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A technology of triclbendazole and a synthetic method, applied in directions such as organic chemistry, can solve problems such as unmentioned substances and product purity, and achieve the effect of low price
Active Publication Date: 2018-12-21
暨明医药科技(苏州)有限公司
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[0010] CN104230815 has different cyclization methods. S-methylisourea sulfuric acid is used instead of carbon disulfide to obtain triclabendazole in one step, but the patent does not mention related substances and product purity
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Embodiment 1
[0048] intermediate 5 Preparation of:
[0049] 4-Chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (50 g, 0.15 mol) and triethylamine (75.8 g, 0.75 mol) were dissolved in dichloromethane (300 ml). Under the condition of nitrogen protection, cool to 0~10°C, add dropwise a solution of trichlorosilane (71.1g, 0.53mol) in dichloromethane (100ml), keep the temperature not higher than 10°C during the dropping process; after the dropwise addition, React at 15~20°C for 12 hours; quench the reaction with saturated sodium bicarbonate solution, adjust the pH to 8~9, stir for 0.5 hours; let stand to separate the liquid, wash with water to obtain the intermediate 5 dichloromethane solution.
[0050] Add ethanol (500ml) to the above solution, distill at normal pressure until the boiling point of the distillate is above 78°C (ethanol needs to be added in the middle, the final volume is about 500ml), and the intermediate is obtained 5 weak. In another reaction flask, dissolve potassium hydrox...
Embodiment 2
[0055] intermediate 5 Preparation of:
[0056] 4-Chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (50g, 0.15mol) and triethylamine (60.6g, 0.60mol) were dissolved in dichloromethane (300ml). Under the condition of nitrogen protection, cool to 0~10°C, add dropwise a solution of trichlorosilane (80.5g, 0.60mol) in dichloromethane (100ml), keep the temperature not higher than 10°C during the dropping process; after the dropwise addition, React at 15~20°C for 12h; quench the reaction with saturated sodium bicarbonate solution, adjust the pH to 8~9, stir for 0.5h; let stand to separate the liquid, wash with water to obtain the intermediate 5 dichloromethane solution.
[0057] Add ethanol (500ml) to the above solution, distill at normal pressure until the boiling point of the distillate is above 78°C (ethanol needs to be added in the middle, the final volume is about 500ml), and the intermediate is obtained 5 weak. In another reaction bottle, dissolve potassium hydroxide (9.8g, 0.1...
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Abstract
The invention discloses a synthesis method of triclabendazole, comprising the following steps: reducing 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline as a raw material in an organic solvent by trichlorosilane, thus obtaining an intermediate compound; directly making ring closing reaction with carbon disulfide in the presence of potassium hydroxide, thus preparing an intermediate; enabling the intermediate and dimethyl carbonate to make methylation reaction under DBU catalysis, thus finally preparing triclabendazole. Through the process, a nitro reduction method is improved, the requirementsfor equipment are reduced, and post-treatment steps are simplified; by combining the nitro reduction and the cyclization into a one-step reaction, the operation procedure is simplified and the yield is increased; by changing a feeding sequence in the process of cyclization, the release rate of hydrogen sulfide is controlled, and the influence on environment is reduced. Replacing dimethyl sulfate or methyl iodide with dimethyl carbonate for methylation is more environmentally friendly; the obtained triclabendazole meets the European Pharmacopeas Standards in terms of all indicators, the total yield can reach 55-60%, indicating an obviously improved process and a promising prospect in industrial application.
Description
technical field [0001] The invention relates to a synthesis method of triclabendazole, which belongs to the technical field of organic synthesis. Background technique [0002] Triclobendazole, also known as Ganzhijing, is Triclabendazole in English, and its chemical name is 5-chloro-6-(2,3-dichlorophenoxy)-2-methylthio-1H-benzimidazole. The structural formula of this compound is for: [0003] [0004] Triclobendazole is a high-efficiency anti-liver fluke drug, which has obvious killing effect on adults and larvae of liver fluke, which is better than nitrophenol. It is safe to take orally, has few side effects, and is well tolerated. It is the drug of choice for the treatment of liver fluke. The market prospect of this drug is relatively broad. [0005] US4197307 (1978) & US4205077 (1978) & US5322853 (1993), the synthetic method of triclabendazole described takes 2,3-dichlorophenol and 2-nitro-4,5-dichloroaniline as starting raw materials, by Solvent-free reaction can ...
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