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

반응식

HRID 1910028 반응식
[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]

참가 물질

8

반응물 4

HCID 10796Cesium carbonateHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 49761741Potassium benzyl N-[2-(trifluoroboranuidyl)ethyl]carbamateHCID 66823868bis(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

생성물 1

HCID 66823788bis(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}imidodicarbonate수율 60.1%

시약·촉매·용매 3

HCID 167845palladium(II) acetate촉매HCID 962Water용매HCID 1140Toluene용매

반응 조건

온도
95 °C

실험 절차

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]+.

후처리

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

출처 및 근거

ORD 기록
ord-aa42297d1a0a4bf5915ad603909f3a57
출처 데이터셋
uspto-grants-2013_12
특허 번호
US08598156B2

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