Potassium Carbonate → (S)-tert-butyl 2-(5-(4-(6-(2-((S)-1-((2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

HRID 1751359Notes

Reaction equation

HRID 1751359 reaction equation
[F:1][CH:2]([F:43])[O:3][C@H:4]([CH3:42])[C@H:5]([NH:37][C:38](=[O:41])[O:39][CH3:40])[C:6](=[O:36])[N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](B4OC(C)(C)C(C)(C)O4)[CH:23]=3)[CH:18]=2)=[CH:15][N:16]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([C:51]2[NH:55][C:54]([C@@H:56]3[CH2:60][CH2:59][CH2:58][N:57]3[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=2)=[CH:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[F:1][CH:2]([F:43])[O:3][C@H:4]([CH3:42])[C@H:5]([NH:37][C:38]([O:39][CH3:40])=[O:41])[C:6]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:45]2[CH:46]=[CH:47][C:48]([C:51]4[NH:55][C:54]([C@@H:56]5[CH2:60][CH2:59][CH2:58][N:57]5[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=4)=[CH:49][CH:50]=2)[CH:21]=[CH:20]3)=[CH:15][N:16]=1)=[O:36]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 56605031(S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateHCID 67681934HCID 67681934, compound

Product 1

HCID 86708711(S)-tert-butyl 2-(5-(4-(6-(2-((S)-1-((2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateYield 45%

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

To a solution of methyl (2S,3R)-3-(difluoromethoxy)-1-oxo-1-((S)-2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (120 mg, 0.20 mmol), (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (87 mg, 0.22 mmol), and tetrakistriphenylphosphine palladium(0) (23 mg, 0.020 mmol) in dimethoxyethane (2 mL) was added a 2M aqueous potassium carbonate solution (0.40 mL, 0.80 mmol). The mixture was degassed with a stream of argon for 15 minutes, and then heated to 85° C. for three hours. The reaction was diluted with ethyl acetate, cooled to room temperature and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting residue was purified by flash chromatography to yield (S)-tert-butyl 2-(5-(4-(6-(2-((S)-1-((2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (70 mg, 45%). LCMS-ESI+: calculated for C42H47F2N7O6: 783.86. observed [M+1]+: 784.72.

Workup

  1. customThe mixture was degassed with a stream of argon for 15 minutes
  2. additionThe reaction was diluted with ethyl acetate
  3. temperaturecooled to room temperature
  4. filtrationfiltered through Celite
  5. washThe filtrate was washed with water and brine
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated
  8. customThe resulting residue was purified by flash chromatography

Sources & evidence

ORD record
ord-b2cf7902d2174788ae35b46fd3a74269
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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