)
10. filtrationfiltered
11. customThe filtrate was rotary evaporated
12. customthe crude product was purified by flash column chromatography (10% ethyl acetate in hexanes as eluent)

ORD record

ord-ed5d59f59249431cb627c5abd0387a92

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09409898B2