Diethyl Oxalate → Ethyl 5-(benzyloxy)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-carboxylate

HRID 458676Notes

Reaction equation

HRID 458676 reaction equation
[C:1](OCC)(=O)[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:11]([O:18][CH2:19][C:20]([O:22]CC)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[O-]CC.[Na+].S(O)(O)(=O)=O.[CH3:36][S:37][C:38](=[NH:40])[NH2:39]>C(O)C.C(O)(=O)C>[CH2:5]([O:4][C:2]([C:1]1[N:39]=[C:38]([S:37][CH3:36])[NH:40][C:20](=[O:22])[C:19]=1[O:18][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:3])[CH3:6]

Participants

8

Reactant 5

HCID 7268Diethyl OxalateHCID 24758Sodium hydrideHCID 752702-Methyl-2-thiopseudourea sulfateHCID 290299Ethyl 2-(benzyloxy)acetateHCID 2723922Sodium ethoxide

Product 1

HCID 135772690Ethyl 5-(benzyloxy)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-carboxylateYield 36.2%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 702EthanolSolvent2×

Conditions

Temperature
22 °C

Procedure

A solution of diethyl oxalate (21.06 g, 0.144 mol) and ethyl benzyloxyacetate (28.0 g, 0.144 mol) in dry tetrahydrofliran (200 ml) was treated at 22° C. with sodium hydride (6.34 g of a 60% dispersion in mineral oil, 0.158 mol). Ethanol (0.05 ml) was added and the resulting mixture was stirred at 22° C. for 18 h. The tetrahydrofuran was then evaporated under reduced pressure and the residual orange syrup was dissolved in a solution of sodium ethoxide (0.072 mol prepared from 1.65 g of sodium) in ethanol (200 ml). Powdered 2-methyl-2-thiopseudourea sulfate (20.1 g, 0.072 mol) was added and the resulting mixture was heated at 60° C. for 6 h. Acetic acid (5 ml) was then added to the gel-like reaction mixture and the ethanol was evaporated under reduced pressure. The residual paste was partitioned between water and dichloromethane and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel (elution with a gradient of ethyl acetate 0–20% in toluene) followed by crystallization from ethyl acetate-hexane gave 8.34 g (18% yield) of the title ester as white needles; mp 109–110° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.35 (3H, t, J=7.1 Hz, CH3), 2.62 (3H, s, SCH3), 4.37 (2H), q, J=7.1 Hz, CH2), 5.28 (2H, s, OCH2), 7.35–7.52 (5H, m, aromatics), 12.2 (1H, broad s, NH). Anal. Calcd for C15H16N2O4S: C, 56.23; H, 5.03; N, 8.74. Found: C, 56.23; H, 4.86; N, 8.76.

Workup

  1. customThe tetrahydrofuran was then evaporated under reduced pressure
  2. temperaturethe resulting mixture was heated at 60° C. for 6 h
  3. customthe ethanol was evaporated under reduced pressure
  4. customThe residual paste was partitioned between water and dichloromethane
  5. extractionthe aqueous phase was extracted twice with dichloromethane
  6. washThe combined organic phases were washed with saturated sodium bicarbonate, brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. concentrationconcentrated under reduced pressure
  9. washChromatography on silica gel (elution with a gradient of ethyl acetate 0–20% in toluene)
  10. customfollowed by crystallization from ethyl acetate-hexane

Sources & evidence

ORD record
ord-eeb48d57e9a84e9db315095f57cca3b1
Source dataset
uspto-grants-2007_03
Patent number
US07192948B2

Reaction notes

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