Potassium Carbonate → tert-butyl(2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

HRID 1412982Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1412982
[CH3:1][O:2][C:3](=[O:49])[NH:4][C@@H:5]([CH:46]([CH3:48])[CH3:47])[C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:14][CH3:15])[CH2:10][C@H:9]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]1[C:29]2[C:34]([CH2:35][O:36][C:23]=1[CH:22]=3)=[CH:33][C:32](B1OC(C)(C)C(C)(C)O1)=[CH:31][CH:30]=2)=[O:7].Br[C:51]1[NH:55][C:54]([C@@H:56]2[CH2:60][CH2:59][CH2:58][N:57]2[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:14]([O:13][C@@H:11]1[CH2:12][N:8]([C:6](=[O:7])[C@H:5]([CH:46]([CH3:47])[CH3:48])[NH:4][C:3]([O:2][CH3:1])=[O:49])[C@H:9]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32]([C:51]2[NH:55][C:54]([C@@H:56]4[CH2:60][CH2:59][CH2:58][N:57]4[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=2)=[CH:31][CH:30]=3)[CH2:10]1)[CH3:15]

Komponenten

8

Edukt 3

HCID 11430Potassium CarbonateHCID 56605192tert-Butyl (2S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylateHCID 178468187methyl [(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate

Produkt 1

HCID 178468190tert-butyl(2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylateAusbeute 33,7 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 6228DimethylformamideLösungsmittelHCID 80711,2-DimethoxyethaneLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

To a solution of methyl[(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate (0.41 g, 0.61 mmol) in a mixture of DME (6.1 mL) and DMF (1.0 mL) was added (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.39 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 1.0 mL, 2.0 mmol). The solution was degassed with argon for 5 min and heated, with stirring, to 85° C. for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford tert-butyl(2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (0.16 g, 33%).

Aufarbeitung

  1. customThe solution was degassed with argon for 5 min
  2. temperatureheated
  3. temperatureThe solution was cooled to room temperature
  4. additiondiluted with EtOAc
  5. washThe organic layer was washed with water and brine
  6. dry with materialThe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated under reduced pressure
  8. customThe crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/Hexanes to 80% MeOH/EtOAc)

Quellen und Nachweise

ORD-Eintrag
ord-38db7101f97a4dc2b6d19e0ebb6b620a
Quelldatensatz
uspto-grants-2014_12
Patentnummer
US08921341B2

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