Methyl Nicotinate → [2,2-Dimethyl-3-(3-oxo-3-pyridin-3-yl-propionyl)cyclobutyl]acetic acid tert-butyl ester

HRID 432853Notes

Reaction equation

HRID 432853 reaction equation
[C:1]([O:5][C:6](=[O:17])[CH2:7][CH:8]1[CH2:11][CH:10]([C:12](=[O:14])[CH3:13])[C:9]1([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2].[C:18](OC)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>C1COCC1>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH:8]1[CH2:11][CH:10]([C:12](=[O:14])[CH2:13][C:18](=[O:25])[C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:9]1([CH3:16])[CH3:15])([CH3:4])([CH3:2])[CH3:3]

Participants

4

Reactant 2

HCID 7151Methyl NicotinateHCID 206090683-Acetyl-2,2-dimethylcyclobutylacetic acid tert-butyl ester

Product 1

HCID 20609066[2,2-Dimethyl-3-(3-oxo-3-pyridin-3-yl-propionyl)cyclobutyl]acetic acid tert-butyl esterYield 49.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
5 °C

Procedure

Tert-butyl ester 7 (47.7 g, 199 mmol) and methyl nicotinate (27.3 g, 199 mmol) were dissolved in THF (1 L) and cooled to 5° C. KOBut (44.6 g, 398 mmol) was added in 4 portions over 1 h. The reaction was stirred at 0° C. for 2 h. The reaction was quenched with saturated NH4Cl (200 mL) and concentrated to an oil. The residue was dissolved in EtOAc and washed with saturated NH4Cl (300 mL×3). The combined aqueous layers were extracted with EtOAc (100 mL×2). The organic layers were combined and dried with brine and MgSO4 and concentrated in vacuo. The residue was purified by chromatography (hexane-EtOAc, 2:1 to 1:1). Diketone 9 (33.8 g, 49%) was obtained as a yellow crystalline solid; the methyl ester of 7 (16.2 g, 26%) and a mixture (1:1) of both esters (11.5 g, 17%) were also collected as yellow crystalline solids.

Workup

  1. additionKOBut (44.6 g, 398 mmol) was added in 4 portions over 1 h
  2. customThe reaction was quenched with saturated NH4Cl (200 mL)
  3. concentrationconcentrated to an oil
  4. dissolutionThe residue was dissolved in EtOAc
  5. washwashed with saturated NH4Cl (300 mL×3)
  6. extractionThe combined aqueous layers were extracted with EtOAc (100 mL×2)
  7. dry with materialdried with brine and MgSO4
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by chromatography (hexane-EtOAc, 2:1 to 1:1)

Sources & evidence

ORD record
ord-d014e95bbcc14e5da2e6fb50519c5a46
Source dataset
uspto-grants-2003_12
Patent number
US06664277B1

Reaction notes

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