Water → 3-(1-Piperazinyl)-1,2-benzisothiazole monohydrochloride

Temperature

100 °C

Anhydrous piperazine (49.4 g, 0.57 mol) and t-butanol (10 mL) were added to a dry, 300 mL round bottom flask equipped with a mechanical stirrer, thermometer, condenser topped with a nitrogen inlet, and pressure-equalizing dropping funnel. After the flask was purged with nitrogen, it was heated to 100° C. in an oil bath. A solution of 3-chloro-1,2-benzisothiazole (19.45 g, 0.11 mol) in t-butanol (10 mL) was added to the addition, funnel, and then slowly added to the reaction flask over 20 minutes to moderate an exothermic reaction (112-118° C.). Once addition was complete the yellow solution was heated to reflux (121° C.) and then maintained at reflux for 24 hours. Thin-layer chromatography showed that the reaction was complete. The reaction mixture was cooled to 85° C. and 120 mL of water was added. The hazy solution was filtered and the filter cake rinsed with 60 mL of t-butanol/water (1:1) solution. The pH of the combined filtrate and wash was adjusted to 12.2 with 50% aqueous caustic. The aqueous solution was extracted with toluene (200 mL), the layers were separated, and the aqueous layer was extracted with fresh toluene (100 mL). The combined toluene layers were washed with water (75 mL), and then the toluene solution was concentrated in vacuo at 48° C. to 90 mL. Isopropanl (210 mL) was added to the concentrate and then the pH was slowly adjusted to 3.8 with 7.6 mL of concentrated hydrochloric acid. The resulting slurry was cooled to 0° C., granulated for 45 min, and then filtered. The filter cake was washed with cold isopropanol (50 mL) and then dried in vacuo at 40° C. to afford 23.59 g (80% yield) of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride as an off white solid.

1. customequipped with a mechanical stirrer
2. customthermometer, condenser topped with a nitrogen inlet
3. customAfter the flask was purged with nitrogen, it
4. additionslowly added to the reaction flask over 20 minutes
5. customan exothermic reaction (112-118° C.)
6. additionOnce addition
7. temperaturewas heated
8. temperatureto reflux (121° C.)
9. temperaturemaintained
10. temperatureat reflux for 24 hours
11. temperatureThe reaction mixture was cooled to 85° C.
12. filtrationThe hazy solution was filtered
13. washthe filter cake rinsed with 60 mL of t-butanol/water (1:1) solution
14. washThe pH of the combined filtrate and wash
15. extractionThe aqueous solution was extracted with toluene (200 mL)
16. customthe layers were separated
17. extractionthe aqueous layer was extracted with fresh toluene (100 mL)
18. washThe combined toluene layers were washed with water (75 mL)
19. concentrationthe toluene solution was concentrated in vacuo at 48° C. to 90 mL
20. additionIsopropanl (210 mL) was added to the
21. concentrationconcentrate
22. temperatureThe resulting slurry was cooled to 0° C.
23. filtrationfiltered
24. washThe filter cake was washed with cold isopropanol (50 mL)
25. customdried in vacuo at 40° C.

ORD record

ord-f05a433951584b8d93cf38c3e41caaa5

Source dataset

uspto-grants-2000_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06111105