Ammonia → HCID 69820399, compound

1.27 g (3.3 mmol) of 2-[bis(1-oxopropyl)amino]-3-thien-2-ylbenzenesulphonyl chloride are added portionwise, at 0° C., to a solution of 1.35 g (3.0 mmol) of phenylmethyl (S)-4-[4-amino-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylate hydrochloride and 0.96 ml (6.9 mmol) of triethylamine (TEA) in 15 ml of dichloromethane. The mixture is allowed to warm slowly to room temperature and the reaction is continued for 18 hours. The reaction mixture is taken up in 250 ml of ethyl acetate and is washed with 100 ml of 1N hydrochloric acid solution and with 100 ml of saturated sodium hydrogen carbonate solution and with 100 ml of saturated sodium chloride solution. The resulting product is dried over sodium sulphate and is filtered and then concentrated under reduced pressure. The residue obtained is taken up in 100 ml of tetrahydrofuran (THF) and is cooled to 0° C. and then treated for 5 minutes with a stream of ammonia. The mixture is allowed to warm to room temperature. After 4 hours, the reaction mixture is concentrated under reduced pressure. The residue obtained is taken up in 250 ml of ethyl acetate, washed with 50 ml of 1N hydrochloric acid solution and then with 50 ml of saturated sodium hydrogen carbonate solution and with 50 ml of saturated sodium chloride solution. The resulting product is dried over sodium sulphate and filtered and then concentrated under reduced pressure. The residue obtained is taken up in 1.2 ml of acetic acid, cooled to 0° C. and then treated with a 5N solution of hydrogen bromide in 1.2 ml of acetic acid, added dropwise. The mixture is allowed to warm to room temperature. After 4 hours, the reaction mixture is concentrated under reduced pressure. The residue obtained is taken up in 250 ml of ethyl acetate and is washed with 50 ml of saturated sodium hydrogen carbonate solution and then with 50 ml of saturated sodium chloride solution. The resulting product is dried over sodium sulphate and filtered and is then concentrated after addition of a 0.1N solution of hydrogen chloride in 40 ml of isopropanol. The residue obtained is purified by chromatography on an RP18 column, eluting with an acetonitrile/water gradient of from 5/95 to 30/70. 0.36 g of (S)-N-[2-[[[1-[(4-ethylpiperid-3-yl)carbonyl]-4-piperid-4-ylbutyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide hydrochloride is obtained.

1. washis washed with 100 ml of 1N hydrochloric acid solution and with 100 ml of saturated sodium hydrogen carbonate solution and with 100 ml of saturated sodium chloride solution
2. dry with materialThe resulting product is dried over sodium sulphate
3. filtrationis filtered
4. concentrationconcentrated under reduced pressure
5. customThe residue obtained
6. temperatureis cooled to 0° C.
7. temperatureto warm to room temperature
8. waitAfter 4 hours
9. concentrationthe reaction mixture is concentrated under reduced pressure
10. customThe residue obtained
11. washwashed with 50 ml of 1N hydrochloric acid solution
12. dry with materialThe resulting product is dried over sodium sulphate
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure
15. customThe residue obtained
16. temperaturecooled to 0° C.
17. additionadded dropwise
18. temperatureto warm to room temperature
19. waitAfter 4 hours
20. concentrationthe reaction mixture is concentrated under reduced pressure
21. customThe residue obtained
22. washis washed with 50 ml of saturated sodium hydrogen carbonate solution
23. dry with materialThe resulting product is dried over sodium sulphate
24. filtrationfiltered
25. concentrationis then concentrated
26. additionafter addition of a 0.1N solution of hydrogen chloride in 40 ml of isopropanol
27. customThe residue obtained
28. customis purified by chromatography on an RP18 column
29. washeluting with an acetonitrile/water gradient of from 5/95 to 30/70

ORD record

ord-b26cc225b0db4c15a83befac5de55ed2

Source dataset

uspto-grants-2004_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06680329B2