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 1751393Notes

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]

Participants

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

customThe resulting mixture was degassed
temperatureAfter cooling to room temperature
additionthe reaction was diluted with ethyl acetate
washThe organics were washed with water and brine
dry with materialdried (Na2SO4)
concentrationconcentrated
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

Loading…