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

HRID 1431801Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1431801
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[C:41]4[C:17](=[C:18]5[C:38](=[CH:39][CH:40]=4)[C:22]4[N:23]=[C:24]([C@@H:26]6[CH2:30][CH2:29][CH2:28][N:27]6[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:25][C:21]=4[CH:20]=[CH:19]5)[O:16][CH2:15][C:13]=3[CH:14]=2)O1.Br[C:44]1[NH:48][C:47]([C@@H:49]2[CH2:53][CH2:52][CH2:51][N:50]2[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[N:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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].CN(C)C=O>[CH3:62][O:61][C:60]([NH:59][C@H:55]([C:54]([N:50]1[CH2:51][CH2:52][CH2:53][C@@H:49]1[C:47]1[NH:48][C:44]([C:9]2[CH:10]=[CH:11][C:12]3[C:41]4[C:17](=[C:18]5[C:38](=[CH:39][CH:40]=4)[C:22]4[N:23]=[C:24]([C@@H:26]6[CH2:30][CH2:29][CH2:28][N:27]6[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:25][C:21]=4[CH:20]=[CH:19]5)[O:16][CH2:15][C:13]=3[CH:14]=2)=[CH:45][N:46]=1)=[O:64])[CH:56]([CH3:58])[CH3:57])=[O:63]

Komponenten

8

Edukt 4

HCID 80711,2-DimethoxyethaneHCID 11430Potassium CarbonateHCID 56605304methyl ((S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamateHCID 86688819tert-butyl (2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3',4': 5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate

Produkt 1

HCID 86688818tert-butyl (2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylateAusbeute 46,6 %

Reagenzien, Katalysatoren, Lösungsmittel 3

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

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

A mixture of tert-butyl (2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′: 5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (450 mg, 0.79 mmol), methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (325 mg, 0.87 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.02 mmol), PdCl2(dppf) (35 mg, 0.05 mmol), 2M aqueous potassium carbonate (1.2 mL, 2.4 mmol), dimethoxyethane (6.8 mL) and dimethylformamide (1.2 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85° C. for 2.5 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography (EtOAc/MeOH) to yield tert-butyl (2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3′,4′: 5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (270 mg, 46% yield).

Aufarbeitung

  1. customwas degassed with argon for 15 minutes
  2. temperatureUpon completion, the reaction was cooled to room temperature
  3. additiondiluted with ethyl acetate
  4. filtrationfiltered through Celite
  5. washThe filtrate was washed with water and brine
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated
  8. customThe resulting crude material was purified by flash column chromatography (EtOAc/MeOH)

Quellen und Nachweise

ORD-Eintrag
ord-7fdd794719d444da9d9d8b3d5f0025b6
Quelldatensatz
uspto-grants-2015_01
Patentnummer
US08940718B2

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