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A technology of arbekacin and synthetic method, which is applied in the field of synthesis of aminoglycoside antibiotics, can solve the problems of product stability impact, product stability impact, poor selectivity, etc., and achieve easy industrial production, reduce production cost, and yield Improved effect
Inactive Publication Date: 2015-03-25
CHANGZHOU FANGYUAN PHARMA
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Problems solved by technology
The first kind uses 2-formylmercaptobenzothiazole as protecting group, at first needs to prepare 2-formylmercaptobenzothiazole, and the side chain of selection also needs to use 2-formylmercaptobenzothiazole as protecting group simultaneously, and this just Increased costs, but also caused pollution to the environment
The third hexamethyldisilazide, this method requires the use of acetonitrile, hydrazine hydrate and other toxic reagents, and if the protecting group is removed, it will be refluxed at high temperature under strong alkaline conditions, which will have an impact on the stability of the product , the cost is also higher
The second is BOC protection. Since this method directly adds 4 BOCs, it is very easy to protect the fifth amino group. The selectivity is relatively poor and the yield is low. At the same time, the side chain protecting group used also needs to be in a strong base. Removal under certain conditions has a great impact on the stability of the product
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Embodiment 1）
[0021] (a) Synthesis of 3,2',6'-tri-N-tert-butoxycarbonyl-3',4'-dideoxykanamycin B:
[0022] Dissolve 1 g of 3',4'-dideoxy-3',4' didehydro-kanamycin B (dibekacin) and 30 g of dimethylformamide (DMF), add zinc acetate, fully Stir to complete the complexation; put in 1.2 grams of di-tert-butyl dicarbonate, react for 1 hour, and determine the end point by TLC;
[0023] Then the reaction solution was diluted with water, and the filtrate was adsorbed on the cation exchange [NH 4 + ]-type resin column, after washing with a large amount of water, elute with ammonia water, collect the components with three protected compounds, and concentrate to dryness under reduced pressure to obtain a yellow solid 3,2',6'-tri-N-tert-butoxycarbonyl -3'.4'-Dideoxy-3',4'Didehydro-Kanamycin B;
[0024] (b) Synthesis of 1-tert-butoxyamido-3-hydroxybutyric acid
[0025] In an aqueous solution of 1.74 grams of sodium bicarbonate and 56 grams of 1,4-dioxane, add 2.25 grams of 2-hydroxy-4-aminobutyric a...
Embodiment 2）
[0033] (a) Synthesis of 3,2',6'-tri-N-tert-butoxycarbonyl-3',4'-dideoxykanamycin B:
[0034] Dissolve 1 g of 3',4'-dideoxy-3',4' didehydro-kanamycin B (dibekacin) and 30 g of dimethylformamide (DMF), add C1-5 carboxyl The divalent transition metal zinc acetate of the acid is fully stirred to make it complexed completely; drop into 1.2 grams of di-tert-butyl dicarbonate, react for 1 hour, and determine the end point by TLC;
[0035] Then the reaction solution was diluted with water, and the filtrate was adsorbed on the cation exchange [NH 4 + ]-type resin column, after washing with a large amount of water, elute with ammonia water, collect the components with three protected compounds, and concentrate to dryness under reduced pressure to obtain a yellow solid 3,2',6'-tri-N-tert-butoxycarbonyl -3'.4'-Dideoxy-3',4'Didehydro-Kanamycin B;
[0036] (b) Synthesis of 1-tert-butoxyamido-3-hydroxybutyric acid
[0037] In an aqueous solution of 1.74 grams of sodium bicarbonate and 56...
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Abstract
The present invention relates to an arbekacin synthesis method. According to the arbekacin synthesis method, di-tert-butyl dicarbonate is adopted as a protection agent, tert-butyloxycarbonyl protection is performed on three amino groups on the sites C3, C2' and C6' of 3',4'-dideoxy-3',4' didehydro-kanamycin B, difference between the remaining free amino groups on the site 1 and the site 3' is adopted to directly and selectively introduce the side chain on the amino group on the site 1, the amino-protected 1-tert-butoxy amide-3-hydroxybutyric acid is directly adopted as an acylation reagent of the amino group on the site 1, and hydrolysis with an acid is adopted to remove the tert-butyloxycarbonyl protection. According to the present invention, the operations of the method are simple, the reaction condition and the protection group removing condition are mild, the separation purification of the product obtained from the reaction is easy compared with the separation purification of the product obtained by adopting other types of the amino acid protection agents, the one-pot reaction is adopted, the concurrent deprotection is adopted, the product yield is high, the production cost is reduced, the industrial production is easily achieved, and hydrazine hydrate and other hazardous compounds are not used so as to provide the advantages of low environment pollution.
Description
technical field [0001] The invention relates to a synthesis method of aminoglycoside antibiotics, in particular to a synthesis method of arbekacin. Background technique [0002] Arbekacin is a drug that has strong antibacterial activity against gentamicin, kanamycin and amikacin-resistant bacteria, and is clinically used for infections of the respiratory tract and urinary tract. It is the most effective among many aminoglycoside antibiotics. In February 2005, Arbekacin was listed by the World Health Organization as one of the most important antibiotics in the 21st century. [0003] At present, there are mainly three kinds of amino protecting groups selected in the synthetic method of arbekacin: the first is 2-formylmercaptobenzothiazole, the second is BOC, and the third is hexamethyldisilazide. The first kind uses 2-formylmercaptobenzothiazole as protecting group, at first needs to prepare 2-formylmercaptobenzothiazole, and the side chain of selection also needs to use 2-f...
Claims
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