Potassium Phosphate, Tribasic → 2-[5-(6-{4-[2-(1-tert-butyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 72012Notes

Reaction equation

HRID 72012 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[C:48]([O:52][C:53]([N:55]1[CH2:59][CH2:58][CH2:57][CH:56]1[C:60]1[NH:61][C:62]([C:65]2[CH:74]=[CH:73][C:72]3[C:67](=[CH:68][CH:69]=[C:70](Br)[CH:71]=3)[CH:66]=2)=[CH:63][N:64]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[C:48]([O:52][C:53]([N:55]1[CH2:59][CH2:58][CH2:57][CH:56]1[C:60]1[NH:61][C:62]([C:65]2[CH:74]=[CH:73][C:72]3[C:67](=[CH:68][CH:69]=[C:70]([C:21]4[CH:20]=[CH:19][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:17][CH:16]=5)=[CH:23][CH:22]=4)[CH:71]=3)[CH:66]=2)=[CH:63][N:64]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49]

Participants

8

Reactant 5

HCID 62657Potassium Phosphate, TribasicHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 547756232-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl esterHCID 58185449tert-butyl (2S)-2-[5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

Product 1

HCID 666200632-[5-(6-{4-[2-(1-tert-butyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl esterYield 10.4%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
85 °C

Procedure

To a solution of 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.39 g, 1.0 mmol) and bis(pinacolato)diborane (0.31 g, 1.2 mmol, 1.2 equiv.) in dioxane (5 mL) was added KOAc (0.30 g, 3.0 mmol, 3 equiv.) and Pd(dppf)Cl2 (0.04 g, 0.05 mmol, 0.05 equiv.). The slurry was degassed with argon for 5 minutes and heated to 85° C. for 2.5 hours. The resulting solution was cooled to room temperature and 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.45 g, 1.0 mmol, 1 equiv.) and K3PO4 (aqueous, 2 M, 1.75 mL, 3.5 mmol, 3.5 equiv.) was added. The reaction mixture was heated to 85° C. for 6 hours. The slurry was filtered through CELITE and concentrated. The crude product was purified by column chromatography (SiO2, 50→100% EtOAc in Hexanes (2% MeOH)) and preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) to provide 2-[5-(6-{4-[2-(1-tert-butyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.07 g, 10%) as a white powder. LCMS-ESI+: calc'd for C40H46N6O4: 674.4 (M+). Found: 675.6 (M+H+).

Workup

  1. customThe slurry was degassed with argon for 5 minutes
  2. temperatureThe resulting solution was cooled to room temperature
  3. temperatureThe reaction mixture was heated to 85° C. for 6 hours
  4. filtrationThe slurry was filtered through CELITE
  5. concentrationconcentrated
  6. customThe crude product was purified by column chromatography (SiO2, 50→100% EtOAc in Hexanes (2% MeOH)) and preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid))

Sources & evidence

ORD record
ord-2c8d4a099a4d45c28511fdfdbd3ac0c0
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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