Potassium Carbonate → 3-(6-{4'-[2-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-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 71871Notes

Reaction equation

HRID 71871 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH:39]([C:40]2[NH:44][C:43]3[CH:45]=[C:46]([C:49]4[CH:54]=[CH:53][C:52](B5OC(C)(C)C(C)(C)O5)=[CH:51][CH:50]=4)[CH:47]=[CH:48][C:42]=3[N:41]=2)[CH:38]2[CH2:64][CH:35]1[CH2:36][CH2:37]2)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>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:27]([O:31][C:32]([N:34]1[CH:39]([C:40]2[NH:44][C:43]3[CH:45]=[C:46]([C:49]4[CH:54]=[CH:53][C:52]([C:23]5[CH:22]=[CH:21][C:20]([C:17]6[NH:16][C:15]([CH:14]7[CH2:13][C:10]8([CH2:11][CH2:12]8)[CH2:9][N:8]7[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[N:19][CH:18]=6)=[CH:25][CH:24]=5)=[CH:51][CH:50]=4)[CH:47]=[CH:48][C:42]=3[N:41]=2)[CH:38]2[CH2:64][CH:35]1[CH2:36][CH2:37]2)=[O:33])([CH3:30])([CH3:28])[CH3:29]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 666203726-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl esterHCID 666208183-{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

Product 1

HCID 666204783-(6-{4'-[2-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterYield 30%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (101 mg, 0.243 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 (150 mg, 0.291 mmol, 1.2 eq.), tetrakis(triphenylphosphine)palladium (5%, 17 mg) and 2M potassium carbonate aqueous solution (5 eq., 0.73 mL) in 1.5 mL DME was heated to 90° C. under Are overnight. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexane) to give 3-(6-{4′-[2-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-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 (53 mg, yield 26%). LCMS-ESI−: calc'd for C44H50N6O4: 726.91. Found: 727.2 (M+H+).

Workup

  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, 50 to 100% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-fe7457b1b61e42339f75992d728681b7
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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