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

HRID 1438361Notes

Reaction equation

HRID 1438361 reaction equation
[C:1](OC)(=O)[CH2:2][C:3]([CH3:5])=O.[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][CH2:5][CH2:3][CH2:2][CH2:1]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 866100606-Cyclopentyl-6-[2-(5-ethoxy-2-ethylpyridin-4-yl)ethyl]dihydro-2H-pyranYield 108.9%

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 1N 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, 3H), 1.43 (t, J=6.8 Hz, 3H), 1.50-2.05 (br m, 9H), 2.34 (m, 2H), 2.62-2.77 (m, 6H), 3.44 (m, 2H), 4.11 (q, J=6.8 Hz, 2H), 6.90 (s, 1H), 8.08 (s, 1H).

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-5e7e7d8768f5474895ebdf25f58ca0de
Source dataset
uspto-grants-2009_11
Patent number
US07622605B2

Reaction notes

Loading…