Diisopropylethylamine → 2-(1-(tert-Butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide

Participants

Reaction Conditions

Reaction Steps

DIPEA (0.629 mL, 4.41 mmol) was dissolved in THF (20 mL) and cooled to about −78° C. n-Butylithium (1.77 mL, 4.41 mmol) was then added, and the reaction mixture was warmed to about 0° C. for 10 minutes, then re-cooled to about −78° C. Then, 1-(tert-butyldimethylsilyl)pyrrolidin-2-one (0.800 g, 4.01 mmol) was added, and the reaction mixture was warmed to 23° C. and stirred for 1 hour. The reaction was then re -chilled to −78° C., and 2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.600 g, 2.01 mmol) was then added dropwise as a solution in THF (3 mL). The reaction mixture was stirred cold for 30 minutes, then was allowed to slowly warm to room temperature. After 1 hour, the reaction was quenched with a NH4Cl solution and extracted with diethyl ether. The organics were washed with brine, dried over Na2SO4, and concentrated. The resulting oil was purified by flash column chromatography using 0-40% acetone/hexanes as eluent provided the intermediate 2-(1-(tert -butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.604 g, 1.31 mmol). 1H NMR analysis indicated a mixture of molecules present favoring the desired product of about 5:1 over main byproduct. The mixture carried through to the deprotection step without further purification. 2-(1-(tert-Butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (0.604 g, 1.31 mmol) was dissolved in THF (13 mL) and added was tetrabutylammonium fluoride (TBAF, 1.96 mL, 1.96 mmol). The reaction mixture was stirred for 30 minutes. The reaction product was concentrated onto CELITE® and purified by flash column chromatography using 40-100% acetone/hexanes as eluent providing the title compound (0.204 g, 30% over 2 steps).

Provenance & Evidence