Diethyl Malonate → Ethyl 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate

HRID 601123Notes

Reaction equation

HRID 601123 reaction equation
[H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7]CC)=O.[CH2:14]([N:21]1[C:26]2[N:27]=[CH:28][CH:29]=[CH:30][C:25]=2C(=O)[O:23][C:22]1=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(N(C)C)=O>[CH2:14]([N:21]1[C:26]2[C:25](=[CH:30][CH:29]=[CH:28][N:27]=2)[C:5]([OH:7])=[C:4]([C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:22]1=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1

Participants

5

Reactant 3

HCID 7761Diethyl MalonateHCID 24758Sodium hydrideHCID 134251031-Benzyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione

Product 1

HCID 54729304Ethyl 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylateYield 68.7%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

To a slurry of sodium hydride (60%, 0.118 g, 2.95 mmol) in anhydrous dimethylacetamide (6 mL) at 0° C. under N2 was added diethyl malonate (0.472 g, 2.95 mmol) dropwise over 5 minutes. The mixture was stirred at ambient temperature for 1 hour, reacted with the product of Example 15A (0.50 g, 1.97 mmol), and heated at 120° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and cold water, and adjusted to pH to 5 with 1 M HCl. The aqueous layer was extracted with ethyl acetate (2×100 mL) and the combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was recrystallized from methanol to give the title compound as a white solid (0.439 g, 68%). MS (ESI+) m/z 325.0 (M+H)+, 347.0 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) δ 1.30 (t, J=7.17 Hz, 3H), 4.32 (q, J=7.23 Hz, 2H), 5.55 (s, 2H), 7.23 (m, 5H), 7.37 (dd, J=7.91, 4.60 Hz, 1H), 8.45 (dd, J=7.91, 2.02 Hz, 1H), 8.71 (dd, J=4.78, 1.84 Hz, 1H), 13.00 (s, 1H).

Workup

  1. temperatureheated at 120° C. for 3 hours
  2. temperatureThe mixture was cooled to ambient temperature
  3. custompartitioned between ethyl acetate and cold water
  4. extractionThe aqueous layer was extracted with ethyl acetate (2×100 mL)
  5. washthe combined extracts were washed with brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under vacuum
  9. customThe residue was recrystallized from methanol

Sources & evidence

ORD record
ord-28d4d62817d3406ca04338d633df503b
Source dataset
uspto-grants-2011_03
Patent number
US07902203B2

Reaction notes

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