Cesium carbonate → bis(1,1-dimethylethyl) {3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-({[(phenylmethyl)oxy]carbonyl}amino)ethyl]furo[3,2-c]pyridin-4-yl}imidodicarbonate

HRID 1910028

Reaction equation

[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:27][CH:28]=[C:29](I)[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[CH2:46]([O:53][C:54](=[O:62])[NH:55][CH2:56][CH2:57][B-](F)(F)F)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[K+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:27][CH:28]=[C:29]([CH2:57][CH2:56][NH:55][C:54]([O:53][CH2:46][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)=[O:62])[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]

Participants

Conditions

Temperature: 95 °C

Procedure

A mixture of bis(1,1-dimethylethyl) (3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-yl)imidodicarbonate (302 mg, 0.413 mmol), potassium benzyl-N-[2-(trifluoroboranuidyl)ethyl]carbamate (90 mg, 0.316 mmol), palladium(II) acetate (9 mg, 0.040 mmol), RuPhos (38 mg, 0.081 mmol), and cesium carbonate (403 mg, 1.237 mmol) in Toluene (3 mL) and Water (1 mL) was degassed with Nitrogen for 10 minutes. The 25 mL vial was then capped and it was stirred vigorously at 95° C. for 16 hours. LCMS showed complete consumption of starting material and good conversion to the desired product, along with a 23% peak corresponding to the de-iodo byproduct. It was cooled, diluted with ethyl acetate (15 mL), and washed with a mixture of water (5 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous phase was back-extracted with EtOAc (15 mL), and the combined organic phases were washed with brine (1×15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 40 g SiO2, 5%-70% EtOAc in hexanes gradient over 55 minutes) to give bis(1,1-dimethylethyl) {3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-({[(phenylmethyl)oxy]carbonyl}amino)ethyl]furo[3,2-c]pyridin-4-yl}imidodicarbonate (149 mg, 0.190 mmol, 46.1% yield) as an off-white foam. LC/MS (ES) m/z=783.9 [M+H]+.

Workup

customwas degassed with Nitrogen for 10 minutes
customThe 25 mL vial was then capped
customconsumption of starting material and good conversion to the desired product
temperatureIt was cooled
additiondiluted with ethyl acetate (15 mL)
washwashed with a mixture of water (5 mL) and saturated aqueous NaHCO3 (10 mL)
extractionThe aqueous phase was back-extracted with EtOAc (15 mL)
washthe combined organic phases were washed with brine (1×15 mL)
dry with materialdried (Na2SO4)
filtrationfiltered
concentrationconcentrated in vacuo
customThe residue was purified by flash chromatography (Analogix, 40 g SiO2, 5%-70% EtOAc in hexanes gradient over 55 minutes)

Sources & evidence

ORD record: ord-aa42297d1a0a4bf5915ad603909f3a57
Source dataset: uspto-grants-2013_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08598156B2

Linked notes

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