3,5-Difluoroaniline → 8-[(1R)-1-(3,5-difluoroanilino)ethyl]-N,N-dimethyl-2-morpholin-4-yl-4-oxochromene-6-carboxamide

HRID 572750Notes

Reaction equation

Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH:11][C:10]2=[O:21])[CH3:4].[F:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([F:35])[CH:34]=1)[NH2:31]>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([NH:31][CH:3]([C:5]2[CH:6]=[C:7]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:8]=[C:9]3[C:14]=2[O:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]3=[O:21])[CH3:4])[CH:32]=[C:33]([F:35])[CH:34]=1

Participants

Conditions

Temperature: 50 °C

Procedure

To a suspension of 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (3.63 g, 7.41 mmol, as described in Example 3.03) in DMF (35 mL) under nitrogen was added 3,5-difluoroaniline (3.82 g, 29.62 mmol). The resulting yellow solution was stirred at 50° C. for 5 hrs. The reaction mixture was concentrated to dryness, then purified by flash chromatography on silica gel eluting with 1 to 7% methanol in DCM. The solvent was evaporated to dryness to afford 8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.32 g, 68.5%) as a pale yellow solid. Mass Spectrum: M+H+ 458. NMR Spectrum: (DMSOd6) 1.52 (d, 3H), 2.74 (s, 3H), 2.95 (s, 3H), 3.50-3.64 (m, 4H), 3.70-3.79 (m, 4H), 4.97-5.05 (m, 1H), 5.60 (m, 1H), 6.15 (dd, 2H), 6.22 (tt, 1H), 6.96 (d, 1H), 7.54 (d, 1H), 7.81 (d, 1H).

Workup

concentrationThe reaction mixture was concentrated to dryness
custompurified by flash chromatography on silica gel eluting with 1 to 7% methanol in DCM
customThe solvent was evaporated to dryness

Sources & evidence

ORD record: ord-ab8fb6ebaa3a4775b1019a093f578e13
Source dataset: uspto-grants-2015_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09029374B2

Reaction notes

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