Tetrabutylammonium Fluoride → N-[3-chloro-1-(3-pyridyl)pyrazol-4-yl]-N-ethyl-2-(2-oxopyrrolidin-3-yl)acetamide

HRID 929317Notes

Reaction equation

HRID 929317 reaction equation
[Si]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([N:16]([C:19]2[C:20]([Cl:30])=[N:21][N:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:23]=2)[CH2:17][CH3:18])=[O:15])[C:9]1=[O:31])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:30][C:20]1[C:19]([N:16]([CH2:17][CH3:18])[C:14](=[O:15])[CH2:13][CH:10]2[CH2:11][CH2:12][NH:8][C:9]2=[O:31])=[CH:23][N:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=1

Participants

4

Reactant 2

HCID 2724141Tetrabutylammonium FluorideHCID 1317351162-(1-(tert-Butyldimethylsilyl)-2-oxopyrrolidin-3-yl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide

Product 1

HCID 118023435N-[3-chloro-1-(3-pyridyl)pyrazol-4-yl]-N-ethyl-2-(2-oxopyrrolidin-3-yl)acetamideYield 44.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

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).

Workup

  1. customThe mixture carried through to the deprotection step without further purification
  2. additionadded
  3. concentrationThe reaction product was concentrated onto CELITE®
  4. custompurified by flash column chromatography

Sources & evidence

ORD record
ord-07c2078bf96a46a2b249e214f8fd0243
Source dataset
uspto-grants-2016_03
Patent number
US09295260B2

Reaction notes

Loading…