Potassium Carbonate → tert-butyl 2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

HRID 1751386Notes

Reaction equation

HRID 1751386 reaction equation
[CH3:1][CH:2]([CH3:46])[C@H:3]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C:4](=[O:40])[N:5]1[C@H:10]([C:11]2[NH:12][C:13]([C:16]3[CH:29]=[CH:28][C:27]4[C:26]5[C:21](=[CH:22][C:23](B6OC(C)(C)C(C)(C)O6)=[CH:24][CH:25]=5)[CH2:20][CH2:19][C:18]=4[CH:17]=3)=[CH:14][N:15]=2)[C@@H:9]2[CH2:39][C@H:6]1[CH2:7][CH2:8]2.Br[C:48]1[N:49]=[C:50]([C@@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[NH:51][CH:52]=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]>[CH3:44][O:43][C:42]([NH:41][C@@H:3]([CH:2]([CH3:46])[CH3:1])[C:4]([N:5]1[C@H:10]([C:11]2[NH:12][C:13]([C:16]3[CH:17]=[C:18]4[C:27]([C:26]5[CH:25]=[CH:24][C:23]([C:48]6[NH:49][C:50]([CH:53]7[CH2:57][CH2:56][CH2:55][N:54]7[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:51][CH:52]=6)=[CH:22][C:21]=5[CH2:20][CH2:19]4)=[CH:28][CH:29]=3)=[CH:14][N:15]=2)[C@@H:9]2[CH2:39][C@H:6]1[CH2:7][CH2:8]2)=[O:40])=[O:45]

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 56605192tert-Butyl (2S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylateHCID 86708724methyl (S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate

Product 1

HCID 86708723tert-butyl 2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateYield 56%

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 methyl (S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate (˜0.67 mmol), (S)-tert-butyl 2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (266 mg, 0.84 mmol), tetrakis(triphenylphosphine) palladium(0) (23 mg, 0.02 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (30 mg, 0.04 mmol) in a mixture of 1,2-dimethoxyethane (10.0 mL) and dimethylformamide (2 mL) was added a solution of potassium carbonate (2M in water, 1.0 mL, 2.0 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 2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (182 mg, 56%)

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-c40a43048b984ea8953139e85723f529
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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