Butyl bromide → (E)-3-{1'-tert-butoxycarbonyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester

HRID 2046709Notes

Reaction equation

HRID 2046709 reaction equation
[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[H-].[Na+].Br[CH2:33][CH2:34][CH2:35][CH3:36]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:12]([CH2:33][CH2:34][CH2:35][CH3:36])[C:11](=[O:27])[C:10]=2[CH:28]=1

Participants

5

Reactant 3

HCID 8002Butyl bromideHCID 24758Sodium hydrideHCID 66932321(E)-3-{1'-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester2×

Product 1

HCID 58147941(E)-3-{1'-tert-butoxycarbonyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl esterYield 39.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
4 °C

Procedure

(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (Intermediate 5 STEP B, 500 mg, 1.24 mmol) was dissolved in dry DMF (4.5 ml) and added dropwise to a stirred suspension of NaH (60% oil dispersion, 59.6 mg, 1.49 mmol) in dry DMF (4.5 ml) cooled at 4° C. The mixture was stirred for 10 min at 0° C. and then 1-bromobutane (0.205 ml, 1.86 mmol) was added dropwise. The resulting yellow solution was stirred overnight at RT and then partitioned between EtOAc and saturated solution of NH4Cl. The organic layer was rinsed twice with water, dried over Na2SO4 and concentrated to dryness. The crude mixture was purified by column chromatography (eluent:petroleum ether:AcOEt 75:25) to give (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester as white foam (225 mg).

Workup

  1. stirringThe resulting yellow solution was stirred overnight at RT
  2. custompartitioned between EtOAc and saturated solution of NH4Cl
  3. washThe organic layer was rinsed twice with water
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated to dryness
  6. customThe crude mixture was purified by column chromatography (eluent:petroleum ether:AcOEt 75:25)

Sources & evidence

ORD record
ord-60b6b27570414a90ad73cc1adbb0d27b
Source dataset
uspto-grants-2013_11
Patent number
US08592444B2

Reaction notes

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