Toluene → 2-[4-(4-{4-[2-(1-tert-butylcarbamyl-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenyl}-2-oxo-2H-pyridin-1-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1185654

反応式

HRID 1185654 の反応式
C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:15](C2C=CC(C3C=CNC(=O)C=3)=CC=2)=[CH:16][N:17]=1)=[O:7])(C)(C)C.[OH-:39].C([N+:44]([CH2:53][CH2:54]CC)([CH2:49][CH2:50]CC)CCCC)CCC.[C:57]([O:61][C:62]([N:64]1[CH2:68][CH2:67][CH2:66][CH:65]1[C:69]1[N:70]([CH2:75][O:76][CH2:77][CH2:78][Si:79]([CH3:82])([CH3:81])[CH3:80])[CH:71]=[C:72](Br)[N:73]=1)=[O:63])([CH3:60])([CH3:59])[CH3:58].C(OC(N1CCCC1C1[NH:96][C:97]([C:100]2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=[CH:98]N=1)=O)(C)(C)C.[CH3:115]Cl.[H-].[Na+].[C:119]1([CH3:125])[CH:124]=[CH:123][CH:122]=[CH:121][CH:120]=1>C(O)C.CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.[Cu]I.C(#N)C>[C:57]([O:61][C:62]([N:64]1[CH2:68][CH2:67][CH2:66][CH:65]1[C:69]1[N:70]([CH2:75][O:76][CH2:77][CH2:78][Si:79]([CH3:82])([CH3:81])[CH3:80])[CH:71]=[C:72]([N:44]2[CH:49]=[CH:50][C:125]([C:119]3[CH:124]=[CH:123][C:122]([C:15]4[N:14]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6](=[O:7])[NH:96][C:97]([CH3:100])([CH3:115])[CH3:98])=[N:17][CH:16]=4)=[CH:121][CH:120]=3)=[CH:54][C:53]2=[O:39])[N:73]=1)=[O:63])([CH3:60])([CH3:59])[CH3:58]

参加物

14

反応物 7

HCID 1140TolueneHCID 6327Methyl ChlorideHCID 24758Sodium hydrideHCID 2723671Tetrabutylammonium HydroxideHCID 574497592-{4-[4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]-1h-imidazol-2-yl}pyrrolidine-1-carboxylic acid tert-butyl esterHCID 666201592-[4-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester2 回HCID 666201862-[5-[4-(2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

生成物 1

HCID 867627932-[4-(4-{4-[2-(1-tert-butylcarbamyl-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenyl}-2-oxo-2H-pyridin-1-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

試薬・触媒・溶媒 6

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)触媒2 回HCID 67553Tetrabutylammonium Iodide触媒HCID 702Ethanol溶媒HCID 6228Dimethylformamide溶媒2 回HCID 6342Acetonitrile溶媒HCID 8857Ethyl Acetate溶媒

実験手順

To a solution of 2-[5-[4-(2-Oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.3027 g) in ethanol (5.0 mL) was added tetrabutylammonium hydroxide (0.375 mL of 1.5 M solution) and reaction mixture stirred for 1 hour., then concentrated to give a colorless oil. Residue was lyophilized from acetonitrile to give a yellow residue. To this residue was added 2-[4-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.301 g, prepared by reacting 2-(4-Bromo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared according to WO2008021927 A2) with 2-(trimethylsilyl)ethoxy]methyl chloride using sodium hydride in DMF) and mixture co-evaporated with toluene (15 mL). DMF (1.0 mL) and copper(I) iodide (0.035 g) were added and the reaction mixture was stirred at 95° C. for 24 hour, protected from light. To the reaction mixture was added tetrabutylammonium iodide (50 mg) and reaction continued for 2 days. Added more 2-[4-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.35 g) and copper(I) iodide (0.050 g) and reaction continued for 24 hours. Reaction mixture was cooled and diluted with ethyl acetate and washed with 3N ammonium hydroxide. The aqueous layer was back-extracted with ethyl acetate (2×). The combined organic layer was washed with 3N ammonium hydroxide, H2O, brine and dried (MgSO4) then concentrated and purified by flash column chromatography (silica gel, 0 to 10% isopropanol/hexane) to give impure product that was repurified by preparative reverse phase HPLC (Gemini, 25 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give 2-[4-(4-{4-[2-(1-tert-butylcarbamyl-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenyl}-2-oxo-2H-pyridin-1-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.042 g): LCMS-ESI+: calc'd for C47H72N7O7Si2: 903.28 (M+H+). Found: 902.2, 903.2 (M+H+).

後処理

  1. concentration, then concentrated
  2. customto give a colorless oil
  3. customto give a yellow residue
  4. customprepared
  5. stirringthe reaction mixture was stirred at 95° C. for 24 hour
  6. additionTo the reaction mixture was added
  7. waitcontinued for 2 days
  8. additionAdded more
  9. waitcontinued for 24 hours
  10. customReaction mixture
  11. temperaturewas cooled
  12. washwashed with 3N ammonium hydroxide
  13. extractionThe aqueous layer was back-extracted with ethyl acetate (2×)
  14. washThe combined organic layer was washed with 3N ammonium hydroxide, H2O, brine
  15. dry with materialdried (MgSO4)
  16. concentrationthen concentrated
  17. custompurified by flash column chromatography (silica gel, 0 to 10% isopropanol/hexane)
  18. customto give impure product that
  19. customwas repurified by preparative reverse phase HPLC (Gemini, 25 to 100% ACN/H2O+0.1% TFA)

出典と根拠

ORDレコード
ord-348bc6b26d8e42d88e9d94b1086ce9cf
出典データセット
uspto-grants-2014_03
特許番号
US08669234B2

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