Potassium Carbonate → 2-(5-{9,9-Difluoro-7-[2-(2-Boc-2-aza-bicyclo[2.2.1]hept-3-yl)-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 71876Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 71876
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][C:24](Br)=[CH:25][CH:26]=4)[C:21]([F:33])([F:32])[C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39]([N:41]1[CH:46]([C:47]2[NH:51][C:50]3[CH:52]=[C:53](B4OC(C)(C)C(C)(C)O4)[CH:54]=[CH:55][C:49]=3[N:48]=2)[CH:45]2[CH2:65][CH:42]1[CH2:43][CH2:44]2)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.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].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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:53]5[CH:54]=[CH:55][C:49]6[N:48]=[C:47]([CH:46]7[CH:45]8[CH2:65][CH:42]([CH2:43][CH2:44]8)[N:41]7[C:39]([O:38][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:40])[NH:51][C:50]=6[CH:52]=5)=[CH:25][CH:26]=4)[C:21]([F:33])([F:32])[C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Komponenten

9

Edukt 3

HCID 11430Potassium CarbonateHCID 66620440(1R,3S,4S)-3-[6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl esterHCID 666205612-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

Produkt 1

HCID 666207732-(5-{9,9-Difluoro-7-[2-(2-Boc-2-aza-bicyclo[2.2.1]hept-3-yl)-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl esterAusbeute 77 %

Reagenzien, Katalysatoren, Lösungsmittel 5

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 962WaterLösungsmittelHCID 80711,2-DimethoxyethaneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

A mixture of 2-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (324 mg, 0.627 mmol), 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.1 eq., 304 mg), [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3%, 15 mg), tetrakis(triphenylphosphine)palladium (3%, 22 mg) and potassium carbonate (3.3 eq., 285 mg) in 10 mL DME and 3 mL water was heated to 90° C. under Argon for 3 hours. The reaction mixture was cooled and diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(5-{9,9-Difluoro-7-[2-(2-Boc-2-aza-bicyclo[2.2.1]hept-3-yl)-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (361 mg, yield 77%). LCMS-ESI−: calc'd for C43H46F2N6O4: 748.86. Found: 749.2 (M+H+).

Aufarbeitung

  1. temperatureThe reaction mixture was cooled
  2. washwashed with saturated sodium bicarbonate solution
  3. dry with materialThe organic layer was dried (MgSO4)
  4. concentrationconcentrated
  5. custompurified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane)

Quellen und Nachweise

ORD-Eintrag
ord-34704f9565454f94b7460d0d6c83f111
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08822430B2

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