Lithium Hexamethyldisilazide → (R)-4-benzyl-3-[(S)-2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one

HRID 1013795Notes

Reaction equation

HRID 1013795 reaction equation
[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][C:33]=1[Cl:47]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:31][C:32]1[C:33]([Cl:47])=[CH:34][C:35]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:36][C:37]=1[Cl:38])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 10858190(R)-4-Benzyl-3-pent-4-enoyloxazolidin-2-oneHCID 592994282-Bromomethyl-1,3-dichloro-5-benzyloxy-benzene

Product 1

HCID 66671784(R)-4-benzyl-3-[(S)-2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-oneYield 86%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-75 °C

Procedure

Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (345 g, 1.33 mol) and THF (1.8 L) in a 12 L 3-neck round bottom flask, with internal temperature probe/nitrogen inlet and addition funnel, under a nitrogen atmosphere and cool to −75° C. Transfer 1 M LiHMDS (1.6 L) to the addition funnel and add at a rate such that the internal temperature does not reach above −60° C. After the addition is complete, allow the reaction to stir at −25° C. for 30 min then cool to about −60° C. At this point add solid 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene portionwise over 5 min. When the addition is complete, transfer the reaction vessel to a −10° C. acetone bath and maintain the internal reaction temperature below 10° C. for 1 hr. Cool the mixture to 0° C. then quench with 2 L aqueous 1N hydrochloric acid. Transfer the mixture to a 22 L separatory funnel and dilute with 2.5 L water and 2 L ether. Separate the layers and extract the aqueous layer with ether. Dry the combined organic phase over anhydrous magnesium sulfate, filter and concentrate to 800 g of a thick oil. Purify by silica gel chromatography using hexanes:ethyl acetate to obtain 597 g, (86%) of a colorless oil.

Workup

  1. additionwith internal temperature probe/nitrogen inlet and addition funnel
  2. additionadd at a rate such that the internal temperature
  3. customdoes not reach above −60° C
  4. additionAfter the addition
  5. customthe reaction
  6. stirringto stir at −25° C. for 30 min
  7. temperaturethen cool to about −60° C
  8. additionWhen the addition
  9. customto a −10° C.
  10. temperaturemaintain the internal reaction temperature below 10° C. for 1 hr
  11. temperatureCool the mixture to 0° C.
  12. customthen quench with 2 L aqueous 1N hydrochloric acid
  13. additionTransfer the mixture to a 22 L separatory funnel and dilute with 2.5 L water and 2 L ether
  14. customSeparate the layers
  15. extractionextract the aqueous layer with ether
  16. dry with materialDry the combined organic phase over anhydrous magnesium sulfate
  17. filtrationfilter
  18. concentrationconcentrate to 800 g of a thick oil
  19. customPurify by silica gel chromatography

Sources & evidence

ORD record
ord-008791fa9ce44105b3bd2d875aa3d80a
Source dataset
uspto-grants-2011_07
Patent number
US07981918B2

Reaction notes

Loading…