Morpholine → 4-Fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester

HRID 2229573Notes

Reaction equation

C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14](Br)[C:13]([F:17])=[CH:12][C:11]=1[O:18][CH3:19].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:7][O:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:13]([F:17])=[CH:12][C:11]=1[O:18][CH3:19]

Participants

Conditions

Temperature: 100 °C

Procedure

In a flame-dried flask, under a nitrogen atmosphere, oven-dried cesium carbonate (4.33 g, 13.3 mmol) was combined with palladium acetate (85.3 mg, 0.380 mmol) and R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.355 g, 0.570 mmol). While under a constant nitrogen flow, the mixture was dissolved in toluene (0.76 mL) and treated with 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (2.50 g, 9.50 mmol) and morpholine (0.995 mL, 11.4 mmol). After being heated to 100° C. for 24 h, the reaction was cooled to room temperature, diluted with ether, filtered and concentrated. Purification by MPLC (ethyl acetate in heptane) provided 4-fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (1.20 g, 47%): 1H NMR (DMSO-d6 300 MHz) δ 7.33 (d, J=9.9 Hz, 1H), 7.08 (d, J=14.4 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.70 (t, J=4.7 Hz, 4H), 2.90 (t, J=4.5 Hz, 4H).

Workup

temperaturethe reaction was cooled to room temperature
filtrationfiltered
concentrationconcentrated
customPurification by MPLC (ethyl acetate in heptane)

Sources & evidence

ORD record: ord-ce9abf2d059f405cba790101c8ce9a00
Source dataset: uspto-grants-2002_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06420426B1

Reaction notes

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