A kind of preparation method of flumazenil

Abstract

The invention discloses a preparation method of flumazenil, belonging to the field of drug synthesis. The method of the present invention uses 5-fluoro-2-nitrobenzoic acid as a raw material, through condensation with sarcosinate, and then performing ring closure while reducing, to obtain 7-fluoro-3,4-dihydro-4-methyl ‑1H‑[1,4]benzodiazepine‑2,5‑dione; finally, flumazenil is obtained through halogenation and cycloaddition. Synthesis of flumazenil key intermediate 7-fluoro-3,4-dihydro-4-methyl-1H-[1,4]benzodiazepine-2,5-dione provided by the present invention The method adopts a green synthesis process, and carries out an intramolecular ring closure reaction while reducing the nitro group. Compared with the known flumazenil synthesis method, it does not need to use strong oxidants, highly toxic reagents (such as ethyl chloroformate), etc., and the yield rate is higher.

Description

A kind of preparation method of flumazenil technical field The present invention relates to the field of pharmaceutical synthesis, be specifically related to a kind of preparation method of flumazenil. Background technique Flumazenil (Flumazenil, FMZ) is the specificity of benzodiazepines (Benzodiazepines, BZDs). Sex blockers, commonly used in clinical detoxification, wake-up and diagnosis of BZDs. In addition, studies have shown that FMZ is effective in ethanol poisoning, al Alzheimer's disease (AD) has a certain therapeutic effect. The synthetic method of flumazenil mainly contains following a, b, c, d, five ways of e: The synthetic route a of flumazenil (seeing Fig. 1): be starting with 2-amino-5-fluorobenzoic acid, phosgene or chloroformate Raw material, obtain 6-fluoroisatinic anhydride through condensation ring closure, obtain 7-fluorine-3.4-dihydro-4-methyl-2H-1 through sarcosine condensation again, 4-benzodiazepine-2,5(1H)-dione (hereinafter referred to ...

AI Technical Summary

Problems solved by technology

Wherein path a, b, c all prepare this intermediate by anthranilic acid method, and the chloroformic ester compound or phosgene used in this step are all highly toxic, pollute water source and environment relatively, and reaction conditions require Strict, improper operation can easily reduce the yield or fail the reaction

The route d uses the isatin oxidation method to prepare the intermediate. This method is commonly used with chromium trioxide or peroxyacid, which will easily increase the related substances of flumazenil and affect the efficacy and safety.

[0010] In the above-mentioned synthetic pathway e of flumazenil, midazolam is constructed by the Wohl–Ziegler reaction. This step often uses highly toxic non-polar solvents such as benzene and carbon tetrachloride, which are harmful to experimenters, the environment, and the quality of the final product. It is easy to produce poison; and the path is cumbersome, the reaction conditions are harsh, and the economic benefit is low, which is not conducive to large-scale production of enterprises

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