Citric Acid → [(S)-2-(4-Benzyloxy-phenyl)-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl ester

HRID 1432339Notes

Reaction equation

HRID 1432339 reaction equation
[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C@@H:24]1[CH2:28][CH2:27][C:26](=[O:29])[O:25]1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31]N1C(=O)N(C)CCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CI.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C@@H:24]1[CH2:28][C@@H:27]([CH3:31])[C:26](=[O:29])[O:25]1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

9

Reactant 6

HCID 311Citric AcidHCID 1032Propionic AcidHCID 6328Methyl iodideHCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-HCID 2733832Lithium HexamethyldisilazideHCID 54401688[(S)-2-(4-Benzyloxy-phenyl)-1-((S)-5-oxo-tetrahydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl ester

Product 1

HCID 86612514[(S)-2-(4-Benzyloxy-phenyl)-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl esterYield 73.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

[(S)-2-(4-Benzyloxy-phenyl)-1-((S)-5-oxo-tetrahydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl ester (2.9 g, 7.04 mmol) is dissolved in THF (10 ml) and DMPU (1.34 ml, 10.6 mmol, 1.5 eq). A 1 M solution of lithium hexamethyldisilazide in THF (14.1 ml, 14.1 mmol, 2 eq) is added at −78° C. over 40 min and the mixture is stirred for another 20 min. Methyliodide (0.88 ml, 14.1 mmol, 2 eq) is added dropwise and the mixture is stirred for another 3 h at −78° C. before adding propionic acid (2.69 ml, 36 mmol, 5 eq) and water. After warming up to rt the mixture is poured on 10% citric acid (50 ml) and extracted with EtOAc. The organic layer is washed with bicarbonate and brine, dried over magnesium sulfate and evaporated. The crude product is purified by chromatography on silica (hexane/EtOAc 8/2 to 7/3) followed by recrystallization from hexane/DCM to give 2.2 g white solid.

Workup

  1. stirringthe mixture is stirred for another 3 h at −78° C.
  2. extractionextracted with EtOAc
  3. washThe organic layer is washed with bicarbonate and brine
  4. dry with materialdried over magnesium sulfate
  5. customevaporated
  6. customThe crude product is purified by chromatography on silica (hexane/EtOAc 8/2 to 7/3)
  7. customfollowed by recrystallization from hexane/DCM

Sources & evidence

ORD record
ord-ff85f98762d145f5837296ab64e6291a
Source dataset
uspto-grants-2009_11
Patent number
US07612054B2

Reaction notes

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