Methyl acetoacetate → 6-Cyclopentyl-6-[2-(5-ethoxy-2-ethylpyridin-4-yl)ethyl]dihydro-2H-pyran-2,4(3H)-dione

HRID 859777Notes

Reaction equation

HRID 859777 reaction equation
[C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Li+].CC([N-]C(C)C)C.[CH:17]1([C:22](=[O:36])[CH2:23][CH2:24][C:25]2[C:30]([O:31][CH2:32][CH3:33])=[CH:29][N:28]=[C:27]([CH2:34][CH3:35])[CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:17]1([C:22]2([CH2:23][CH2:24][C:25]3[C:30]([O:31][CH2:32][CH3:33])=[CH:29][N:28]=[C:27]([CH2:34][CH3:35])[CH:26]=3)[O:36][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5]2)[CH2:21][CH2:20][CH2:19][CH2:18]1

Participants

7

Reactant 5

HCID 7757Methyl acetoacetateHCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 2724682Lithium diisopropylamideHCID 587642861-Cyclopentyl-3-(5-ethoxy-2-ethyl-pyridin-4-yl)-propan-1-one

Product 1

HCID 587641966-Cyclopentyl-6-[2-(5-ethoxy-2-ethylpyridin-4-yl)ethyl]dihydro-2H-pyran-2,4(3H)-dioneYield 100.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Methyl acetoacetate (1.2 mL, 10.9 mmol) was added to a cooled −50° C. suspension of LDA [prepared from diisopropylamine (3.0 mL, 21.8 mmol), and n-BuLi (8.7 mL, 21.8 mmol) dissolved in THF (30 mL)]. The reaction was stirred for 30 mins and then a solution of 1-cyclopentyl-3-(5-ethoxy-2-ethyl-pyridin-4-yl)-propan-1-one (1.0 g, 3.6 mmol) dissolved in THF (30 mL) was added. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was poured into 1 N NaOH and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. The residue was dissolved in methanol (100 mL), treated with potassium carbonate (1.5 g, 10.9 mmol), and refluxed under N2 for 120 mins. The reaction mixture was partitioned between H2O and IPE. The aqueous layer was made neutral with 1 N HCl and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated to give the product (1.3 g, 99% yield). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=7.6 Hz, 3 H), 1.43 (t, J=6.8 Hz, 3 H), 1.50–2.05 (br m, 9 H), 2.34 (m, 2 H), 2.62–2.77 (m, 6 H), 3.44 (m, 2 H), 4.11 (q, J=6.8 Hz, 2 H), 6.90 (s, 1 H), 8.08 (s, 1 H).

Workup

  1. additionwas added
  2. stirringstirred for 2 hours
  3. extractionextracted with EtOAc
  4. dry with materialThe organic layers were dried over MgSO4
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in methanol (100 mL)
  7. temperaturerefluxed under N2 for 120 mins
  8. customThe reaction mixture was partitioned between H2O and IPE
  9. extractionextracted with EtOAc
  10. dry with materialThe organic layers were dried over MgSO4
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-62281f76b6dd4f518ab5cb81e53afe71
Source dataset
uspto-grants-2006_12
Patent number
US07151105B2

Reaction notes

Loading…