Introduction to Tetraisole Hydrochloride

Tetraisole hydrochloride is a white crystalline powder, odorless, with a bitter and astringent taste. Easy to dissolve in water and methanol, slightly soluble in ethanol, extremely slightly soluble in chloroform, and insoluble in acetone. Its main use is as an intermediate of levamisole hydrochloride, an anthelmintic drug, and an anti-helminth drug. Used for infections caused by roundworms, fishing worms, and pinworms. At present, the production of chemical products such as pharmaceuticals and dyes in China has been steadily increasing, which in turn has driven the demand for tetraimidazole hydrochloride to continue to grow steadily, and the demand for intermediates in the market has further expanded.

Figure 1 Characteristics of Tetramisole hydrochloride

How to Prepare Tetramisole Hydrochloride?

Tetraisole hydrochloride is an important veterinary insecticide with significant application value in the pharmaceutical industry. In 1996, Zheng Neneneba Bo, Miao Chenggang, and others published a study on the synthesis process and post-treatment technology of tetrazole hydrochloride. The route involves using epichlorohydrin and ethanolamine as raw materials to prepare nitroimidazole hydrochloride through addition, salt formation, chlorination, cyclization, re-chlorination, re-cyclization, salt formation, and purification. However, this method generates a large amount of by-products (resin) during the chlorination step, making the operation more difficult and resulting in low yields, making it unsuitable for industrial-scale production.

Preparation Method

A method for preparing Tetramisole hydrochloride is disclosed in CN103242347B. The preparation method of Tetramisole hydrochloride is achieved through the following steps:

1. Epichlorohydrin and ethanolamine are added to a reaction vessel in a molar ratio of 1: (4.5-5.5). The mixture is heated to 40-80°C and stirred for 2-4 hours. The resulting addition product is obtained by filtration.

2. An organic solvent and Lewis acid a are added to the addition product obtained in step 1. The mixture is stirred, and then dichloromethane is added in a molar ratio of 1: (2-2.6) concerning the addition product and dichloromethane at 20-30°C. The temperature is then raised to 40-60°C, and the reaction is carried out for 2-4 hours. The resulting chlorination product is obtained by filtration.

3. Deionized water is added to the chlorination product obtained in step 2. The mixture is heated to 80-90°C, and a sodium hydroxide solution is added dropwise to adjust the pH of the system to 2-2.3. After 4-6 hours of reaction, concentrated hydrochloric acid is added dropwise to adjust the pH of the system to 1.5-3. Then, thiourea is added, and the mixture is heated under reflux for 6-9 hours. After cooling to 0°C, the cyclization product is precipitated.

4. The cyclization product obtained in step 3, concentrated hydrochloric acid, and Lewis acid b are sequentially added to a reaction vessel. The mixture is heated to 40-60°C and reacted for 1-4 hours, then cooled to 15-20°C. Sodium hydroxide solution is added to adjust the pH of the system to 9-11, and the mixture is kept warm for 25-35 minutes. The temperature is then raised to 60-70°C and kept warm for 10-20 minutes. The resulting tetramisole product is precipitated after cooling to below 20°C.

5. Deionized water is added to the tetramisole product obtained in step 4. Concentrated hydrochloric acid is added dropwise at 25-35°C to adjust the pH of the system to 3-4. The mixture is then heated to 60-70°C and kept warm for 10-20 minutes. The Tetramisole hydrochloride is precipitated after cooling to below 20°C.

The concentrated hydrochloric acid mentioned above has a mass concentration of 25%-35%. The organic solvent in step 2 can be benzene, toluene, xylene, dichloromethane, dichloroethane, or chloroform. Lewis acid in step 2 can be ferric chloride, titanium tetrachloride, zinc chloride, magnesium dichloride, lithium chloride, or phosphorus trichloride. Lewis acid b in step 4 can be aluminum trichloride, ferric chloride, titanium tetrachloride, zinc chloride, magnesium dichloride, tin(II) chloride, lithium chloride, or phosphorus trichloride.

Reference

[1] Amin A S, Dessouki H A. Facile colorimetric methods for the quantitative determination of tetramisole hydrochloride[J]. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2002, 58(12): 2541-2546.

[2] van Den Bossche H, Janssen P A J. The biochemical mechanism of action of the antinematodal drug tetramisole[J]. Biochemical Pharmacology, 1969, 18(1): 35-42.