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

HRID 71860Notes

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]2C=CC(Br)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C(C2NC3C=C(C4C=CC(B5OC(C)(C)C(C)(C)O5)=CC=4)C=CC=3N=2)C2CC1CC2)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(OC(N1C(C2NC3C=C(C4[CH:96]=[CH:95][C:94]([C:97]5[CH:102]=[CH:101][C:100]([C:103]6[CH:125]=[CH:124][C:106]7[N:107]=[C:108]([CH:110]8[CH:115]9[CH2:116][CH:112]([CH2:113][CH2:114]9)[N:111]8[C:117]([O:119][C:120]([CH3:123])([CH3:122])[CH3:121])=[O:118])[NH:109][C:105]=7[CH:104]=6)=[CH:99][CH:98]=5)=CC=4)C=CC=3N=2)C2CC1CC2)=O)(C)(C)C>COCCOC.C(OCC)(=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>[C:120]([O:119][C:117]([N:111]1[CH:110]([C:108]2[NH:109][C:105]3[CH:104]=[C:103]([C:100]4[CH:99]=[CH:98][C:97]([C:94]5[CH:95]=[CH:96][C:18]([C:15]6[NH:14][C:13]([CH:9]7[CH2:10][CH2:11][CH2:12][N:8]7[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:17][CH:16]=6)=[CH:19][CH:20]=5)=[CH:102][CH:101]=4)[CH:125]=[CH:124][C:106]=3[N:107]=2)[CH:115]2[CH2:116][CH:112]1[CH2:113][CH2:114]2)=[O:118])([CH3:122])([CH3:121])[CH3:123]

Participants

Conditions

Temperature: 90 °C

Procedure

A mixture of 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (295 mg, 0.573 mmol, 1 eq.), 3-{6-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-benzoimidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (269 mg, 0.687 mmol), tetrakis(triphenylphosphine)palladium (5%, 33 mg) and 2M potassium carbonate aqueous solution (5 eq., 1.43 mL) in 5 mL DME was heated to 90° C. under Argon overnight. 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, 50 to 100% ethyl acetate/hexane) to give 3-(6-{4′-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (163 mg, yield 40%) and trace amount of byproduct 3-(6-{4′-[2-(2-Boc-2-aza-bicyclo[2.2.1]hept-3-yl)-3H-benzoimidazol-5-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. LCMS-ESI− of 3-(6-{4′-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester: calc'd for C42H48N6O4: 700.87. Found: 701.1 (M+H+).

Workup

temperatureThe reaction mixture was cooled
washwashed with saturated sodium bicarbonate solution
dry with materialThe organic layer dried (MgSO4)
concentrationconcentrated
custompurified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexane)

Sources & evidence

ORD record: ord-081c7f0f1ba44c34873bb94202eaadbc
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08822430B2

Reaction notes

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