New synthetic method of arbekacin and intermediate of dibekacin thereof

Abstract

The invention relates to a new synthetic method of arbekacin and an intermediate of dibekacin thereof. The method adopts kanamycin B as an initial synthetic raw material; five amino groups of kanamycin B are protected by butoxycarbonyl; 4''-position and 6''-position hydroxyls are protected by aldol condensation; 3'-position and 2''-position hydroxyls are selectively acylated; a 4'-position hydroxyl is sulfonylated; then an epoxy structure is formed; the epoxy structure is treated by potassium n-butylxanthate to form double bonds; and catalytic hydrogenation is performed to obtain dibekacin; dibekacin is used as a raw material; all amino groups and hydroxyls of the dibekacin are protected by hexamethyl disilyamine; side chain connection of 1-position amino group is performed with synthetic active ester; the silyl protection is removed; and finally arbekacin is obtained by hydrazine hydrate hydrazinolysis. The synthetic method is simple in operation, high in yield, friendly for environment, low in production cost, and quite suitable for industrial production.

Description

technical field [0001] The invention relates to an organic synthesis method, in particular to a synthesis method of arbekacin and its intermediate dibekacin. Background technique [0002] Since Waksman et al. discovered streptomycin produced by Streptomyces in 1944, there have been more than 3,000 natural and semi-synthetic aminoglycoside antibiotics reported, including nearly 200 natural aminoglycoside antibiotics produced by microorganisms. Aminoglycoside antibiotics have the characteristics of broad antibacterial spectrum, complete sterilization, good synergistic effect with β-lactam and other antibiotics, and post-antibiotic effect on many pathogenic bacteria. Although the use of aminoglycoside antibiotics has been limited by the emergence of bacterial resistance, oto- and nephrotoxicity, and the widespread use of beta-lactam antibiotics, they remain the treatment of choice for serious infections with life-threatening Gram-negative bacteria A class of important drugs is...

AI Technical Summary

Problems solved by technology

[0016] (1) In reaction A, the sulfonylation reagent adopted can affect the exposed hydroxyl, causing a decline in yield; because methanesulfonyl chloride itself is highly toxic, if it is used, it will cause serious environmental pollution, which is harmful to the environment. The health of the operator can also pose a hazard

[0017] (2) in reaction D, the consumption of sodium iodide and zinc powder is excessive, and the add-on of zinc powder is 5~10 times of product 3, and the add-on of sodium iodide is 10 times of product 3, this aspect will Serious iodine pollution is produced, which brings environmental pressure. On the other hand, during the post-reaction treatment, due to the excessive addition of zinc powder, emulsification often occurs during the extraction operation, making post-treatment difficult.

In addition, the 2" hydroxyl group is often replaced by iodide anions during the reaction, which leads to a decrease in yield.

[0018] (3) When removing the protective groups on the five amino groups and the 2" hydroxyl group, the method adopted is the liquid ammonia / metal sodium reduction method. Because this method needs to react under the condition of -65°C, and needs to add a large amount of Sodium metal, which not only has difficulties in scale-up production, but also has considerable danger in operation

[0019] (4) The catalyst used in the hydrogenation reduction is platinum oxide, which will cause an increase in production costs due to the high price of platinum oxide itself

[0020] (5) The step of synthesizing dibekacin with this method is too long, and the total yield is only 10%, which has great disadvantages no matter in terms of economic benefits or large-scale production

[0037] (2) When carrying out the protection of amino in reaction A, if adopt ethyl chloroformate to carry out amino protection, because ethyl chloroformate itself has stronger toxicity, if adopt it, can cause serious environmental pollution, to the health of operator also cause harm

[0044] (1) In reaction A and reaction B, two kinds of reagents have been adopted to protect amino groups respectively, which will bring inconvenience in operation, and then affect the yield, and the solvent used in reaction A is dimethyl sulfoxide, which will cause Difficulty postprocessing

[0045] (2) The removal of the protecting group R adopts the hydrogenation reduction method, which may also remove part of the side chains at the same time, resulting in a decrease in yield

[0049] Although this method overcomes the problem caused by the use of metal ion complexation in U.S. Patent No. 4,297,485, when the amino group is protected, that is, in the reaction g, the addition of di-tert-butyl dicarbonate is difficult to control, often resulting in product 7 In addition, the starting material used for the synthesis of arbekacin in this patent is unhydrogenated dibekacin, and the catalyst used in the final hydrogenation is platinum oxide, which greatly increases the production cost

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