Diethyl (ethoxymethylene)malonate → Ethyl 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate

HRID 2120772Notes

Reaction equation

HRID 2120772 reaction equation
[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C(O[CH:15]=[C:16]([C:22]([O:24]CC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[N:6][C:7]=1[O:8][CH3:9])[N:10]([CH3:11])[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]2=[O:24]

Participants

3

Reactant 2

HCID 6871Diethyl (ethoxymethylene)malonateHCID 234358665-iodo-6-methoxy-N-methyl-2-pyridinamine

Product 1

HCID 12093314Ethyl 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylateYield 16%

Conditions

Temperature
140 °C

Procedure

6-Methoxy-N-methyl-2-pyridinamine (17.24 g, 124 mmol) is dissolved in DMF (160 mL) and cooled to 0° C. followed by the addition of NIS (28 g, 124 mmol, 1 equiv), at a rate which keeps the reaction temperature below 10° C. The reaction is then allowed to warm to room temperature and stirred for 1 h. The reaction is distilled to dryness in vacuo and the residue is dissolved in CH2Cl2 and passed through a silica plug eluting with heptane/EtOAc (9/1) affording 32 g of crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine. The crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine is dissolved in diethyl ethoxymethylenemalonate (32 mL) and the mixture is heated at 140° C. for 2 h, then cooled to room temperature and passed through a silica plug eluting with heptane/EtOAc (19/1, 0/1). The product is then dissolved in Eaton's reagent (132 mL) and heated at 100° C. for 40 min, cooled to rt and poured into Na2CO3. The basic aqueous layer is then extracted with CH2Cl2 (3×), washed with water, and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (heptane/EtOAc, 4/1, 1/1, CH2Cl2/MeOH 19/1) the desired product is then triturated with MeOH to afford 7.9 g (16%) of ethyl 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate. Physical characteristics are as follows: 1H NMR (CDCl) δ9.04, 8.52, 4.41, 4.13, 3.91, 1.43; IR (diffuse reflectance) 2491, 2427, 2350, 2282, 2242, 1678, 1632, 1613, 1579, 1384, 1309, 1275, 1227, 1106, 804, cm−1; MS (EI) m/z 388, 344, 343, 317, 316, 185, 159, 86, 84, 51; Anal calcd for C13H13IN2O4: C, 40.23; H, 3.38; N, 7.22. Found: C, 40.20; H, 3.40; N, 7.16

Workup

  1. temperaturecooled to room temperature
  2. washeluting with heptane/EtOAc (19/1, 0/1)
  3. dissolutionThe product is then dissolved in Eaton's reagent (132 mL)
  4. temperatureheated at 100° C. for 40 min
  5. temperaturecooled to rt
  6. additionpoured into Na2CO3
  7. extractionThe basic aqueous layer is then extracted with CH2Cl2 (3×)
  8. washwashed with water, and brine
  9. dry with materialdried (MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe residue is purified by silica gel chromatography (heptane/EtOAc, 4/1, 1/1, CH2Cl2/MeOH 19/1) the desired product
  13. customis then triturated with MeOH

Sources & evidence

ORD record
ord-6f7a56427e1f4ab3b9acbfeac57c1678
Source dataset
uspto-grants-2004_02
Patent number
US06693114B2

Reaction notes

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