Method for preparing high-purity 7-chloro-5-phenyl-benzodiazepine-2-one

Abstract

The invention relates to a method for preparing a high-purity important intermediate of alprazolam, namely 7-chloro-5-phenyl-benzodiazepine-2-one. The method comprises the following steps: after a ring-closure reaction taking 2-chloroacetylamino-5-chloro-diphenyl ketone and hexamethylenetetramine as main raw materials, performing vacuum concentration to dryness, and directly adding a refining solvent for clear dissolution; then, washing and layering, and dropwise adding dilute acid for salifying; adding alkaline water into the separated salt in purified water, and freeing to obtain 7-chloro-5-phenyl-benzodiazepine-2-one of which the HPLC (high performance liquid chromatography) purity is not lower than 99.0%. In the method, the end point of the concentration operation after complete reaction is easy to control, the HPLC purity of the product is remarkably increased, and the interference of unavoidable impurities on later preparation of alprazolam is avoided.

Description

technical field [0001] The invention relates to a method for preparing high-purity alprazolam important intermediate 7-chloro-5-phenyl-benzodiazepin-2-one, which belongs to the technical field of pharmaceutical synthesis technology. Background technique [0002] 7-Chloro-5-phenyl-benzodiazepine-2-one is a key intermediate in the synthesis of benzodiazepine sedative-hypnotics such as alprazolam and diazepam. The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-α]benzodiazepine. CNS depressants developed. Because it contains a metabolically stable triazole ring in its molecule, its physiological activity is stronger than that of general benzodiazepines, and its sedative and hypnotic effects are 25-30 times and 3.5-11.3 times that of diazepam, respectively. And it also has obvious antiepileptic and antidepressant effects. The existing alprazolam synthesis process has the phenomenon that the purity of the intermediates is not high, and the fina...

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Problems solved by technology

The HPLC purity of the intermediate prepared according to the literature process is not high, and without further refining treatment, a large amount of impurities will be brought into the subsequent process, which will eventually lead to the detection of related substances in the quality index of the finished alprazolam exceeding the limit

The main problem in the intermediate preparation process is: in the reaction process, the phenomenon that the condenser is blocked due to the sublimation of ammonium bicarbonate or ammonium carbonate often occurs, and there is a potential safety hazard; the concentration end point at the end of the reaction is not easy to control, and the solvent evaporates Too little amount directly affects the cyclization yield, and the situation that the material is colloidal and cannot be separated due to the difficulty of discharging due to the large amount of steaming is easy to occur; the resulting intermediate 7-chloro-5-phenyl-benzodiazepine The HPLC purity of the crude product of -2-ketone is only about 85%; the solubility of the intermediate in ethanol is not large, and the effect of recrystallization in solvent ethanol to remove impurities is not ideal. The HPLC purity of the fine product can only reach about 95%, and the impurities contained in it Bringing into the follow-up reaction, there will be a step-by-step amplification effect of impurities, which will easily cause the quality of the finished alprazolam to be unstable, and the phenomenon of being forced to rework and refine due to the detection of related substances in the finished product exceeds the standard

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