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

HRID 1751393
Notes
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Reaction equation

HRID 1751393 reaction equation
[CH3:1][CH:2]([CH3:44])[CH:3]([NH:39][C:40](=[O:43])[O:41][CH3:42])[C:4](=[O:38])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([C:19]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][C:20]=4[CH2:21][O:22]3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.Br[C:46]1[CH:47]=[CH:48][C:49]2[N:53]=[C:52]([C@@H:54]3[C@@H:59]4[CH2:60][C@@H:56]([CH2:57][CH2:58]4)[N:55]3[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[NH:51][C:50]=2[CH:68]=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]>[CH3:42][O:41][C:40]([NH:39][C@@H:3]([CH:2]([CH3:44])[CH3:1])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([C:19]4[CH:28]=[CH:27][C:26]([C:47]5[CH:46]=[CH:68][C:50]6[N:51]=[C:52]([CH:54]7[C@@H:59]8[CH2:60][CH:56]([CH2:57][CH2:58]8)[N:55]7[C:61]([O:63][C:64]([CH3:66])([CH3:65])[CH3:67])=[O:62])[NH:53][C:49]=6[CH:48]=5)=[CH:25][C:20]=4[CH2:21][O:22]3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:38])=[O:43].[CH3:42][O:41][C:40]([NH:39][C@@H:3]([CH:2]([CH3:44])[CH3:1])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([C:19]4[CH:28]=[CH:27][C:26]([C:47]5[CH:46]=[CH:68][C:50]6[N:51]=[C:52]([CH:54]7[CH:59]8[CH2:60][CH:56]([CH2:57][CH2:58]8)[N:55]7[C:61]([O:63][C:64]([CH3:66])([CH3:65])[CH3:67])=[O:62])[NH:53][C:49]=6[CH:48]=5)=[CH:25][C:20]=4[CH2:21][O:22]3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:38])=[O:43]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 3

HCID 11430Potassium CarbonateHCID 675058682-Azabicyclo(2.2.1)heptane-2-carboxylic acid, 3-(6-bromo-1H-benzimidazol-2-yl)-, 1,1-dimethylethyl ester, (1R,3S,4S)-HCID 69675075methyl 3-methyl-1-oxo-1-((S)-2-(5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

Product 2

HCID 69675206
(4S)-tert-butyl 3-(6-(3-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-8-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate
HCID 86708726tert-butyl 3-(6-(3-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-8-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylateYield 171%

Reagents, catalysts & solvents 4

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 44119782Bis(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 methyl 3-methyl-1-oxo-1-((S)-2-(5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (196 mg, 0.32 mmol), (1R,3S,4S)-tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (166 mg, 0.42 mmol), tetrakis(triphenylphosphine) palladium(0) (10 mg, 0.01 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (12 mg, 0.02 mmol) in a mixture of 1,2-dimethoxyethane (5 mL) and dimethylformamide (1 mL) was added a solution of potassium carbonate (2M in water, 0.51 mL, 0.31 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 S)-tert-butyl 4S)-tert-butyl 3-(6-(3-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-8-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (215 mg, 85%) LCMS-ESI+: calculated for C45H51N7O6: 785.95; observed [M+1]+: 786.43.

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-3a48c357756241a5bd40a50962f79ca4
Source dataset
uspto-grants-2015_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09156823B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes