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

HRID 442Notes

Reaction equation

HRID 442 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 65.89%

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 (18:00) for 15 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 (173 mg, 65.9 %) as a clear yellow foam. LCMS and NMR are OK.

Sources & evidence

ORD record
ord-e9a88816e360448bba740f2afb6125ad
Source dataset
750 AstraZeneca ELN dataset
Original link
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Reaction notes

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