Oxalyl chloride → Ethyl 3-(4-methoxy-2-(methylthio)pyrimidin-5-yl)-3-oxopropanoate

HRID 1160435Notes

Reaction equation

HRID 1160435 reaction equation
[CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[C:5]([S:12][CH3:13])[N:4]=1.[C:14](Cl)(=[O:18])[C:15](Cl)=O.[Mg+2].[Cl-].[Cl-].C([O-])(=O)[CH2:24][C:25]([O-])=[O:26].C([Mg+2])C>C1(C)C=CC=CC=1.C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([C:9](=[O:11])[CH2:24][C:25]([O:18][CH2:14][CH3:15])=[O:26])=[CH:7][N:6]=[C:5]([S:12][CH3:13])[N:4]=1

Participants

9

Reactant 4

HCID 65578Oxalyl chlorideHCID 5360315Magnesium ChlorideHCID 128290034-Methoxy-2-(methylsulfanyl)pyrimidine-5-carboxylic acidHCID 178525631HCID 178525631, compound

Product 1

HCID 25222986Ethyl 3-(4-methoxy-2-(methylthio)pyrimidin-5-yl)-3-oxopropanoateYield 52.4%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 4-methoxy-2-(methylthio)pyrimidine-5-carboxylic acid (10.92 g, 54.6 mmol) and oxalyl chloride (19.0 mL, 217.8 mmol) in toluene (100 mL) was heated at 100° C. for 1 h. The solvent was removed under reduced pressure and the crude acid chloride was used without purification in the next step. To a solution of MgCl2 (7.80 g, 81.9 mmol) and ethyl magnesium malonate (14.10 g, 82.6 mmol) in THF (100 mL) was added the above acid chloride in THF (100 mL) at 0° C. followed by TEA (15.0 mL, 107.6 mmol). The reaction mixture was stirred at 0° C. for 30 min and at rt for 2 h. EtOAc (200 mL) and H2O (100 mL) were added and stirred for additional 30 min. The layers were separated and the organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated. The crude was purified by flash chromatography (15% EtOAc/hexanes) to yield the desired compound as a white solid (7.73 g, 52%). MS (m/z): 271 (MH+). 1H NMR (CDCl3) δ: 12.65 (s, 1H×⅔), 8.85 (s, 1H×⅓), 8.84 (s, 1H×⅔), 6.03 (s, 1H×⅔), 4.26 (q, 2H×⅔), 4.19 (q, 2H×⅓), 4.10 (s, 3H×⅔), 4.09 (s, 3H×⅓), 3.92 (s, 2H×⅓), 2.60 (s, 3H×⅓), 2.59 (s, 3H×⅔), 1.34 (t, 3H×⅔), 1.26 (3H×⅓).

Workup

  1. customThe solvent was removed under reduced pressure
  2. customthe crude acid chloride was used without purification in the next step
  3. stirringstirred for additional 30 min
  4. customThe layers were separated
  5. washthe organic layer was washed with brine (100 mL)
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customThe crude was purified by flash chromatography (15% EtOAc/hexanes)

Sources & evidence

ORD record
ord-3350cccbda1d4063ab1a4280be5f4e04
Source dataset
uspto-grants-2010_10
Patent number
US07816406B2

Reaction notes

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