Potassium Carbonate → (1S,3R)-tert-butyl 3-(6-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methyl-butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

HRID 1751395Notes

Reaction equation

HRID 1751395 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[C:21]4[C:16](=[CH:17][C:18]([C:22]5[CH:23]=[CH:24][C:25]6[N:29]=[C:28]([C@H:30]7[CH:35]8[CH2:36][C@H:32]([CH2:33][CH2:34]8)[N:31]7[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH:27][C:26]=6[CH:44]=5)=[CH:19][CH:20]=4)[O:15][CH2:14][C:13]=3[CH:45]=2)O1.Br[C:48]1[NH:52][C:51]([C@@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:58](=[O:68])[C@@H:59]([NH:63][C:64](=[O:67])[O:65][CH3:66])[CH:60]([CH3:62])[CH3:61])=[N:50][CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.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]>[CH3:66][O:65][C:64]([NH:63][C@@H:59]([CH:60]([CH3:62])[CH3:61])[C:58]([N:54]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:51]1[NH:52][C:48]([C:9]2[CH:10]=[CH:11][C:12]3[C:21]4[C:16](=[CH:17][C:18]([C:22]5[CH:23]=[CH:24][C:25]6[N:29]=[C:28]([C@H:30]7[CH:35]8[CH2:36][C@H:32]([CH2:33][CH2:34]8)[N:31]7[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[NH:27][C:26]=6[CH:44]=5)=[CH:19][CH:20]=4)[O:15][CH2:14][C:13]=3[CH:45]=2)=[CH:49][N:50]=1)=[O:68])=[O:67]

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 56605304methyl ((S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamateHCID 86708729(1S,3R)-tert-butyl 3-(6-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Product 1

HCID 86708728(1S,3R)-tert-butyl 3-(6-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methyl-butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylateYield 20.2%

Reagents, catalysts & solvents 4

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

To a solution of (1S,3R)-tert-butyl 3-(6-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (275 mg, 0.44 mmol), methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (221 mg, 0.55 mmol), tetrakis(triphenylphosphine) palladium(0) (20 mg, 0.02 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (26 mg, 0.04 mmol) in a mixture of 1,2-dimethoxyethane (5.0 mL) and dimethylformamide (1 mL) was added a solution of potassium carbonate (2M in water, 0.7 mL, 1.3 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield (1S,3R)-tert-butyl 3-(6-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methyl-butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (70 mg, 20%). LCMS-ESI+: calculated for C45H51N7O6: 785.95; observed [M+1]+: 786.85.

Workup

  1. customThe resulting mixture was degassed
  2. temperatureAfter cooling to room temperature
  3. additionthe reaction was diluted with ethyl acetate
  4. washThe organics were washed with water and brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customThe crude residue was purified by flash chromatography

Sources & evidence

ORD record
ord-9d45394c64664a0391003ec5779c474c
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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