p-Toluenesulfonic acid → HCID 57900310, compound

Temperature

80 °C

To a solution of in 8-bromo-N-isopropyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (180 mg, 0.49 mmol) in 5 mL toluene was added phosphorus pentachloride (0.184 g, 0.88 mmol) under nitrogen and the reaction mixture was heated at 80° C. for 2 h. The mixture was cooled and carefully concentrated. The crude residue was dissolved in 10 mL THF and treated sequentially with formyl hydrazine (118 mg, 2.0 mmol) and potassium carbonate (0.340 g, 2.46 mmol). The mixture was stirred overnight at room temperature, diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The crude residue was dissolved in toluene (10 mL) and treated with p-toluenesulfonic acid (15 mg, 0.087 mmol). The whole was sealed and heated at 90° C. for 15 min. The reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate and washed with water, sodium bicarbonate and brine. The organics were dried over sodium sulfate and concentrated to give 224 as the crude product which could be used without purification in subsequent operations. A small amount was purified by reverse-phase HPLC for analytical purposes. 1H NMR (dmso-d6, 400 MHz) δ 11.9 8.84 (s, 1H), 7.65 (d, 1H), 7.45 (s, 1H), 7.32-7.27 (m, 2H), 4.75 (m, 1H), 4.34 (t, 2H), 3.25 (t, 2H), 1.48 (d, 6H). MS (ESI) 392.1

1. temperatureThe mixture was cooled
2. concentrationcarefully concentrated
3. dissolutionThe crude residue was dissolved in 10 mL THF
4. extractionextracted with ethyl acetate
5. washThe combined organics were washed with brine
6. dry with materialdried over sodium sulfate
7. concentrationconcentrated
8. dissolutionThe crude residue was dissolved in toluene (10 mL)
9. customThe whole was sealed
10. temperatureheated at 90° C. for 15 min
11. temperatureThe reaction mixture was cooled to room temperature
12. concentrationconcentrated
13. additiondiluted with ethyl acetate
14. washwashed with water, sodium bicarbonate and brine
15. dry with materialThe organics were dried over sodium sulfate
16. concentrationconcentrated

ORD record

ord-4d37f98112a14c1a84a577cb2bfb9597

Source dataset

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08399690B2