Acetic Acid → Ethyl 3-(3,5-dibromopyridin-4-yl)propanoate

HRID 714059Notes

Reaction equation

HRID 714059 reaction equation
[Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:17])[C:15]=1[CH3:16].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].CC(O)=O>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:17])[C:15]=1[CH2:16][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 7748Ethyl bromoacetateHCID 8193383,5-Dibromo-4-methylpyridineHCID 2724682Lithium diisopropylamide

Product 1

HCID 86685955Ethyl 3-(3,5-dibromopyridin-4-yl)propanoateYield 32%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of LDA (0.308 mol) [generated from N,N-diisopropylamine (31.2 g, 0.308 mol) and n-BuLi (123 mL, 0.308 mol, 2.5M in hexane) in 800 mL THF] was added slowly a solution of 3,5-dibromo-4-methylpyridine (70 g, 0.28 mol) in THF (300 mL) while the inner temperature was maintained below −70° C. After the addition, the resulting mixture was stirred for another 30 min at −78° C. before ethyl bromoacetate (116.9 g, 0.7 mol) was slowly added and the reaction mixture was stirred at −78° C. for another 1.5 h. 10% aq. AcOH was added (resulting pH=4-5), and the reaction was allowed to warm up to room temperature. After evaporation of solvent, the residue was poured into sat. aq. NaHCO3 solution, and was extracted with EtOAc (1 L×3). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by column chromatography (n-pentane:EtOAc=15:1˜5:1) to afford the title compound (30 g, 32%) as a gray solid. MS: 337.7 (M+H+, 2 Br).

Workup

  1. temperaturewas maintained below −70° C
  2. additionAfter the addition
  3. additionwas slowly added
  4. custom(resulting pH=4-5)
  5. temperatureto warm up to room temperature
  6. customAfter evaporation of solvent
  7. additionthe residue was poured into sat. aq. NaHCO3 solution
  8. extractionwas extracted with EtOAc (1 L×3)
  9. washThe combined organic layers were washed with brine
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customto give a crude product which
  14. customwas purified by column chromatography (n-pentane:EtOAc=15:1˜5:1)

Sources & evidence

ORD record
ord-23690defede94de893d779e37ecff661
Source dataset
uspto-grants-2015_11
Patent number
US09187429B2

Reaction notes

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