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

HRID 596

Reaction equation

HRID 596 reaction equation
CN(C)C(=O)c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1.Fc1cc(F)cc(Br)c1>C1COCCO1.CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21.CC1(C)c2cccc([PH+](c3ccccc3)c3ccccc3)c2Oc2c([PH+](c3ccccc3)c3ccccc3)cccc21.Fc1c[c-]cc(F)c1.O=C([O-])[O-].[Br][Pd+].[Cs+].[Cs+]>CN(C)C(=O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1

Participants

7

Reactant 2

HCID 1363131-Bromo-3,5-difluorobenzeneHCID 86672428N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide

Product 1

HCID 665592438-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamideYield 33.8%

Reagents, catalysts & solvents 4

HCID 10796Cesium carbonateReagentHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 178418186HCID 178418186, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Pd complexe (2.96 mg, 3.37 µmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (25 mg, 0.07 mmol), 1-bromo-3,5-difluorobenzene (8.53 µl, 0.07 mmol) and cesium carbonate (32.9 mg, 0.10 mmol) dissolved in 1,4-dioxane (0.5 ml) under argon. The resulting suspension was degased with argon and then stirred at 80 °C for 3.5 hours. Lcms showed complete reaction. The reaction mixture was allowed to cool to room temperature, filtered and concentrated. The crude product was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (11.00 mg, 33.8 %) as a pale beige foam. LCMS and NMR are OK

Sources & evidence

ORD record
ord-c1f0d60afc5d442f82c1963456675035
Source dataset
750 AstraZeneca ELN dataset
Original link
View source

Linked notes

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