Safe and non-toxic method for removing nickel ion impurities in peramivir trihydrate intermediate M9

Abstract

The invention provides a safe and nontoxic method for removing nickel ion impurities in a peramivir trihydrate intermediate M9. The method comprises the following steps: adding pure water into a reaction kettle containing a peramivir trihydrate crude product at a temperature of -5-5 DEG C; dropwise adding an acidic solution to obtain a first solution after dropwise adding is finished; adding purewater into the first solution again, heating to 15-20 DEG C, keeping the temperature for 20-40 minutes, adding activated carbon, and stirring for 20-40 minutes to obtain a second solution; centrifugally separating the second solution to obtain centrifugal filtrate and a first filter cake; leaching the first filter cake with purified water, and combining the leaching filtrate with the centrifugal filtrate to obtain a third solution; and carrying out washing, crystallizing and other treatments on the third solution to finally obtain the purified peramivir trihydrate. According to the method, nickel ion impurities in peramivir trihydrate can be effectively removed, sodium nitrite is prevented from being used in the process, generation of genotoxic impurities is avoided, and the safety of themedicine is greatly improved.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a safe and nontoxic method for removing nickel ion impurities in peramivir trihydrate intermediate M9. Background technique [0002] There are few reports on the synthetic route of peramivir. Due to the particularity of its structure, each route is similar, and there is no major difference, which is mainly reflected in the difference of individual intermediates and reaction reagents. The peramivir intermediate M8 is an important intermediate used in all routes. The preparation of peramivir requires the reduction of M8 to obtain M9 through the intermediate. [0003] [0004] The difference is that the reducing agent used is different from the post-treatment. Among them, the sodium borohydride / nickel chloride reduction system has mild conditions, does not require special equipment, and is easy to operate. It is currently the main route of choice in the synthesis of ...

AI Technical Summary

Problems solved by technology

This route introduces sodium nitrite in the post-treatment process. As a complexing agent for nickel ions, nitrite has the advantages of strong complexing ability and good solubility, and can better remove nickel ions in the reaction system without being absorbed by the system. It is reduced to metal shavings or nickel boride, but there are amino groups in the peramivir structure, which react with nitroso groups to generate potential genotoxic impurities. here comes the potential risk

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