Hydrochloric Acid → 4-(4-Amino-3-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester

Temperature

80 °C

Sodium sulfite (1.5 g, 11.9 mmol) and NaHCO3 (1.12 g, 13.3 mmol) were dissolved in water (30 mL) and 4-acetylamino-3-nitro-benzenesulfonyl chloride (1.94 g, 7 mmol) was added. Ethanol (10 mL) and the mixture was stirred for 6 h at rt. Aqueous NaOH (10N, 6 mL, 60 mmol) was added and the reaction was heated to 80° C. for 2 h. The solution was brought to pH˜8 with conc. HCl, and the solvent was removed in vacuo. DMF (15 mL) was added, the mixture was stirred for 15 min, and the inorganic salts were then allowed to settle. The DMF was removed via syringe, the salts were washed with a second portion of DMF (10 mL), and the combined DMF solution was slowly added to a 0° C. solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 931 mg, 3.5 mmol) in DMF (15 mL). The solution was stirred for 0° C. for 1 h then overnight at rt. The DMF was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (30 mL). The layers were separated and the organic layer was washed with aq NaHCO3 (2×20 mL), water (30 mL), and brine (30 mL), then dried over sodium sulfate. The solution was concentrated and the residue was dissolved in THF (20 mL) and cooled to −78° C. A solution of sodium methoxide in methanol (1M, 7 mL, 7 mmol) was added dropwise and the reaction was stirred for 30 min. Acetic acid (500 μL) was added followed by EtOAc (100 mL). The solution was washed with NaHCO3 (3×30 mL), brine (40 mL), and was dried over sodium sulfate. Concentration and chromatography of the residue yielded the title compound (381 mg, 28%) as a yellow solid. 1H-NMR (CDCl3): δ 10.56 (br s, 2H), 9.04 (d, 1H, J=8.8 Hz), 8.89 (d, 1H, J=2.3 Hz), 8.22 (dd, 1H, J=2.3, 9.1 Hz), 8.04 (s, 1H), 3.90 (s, 3H), 2.64 (s, 3H), 2.35 (s, 3H).

1. customthe solvent was removed in vacuo
2. additionDMF (15 mL) was added
3. customThe DMF was removed via syringe
4. washthe salts were washed with a second portion of DMF (10 mL)
5. stirringThe solution was stirred for 0° C. for 1 h
6. customovernight
7. customat rt
8. customThe DMF was removed in vacuo
9. customthe residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (30 mL)
10. customThe layers were separated
11. washthe organic layer was washed with aq NaHCO3 (2×20 mL), water (30 mL), and brine (30 mL)
12. dry with materialdried over sodium sulfate
13. concentrationThe solution was concentrated
14. dissolutionthe residue was dissolved in THF (20 mL)
15. temperaturecooled to −78° C
16. stirringthe reaction was stirred for 30 min
17. washThe solution was washed with NaHCO3 (3×30 mL), brine (40 mL)
18. dry with materialwas dried over sodium sulfate
19. concentrationConcentration and chromatography of the residue

ORD record

ord-e8b6c6a39f1c4443a41b457dc7f90088

Source dataset

uspto-grants-2006_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07109354B2