Potassium Carbonate → tert-butyl (2S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

HRID 2172486Notes

Reaction equation

[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][N:7]([C:9](=[O:20])[CH:10]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:11]([O:13][CH3:14])[CH3:12])[CH:6]([C:21]2[NH:25][C:24]3[C:26]4[C:31]([CH:32]=[CH:33][C:23]=3[N:22]=2)=[CH:30][C:29]2[C:34]3[C:39]([CH2:40][O:41][C:28]=2[CH:27]=4)=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=3)[CH2:5]1.I[C:52]1[NH:56][C:55]([C@@H:57]2[CH2:61][CH2:60][CH2:59][N:58]2[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[N:54][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=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]>[CH3:18][O:17][C:16]([NH:15][C@H:10]([C:9]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:21]1[NH:25][C:24]2[C:26]3[C:31]([CH:32]=[CH:33][C:23]=2[N:22]=1)=[CH:30][C:29]1[C:34]2[C:39]([CH2:40][O:41][C:28]=1[CH:27]=3)=[CH:38][C:37]([C:52]1[NH:56][C:55]([C@@H:57]3[CH2:61][CH2:60][CH2:59][N:58]3[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[N:54][CH:53]=1)=[CH:36][CH:35]=2)=[O:20])[C@@H:11]([CH3:12])[O:13][CH3:14])=[O:19]

Participants

Conditions

Temperature: 90 °C

Procedure

To a solution of methyl (1-{4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methoxy-1-oxobutan-2-yl)carbamate (0.15 g, 0.22 mmol) in a mixture of DMSO (2.0 mL) and dioxane (2.0 mL) was added (S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.15 g, 0.40 mmol), tetrakis(triphenylphosphine)palladium (0.028 g, 0.024 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.018 g, 0.025 mmol), and aqueous potassium carbonate (2M, 0.35 mL, 0.70 mmol). The solution was degassed with argon for 5 min and heated, with stirring, to 90° C. for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The remaining solution was basified with aqueous bicarbonate and extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide tert-butyl (2S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.013 g, 7%).

Workup

customThe solution was degassed with argon for 5 min
temperatureheated
temperatureThe solution was cooled to room temperature
additiondiluted with EtOAc
washThe organic layer was washed with water and brine
dry with materialThe combined organic layers were dried over Na2SO4
concentrationconcentrated under reduced pressure
customThe crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA)
concentrationconcentrated under reduced pressure
customto remove volatile organics
extractionextracted with CH2Cl2 (3×)
dry with materialThe combined organic layers were dried over Na2SO4
concentrationconcentrated under reduced pressure

Sources & evidence

ORD record: ord-a82d66148b8b488290e89318a76b7aff
Source dataset: uspto-grants-2015_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09051340B2

Reaction notes

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