Hydrochloric Acid → 1H,2H,4H-thieno(3,2-d)(1,3)oxazine-2,4-dione

A mixture of methyl 3-aminothiophene-2-carboxylate (63 mmol, 10.0 g) and ethyl chloroformate (50 ml) was refluxed for 2 hrs and then evaporated to dryness. The residue was dissolved in ethanol (130 ml) and sodium hydroxide (NaOH, 65 mmol, 3.84 g) in water (35 ml) was added. After stirring at room temperature for 48 hrs the mixture was acidified with 1M HCl and diluted with water. The precipitate was collected, washed with water, dried under vacuum and recrystallized from toluene/heptane resulting in 3-ethoxycarbonylamino-thiophene-2-carboxylic acid, (10.2 g, 73%). This acid, (23.2 nanol, 5.0 g), and phosphorus tribromide (12 mmol, 1.14 ml) were dissolved in 1,4-dioxane (50 ml). The mixture was stirred at 100° C. for 2 hrs and then cooled before it was concentrated on a rotary evaporator. The precipitate formed upon addition of toluene was isolated by filtration giving 1H-thieno[3,2-d][1,3]oxazine-2,4-dione (3.96. g, 100%). This intermediate (20.6 mmol, 3.5 g) was dissolved in DMA (40 ml) and cooled on an ice-bath. NaH (22.7 mmol, 780 mg) was added followed by addition of methyl iodide (25 mmol, 1.6 ml). The mixture was stirred at room temperature overnight and then diethyl malonate (25 mmol, 3.85 ml) and NaH (22.7 mmol, 780 mg) were added. After the addition the mixture was heated at 85° C. for 2 hrs and then the mixture was cooled. Water was added and the mixture was acidified with 1 M HCl and extracted with chloroform. The extract was dried, concentrated, and chromatographed (SiO2, chloroform/methanol/acetic acid; 40/1/0.1) to yield the title compound (1.4 g, 26%).

1. temperaturewas refluxed for 2 hrs
2. customevaporated to dryness
3. dissolutionThe residue was dissolved in ethanol (130 ml)
4. customThe precipitate was collected
5. washwashed with water
6. customdried under vacuum
7. customrecrystallized from toluene/heptane resulting in 3-ethoxycarbonylamino-thiophene-2-carboxylic acid, (10.2 g, 73%)
8. stirringThe mixture was stirred at 100° C. for 2 hrs
9. temperaturecooled before it
10. concentrationwas concentrated on a rotary evaporator
11. customThe precipitate formed upon addition of toluene
12. customwas isolated by filtration

ORD record

ord-7ed4560e9d4748a78a8a28ac367dd5f2

Source dataset

uspto-grants-2009_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07553849B2