The preparation method of clobazam

Abstract

The invention provides a preparation method of clobazam. The preparation method comprises the following steps: (1), using 2-nitro-5-chlorodiphenylamine and ethyl malonyl chloride as raw materials, performing a reflow reaction in an organic solvent, after the reaction, decompressing the organic solvent in the reaction system, then performing evaporation to dryness, and adding a refining solvent for refining treatment so as to obtain a compound as shown in a formula II; (2), performing zinc powder reduction on the compound as shown in the formula II, and performing ammonolysis cyclization so as to obtain a compound as shown in a formula III; (3) enabling the compound as shown in the formula III to react with methyl iodide in an alkaline alcohol solution so as to obtain the clobazam, wherein alkali is one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide. The clobazam prepared by the method is few in impurities and high in purity.

Description

technical field [0001] The invention belongs to the technical field of preparation of 1,5-benzodiazepine derivatives, and in particular relates to a preparation method of clobazam. Background technique [0002] Epilepsy is a group of highly synchronized and often self-limited abnormal discharges of brain neurons caused by known or unknown etiology, with recurrent, transient, and usually stereotyped central nervous system function A syndrome characterized by abnormalities. According to WHO statistics, there are currently about 50 million people with epilepsy worldwide, 80% of whom are in developing countries. There are also 2 million new cases of epilepsy each year. The prevalence of epilepsy in developed countries, countries with economic transition, developing countries and underdeveloped countries are 5.0‰, 6.1‰, 7.2‰, 11.2‰ respectively. [0003] Data show that the prevalence of epilepsy in my country is 7‰, which is close to the incidence rate of 7.2‰ in developing co...

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Problems solved by technology

[0004] Similar products currently on the market are used to treat epilepsy, such as phenytoin sodium, phenobarbital, carbamazepine and sodium valproate, etc., but they have the following defects: (1) before the blood drug concentration reaches the level of adequate seizure control It usually takes several days or weeks; (2) Each drug has a significant effect on a certain form of epilepsy, but it cannot have an effect on all types of epilepsy; (3) For status epilepticus, it cannot be quickly effective

[0008] When preparing clobazam (I), the above-mentioned patents use strong bases such as sodium amide ethylate, etc., which are relatively strong, and can not only capture the hydrogen on the N position and form clobazam with methyl iodide, but also capture the compound III-5 Hydrogen is added to the methylene on the member ring to form a carbanion, which reacts with methyl iodide to form impurity IV. The above synthetic route leads to low purity of the synthesized clobazam, which affects its efficacy and application

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