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

HRID 71875Notes

Reaction equation

HRID 71875 reaction equation
[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[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[NH:50][C:49]2[CH:51]=[C:52](B3OC(C)(C)C(C)(C)O3)[CH:53]=[CH:54][C:48]=2[N:47]=1)=[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:52]5[CH:53]=[CH:54][C:48]6[N:47]=[C:46]([CH:42]7[CH2:43][CH2:44][CH2:45][N:41]7[C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:40])[NH:50][C:49]=6[CH:51]=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]

Participants

9

Reactant 3

HCID 11430Potassium CarbonateHCID 566054092-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl esterHCID 666205612-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 666201802-(5-{9,9-Difluoro-7-[2-(1-Boc-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl esterYield 43.3%

Reagents, catalysts & solvents 5

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

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 (137 mg, 0.265 mmol), 2-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1 eq., 110 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5%, 11 mg), tetrakis(triphenylphosphine)palladium (5%, 16 mg) and potassium carbonate (2 eq., 73 mg) in 4 mL DME and 2 mL water was heated to 90° C. for 2 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer 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-(1-Boc-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-9H-fluoren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (83 mg, yield 43%). LCMS-ESI−: calc'd for C41H44F2N6O4: 722.82. Found: 723.1 (M+H+).

Workup

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

Sources & evidence

ORD record
ord-0d7d00fa53ba4f148cbdec5d9c1b1c61
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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