1-Bromo-3,5-difluorobenzene → methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate

HRID 441Notes

Reaction equation

HRID 441 reaction equation
COC(=O)c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1.Fc1cc(F)cc(Br)c1>C1COCCO1.CC(=O)O.CC(=O)O.CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21.O=C([O-])[O-].[Cs+].[Cs+].[Pd]>COC(=O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1

Participants

7

Reactant 2

HCID 1363131-Bromo-3,5-difluorobenzeneHCID 86672405methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate

Product 1

HCID 86672406methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylateYield 52.18%

Reagents, catalysts & solvents 4

HCID 10796Cesium carbonateReagentHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 4144353Palladium (II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

diacetoxypalladium (6.26 mg, 0.03 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (200 mg, 0.56 mmol), 1-bromo-3,5-difluorobenzene (0.080 ml, 0.70 mmol) and cesium carbonate (273 mg, 0.84 mmol) dissolved in 1,4-dioxane (8 ml). The resulting suspension was degased with argon and then stirred at 100 °C (15:00) for 18 hours. The reaction mixture was allowed to cool to room temperature, filtered and concentrated. The crude product was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (137 mg, 52.2 %) as a clear yellow foam. LCMS and NMR are OK.

Sources & evidence

ORD record
ord-e061647f5f0c433f84efb82229734131
Source dataset
750 AstraZeneca ELN dataset
Original link
View source

Reaction notes

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