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

Reaction equation

HRID 79682 reaction equation
[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]

Participants

13

Reactant 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

Product 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

Reagents, catalysts & solvents 7

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 67553Tetrabutylammonium IodideCatalystHCID 702EthanolSolventHCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

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+).

Workup

  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)

Sources & evidence

ORD record
ord-6d293719343242ff9a57b68517b81430
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Linked notes

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