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Convenient high-yield Arbekacin synthesis method

A technology of arbekacin and synthetic methods, applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve problems such as complex synthesis process and affecting product yield

Inactive Publication Date: 2015-01-21
FUJIAN BOMEI BIOLOGICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, during ammonolysis and deprotection, higher concentration of ammonia water tends to cause the part of the connected side chain to be ammonolyzed, thereby affecting the product yield
[0011] Furthermore, the condensation of the active ester with the protectant makes the synthetic process too complicated

Method used

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  • Convenient high-yield Arbekacin synthesis method
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  • Convenient high-yield Arbekacin synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 Preparation of 3,2',6'-triformylamino-3',4'-dideoxykanamycin B

[0051] In a 500ml three-neck round bottom flask, add 3', 4'-dideoxykanamycin B (9.02 grams, 0.02mol), DMSO 150ml, stir for 10min, add 13.2g of zinc acetate, and stir at room temperature for 5 hours until The solution was clear. 2-formylmercaptobenzothiazole (12.88 g, 0.066 mol) was added, and the reaction was continued to stir at room temperature for 3 hours, and the end point of the reaction was judged by TLC.

[0052] The reaction solution was slowly poured into 400ml of water, a white precipitate was formed, stirred for about 0.5 hours, the pH was adjusted to 6-7 with ammonia water, the insoluble matter was filtered off, the filter residue was washed repeatedly with appropriate amount of water, and the filtrate was combined.

[0053] The filtrate is adsorbed on 800ml 732[NH 4 + ]-type resin, washed with a large amount of water and eluted with 0.3N ammonia water, collected the components wit...

Embodiment 2

[0055] The preparation of embodiment two (S)-4-formamido-2-hydroxybutyric acid

[0056] In a 250ml three-neck round bottom flask, add sodium carbonate (15.9 g, 0.15 mol) and 120 ml of water, and stir until completely dissolved. Add (S)-4-amino-2-hydroxybutyric acid (HABA) (11.9 g, 0.1 mol) to the above solution, stir and dissolve until completely clear, and check that the pH is above 10. Add 20ml of methanol solution and continue stirring for 30min. Slowly drop in 2-formylmercaptobenzothiazole (self-made, 21.5 g, 0.11 mol) dissolved in 10 ml of methanol solution, and the addition is completed in about 15 minutes. Stirring was continued at room temperature for an hour until the HABA spots disappeared completely in TLC. Developing agent: CHCl 3 -MeOH-NH 4 OH (25%) 4:4:1 (V / V / V), developer: 5% phosphomolybdic acid ethanol solution.

[0057] The above reaction solution was filtered to remove white solid, and the filtrate was concentrated to remove methanol. The residue was w...

Embodiment 3

[0058] The preparation of embodiment three Arbekacin

[0059] In a 250ml three-neck round bottom flask, add 3,2',6'-triformylamino-3',4'-dideoxykanamycin B (5.35 g, 0.01mol), methanol 40ml, 1-hydroxybenzo Triazole (HOBT 2.03 g, 0.015 mol), TEA 0.5 ml, stirred at room temperature until completely dissolved. Add (S)-4-formylamino-2-hydroxybutyric acid in tetrahydrofuran (12.94ml, 0.00085mol / ml), ice-water bath at 5-10°C, slowly add DCCI (3.12g, 0.015mol) ) was dissolved in 30ml of methanol solution, and the addition was completed in about 45 minutes. Stir the reaction at the same temperature for 6 hours, and check with TCL until the raw material spots completely disappear. Developing agent: CH 2 Cl 2 -MeOH-NH 4 OH (25%) 50:35:5 (V / V / V), iodine vapor color development.

[0060] The reaction solution was concentrated to dryness, and H 2 O 10ml, methanol 10ml, stirred at room temperature to dissolve. At 0-5°C, slowly add 50ml of 0.5M HCl dropwise, and control the addition f...

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Abstract

The invention discloses a convenient high-yield Arbekacin synthesis method which comprises the following steps: using 2-formyl mercaptobenzothiazole as the protection reagent to carry out formylation protection on three amino groups on the C3 site, C2' site and C6' site of 3',4'-dibekacin B; based on the difference between other free amino groups on the C1 site and the amino group on the C3'' site in activity, directly introducing side chains to the amino groups on the C1 site optionally; directly using (S)-4-formylamino-2-hydroxy-butanoic acid with the protected amino groups as the acylation reagent for the amino groups on C1 site; and hydrolyzing with moderate acid to remove the formacyl protection. In the whole process, the yield is more than 50%. The whole process is simple, easy to control and high in yield, thereby being applicable to industrial production.

Description

【Technical field】 [0001] The invention relates to an organic synthesis method, in particular to a simple and high-yield arbekacin synthesis method. 【Background technique】 [0002] Arbekacin (Arbekacin 1) is a double chemically modified semi-synthetic aminoglycoside antibiotic developed by Japan Meiji Seika Co., Ltd. and launched in 1990. The therapeutic agent is mainly used for treating infections caused by various drug-resistant bacteria, especially for treating methicillin-resistant Staphylococcus aureus (MRSA) infections, and has received extensive clinical attention and use. [0003] The synthesis of arbekacin is based on 3′; 4′-dideoxykanamycin B (Debekacin 2) as a raw material, and debekacin itself is already a semi-synthetic antibiotic product on the market; through Various means, selectively in the C of dibekacin molecule 1 Arbekacin is formed by introducing S(-)-4-amino-1-hydroxybutyryl side chain into the amino group. Its unique pharmacological activity is achie...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/234C07H1/00
Inventor 赵宁李琳陈梅金陈伟煌许锡南
Owner FUJIAN BOMEI BIOLOGICAL TECH CO LTD
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