Chlorotrimethylsilane → 1,1-dimethylethyl (4R)-4-(([(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pentanoate

HRID 1714565Notes

Reaction equation

HRID 1714565 reaction equation
BrCCBr.Cl[Si](C)(C)C.[CH3:10][C:11]([O:14][C:15]([NH:17][C@@H:18]([CH2:28]I)[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:16])([CH3:13])[CH3:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.I[C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]=[C:61]3[C:66]([CH3:67])=[CH:65][CH:64]=[CH:63][N:62]3[CH:68]=2)=[CH:55][CH:54]=1>CN(C=O)C.CCOC(C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:10][C:11]([O:14][C:15]([NH:17][C@@H:18]([CH2:28][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]=[C:61]3[C:66]([CH3:67])=[CH:65][CH:64]=[CH:63][N:62]3[CH:68]=2)=[CH:55][CH:54]=1)[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:16])([CH3:13])[CH3:12]

Participants

10

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 80271Tri-o-tolylphosphineHCID 173895682-(4-Iodophenyl)-8-methylimidazo[1,2-a]pyridineHCID 575942331,1-dimethylethyl (4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-iodopentanoate

Product 1

HCID 672783711,1-dimethylethyl (4R)-4-(([(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pentanoateYield 90%

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A flask containing zinc dust (6.0 equiv, 325 mesh, Strem) was heated with a heat gun while evacuating and filling with nitrogen (3 times). Under nitrogen, degassed DMF (14 mL) was added via syringe followed by 1,2-dibromoethane (0.35 equiv). The grey reaction mixture was stirred in an oil bath at 100° C. for 15 minutes and then cooled to room temperature. Chlorotrimethylsilane (0.25 equiv) was added to the mixture via syringe and the reaction was stirred at room temperature for 30 minutes. A solution of 1,1-dimethylethyl (4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-iodopentanoate (2.0 g, 1.2 equiv) in degassed DMF (14 mL) was added to the reaction mixture via cannula. The flask containing the solution was rinsed with degassed DMF (4 mL) and cannulated into the reaction mixture. The reaction was stirred at room temperature for 1 hour. Then, tris(dibenzylideneacetone)dipalladium (0) (2.5 mol %), tri-o-tolylphosphine (10 mol %) and 2-(4-iodophenyl)-8-methylimidazo[1,2-a]pyridine (1.4 g, 1.0 equiv) were added through the top all at once. The reaction mixture was stirred at room temperature for 17 hours. The reaction was diluted with EtOAc (40 mL) and filtered through Celite®. The filtrate was washed with H2O (20 mL) and brine (20 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 5-90% EtOAc/hexanes) afforded the title compound as a white solid (90%). ESMS [M+H]+=480.4.

Workup

  1. temperaturewas heated with a heat gun
  2. customwhile evacuating
  3. customUnder nitrogen, degassed DMF (14 mL)
  4. additionwas added via syringe
  5. temperaturecooled to room temperature
  6. stirringthe reaction was stirred at room temperature for 30 minutes
  7. additionThe flask containing the solution
  8. washwas rinsed with degassed DMF (4 mL)
  9. stirringThe reaction was stirred at room temperature for 1 hour
  10. stirringThe reaction mixture was stirred at room temperature for 17 hours
  11. filtrationfiltered through Celite®
  12. washThe filtrate was washed with H2O (20 mL) and brine (20 mL)
  13. dry with materialthe organic layer was dried over MgSO4
  14. concentrationconcentrated in vacuo
  15. customPurification by silica gel chromatography (Analogix IF280, 5-90% EtOAc/hexanes)

Sources & evidence

ORD record
ord-14f11e76fb504a898ded9e93833ea675
Source dataset
uspto-grants-2010_09
Patent number
US07795448B2

Reaction notes

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