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 1185809ノート

反応式

HRID 1185809 の反応式
[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]

参加物

10

反応物 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

生成物 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

試薬・触媒・溶媒 4

HCID 962Water溶媒HCID 6342Acetonitrile溶媒HCID 8857Ethyl Acetate溶媒2 回HCID 312751,4-Dioxane溶媒

反応条件

温度
80 °C

実験手順

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 dissolved 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)+.

後処理

  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. dissolutionThe obtained residue was dissolved in acetonitrile (3 mL)
  8. stirringThe mixture was stirred at room temperature for 16 hours
  9. washThe organic layer was washed with NaHCO3 solution and water
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customThe obtained residue was purified by flash chromatography

出典と根拠

ORDレコード
ord-186a57f24df54e2ba2a1ce265dc85ef9
出典データセット
uspto-grants-2014_03
特許番号
US08669234B2

反応ノート

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