Diisopropylamine → ethyl 3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate

HRID 420215Notes

Reaction equation

HRID 420215 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27]([C:29]3[N:30]=[CH:31][N:32]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:33]=3)=[O:28])[CH:23]=2)[CH:18]=1)=[O:16].[Cl-].[NH4+].[C:55]([O:58][CH2:59][CH3:60])(=[O:57])[CH3:56]>CCCCCC.C1COCC1>[OH:28][C:27]([C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([C:15]([NH:14][CH3:13])=[O:16])[CH:18]=2)[CH:23]=1)([C:29]1[N:30]=[CH:31][N:32]([C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:33]=1)[CH2:56][C:55]([O:58][CH2:59][CH3:60])=[O:57]

Participants

8

Reactant 5

HCID 7912DiisopropylamineHCID 8857Ethyl AcetateHCID 25517Ammonium ChlorideHCID 18769037N-methyl-6-((trityl-1H-imidazol-4-yl)carbonyl)-2-naphthamideHCID 178418339Butyllithium

Product 1

HCID 57465806ethyl 3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoateYield 96%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolvent

Conditions

Temperature
-30 °C

Procedure

Under nitrogen atmosphere, 7.1 mL (50.6 mmol, 3 eq) of diisopropylamine was added to 200 mL of THF. At −73˜−68° C., 31.6 mL (50.6 mmol, 3 eq) of a 1.6 M solution of n-butyllithium in hexane was added dropwise over 10 minutes. After stirred at 75˜−68° C. for 10 minutes, 5 mL of ethyl acetate was added dropwise at −75˜−70° C. over 5 minutes. After stirred at −75˜−70° C. for 30 minutes, a solution of 8.8 g (16.8 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 22 mL of THF was added dropwise at −75˜−65° C. over 5 minutes. After stirred at −75˜−65° C. for 30 minutes, the mixture was warmed to −30° C. After stirred for 5 minutes, 50 mL of an aqueous saturated ammonium chloride solution was added dropwise at −70˜−40° C., and a temperature was rised to room temperature. After the layers were separated, the aqueous layer was re-extracted with 100 mL of ethyl acetate. The organic layers were combined, and washed with 50 mL of an aqueous saturated sodium chloride solution. After concentration under reduced pressure, 100 mL of n-heptane was added to the concentration residue, followed by stirring at room temperature for 30 minutes. Crystals were filtered, and washed with 50 mL of n-heptane. Vacuum drying (50° C.) to a constant weight afforded 9.82 g of ethyl 3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 96%).

Workup

  1. stirringAfter stirred at −75˜−70° C. for 30 minutes
  2. stirringAfter stirred at −75˜−65° C. for 30 minutes
  3. stirringAfter stirred for 5 minutes
  4. customwas rised to room temperature
  5. customAfter the layers were separated
  6. extractionthe aqueous layer was re-extracted with 100 mL of ethyl acetate
  7. washwashed with 50 mL of an aqueous saturated sodium chloride solution
  8. concentrationAfter concentration under reduced pressure, 100 mL of n-heptane
  9. additionwas added to the concentration residue
  10. stirringby stirring at room temperature for 30 minutes
  11. filtrationCrystals were filtered
  12. washwashed with 50 mL of n-heptane
  13. customVacuum drying (50° C.) to a constant weight

Sources & evidence

ORD record
ord-ab15232638774cc1bf8812f2be6f646f
Source dataset
uspto-grants-2012_01
Patent number
US08093403B2

Reaction notes

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