1,1'-Carbonyldiimidazole → 4-((tert-Butoxycarbonyl)amino)-3-oxobutanoic acid ethyl ester

HRID 1056102Notes

Reaction equation

HRID 1056102 reaction equation
C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([NH:20][CH2:21][C:22]([OH:24])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl-].[Mg+2].[Cl-].[C:28]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:29]C([O-])=O.[K+]>C1COCC1>[C:16]([O:15][C:13]([NH:20][CH2:21][C:22](=[O:24])[CH2:29][C:28]([O:34][CH2:35][CH3:36])=[O:33])=[O:14])([CH3:17])([CH3:18])[CH3:19]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 78288N-(tert-butoxycarbonyl)glycineHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium Chloride

Product 1

HCID 111285644-((tert-Butoxycarbonyl)amino)-3-oxobutanoic acid ethyl esterYield 74%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

Referenced: J. Med. Chem. 2008, 51 (3), 487-501. At RT, 1,1′-carbonyldiimidazole (13.88 g, 86 mmol) was added to a solution of N-Boc-glycine (Sigma-Aldrich Chemical Company, Inc.) (10.00 g, 57.1 mmol) in THF (200 mL) and the mixture was stirred for 3 h. Magnesium chloride (10.87 g, 114 mmol) and potassium ethyl malonate (Sigma-Aldrich Chemical Company, Inc.) (19.43 g, 114 mmol) were added and the resulting suspension was heated in an oil bath at 50° C. for 18 h. The reaction mixture was concentrated under reduced pressure. The off-white residue was treated with EtOAc (300 mL), then washed sequentially with 5% sodium bisulfate (2×25 mL), saturated NaHCO3 (2×50 mL), and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by chromatography through a Thomson Single Step pre-packed silica gel column (160 g, eluted with a gradient of 0-75% EtOAc in hexanes) to provide ethyl 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate (10.33 g, 42.1 mmol, 74% yield) as a colorless viscous oil after drying under vacuum overnight. 1H NMR (400 MHz, CDCl3) δ ppm 5.16 (1H, d, J=5.7 Hz), 4.21 (2H, m), 4.08-4.16 (2H, m), 3.48 (2H, s), 1.45 (9H, s), 1.29 (3H, m). m/z (ESI, +ve) 268.0 (M+Na)+.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. additionThe off-white residue was treated with EtOAc (300 mL)
  3. washwashed sequentially with 5% sodium bisulfate (2×25 mL), saturated NaHCO3 (2×50 mL), and brine (25 mL)
  4. dry with materialThe organic layer was dried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was purified by chromatography through a Thomson Single Step pre-packed silica gel column (160 g
  8. washeluted with a gradient of 0-75% EtOAc in hexanes)

Sources & evidence

ORD record
ord-f5db5e460e224167b2b2394f01a51386
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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