N-Boc-pyrrolidine → 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 79682

Reaktionsgleichung

Reaktionsgleichung von HRID 79682
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25]1[N:26]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][NH:39][C:38](=[O:42])[CH:37]=3)=[CH:32][CH:31]=2)=[CH:28][N:29]=1)=O)(C)(C)C.[OH-].[CH2:52]([N+](CCCC)(CCCC)CCCC)CCC.C(OC(N1CCCC1C1[NH:82][C:83]([C:86]2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=[CH:84]N=1)=O)(C)(C)C.C(OC(N1CCCC1[C:113]1[N:114]([CH2:119][O:120][CH2:121][CH2:122][Si:123]([CH3:126])([CH3:125])[CH3:124])[CH:115]=[C:116](Br)[N:117]=1)=O)(C)(C)C>C(O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.[Cu]I.CN(C=O)C.C1(C)C=CC=CC=1.C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:113]1[N:114]([CH2:119][O:120][CH2:121][CH2:122][Si:123]([CH3:124])([CH3:125])[CH3:126])[CH:115]=[C:116]([N:39]2[CH:40]=[CH:41][C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:27]4[N:26]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:48])([CH3:50])[CH3:49])[C:25]([CH:21]5[CH2:22][CH2:23][CH2:24][N:20]5[C:18](=[O:17])[NH:82][C:83]([CH3:86])([CH3:52])[CH3:84])=[N:29][CH:28]=4)=[CH:31][CH:32]=3)=[CH:37][C:38]2=[O:42])[N:117]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Komponenten

13

Edukt 5

HCID 643455N-Boc-pyrrolidineHCID 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 esterHCID 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

Produkt 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

Reagenzien, Katalysatoren, Lösungsmittel 7

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Katalysator2×HCID 67553Tetrabutylammonium IodideKatalysatorHCID 702EthanolLösungsmittelHCID 1140TolueneLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 6342AcetonitrileLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

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: 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)ethoxylmethyl 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+).

Aufarbeitung

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

Quellen und Nachweise

ORD-Eintrag
ord-6d293719343242ff9a57b68517b81430
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08841278B2

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