Acetic Acid → (3-(4-fluorophenyl)-1H-pyrazol-5-yl)methanol

HRID 1777415Notes

Reaction equation

HRID 1777415 reaction equation
C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17](OCC)=[O:18])[NH:14][N:13]=2)=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:16]=[C:15]([CH2:17][OH:18])[NH:14][N:13]=2)=[CH:10][CH:11]=1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 583549Ethyl 3-(4-fluorophenyl)-1h-pyrazole-5-carboxylateHCID 21226445Aluminium lithium hydride

Product 1

HCID 49756939(3-(4-fluorophenyl)-1H-pyrazol-5-yl)methanol

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

In a further embodiment, a pyrazole cyclization reaction is provided in Scheme 14A. 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 pyrazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydrazine hydrate to provide ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol and glacial acetic acid for about 2 to 16 hours. Ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate is then reduced with lithium aluminum hydride to provide 3-(4-fluorophenyl)-1H-pyrazol-5-yl-methanol. In one embodiment, the reduction is performed in THF at a temperature of about 0° C. to about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde is then formed by oxidizing 3-(4-fluorophenyl)-1H-pyrazole-5-methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.

Sources & evidence

ORD record
ord-794821120fe2483f9a65092f6d0707f3
Source dataset
uspto-grants-2016_02
Patent number
US09266873B2

Reaction notes

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