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 1751707Notes

Reaction equation

HRID 1751707 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

8

Reactant 3

HCID 11430Potassium CarbonateHCID 58498756(S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylateHCID 178494459HCID 178494459, compound

Product 1

HCID 178495661tert-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-carboxylateYield 7.4%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 679Dimethyl SulfoxideSolventHCID 312751,4-DioxaneSolvent

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 back extracted 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

  1. customThe solution was degassed with argon for 5 min
  2. temperatureheated
  3. temperatureThe solution was cooled to room temperature
  4. additiondiluted with EtOAc
  5. washThe organic layer was washed with water and brine
  6. extractionThe aqueous layers were back extracted with EtOAc (3×)
  7. dry with materialThe combined organic layers were dried over Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. customThe crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA)
  10. concentrationconcentrated under reduced pressure
  11. customto remove volatile organics
  12. extractionextracted with CH2Cl2 (3×)
  13. dry with materialThe combined organic layers were dried over Na2SO4
  14. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-ab0ab79435d94b1086fa668a8ef49776
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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