Water → HCID 69076227, compound

HRID 1987811Notes

Reaction equation

HRID 1987811 reaction equation
[NH2:1][C:2]1[C:3]([C:8]([O:10]CC)=O)=[C:4]([CH3:7])[S:5][CH:6]=1.C([CH:15]([C:19](Cl)=[O:20])[C:16](Cl)=[O:17])C.[H-].[Na+].O.[O:25]1CCO[CH2:27][CH2:26]1>>[CH2:26]([O:25][C:19]([C:15]1[C:16](=[O:17])[NH:1][C:2]2[C:3]([C:8]=1[OH:10])=[C:4]([CH3:7])[S:5][CH:6]=2)=[O:20])[CH3:27]

Participants

6

Reactant 5

HCID 962WaterHCID 24758Sodium hydrideHCID 312751,4-DioxaneHCID 109209242-Ethylpropanedioyl dichlorideHCID 21568444HCID 21568444, compound

Product 1

HCID 69076227HCID 69076227, compoundYield 52%

Conditions

Temperature
50 °C

Procedure

Ethyl 4-amino-2-methyl-thiophene-3-carboxylate (12.8 mmol, 2.37 g) was dissolved in 1,4-dioxane (20 ml) and ethyl malonyl chloride (90%) (19.2 mmol, 2.73 ml) was added. The reaction mixture was heated at 50° C. for 1 h and was then allowed to reach room temperature. The reaction mixture was poured onto ice (60 g) and the product was collected by filtration, washed with water and dried (3.32 g, 87%). The malonic amide was dissolved in N,N-dimethylacetamide (DMA, 35 ml) and sodium hydride (NaH 60%, 2.0 equiv., 22.1 mmol) was added. The reaction mixture was heated at 60° C. for 1 h. After cooling and addition of water (50 ml) the product was precipitated by addition of 1 M hydrochloric acid (HCl, aq.) (30 ml). The precipitate was collected by filtration and was re-crystallized from ethanol giving 4,5-dihydro-7-hydroxy-1-methyl-5-oxo-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (1.46 g, 52%). The carboxylic acid ethyl ester was dissolved in dimethylformamide (DMA, 40 ml) and NaH (3.0 equiv., 17.3 mmol, 692 mg) was added. The reaction mixture was heated to 40° C. for 15 minutes and was then cooled to 10° C. Iodomethane (1.3 equiv., 7.49 mmol, 0.47 ml) was added, the reaction mixture was stirred at ambient temperature for 2 hrs and was then poured onto 0.5 M HCl (aq) (50 ml). The precipitate was collected by filtration and re-crystallized from ethanol and then again from methyl isobutyl ketone to give the title compound (524 mg, 89%).

Workup

  1. customto reach room temperature
  2. additionThe reaction mixture was poured onto ice (60 g)
  3. filtrationthe product was collected by filtration
  4. washwashed with water
  5. customdried (3.32 g, 87%)
  6. dissolutionThe malonic amide was dissolved in N,N-dimethylacetamide (DMA, 35 ml)
  7. temperatureThe reaction mixture was heated at 60° C. for 1 h
  8. temperatureAfter cooling
  9. customwas precipitated by addition of 1 M hydrochloric acid (HCl, aq.) (30 ml)
  10. filtrationThe precipitate was collected by filtration
  11. customwas re-crystallized from ethanol

Sources & evidence

ORD record
ord-658b1cb5af504b2da365b253e77e43ec
Source dataset
uspto-grants-2009_06
Patent number
US07553849B2

Reaction notes

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