Triethylamine → 3-(1-Piperazinyl)-1,2-benzisothiazole

Crude 3-[bis(hydroxyethyl)]amino-1,2-benzisothiazole (6.0 mmol) was dissolved in 20 ml of acetonitrile and triethylamine (18 mmol). Methanesulfonyl chloride (13 mmol) was dropwise added at 0-4° C. The resulting mixture was stirred at this temperature for 1 hour and at room temperature for 3-5 hours. The reaction mixture was washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in methanol-ammonium hydroxide solution and heated to reflux. After 20-24 hours at reflux, the solution was sampled for thin-layer chromatography (elution with methylene chloride/isopropanol/triethylamine, 15:5:1) which showed that the reaction was complete. Half volume of methanol was evaporated under reduced pressure and water (30 mL) was added, following by toluene (50 ml). Then the separated aqueous layer was washed with fresh toluene (10 ml). The combined toluene layers were washed with water (20 ml) and then treated with decolorizing carbon. The mixture was heated to reflux and filtered hot through celite. The celite cake was rinsed with toluene (10 mL), and the combined washing and filtrate were concentrated at reduced pressure to 10 mL. Isopropanol (22 ml) was added to the concentrate and the yellowish solution was cooled to 20° C. The pH of the solution was slowly adjusted to 3.5-4.0 with of concentrated hydrochloric acid. The resulting slurry was cooled to 0-5° C., stirred for 1 hour, and then filtered. The product was washed with cold isopropanol and dried in vacuum at 40° C. for 24 hours. The title compound (4.32 mmol) was isolated as a light yellow solid in 71% yield (>98.5% purity).

1. washThe reaction mixture was washed with water
2. dry with materialdried over sodium sulfate
3. concentrationconcentrated
4. dissolutionThe residue was dissolved in methanol-ammonium hydroxide solution
5. temperatureheated to reflux
6. temperatureAfter 20-24 hours at reflux
7. aliquotthe solution was sampled for thin-layer chromatography (elution with methylene chloride/isopropanol/triethylamine, 15:5:1) which
8. customHalf volume of methanol was evaporated under reduced pressure and water (30 mL)
9. additionwas added
10. washThen the separated aqueous layer was washed with fresh toluene (10 ml)
11. washThe combined toluene layers were washed with water (20 ml)
12. additiontreated with decolorizing carbon
13. temperatureThe mixture was heated
14. temperatureto reflux
15. filtrationfiltered hot through celite
16. washThe celite cake was rinsed with toluene (10 mL)
17. washthe combined washing
18. concentrationfiltrate were concentrated at reduced pressure to 10 mL
19. additionIsopropanol (22 ml) was added to the
20. concentrationconcentrate
21. temperaturethe yellowish solution was cooled to 20° C
22. temperatureThe resulting slurry was cooled to 0-5° C.
23. stirringstirred for 1 hour
24. filtrationfiltered
25. washThe product was washed with cold isopropanol
26. customdried in vacuum at 40° C. for 24 hours

ORD record

ord-0d134a3b41ff4196b558e7562ab70e0e

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08981095B2