Citric Acid → [(S*)-2-(3-Benzyloxy-phenyl)-1-((2S*,4R*)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl ester

HRID 1432334Notes

Reaction equation

HRID 1432334 reaction equation
[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C@@H:24]1[CH:28]=[CH:27][C:26](=[O:29])[O:25]1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13](OCC2C=CC=CC=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31]N1C(=O)N(C)CCC1.[Li].C[Si]([N-][Si](C)(C)C)(C)C.CI.[C:52]([OH:56])(=O)[CH2:53][CH3:54].[C:57](O)(=O)[CH2:58][C:59](CC(O)=O)([C:61](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][CH:13]=[C:14]([O:56][CH2:52][C:53]2[CH:54]=[CH:61][CH:59]=[CH:58][CH:57]=2)[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

9

Reactant 6

HCID 311Citric AcidHCID 1032Propionic AcidHCID 6328Methyl iodideHCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-HCID 68890839[(S*)-2-(4-Benzyloxy-phenyl)-1-((S*)-5-oxo-2,5-dihydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl esterHCID 86605622Lithium bistrimethylsilylamide

Product 1

HCID 11495571[(S*)-2-(3-Benzyloxy-phenyl)-1-((2S*,4R*)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of [(S*)-2-(4-Benzyloxy-phenyl)-1-((S*)-5-oxo-2,5-dihydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl ester (11.4 g, 27.7 mmol) in THF (35 ml) and DMPU (5 ml, 42 mmol, 1.5 eq) at −78° C. is added dropwise lithium-bis-(trimethylsilyl)-amide (55 ml 1M solution in THF, 55 mmol, 2 eq). After stirring at −78° C. for another 45 min methyliodide is added dropwise and the mixture is stirred another 3 h at −78° C. Propionic acid (10.3 ml, 138 mmol, 5 eq) is added followed by water (10 ml). After warming up to 0° C. a 10% solution of citric acid (72 ml) is added. The reaction mixture is extracted with EtOAc. The organic layer is washed with bicarbonate, 0.1N sodium sulfite and brine, dried over magnesium sulfate and evaporated. Purification by chromatography on silica (hexane/EtOAc 9/1 to 4/1) followed by recrystallization from ether/hexane gives white crystals (8.14 g).

Workup

  1. additionis added dropwise
  2. additionis added
  3. extractionThe reaction mixture is extracted with EtOAc
  4. washThe organic layer is washed with bicarbonate, 0.1N sodium sulfite and brine
  5. dry with materialdried over magnesium sulfate
  6. customevaporated
  7. customPurification by chromatography on silica (hexane/EtOAc 9/1 to 4/1)
  8. customfollowed by recrystallization from ether/hexane

Sources & evidence

ORD record
ord-fd168027a4dd49a89b5072d425dc32a4
Source dataset
uspto-grants-2009_11
Patent number
US07612054B2

Reaction notes

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