Diisopropylamine → 2-tert-Butyl-5-[2-(2,4-difluoro-benzyl)-butyl]-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic Acid Methyl Ester

HRID 132647Notes

Reaction equation

HRID 132647 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[N:19]([CH3:24])[C@@H:18]1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:16].[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH2:37][C@@H:38]([CH2:41]I)[CH2:39][CH3:40]>C1COCC1>[CH3:13][O:14][C:15]([N:17]1[CH2:22][CH:21]([CH2:41][CH:38]([CH2:37][C:31]2[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=2[F:29])[CH2:39][CH3:40])[C:20](=[O:23])[N:19]([CH3:24])[CH:18]1[C:25]([CH3:28])([CH3:27])[CH3:26])=[O:16]

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 69268259(S)-2,4-difluoro-1-(2-iodomethyl-butyl)-benzeneHCID 69268866(S)-2-tert-butyl-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl esterHCID 178418339Butyllithium

Product 1

HCID 692681512-tert-Butyl-5-[2-(2,4-difluoro-benzyl)-butyl]-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic Acid Methyl EsterYield 46.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

A flask was charged with 1.35 mL (9.64 mmol) of diisopropyl amine and 15 mL of dry THF. The solution was cooled to −78° C. and 6.0 mL (9.64 mmol) of 1.6 M n-butyl lithium solution in hexanes was added. The mixture was warmed to 0° C. and stirred for 30 minutes. The mixture was cooled again to −78° C. and 2.0 g (8.76 mmol) of (2S)-2-tert-butyl-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester was added as a solution in 10 mL of THF. This mixture was warmed to 0° C. and stirred for 1 hour. The anion solution was cooled again to −78° C. and 2.99 g (9.64 mmol) of (S)-2,4-difluoro-1-(2-iodomethyl-butyl)-benzene was added as a solution in THF. The mixture was stirred at −78° C. for 4 hours. The reaction mixture was warmed to −21° C. and stirred at that temperature for 5 days. The reaction mixture was quenched with sat. aq. ammonium chloride solution. The crude reaction mixture was extracted with diethyl ether. The ether was removed under reduced pressure, and the crude residue was purified by column chromatography (9:1 hexanes/EtOAc eluent) which gave 1.67 g (46% yield) of the titled compound as a white solid.

Workup

  1. temperatureThe mixture was warmed to 0° C.
  2. temperatureThe mixture was cooled again to −78° C.
  3. temperatureThis mixture was warmed to 0° C.
  4. stirringstirred for 1 hour
  5. temperatureThe anion solution was cooled again to −78° C.
  6. stirringThe mixture was stirred at −78° C. for 4 hours
  7. temperatureThe reaction mixture was warmed to −21° C.
  8. stirringstirred at that temperature for 5 days
  9. customThe reaction mixture was quenched with sat. aq. ammonium chloride solution
  10. customThe crude reaction mixture
  11. extractionwas extracted with diethyl ether
  12. customThe ether was removed under reduced pressure
  13. customthe crude residue was purified by column chromatography (9:1 hexanes/EtOAc eluent) which

Sources & evidence

ORD record
ord-315e91a96aea403580f821ad30cd47d7
Source dataset
uspto-grants-2008_06
Patent number
US07388023B2

Reaction notes

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