Ethanolamine → (E)-3-(5-Bromo-2-methoxy-phenyl)-N-{2-[4-(4-chloro-benzoyl)-piperidin-1-yl]-ethyl}-acrylamide

Temperature

20 °C

To a suspension of 2-(formyl-3-methoxyphenoxy)ethyl polystyrene (AMEBA) resin (ex Novabiochem) (6.85 g, 3.33 mmol) in a mixture of methanol/dichloromethane (60 ml, 1:1 v/v) is added 2-amino ethanol and sodium triacetoxyborohydride (4.00 g, 18.85 mmol) and the mixture shaken for 16 hours at 20° C., then filtered. The resin is washed with methanol, DMF and dichloromethane, then dried under vacuum. A THF/acetonitrile mixture (50 ml, 1:1 v/v) is added to the dried resin followed by iodine (4.80 g, 18.85 mmol), imidazole (1.28 g, 18.85 mmol) and triphenylphosphine (4.90 g,18.85 mmol). The suspension obtained is shaken for 18 hours at 20° C., then filtered. The resin is washed with THF and dried under vacuum. To the freshly prepared resin (0.50 g, 0.35 mmol) is added a solution of (4-chloro-phenyl)-piperidin-4-yl-methanone hydrochloride (0.18 g, 0.70 mmol) dissolved in DMF (2 ml) and diisopropylethylamine (0.36 g, 2.8 mmol). The mixture is heated at 50° C. for 16 hours and then filtered. The resin is washed with DMF. To the washed resin are added (E)-3-(5-Bromo-2-methoxy-phenyl)-acrylic acid (0.27 g, 1.05 mmol), 2-(1H benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate (0.34 g, 1.05 mmol), diisopropylethylamine (0.29 g, 1.05 mmol) and DMF (4 ml) and the mixture is shaken at 20° C. for 16 hours, then washed with DMF and methanol, after which it is treated with trifluoroacetic acid/dichloromethane (6 ml, 1:1 v/v) at 20° C. for 1 hour to remove the product from the resin. The resulting mixture is filtered and the filtrate evaporated under vacuum to give the product, [MH]+506.7.

1. filtrationfiltered
2. washThe resin is washed with methanol, DMF and dichloromethane
3. customdried under vacuum
4. additionA THF/acetonitrile mixture (50 ml, 1:1 v/v) is added to the dried resin
5. customThe suspension obtained
6. stirringis shaken for 18 hours at 20° C.
7. filtrationfiltered
8. washThe resin is washed with THF
9. customdried under vacuum
10. temperatureThe mixture is heated at 50° C. for 16 hours
11. filtrationfiltered
12. washThe resin is washed with DMF
13. stirringthe mixture is shaken at 20° C. for 16 hours
14. washwashed with DMF and methanol
15. additionafter which it is treated with trifluoroacetic acid/dichloromethane (6 ml, 1:1 v/v) at 20° C. for 1 hour
16. customto remove the product from the resin
17. filtrationThe resulting mixture is filtered
18. customthe filtrate evaporated under vacuum
19. customto give the product, [MH]+506.7

ORD record

ord-8abbccf5430a4c708a5d61e9ba086017

Source dataset

uspto-grants-2003_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06670379B2