Preparation method of doxycycline intermediate

Abstract

The invention relates to the technical field of veterinary drugs, in particular to a preparation method of a doxycycline intermediate. The preparation method comprises the following steps: (1) uniformly mixing metacycline p-toluenesulfonate and absolute ethyl alcohol in proportion, dropwise adding concentrated hydrochloric acid, carrying out stirring and uniform mixing, and controlling the temperature of a reaction system at 10-35 DEG C; (2) dropwise adding a zinc borohydride solution into a reaction system obtained in the step (1), and controlling heat preservation reaction time to be 2-5 hours to obtain a feed liquid for later use; and (3) dropwise adding an aqueous sulfosalicylic acid solution into the feed liquid obtained in the step (2) according to a mass ratio of (0.7-1.5): 1 under the condition of 20-30 DEG C, carrying out heat preservation reaction for 4-6 hours, conducting cooling to 0-10 DEG C, and carrying out filtering to obtain the doxycycline sulfosalicylate. By utilizing the preparation method, the conversion rate and selectivity of raw materials and the yield of doxycycline p-toluenesulfonate are improved, and reduction cost and safety risks in a reaction process are reduced.

Description

technical field [0001] The invention relates to the technical field of veterinary medicine, in particular to a preparation method of a doxycycline intermediate. Background technique [0002] Doxycycline is a tetracyclic antibiotic with broad-spectrum antibacterial activity, showing good clinical effects. At present, the preparation method of doxycycline is as follows: starting from oxytetracycline, 11α-chloro-6-methine oxytetracycline p-toluenesulfonate is obtained through chlorination and dehydration, and then through one-step or two-step hydrogenation method Replace the chlorine atom of 11α, and reduce the carbon-carbon double bond at position 6 to produce doxycycline p-toluenesulfonate, and finally refine it into a salt to obtain doxycycline, in which the intermediate of hydrogenation process is metacycline p-toluenesulfonate. The 6th position of doxycycline is a chiral carbon atom, so the hydrogenation step will produce two isomers, α and β, and the biological activity...

AI Technical Summary

Problems solved by technology

The reduction reaction is often catalyzed by a heterogeneous catalyst supported by activated carbon with noble metals. The selectivity of the reduction process is low, and more β impurities are likely to be produced, generally at 5% to 10%. At the same time, the catalytic reaction rate is slow, the reaction conversion rate is low, and the remaining The raw material becomes an impurity that is difficult to be refined in the subsequent steps; in addition, the catalyst itself is expensive, the amount of feed is large and the preparation cost is high

In summary, the preparation process of doxycycline still has the problems of slow hydrogenation reaction rate, low selectivity, and high cost of heterogeneous catalysts used

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