Diisopropylamine → 2-(4-Bromo-2-fluoro-benzyl)-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester

HRID 1192375Notes

Reaction equation

HRID 1192375 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:17][C:18](=[O:29])[CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:16])([CH3:15])[CH3:14].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[C:33]([F:39])[CH:32]=1>C1COCC1>[C:13]([O:17][C:18](=[O:29])[CH:19]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([Br:30])=[CH:32][C:33]=1[F:39])[CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:16])([CH3:15])[CH3:14]

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 27336604-Bromo-2-fluorobenzyl bromideHCID 540966173-Tert-butoxycarbonylamino-propionic acid tert-butyl esterHCID 178418339Butyllithium

Product 1

HCID 675390002-(4-Bromo-2-fluoro-benzyl)-3-tert-butoxycarbonylamino-propionic acid tert-butyl esterYield 77%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

To a stirred solution of diisopropyl amine (1.3 mL, 9.0 mmol) in THF (20 mL) was added n-BuLi (1.6 M solution in hexanes, 5.6 mL, 9.0 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes and then cooled to −78° C. A solution of 3-tert-butoxycarbonylamino-propionic acid tert-butyl ester (1.0 g, 4.1 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at −78° C. for 2 hours. A solution of 4-Bromo-1-bromomethyl-2-fluoro-benzene (1.3 g, 4.9 mmol) in THF (4 mL) was added dropwise. After completion, the dry-ice bath was removed and the reaction was warmed to 0° C. in an ice bath. After stirring at 0° C. for 30 minutes, the reaction was poured into saturated NH4Cl aqueous solution. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexane:EtOAc, 20:1 to 5:1) to give 2-(4-Bromo-2-fluoro-benzyl)-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester (1.35 g, 77%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.20 (d, J=8.0 Hz, 2H), 7.08 (t, J=8.0 Hz, 1H), 4.86 (m, 1H), 3.28 (m, 2H), 2.92 (m, 3H), 1.43 (s, 9H), 1.36 (s, 9H).

Workup

  1. temperaturecooled to −78° C
  2. stirringThe mixture was stirred at −78° C. for 2 hours
  3. customAfter completion, the dry-ice bath was removed
  4. temperaturethe reaction was warmed to 0° C. in an ice bath
  5. stirringAfter stirring at 0° C. for 30 minutes
  6. additionthe reaction was poured into saturated NH4Cl aqueous solution
  7. customThe organic layer was separated
  8. extractionThe aqueous layer was extracted with EtOAc
  9. washThe combined organic layers were washed with brine
  10. customdried
  11. concentrationconcentrated
  12. customThe residue was purified by column chromatography (hexane:EtOAc, 20:1 to 5:1)

Sources & evidence

ORD record
ord-87df00e4904c40e3b84c626a82ae0c56
Source dataset
uspto-grants-2014_03
Patent number
US08680114B2

Reaction notes

Loading…