N-bromobutanimide → 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-[2-(7-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-yl)-2-oxo-ethyl]ester

HRID 417593Notes

Reaction equation

HRID 417593 reaction equation
[CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:34]=[CH:33][C:32]3[C:31]4[C:26](=[CH:27][C:28](Br)=[CH:29][CH:30]=4)[CH2:25][CH2:24][C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([Sn](CCCC)(CCCC)[C:42]([O:44]CC)=[CH2:43])CCC.C1C(=O)N(Br)C(=O)C1.[C:63]([O:67][C:68]([N:70]1[CH:75]([C:76]([OH:78])=[O:77])[CH:74]2[CH2:79][CH:71]1[CH2:72][CH2:73]2)=[O:69])([CH3:66])([CH3:65])[CH3:64].CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C.C(#N)C.O>[CH3:1][O:2][C:3]([NH:4][CH:5]([CH:6]([CH3:8])[CH3:7])[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[C:23]3[C:32]([C:31]4[CH:30]=[CH:29][C:28]([C:42](=[O:44])[CH2:43][O:77][C:76]([CH:75]5[CH:74]6[CH2:79][CH:71]([CH2:72][CH2:73]6)[N:70]5[C:68]([O:67][C:63]([CH3:66])([CH3:64])[CH3:65])=[O:69])=[O:78])=[CH:27][C:26]=4[CH2:25][CH2:24]3)=[CH:33][CH:34]=2)=[CH:19][N:20]=1)=[O:10])=[O:36]

Participants

10

Reactant 5

HCID 67184N-bromobutanimideHCID 81531DiisopropylethylamineHCID 619414Stannane, tributyl(1-ethoxyethenyl)-HCID 150563882-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acidHCID 66620391(1-{2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Product 1

HCID 666200512-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-[2-(7-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-yl)-2-oxo-ethyl]ester

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Pd(Ph3)4 (15 mg, 0.015 mmol) and PdCl2(Ph3)2 (10 mg, 0.015 mmol) were added to a mixture of (1-{2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (200 mg, 0.37 mmol) and tributyl(1-ethoxyvinyl)tin (0.15 mL, 0.44 mL) in 5 mL dioxane. The reaction mixture was flushed with nitrogen, heated at 80° C. for 16 hours, then cooled to ambient temperature. Water (1.5 mL) and NBS (78 mg, 0.44 mmol) was added and the mixture was stirred at room temperature for 40 minutes, then diluted with ethyl acetate (100 mL). Washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was disolved in acetonitrile (3 mL). To it was added a solution of 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (167 mg, 0.69 mmol) and DIPEA (0.11 mL, 0.67 mmol) in 2 mL acetonitrile. The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (100 mL). The organic layer was washed with NaHCO3 solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-[2-(7-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-9,10-dihydro-phenanthren-2-yl)-2-oxo-ethyl]ester as a brown oil (130 mg, 47% over two steps). m/z 754.3 (M+H)+.

Workup

  1. customThe reaction mixture was flushed with nitrogen
  2. temperaturecooled to ambient temperature
  3. washWashed with water and brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. stirringThe mixture was stirred at room temperature for 16 hours
  8. washThe organic layer was washed with NaHCO3 solution and water
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe obtained residue was purified by flash chromatography

Sources & evidence

ORD record
ord-2a4ff8fee4d3409486e0e9d3400b9a19
Source dataset
uspto-grants-2012_01
Patent number
US08088368B2

Reaction notes

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