The synthetic method of dibekacin and arbekacin

A synthesis method and technology of dibekacin are applied in the field of synthesis of dibekacin and arbekacin, which can solve the problems of long process route, health hazards of operators, difficulty in enlarging production, etc., so as to reduce environmental pollution and shorten production time. Three-step reaction, the effect of shortening the production cycle

CN103204887BActive Publication Date: 2016-01-20SHANDONG LIANGFU PHARM CO LTD
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
Publication Date
2016-01-20

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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.
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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...

Examples

Embodiment 1

[0075] (1) Weigh 9.66g (20mmol) of Kanamycin B and 10.6g (100mmol) of anhydrous sodium carbonate, dissolve them in 50mL of water, add 50mL of isopropanol, and weigh di-tert-butyl dicarbonate 26.2g (120mmol) was added to it, reacted at 30°C for 6 hours, filtered, and the filtrate was collected to obtain 1,3,2',6',3''-penta-nitrogen-tert-butoxycarbonyl-kanamycin B18.3g, yield 93%.

[0076] (2) Weigh 1,3,2′,6′,3′′-penta-nitrogen-tert-butoxycarbonyl-kanamycin B18.3g (18.6mmol), anhydrous p-toluenesulfonic acid 0.64g (3.7 mmol), dissolve it in 100mL N,N-dimethylformamide, add 7.7mL (55.8mmol) of 1,1-dimethoxycyclohexane, react at 40°C for 12 hours, stop the reaction, and solution was poured into 1L of water to disperse, filtered, and the filtrate was collected to obtain 1,3,2′,6′,3′′-penta-nitrogen-tert-butoxycarbonyl-4″,6″-oxygen-cyclohexylene- Kanamycin B18.2g, yield 92%.

[0077] (3) Weigh 18.2g (17.1mmol ), dissolved it in 200mL toluene, added 11.4g (25.6mmol) of 2,4,5-trii...

Embodiment 2

[0086] In step (1), the mol ratio of di-tert-butyl dicarbonate, sodium carbonate and kanamycin B is 5:5:1 (i.e. di-tert-butyl dicarbonate 21.8g, sodium carbonate 10.6g, kanamycin B Mycin B9.66g), other steps are with embodiment 1, obtain 1,3,2',6',3''-five-aza-tert-butoxycarbonyl-kanamycin B16.1g, yield is 82 %.

Embodiment 3

[0088] In step (1), the mol ratio of di-tert-butyl dicarbonate, sodium carbonate and kanamycin B is 10:5:1 (i.e. di-tert-butyl dicarbonate 43.6g, sodium carbonate 10.6g, kanamycin B Mycin B9.66g), other steps are with embodiment 1, obtain 1,3,2',6',3''-five-aza-tert-butoxycarbonyl-kanamycin B18.5g, yield is 94 %.