Water → HCID 86684921, compound

Temperature

50 °C

3-(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (300 g, 914 mmol) was dissolved in N,N-dimethylformamide (3.0 L) and potassium carbonate (300 g, 2.17 mol). Then, 2-methylpyridine-4-boronic acid pinacol ester (285 g, 1.3 mol) and water (240 mL) were added. The solution was degassed and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 g, 41 mmol) was added. The mixture was stirred for 20 h at 50° C. After cooling to room temperature, it was poured onto ice cold water (5° C., 5 L) and extracted with ethyl acetate (1×3.5 L, 2×1.5 L). The combined organic extracts were washed with brine/water (1:1 v/v, 750 mL) and brine (750 mL), before methanol (600 mL) was added and the mixture was dried over sodium sulfate. Silica gel (400 g) was added, the slurry was filtered and washed with ethyl acetate/methanol (9:1 v/v, 1.5 L). The combined filtrates were concentrated in vacuo. The residue was suspended in toluene (600 mL) and n-heptane (300 mL) and stirred for 5 min at 60° C. and for 1 h at room temperature. The precipitate was filtered off, washed with toluene/n-heptane (4:1 v/v, 300 mL) and n-heptane (300 mL), and dried in vacuo to afford 230.3 g of brown crystalline material. The crystals were further purified by trituration in isopropanol/heptane (1:1 v/v, 600 mL) for 30 min at room temperature and 30 min at 0-4° C. (ice bath). The precipitate was filtered off, washed with n-heptane/isopropanol (4:1 v/v, 300 mL), and dried in vacuo at 65° C. to yield the title compound as a light brown crystalline solid (215.7 g, 69%). MS (EI): m/z=341.1 [M+H]. 1H NMR (d6-DMSO, 400 MHz): δ 2.48 (t, J=7.2 Hz, 2H), 2.54 (s, 3H), 3.32 (t, J=7.2 Hz, 2H), 6.95 (bs, 1H), 7.41 (bs, 1H), 7.58 (dd, J=1.6 Hz, 5.4 Hz, 1H), 7.68 (s, 1H), 7.77 (d, J=9.1 Hz, 1H), 8.02-8.08 (m, 2H), 8.52 (d, J=5.1 Hz, 1H).

1. customThe solution was degassed
2. temperatureAfter cooling to room temperature
3. additionit was poured onto ice cold water (5° C., 5 L)
4. extractionextracted with ethyl acetate (1×3.5 L, 2×1.5 L)
5. washThe combined organic extracts were washed with brine/water (1:1 v/v, 750 mL) and brine (750 mL), before methanol (600 mL)
6. additionwas added
7. dry with materialthe mixture was dried over sodium sulfate
8. additionSilica gel (400 g) was added
9. filtrationthe slurry was filtered
10. washwashed with ethyl acetate/methanol (9:1 v/v, 1.5 L)
11. concentrationThe combined filtrates were concentrated in vacuo
12. stirringn-heptane (300 mL) and stirred for 5 min at 60° C. and for 1 h at room temperature
13. filtrationThe precipitate was filtered off
14. washwashed with toluene/n-heptane (4:1 v/v, 300 mL) and n-heptane (300 mL)
15. customdried in vacuo

ORD record

ord-1e70beceefc84de5b620c46b259ca9c2

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08796471B2