Potassium Carbonate → 3-(6-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-dibenzothiophen-3-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

HRID 71866Notes

Reaction equation

HRID 71866 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:19]=[CH:20][C:21]3[C:25]4[CH:26]=[CH:27][C:28](Br)=[CH:29][C:24]=4[S:23][C:22]=3[CH:31]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([N:39]1[CH:44]([C:45]2[NH:49][C:48]3[CH:50]=[C:51](B4OC(C)(C)C(C)(C)O4)[CH:52]=[CH:53][C:47]=3[N:46]=2)[CH:43]2[CH2:63][CH:40]1[CH2:41][CH2:42]2)=O)(C)(C)C.[C:64](=[O:67])([O-:66])[O-].[K+].[K+]>COCCOC.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:66][C:64]([N:39]1[CH:44]([C:45]2[NH:46][C:47]3[CH:53]=[C:52]([C:28]4[CH:27]=[CH:26][C:25]5[C:21]6[CH:20]=[CH:19][C:18]([C:15]7[NH:14][C:13]([CH:9]8[CH2:10][CH2:11][CH2:12][N:8]8[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:17][CH:16]=7)=[CH:31][C:22]=6[S:23][C:24]=5[CH:29]=4)[CH:51]=[CH:50][C:48]=3[N:49]=2)[CH:43]2[CH2:63][CH:40]1[CH2:41][CH2:42]2)=[O:67])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 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 666207902-[5-(7-Bromo-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 666211943-(6-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-dibenzothiophen-3-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterYield 70%

Reagents, catalysts & solvents 4

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

Conditions

Temperature
80 °C

Procedure

A mixture of 2-[5-(7-Bromo-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.48 mmol, 1 eq.), 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., 530 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3%, 12 mg), tetrakis(triphenylphosphine)palladium (3%, 17 mg) and 2N potassium carbonate aqueous solution (3.3 eq., 0.8 mL) in 2 mL DME was heated to 80° C. under Argon for 5 hours. The reaction mixture was cooled and diluted 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 a yellow foam 3-(6-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-dibenzothiophen-3-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (245 mg, yield 70%). LCMS-ESI−: calc'd for C42H46N6O4S: 730.92. Found: 731.2 (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-357048b67e594412bfe4012925c82d9e
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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