Tetramisole Hydrochloride is a white crystalline powder that is solid at room temperature (ie 25°C). Its relative molecular mass is 240.75g/mol and its density is 1.17g/cm3. Tetramisole Hcl is easily soluble in water and ethanol, but not easily soluble in acetone and ether. Its solubility in water is 46.6g/L at 25°C. Under the action of light, Tetramisole Hydrochloride may oxidize, but when exposed to room temperature, it can stably maintain its solid form. It is a broad-spectrum antihelminth drug commonly used to treat parasitic infections in humans and animals.
The first method: the reaction between methyl imidazole acetate and 2-chloropropionyl chloride, this method is one of the most commonly used methods in TH synthesis.
The specific process is as follows:
Methyl imidazole acetate and 2-chloropropionyl chloride are key raw materials for the synthesis of Tetramisole Hydrochloride. Methyl imidazole acetate is a white powder,
Synthesis of Tetramisole Hydrochloride steps:
The first step: methyl imidazole acetate and 2-chloropropionyl chloride reaction:
Mix imidazole methyl acetate and 2-chloropropionyl chloride at a ratio of 4:1, and then add an appropriate amount of triethylamine (TEA) catalyst. At this time, the reaction solution will produce a white gel-like precipitate, and then the product is separated and purified by filtration, cooling, washing and other methods.
The second step: react with phenylsulfuric acid:
The product obtained in the first step is reacted with phenylsulfuric acid, and the reaction temperature is carried out at 10-15°C. At this time, the product will become a white precipitate, which can be filtered, washed and dried to obtain simple 2-imidazolylvaleric acid.
The third step: reaction with tert-butylaluminum fluoride:
The product obtained in the second step is reacted with tert-butylaluminum fluoride, and the reaction is carried out with an inert solvent tetrahydrofuran (THF). At this time, the reaction produces a white precipitate, and then the product is separated and purified by filtration, washing, drying and the like.
Step 4: Reaction with 2,3-dichloro-5,6-dicyano-1,4-benzenedione:
Mix the product obtained in the third step with 2,3-dichloro-5,6-dicyano-1,4-benzenedione in a ratio of 1:1, and the obtained product will become a white powder, and can be Soluble in water or ethanol, while producing certain pharmacological effects.
The fifth step: react with HCl:
Dissolve the product obtained in the fourth step in sodium hydroxide (NaOH), and then add an appropriate amount of hydrochloric acid (HCl) to neutralize the reaction. At this time, Tetramisole Hydrochloride is produced, and it can also be purified by filtration, washing, drying and other methods.
By reacting methyl imidazole acetate with 2-chloropropionyl chloride, reacting with phenylsulfuric acid, reacting with tert-butylaluminum fluoride, reacting with 2,3-dichloro-5,6-dicyano-1,4-benzenedi Tetramisole Hydrochloride was successfully synthesized through the steps of ketone reaction and reaction with HCl.
Disadvantages: This method requires harsh reaction conditions and requires a large amount of organic solvents.
The second method: reacting with imidazole acetone and crotonic acid:
The main steps of the method are the preparation of 2-amino-2-methyl-1-propanol (AMP) precursor through reduction reaction in the presence of imidazole acetone and crotonic acid; subsequently, sulfonylation of AMP Reaction, get TH. Specific steps are as follows:
The first step: preparation of imidazole acetone:
In a 250 ml three-neck flask, add 50 ml of acetone and 1.75 g of sodium pyruvate. It was stirred well, and 8 ml of acetaldehyde was slowly added dropwise thereto. Then, 10 mL of methyl tert-butyl ether catalyst was added, and the reaction mixture was stirred. The vial was exposed to room temperature for 15 minutes until the reaction was complete. Finally, 100 mL of deionized water was added, the reaction mixture was filtered, and the filtered liquid was collected.
Step 2: Preparation of Tetramisole Hydrochloride:
In a 250 ml three-neck flask, add 25 g of crotonic acid and 50 ml of 00 grade ethanol, and stir it evenly. Continue stirring, and slowly add the previously prepared imidazole acetone solution to the crotonic acid and 00 grade ethanol mixture. While adding the imidazolium acetone solution, a certain amount of 1M hydrochloric acid was added to adjust the pH value, and the reaction mixture was continuously stirred for 30 minutes. The mixture was then extracted by adding 20 ml of glacial acetic acid and 50 ml of n-hexane. The extract contains Tetramisole Hydrochloride, and through concentration to remove n-hexane and glacial acetic acid, the remaining solid is Tetramisole Hydrochloride.
The preparation method involves reaction with imidazolium acetone and crotonic acid, by adjusting pH, extracting and concentrating, and finally obtaining Tetramisole Hydrochloride as an anthelmintic drug.
Advantages: The reaction conditions are simple and less organic solvents are required.
Disadvantage: higher production cost.
The third method: react imidazole acetone and N, N-dimethyl-N'-nitrohydrazine:
In this method, the precursor of TH is N-(imidazolyl)-N,N-dimethyl-N'-nitrohydrazine (IDI). IDI undergoes a reduction reaction to obtain TH. The detailed reaction steps are as follows:
Step 1: Prepare imidazole acetone:
First, we need to prepare imidazole acetone. The chemical name of imidazole acetone is 2,3,5,6-tetrahydro-6-phenylimidazo(2,1-b)thiazole, which is often used in the manufacture of drugs, dyes and pesticides. Imidazoleacetone can be obtained by reacting 3-phenyl-2,3-dihydrothiazolone with tert-butylamine in the presence of sodium hydroxide.
Step 2: Prepare N,N-Dimethyl-N'-nitrohydrazine:
N,N-Dimethyl-N'-nitrohydrazine (DMNG) is an organic compound with the chemical formula C6H14N4O4, which can be used as a strong oxidant, catalyst and fuel additive. DMNG can be obtained by adding nitric acid and sulfuric acid to dimethylformamide, followed by filtration and drying.
Step 3: Reaction of imidazole acetone and DMNG:
DMNG and imidazolium acetone were added to cyclohexane, followed by phosgene. Phosgene is obtained by reacting ammonia and chlorine under light. After the reaction, the reactant mixture was distilled under reduced pressure to obtain an oil. Then, hydrochloric acid was added, and it was cooled to 0°C. Under the condition of continuous stirring, add 10% by weight excess aqueous solution of acetic anhydride, continue stirring for 20 minutes, and the reaction is completed. Finally, 25% by weight excess sodium hydroxide aqueous solution was slowly added dropwise in an ice-water bath until the color turned dark yellow, and a precipitate was obtained.
Step 4: Preparation of Tetramisole HCL:
Tetramisole HCL can be obtained by reacting the DMNG intermediate obtained in the previous step with alcohol and hydrochloric acid, and the reaction produces by-product methyl-(1-benzyl-2,3-dihydroimidazole-4,5,6-trimethylpyridinium) chloride, by Control the pH to obtain the purity of Tetramisole HCL. After the reaction, the solid product Tetramisole HCL was obtained by filtration and drying.
Advantages: TH can be well developed and applied to the synthesis of some new pesticides and drugs.
Disadvantages: The reaction time is longer, resulting in lower yield and a large amount of waste water.
In summary, there are many different approaches to the synthesis of Tetramisole Hydrochloride. Although each method has its own unique advantages and disadvantages, the appropriate method can be reasonably selected for production according to actual needs and production conditions. The above are the preparation steps of Tetramisole Hydrochloride, some chemicals need to be used carefully. It should be noted that safety regulations should be followed and protective equipment should be worn correctly during the experiment.