Diethyl Malonate → 4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester

HRID 2374351Notes

Reaction equation

HRID 2374351 reaction equation
[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])O[C:11](=[O:15])[C:10]2[N:6]1[CH:7]=[CH:8][CH:9]=2.C(OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[H-].[Na+]>CN(C)C(=O)C.CO>[CH2:22]([O:21][C:19]([C:18]1[C:13](=[O:14])[N:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:16])[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]2[C:11]=1[OH:15])=[O:20])[CH3:23]

Participants

6

Reactant 3

HCID 7761Diethyl MalonateHCID 24758Sodium hydrideHCID 598535694-(3-Methyl-butyl)-6-oxa-3a,4-diaza-indene-5,7-dione

Product 1

HCID 598535874-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl esterYield 55.6%

Reagents, catalysts & solvents 2

HCID 887MethanolCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 4-(3-methyl-butyl)-6-oxa-3a,4-diaza-indene-5,7-dione (Example 1e, 0.080 g, 0.36 mmol) and diethyl malonate (0.58 mL, 3.6 mmol) in N,N-dimethylacetamide (1 mL) was added sodium hydride (0.017 g, 0.43 mmol) and 1 drop of methanol. The reaction mixture was heated to 120° C. and stirred for 16 h. The reaction was allowed to cool to 25° C. and quenched with saturated aqueous ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×3 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/dichloromethane, 2-5%) to afford the desired product, 4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (0.058 g, 0.20 mmol, 55% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (6H, d, J=6.4 Hz), 1.30 (3H, t, J=6.8 Hz), 1.49 (2H, q, J1=15.2 Hz, J2=7.6 Hz), 1.63 (1H, m), 4.23-4.30 (4H, m), 6.56 (1H, m), 6.87 (1H, m), 7.68 (1H, m); LC-MS (ESI) calcd for C15H20N2O4 292.33. found 293.30 [M+H+].

Workup

  1. temperatureto cool to 25° C.
  2. customquenched with saturated aqueous ammonium chloride solution and ethyl acetate
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with ethyl acetate (3×3 mL)
  5. dry with materialThe combined organic layers were dried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by column chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/dichloromethane, 2-5%)

Sources & evidence

ORD record
ord-7411c467abd04e86ac136320fcf55ff9
Source dataset
uspto-grants-2008_12
Patent number
US07462611B2

Reaction notes

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