Hydrochloric Acid → Ethyl 7-(4-propoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate

Temperature

5 °C

Under an argon flow, 30.5 g of crude 2-fluoro-5-(4-propoxyphenyl)benzaldehyde was dissolved in 59 ml of DMF and then cooled to 5° C. After the addition of ethyl 4-mercaptobutyrate (32.6 ml, 229.88 mmol), 1,8-diazabicyclo[5.4.0]-7-undecene (34.4 ml, 229.88 mmol) was dropped slowly, while keeping at 0-10° C. The mixture was heated to 20° C. and stirred at 20-30° C. for 3 hours. At 20-30° C., 590 ml of diethyl carbonate was dropped and subsequently an ethanol solution (156 g, 459.76 mmol) of 20% sodium ethoxide was dropped. After stirring at 20-30° C. for 3 hours, the mixture was cooled to 5° C. After adding 338 ml of a 2N hydrochloric acid while keeping 10° C. or lower, phase separation was conducted. The water layer was extracted with 290 ml of ethyl acetate. The organic layers were combined and washed with 300 ml of water, 300 ml of a 5% aqueous sodium hydrogencarbonate solution and 300 ml of a 5% brine. After the addition of activated carbon, Shirasagi A (3.5 g), followed by the addition of tri-n-butylphosphine (4 ml), the mixture was stirred at room temperature for 20 minutes. After filtration, the residue was washed with 60 ml of ethyl acetate and the filtrate was concentrated under reduced pressure. After addition of 60 ml of isopropyl alcohol, the mixture was concentrated under reduced pressure. Subsequently, 60 ml of isopropyl ether was added and stirred at room temperature. The crystals formed were dissolved on heating under reflux. The solution was cooled for 1.5 hours while being stirred and subsequently stirred for 2 hours while being cooled in ice. After filtration, the residue was washed with 60 ml of ice-cooled isopropyl ether and then dried under vacuum (40° C.), yielding 20.34 g of ethyl 7-(4-propoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate as pale yellow crystals (Yield from 5-bromo-2-fluorobenzaldehyde 48%).

1. additionwas dropped slowly
2. customwhile keeping at 0-10° C
3. temperatureThe mixture was heated to 20° C.
4. stirringAfter stirring at 20-30° C. for 3 hours
5. temperaturethe mixture was cooled to 5° C
6. customwhile keeping 10° C.
7. customlower, phase separation
8. extractionThe water layer was extracted with 290 ml of ethyl acetate
9. washwashed with 300 ml of water, 300 ml of a 5% aqueous sodium hydrogencarbonate solution and 300 ml of a 5% brine
10. additionAfter the addition of activated carbon, Shirasagi A (3.5 g)
11. additionfollowed by the addition of tri-n-butylphosphine (4 ml)
12. stirringthe mixture was stirred at room temperature for 20 minutes
13. filtrationAfter filtration
14. washthe residue was washed with 60 ml of ethyl acetate
15. concentrationthe filtrate was concentrated under reduced pressure
16. additionAfter addition of 60 ml of isopropyl alcohol
17. concentrationthe mixture was concentrated under reduced pressure
18. additionSubsequently, 60 ml of isopropyl ether was added
19. stirringstirred at room temperature
20. customThe crystals formed
21. dissolutionwere dissolved
22. temperatureon heating
23. temperatureunder reflux
24. temperatureThe solution was cooled for 1.5 hours
25. stirringwhile being stirred
26. stirringsubsequently stirred for 2 hours
27. temperaturewhile being cooled in ice
28. filtrationAfter filtration
29. washthe residue was washed with 60 ml of ice-
30. temperaturecooled isopropyl ether
31. customdried under vacuum (40° C.)
32. customyielding

ORD record

ord-d225dc00f8664c299ab5f99cbf659b9c

Source dataset

uspto-grants-2003_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06566535B1