Dimethylformamide → 3-[1-(2-{5-Amino-2-methylphenyl}ethyl)piperidin-4-yl]-5-fluoro-1h-indole

Temperature

90 °C

A 100 mL round bottom flask was charged with 4-nitrophenyloxycarbonyloxyethyl polystyrene (6.6 g, 7.1 mmol), 5-fluoro-3-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-indole (2.7 g, 8.1 mmol), diisopropylethylamine (6.2 mL, 35.6 mmol), 4-dimethylaminopyridine (0.87 g, 7.1 mmol), and dry dimethyl formamide (85 mL). The mixture was stirred at 90° C. for 20 h. After cooling to room temperature, the resin was filtered off and washed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL glass cylinder with a fritte and a three way junction in the bottom. The resin was then treated for 20 min with 80 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2%, w/w), using a flow of nitrogen to agitate the resin (Caution: Generation of carbon dioxide). The resin was filtered off and washed with dry dichloromethane (25 mL), a 1:1 mixture of dichloromethane:triethylamine (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL round bottom flask. Acetonitrile (70 mL), diisopropylethylamine (5.2 mL, 30 mmol) and 2-(2-methanesulfonyloxyethyl)-1-methyl-4-nitrobenzene (3.67 g, 14 mmol) was added. The reaction mixture was heated to 70° C. for 18 h. After cooling to room temperature, the resin was filtered off and washed with dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL round bottom flask and treated with tin(II) chloride dihydrate (60 mL of an 0.5 M solution in DMF). The reaction mixture was stirred for 18 h. at room temperature. The resin was filtered off and washed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3 ×25 mL). The resin was dried in vacuo (20° C., 20 h) to yield the title resin (6.3 g).

1. temperatureAfter cooling to room temperature
2. filtrationthe resin was filtered off
3. washwashed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL)
4. additionThe resin was then treated for 20 min with 80 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid
5. additioncontaining anisole (2%, w/w) and methionine (0.2%, w/w)
6. stirringto agitate the resin (Caution: Generation of carbon dioxide)
7. filtrationThe resin was filtered off
8. washwashed with dry dichloromethane (25 mL)
9. additiona 1:1 mixture of dichloromethane
10. customThe resin was transferred to a 250 mL round bottom flask
11. temperatureThe reaction mixture was heated to 70° C. for 18 h
12. temperatureAfter cooling to room temperature
13. filtrationthe resin was filtered off
14. washwashed with dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL)
15. customThe resin was transferred to a 250 mL round bottom flask
16. additiontreated with tin(II) chloride dihydrate (60 mL of an 0.5 M solution in DMF)
17. stirringThe reaction mixture was stirred for 18 h. at room temperature
18. filtrationThe resin was filtered off
19. washwashed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3 ×25 mL)
20. customThe resin was dried in vacuo (20° C., 20 h)

ORD record

ord-f5365014424445158054a833c6bbe6fc

Source dataset

uspto-grants-2004_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06743809B2