Ethyl Acetoacetate → Methyl 4-(2-(ethoxycarbonyl)-3-oxobutyl)-3-fluorobenzoate

HRID 1617159Notes

Reaction equation

[H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[F:24]>C1COCC1>[CH2:10]([O:9][C:3]([CH:4]([C:5](=[O:6])[CH3:7])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[F:24])=[O:8])[CH3:11]

Participants

Conditions

Temperature: 0 °C

Procedure

Sodium hydride (60% dispersion in mineral oil; 2.45 g) was added portionwise over 10 min to a solution of ethyl acetoacetate (7.5 mL) in THF (60 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 10 min and a solution of methyl 4-(bromomethyl)-3-fluorobenzoate (12.1 g) in THF (40 mL) added over 10 min. The mixture was heated to 65° C. for 15 h and allowed to cool. The mixture was poured cautiously into ice/water (300 mL) and the aqueous extracted with EtOAc. The combined organic phase was dried, filtered and evaporated. The crude product was purified by chromatography eluting with to 20% EtOAc in isohexane to give the subtitle compound as a colorless oil 11.10 g.

Workup

temperatureThe mixture was heated to 65° C. for 15 h
temperatureto cool
extractionthe aqueous extracted with EtOAc
customThe combined organic phase was dried
filtrationfiltered
customevaporated
customThe crude product was purified by chromatography
washeluting with to 20% EtOAc in isohexane

Sources & evidence

ORD record: ord-ca1c8d5b72584366a8963eff21742650
Source dataset: uspto-grants-2014_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08765939B2

Reaction notes

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