The synthetic method of dibekacin and arbekacin

Abstract

The present invention relates to a method for synthesizing dibekacin and arbekacin. The method comprises: using kanamycin B as an initial raw material, protecting five amino groups of the kanamycin B by using t-butyloxycarboryl, protecting hydroxyl of positions 4''and 6'' by aldol condensation, eliminating, in the presence of 2,4,5-triiodo-imidazol, triphenylphosphine, and imidazole, hydroxyl of positions 3' and 4' to form a double bond, removing the protection of the amino groups and the hydroxyl in a hydrochloric methanol solution, and performing catalytic hydrogenation to obtain dibekacin; and using 3',4'-didanosine-3', 4'-didehydro-kanamycin B as a raw material, protecting all the amino groups and hydroxyl by using trimethylsilyl acetate, acylating an amino group of a position 1 by using synthesized active ester, removing the protected groups by sequentially using hydrochloric acid and hydrazine hydrate, and finally, performing catalytic hydrogenation to obtain arbekacin. The synthesizing method is simple in operation, high in yield, environmentally-friendly, low in production cost, and beneficial to industrial production.

Description

technical field [0001] The invention relates to an organic synthesis method, in particular to a synthesis method of dibekacin and arbekacin. Background technique [0002] Since Waksman et al. discovered that Streptomyces produced streptomycin in 1944, more than 3,000 natural and semi-synthetic aminoglycoside antibiotics have been reported, of which nearly 200 are naturally 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 also an indispensable drug in the treatmen...

AI Technical Summary

Problems solved by technology

[0014] (1) In reaction c, the consumption of sodium iodide is excessive, and the addition amount of sodium iodide is 6~10 times of product 2, and serious iodine pollution can be produced on this aspect, brings environmental pressure

In addition, the 2″ hydroxyl group is often also iodized during the reaction, resulting in a decrease in yield

[0015] (2) 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 -60°C, and needs to add a large amount of metal sodium, which not only has difficulties in scale-up production, but also has considerable dangers in operation

[0016] (3) The post-treatment steps of synthesizing dibekacin by this method are complicated, and the products of reactions a, e, and f all need to be separated by ion exchange resin columns, and the products of reactions b, c, and d all need to be extracted with organic solvents, The cost is high, and the production cycle is long, no matter in terms of economic benefits or large-scale production, there are great disadvantages

[0023] (1) When carrying out selective protection of hydroxyl in reaction C, there are many factors affecting the reaction, such as the water content of raw materials and reagents, the amount of benzoyl chloride added and the rate of addition, reaction time and temperature, etc. Selective protection is difficult to control , there are certain problems in mass production

[0024] (2) Pyridine and potassium n-butyl xanthate have been used in reaction E. Although pyridine can be partially recovered, residual pyridine and potassium xanthate have special severe odor and strong toxicity, and there is a lot of waste water in post-treatment. And a large amount of chloroform extraction is required, and there are certain problems in wastewater discharge and waste gas treatment during large-scale production, which will cause serious environmental pollution and cause harm to the health of operators

[0025] (3) The process route is long, there are many unit operations, and the production cycle is long

[0030] (1) In reaction g, the addition of di-tert-butyl dicarbonate is not easy to control, and the activity of the 1-position amino group is not much different from that of other amino groups (such as the 3-position and 3''-position), which often causes the product 7 Low yield and a large number of impurities with similar structures

[0031] (2) In reaction i, the cost of trifluoroacetic acid selected is higher on the one hand, and on the other hand, it is highly volatile and corrosive, and is very harmful to production equipment and operators.

[0035] (1) In reaction I, PHBA, NOP, and DCC are added to the reaction solution together, which will make the acylation reaction occur more easily at the 3-position amino group than at the 1-position amino group, resulting in too many impurities that are similar in structure to the product and are not easy to separate, and The water added in this step will inhibit the acylation reaction, resulting in incomplete reaction

[0036] (2) In reaction I, THF is used as a solvent, on the one hand, the cost is higher, and on the other hand, the acylation reaction activity is not high, resulting in a large amount of active ester added, generating a large amount of impurities at multiple sites of acylation, giving the product Difficulties in the separation and purification of

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