Hydroxyamine hydrochloride → Ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate
Reaction equation
CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:25]O>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:23][N:25]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=2)=[CH:10][CH:9]=1Participants
Procedure
In a further embodiment, an isoxazole cyclization reaction is provided in Scheme 15A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The isoxazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydroxylamine hydrochloride to provide ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol for about 2 hours. Ethyl 5-(4-fluorophenyl)-isoxazole-3-carboxylate is then reduced with lithium aluminum hydride to provide 5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the reduction is performed in THF, at a temperature of about 0° C. to about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde is then formed by oxidizing (5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Sources & evidence
- ORD record
- ord-e1e0335fa4b04205a261e01c3da6a7fc
- Source dataset
- uspto-grants-2016_02
- Patent number
- US09266873B2
Reaction notes
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