Potassium Hydroxide → 6-Bromo-7-fluoro-3-morpholinoquinolin-2-amine

HRID 1029018Notes

Reaction equation

[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[N:9])[CH2:3][CH2:2]1.[OH-].[K+].[NH2:12][C:13]1[CH:20]=[C:19]([F:21])[C:18]([Br:22])=[CH:17][C:14]=1[CH:15]=O>CS(C)=O.O.[NH4+].[Cl-]>[Br:22][C:18]1[CH:17]=[C:14]2[C:13](=[CH:20][C:19]=1[F:21])[N:12]=[C:8]([NH2:9])[C:7]([N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[CH:15]2

Participants

Conditions

Temperature: 80 °C

Procedure

To a solution of 2-morpholinoacetonitrile (1.29 g, 10.26 mmol) in DMSO (13 mL) was added aqueous KOH (11.7 M, 0.276 mL, 3.23 mmol). The reaction was heated at 80° C., and a solution of 2-amino-5-bromo-4-fluorobenzaldehyde (1.41 g, 6.45 mmol) in DMSO (13 mL) was added dropwise over 2.5 h. The reaction mixture was stirred at 80° C. for 14 h. It was then cooled to RT and diluted with water (200 mL) and saturated NH4Cl (5 mL). The aqueous phase was extracted with DCM (2×200 mL). The organic fractions were combined, washed with half-saturated brine (4×300 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (150 mL) which had been deactivated with TEA (15 mL) eluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N to afford 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine.

Workup

temperatureIt was then cooled to RT
extractionThe aqueous phase was extracted with DCM (2×200 mL)
washwashed with half-saturated brine (4×300 mL)
dry with materialdried over sodium sulfate
concentrationconcentrated
customThe residue was purified by column chromatography on silica gel (150 mL) which
washeluting with 75:25:1:0.5 EtOAc/hexane/MeOH/Et3N

Sources & evidence

ORD record: ord-fc8e7c403208483982d3c9fb819a88aa
Source dataset: uspto-grants-2014_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08735384B2

Reaction notes

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