N-Hydroxyphthalimide → Propanoic acid,2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-,1,1-dimethylethyl ester,(2S)-

HRID 708399Notes

Reaction equation

HRID 708399 reaction equation
[OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl[C@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[Li+].[Cl-]>CN(C=O)C.CCOC(C)=O>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][C@@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]

Participants

7

Reactant 4

HCID 10665N-HydroxyphthalimideHCID 11430Potassium CarbonateHCID 433294Lithium ChlorideHCID 10986598(R)-tert-Butyl 2-chloropropanoate

Product 1

HCID 57751243Propanoic acid,2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-,1,1-dimethylethyl ester,(2S)-Yield 38%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Prepared according to Yamawaki et al. Bioorg. Med. Chem. 2007, 15, 6716. To a slurry of N-hydroxyphthalimide (517 mg, 3.17 mmol) and potassium carbonate (657 mg, 4.76 mmol) in DMF (4.5 mL) was added (R)-tert-butyl 2-chloropropanoate (522 mg, 3.17 mmol). Additional DMF (4.5 mL) was added after the slurry became viscous. After stirring for 5 d it was diluted with EtOAc and poured into LiCl soln (5% aq, 90 mL). The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with LiCl (5% aq), brine, dried over Na2SO4 and concd in vacuo. The crude residue was purified by silica gel chromatography (EtOAc-Heptane, 0-50%), affording the title compound (348 mg, 38%) as a white solid. LCMS: Rt=0.89 min, m/z=314.0 (M+23) Method 2m_acidic; 1H NMR (400 MHz, CDCl3) δ 7.87-7.81 (m, 2H), 7.75 (dd, J=5.5, 3.1 Hz, 2H), 4.79 (q, J=6.8 Hz, 1H), 1.61 (s, 3H), 1.46 (s, 9H).

Workup

  1. customPrepared
  2. extractionThe aqueous layer was extracted with EtOAc (3×)
  3. washthe combined organic layers were washed with LiCl (5% aq), brine
  4. dry with materialdried over Na2SO4 and concd in vacuo
  5. customThe crude residue was purified by silica gel chromatography (EtOAc-Heptane, 0-50%)

Sources & evidence

ORD record
ord-1eccd193ff5e4930aacae21068a60763
Source dataset
uspto-grants-2015_11
Patent number
US09174978B2

Reaction notes

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