4-Methylmorpholine → 4-Benzyl-3-[2-(5-benzyloxy-4'-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one

HRID 226549Notes

Reaction equation

HRID 226549 reaction equation
[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26](O)=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.CC(C)(C)C(Cl)=O.[CH2:43]([C@@H:50]1[CH2:54][O:53][C:52](=[O:55])[NH:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[Li]CCCC>C1COCC1>[CH2:43]([CH:50]1[CH2:54][O:53][C:52](=[O:55])[N:51]1[C:26](=[O:27])[CH2:25][C:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=2)[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 62493Pivaloyl chlorideHCID 2734969(R)-4-Benzyl-2-oxazolidinoneHCID 11501912(5-Benzyloxy-4'-trifluoromethyl-biphenyl-3-yl)-acetic acidHCID 178418339Butyllithium

Product 1

HCID 666982364-Benzyl-3-[2-(5-benzyloxy-4'-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-oneYield 72%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a mechanically stirred solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (20 g, 52 mmol) in THF (104 mL) at −78° C. was added N-methyl morpholine (NMM) (6.3 mL, 57 mmol) and trimethylacetyl chloride (7.0 mL, 57 mmol) maintaining the internal temperature below −70° C. This mixture was stirred at −78° C. for 15 minute and 0° C. at 1 h. The white solid was filtered off to receive the anhydride in the filtrate which was cooled back to −78° C. In a separate flask, to a solution of (R)-(+)-4-benzyl-2-oxazolidinone (9.6 g, 54.4 mmol) in THF (109 mL) at −78° C. was added nBuLi (1.6M in hexanes, 34 mL, 54.4 mol), drop-wise, maintaining the internal temperature below −70° C. and stirred at −78° C. for 45 min. This metalated chiral auxiliary was cannulated to the anhydride at −78° C. and warmed to 0° C. over 1.5 h. The resulting mixture was stirred further at 0° C. for 30 minute and quenched by adding excess saturated aqueous NH4Cl solution. The solution was diluted with EtOAc (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×100 mL) and brine (2×100 mL). The solution was dried over MgSO4 and the solvent was removed in vacuo. The crude material was purified by ISCO silica gel column chromatography to yield 20.3 g (72%) of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one as a white solid.

Workup

  1. temperaturemaintaining the internal temperature below −70° C
  2. filtrationThe white solid was filtered off
  3. temperaturewas cooled back to −78° C
  4. temperaturemaintaining the internal temperature below −70° C.
  5. stirringstirred at −78° C. for 45 min
  6. temperaturewarmed to 0° C. over 1.5 h
  7. stirringThe resulting mixture was stirred further at 0° C. for 30 minute
  8. customquenched
  9. additionby adding excess saturated aqueous NH4Cl solution
  10. additionThe solution was diluted with EtOAc (200 mL)
  11. washthe organic phase was washed with saturated aqueous NaHCO3 solution (3×100 mL) and brine (2×100 mL)
  12. dry with materialThe solution was dried over MgSO4
  13. customthe solvent was removed in vacuo
  14. customThe crude material was purified by ISCO silica gel column chromatography

Sources & evidence

ORD record
ord-4dcc7e03208343cea45dda0424c0a7bc
Source dataset
uspto-grants-2009_07
Patent number
US07557244B2

Reaction notes

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