Preparation of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride_Kain Industrial Additive

Background and overview^[1][2]

3-(1-Piperazinyl)-1,2-benzisothiazole hydrochloride can be used as a pharmaceutical and chemical synthesis intermediate. If 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride is inhaled, move the patient to fresh air; if skin contact occurs, remove contaminated clothing and wash thoroughly with soap and water. Rinse the skin and seek medical attention if you feel any discomfort. If contact occurs with eyes, separate the eyelids, rinse with running water or saline, and seek medical attention immediately. If ingested, rinse mouth immediately. Do not induce vomiting and seek medical attention immediately.

Structure

Preparation ^{[2, 5]}

3-(1-Piperazinyl)-1,2-benzisothiazole hydrochloride was prepared as follows: Bis(2-cyanophenyl) disulfide (20.0g, 74.5mmol), without Water piperazine (64.2g, 745mmol), dimethyl sulfoxide (12.8g, 164mmol) and isopropyl alcohol (24mL) were added to a 500mL round-bottomed flask equipped with a mechanical stirrer, thermometer, condenser with nitrogen inlet on top and Connector to bleach scrubber. After purging the flask with nitrogen, the reactants were melted (at about 80°C) and then heated to reflux (110-126°C).

After refluxing for 24 hours, the reddish solution was sampled for thin layer chromatography (eluted with dichloromethane/isopropanol/triethylamine, 15:5:1), indicating completion of the reaction. The solution was cooled to 85-90°C, at which time water (130 mL) was added. The resulting slurry was cooled to 30-35°C. The reaction mixture was then concentrated under reduced pressure (bp = 50-60 °C, 110 mm) to remove approximately 30 mL of distillate. Treat the distillate with bleach to destroy dimethyl sulfide (DMS).

Drager tube (Dragerweck Ag Lubeck, Germany), which selectively detects dimethyl sulfide at ppm levels, indicates that the reaction headspace vapor contains less than 1 ppm residual DMS. A sample of the crude reaction mixture was analyzed by HPLC. The crude reaction mixture contained 3-(1-piperazinyl)-1,2-benzisothiazole (80%), 3,3′-(1,4-piperazinyl)-bis-1,2-benzo isothiazole (4.6%), and 2-(1-piperazinyl)pyrazine (4%). After adding isopropyl alcohol (28 mL) and water (71 mL), the slurry is cooled to 30 °C, granulated for 0.5 h, and then filtered through diatomaceous earth (e.g., Celite) to remove 3,3′-(1,4-piperazine) oxazinyl) – bis-1,2-benzisothiazole. Wash the filter cake with 56 mL of isopropyl alcohol/water (1:1) solution.

Toluene (170 mL) was added to the warm (32°C) filtrate, and the separated aqueous layer was washed with fresh toluene (100 mL). The combined toluene layers were washed with water (100 mL) and then treated with decolorizing carbon, such as DARKO KB-B, (2 g). The Celite filter cake was rinsed with toluene (60 mL), and the combined washings and filtrate were concentrated to 90 mL under reduced pressure. Isopropyl alcohol (220 mL) was added to the concentrate, and the light yellow solution was cooled to 20°C. Slowly adjust the solution to 3.5-4.0 with 9.8 mL concentrated hydrochloric acid. The resulting slurry was cooled to 0-5°C, granulated for 1 hour, and then filtered. The product filter cake was washed with cold isopropyl alcohol (80 mL) and then dried under vacuum at 40 °C for 24 h. The title compound 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride (43.2 g) was isolated as a light yellow solid in 77.6% yield (98.5% hplc purity).

Main reference materials

[1] US5935960 Pro-drugs of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)- 6-chloro-1,3-dihy dro-2H -indol-2-one