Citric Acid → 3-[(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one

HRID 1250996Notes

Reaction equation

HRID 1250996 reaction equation
[C:1]([N:5]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[C:6]1=[O:20])(=[O:4])[CH2:2][CH3:3].C([Mg]Cl)CCC.C(O[C@H:31]1[NH:34][C:33](=[O:35])[C@@H:32]1[C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH3:37])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[Si:39]([O:38][C@@H:36]([C@@H:32]1[C@@H:31]([C@@H:2]([CH3:3])[C:1]([N:5]2[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[O:9][C:8]3[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=3[C:6]2=[O:20])=[O:4])[NH:34][C:33]1=[O:35])[CH3:37])([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:40])[CH3:41]

Participants

7

Reactant 4

HCID 311Citric AcidHCID 10935078AzetidonHCID 158376183-propionyl-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-oneHCID 178418265HCID 178418265, compound

Product 1

HCID 103458983-[(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-oneYield 53%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
5 °C

Procedure

Under a nitrogen atmosphere, 273 mg (1.0 mmol) of 3-propionyl-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1′-cyclohexan]-4-one was charged in a 30-ml three-necked flask to dissolve it in 2 ml of tetrahydrofuran. To the resulting solution, 2.44 ml (2.2 mmol) of a tetrahydrofuran solution (0.9M) of n-butylmagnesium chloride was slowly added dropwise at room temperature. The resulting mixture was reacted for 25 minutes under the same conditions. After cooling to 5° C., 2 ml of a tetrahydrofuran solution of 287 mg (1.0 mmol) of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one was added at the same temperature. The resulting mixture was stirred for 15 minutes, added with 10 ml of ethyl acetate and then added dropwise with 2 ml of a 10% aqueous solution of citric acid. After separation, the organic layer was washed with 2 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by column chromatography, whereby 263 mg (0.53 mmol) of a condensation product was obtained (yield: 53%, β:α=92:8).

Workup

  1. customThe resulting mixture was reacted for 25 minutes under the same conditions
  2. customAfter separation
  3. washthe organic layer was washed with 2 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of a saturated aqueous solution of sodium chloride
  4. dry with materialdried over anhydrous magnesium sulfate
  5. distillationdistilled
  6. customto remove the solvent
  7. customThe residue was purified by column chromatography

Sources & evidence

ORD record
ord-0eab90b07b704c32ae45d4d0f3266bc1
Source dataset
uspto-grants-2002_01
Patent number
US06340751B1

Reaction notes

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