Methanol → 4-(3-Bromo-4-fluoro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester

Temperature

-78 °C

3-Bromo-4-fluoro-benzenesulfonyl chloride ((Example 319: part b) 1.9 g, 6.83 mmol) and sodium bicarbonate (1.15 g, 13.66 mmol) was suspended in 16 mL of water at 70° C. A solution of sodium sulfite (1.64 g, 13 mmol) in 15 mL of water was added in 3 portions over 3 h. The mixture was stirred for 16 h, 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. 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 (1.42 g) was dissolved in THF (20 mL) and cooled to −78° C. A solution of sodium methoxide in methanol (1M, 5 mL, 5 mmol) was added dropwise and the reaction was stirred for 30 min at −78° C. 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 (502 mg, 17%) as a yellow solid. 1H-NMR (CDCl3): δ 8.16 (dd, 1H, J=2.3, 6.3 Hz), 7.94 (s, 1H), 7.91 (ddd, 1H, J=2.6, 4.4, 8.6 Hz), 7.39 (dd, 1H, J=5.3, 8.6 Hz).

1. customthe solvent was removed in vacuo
2. additionDMF (15 mL) was added
3. stirringthe mixture was stirred for 15 min
4. customThe DMF was removed via syringe
5. washthe salts were washed with a second portion of DMF (10 mL)
6. stirringThe solution was stirred for 0° C. for 1 h
7. customThe DMF was removed in vacuo
8. customthe residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (30 mL)
9. customThe layers were separated
10. washthe organic layer was washed with aq NaHCO3 (2×20 mL), water (30 mL), and brine (30 mL)
11. dry with materialdried over sodium sulfate
12. concentrationThe solution was concentrated
13. dissolutionthe residue (1.42 g) was dissolved in THF (20 mL)
14. stirringthe reaction was stirred for 30 min at −78° C
15. washThe solution was washed with NaHCO3 (3×30 mL), brine (40 mL)
16. dry with materialwas dried over sodium sulfate
17. concentrationConcentration and chromatography of the residue

ORD record

ord-a8a16afdf2424888ad1b81fea2dfe945

Source dataset

uspto-grants-2006_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07138530B2