(3-Chloro-2-fluorophenyl)hydrazine → 4-(6-chloro-3-ethyl-7-fluoro-1H-indol-2-yl)-2-hydroxy-benzoic acid methyl ester

HRID 1160795Notes

Reaction equation

[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][CH3:13])=[CH:6][C:5]=1[OH:15].[Cl:17][C:18]1[C:19]([F:26])=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:24][C:20]3[C:21]([C:11]=2[CH2:12][CH3:13])=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=3[F:26])=[CH:6][C:5]=1[OH:15]

Participants

Conditions

Temperature: 120 °C

Procedure

A mixture of 4-butyryl-2-hydroxy-benzoic acid methyl ester (60 mg, 0.27 mmol), (3-chloro-2-fluoro-phenyl)-hydrazine (Apollo Scientific, Ltd., 54 mg, 0.27 mmol), and zinc chloride (110 mg, 0.8 mmol) in acetic acid (2 mL) is purged with nitrogen for 5 minutes and then heated in a sealed tube at 120° C. for 2 hours. The mixture is cooled to room temperature and diluted with ethyl acetate. The resulting mixture is sequentially washed with saturated aqueous Na2CO3 and saturated aqueous NaCl, and finally dried over sodium sulfate. After concentration, the crude product is purified via silica gel flash column chromatography (10% ethyl acetate in hexanes) to afford 4-(6-chloro-3-ethyl-7-fluoro-1H-indol-2-yl)-2-hydroxy-benzoic acid methyl ester as a light yellow solid: ESMS m/z 348.1 (M+H+).

Workup

customis purged with nitrogen for 5 minutes
temperatureThe mixture is cooled to room temperature
additiondiluted with ethyl acetate
washThe resulting mixture is sequentially washed with saturated aqueous Na2CO3 and saturated aqueous NaCl
dry with materialfinally dried over sodium sulfate
concentrationAfter concentration
customthe crude product is purified via silica gel flash column chromatography (10% ethyl acetate in hexanes)

Sources & evidence

ORD record: ord-c96e38f34770433eaef37cda5194a561
Source dataset: uspto-grants-2010_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07816542B2

Reaction notes

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