(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one → (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one

HRID 1096369

Reaction equation

HRID 1096369 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:16][C:17]([OH:19])([CH3:28])[CH3:18])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 59635654(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-oneHCID 178418573HCID 178418573, compound

Product 1

HCID 59635628(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-oneYield 46%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (5.25 g, 12.1 mmol) in anhydrous THF (100 mL) was added dropwise methylmagnesium bromide (20 mL, 60 mmol) at −78° C. under nitrogen. Then the mixture was stirred at rt for 2 h. The reaction mixture was cooled in an ice bath and quenched with aqueous NH4Cl. The layers were separated. The aqueous layer was extracted with EtOAc (15 mL), washed with a brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC and chiral HPLC to afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one (2.5 mg, 46%). 1H NMR (CDCl3): 1.08 (s, 3H), 1.12 (s, 3H), 1.48 (m, 3H), 1.99 (m, 1H), 2.10-2.24 (m, 4H), 2.35 (m, 1H), 2.85 (m, 1H), 5.61 (m, 1H), 6.80 (m, 2H), 6.99 (m, 2H), 7.15-7.28 (m, 5H).

Workup

  1. temperatureThe reaction mixture was cooled in an ice bath
  2. customquenched with aqueous NH4Cl
  3. customThe layers were separated
  4. extractionThe aqueous layer was extracted with EtOAc (15 mL)
  5. washwashed with a brine (30 mL)
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customto give the crude product, which
  9. customwas purified by preparative HPLC and chiral HPLC

Sources & evidence

ORD record
ord-ba359a9a10a24340a608ff42d778d25c
Source dataset
uspto-grants-2012_03
Patent number
US08138178B2

Linked notes

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