Synthesis method of amikacin

A technology of amikacin and synthesis method, which is applied in the field of medicine, can solve problems such as employee health damage, environmental hazards, and environmental hazards, and achieve the effects of reducing employee health damage, shortening reaction time, and increasing product yield

Active Publication Date: 2017-06-20
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above route has the following problems: (1) 7 hydroxyl groups and 4 amino groups of Kanamycin A need to be fully silanized for protection, requiring a longer reaction time; (2) in order to improve the activity of the PHBA carboxyl group, use NOP and PHBA to form The active ester is acylated, and the active ester is removed from the NOP after the acylation reaction
This not only causes the complexity of the process, but also because NOP is a highly sensitizing substance, it will cause damage to the health of workers when used as a raw material and as a by-product in the aftertreatment process (such as separating out NOP in the recovery of acetone); (3) in actual production, Most of the NOP as a by-product enters the hydrazinolysis step with the material, and NOP forms phthalic hydrazide under the action of hydrazine. Due to the poor purity of phthalic hydrazide, the reuse value is low. In addition, the by-product It is not easy to biodegrade and has great harm to the environment. The general treatment method is incineration, but it still causes certain harm to the environment.

Method used

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  • Synthesis method of amikacin
  • Synthesis method of amikacin
  • Synthesis method of amikacin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1) Weigh 48.5g (0.1mol) of kanamycin A, add 460ml of acetonitrile, 115ml of hexamethyldisilazane, 1ml of trimethylchlorosilane, reflux for 5 hours, and detect after the liquid becomes clear Density ρ=1.03g / ml, spray-dried to obtain 101.2g of powdered silanized compound;

[0044]2) Add the above-mentioned powdered silanized compound, 27.4g of PHBA, and 600ml of acetone to a 1000ml three-necked flask, stir for 30 minutes to dissolve, cool down to -20°C, add 50ml of acetone solution containing 19.4g of DCC in 1 minute, and continue the reaction for 30 minutes Acylated products are obtained;

[0045] 3) adding concentrated hydrochloric acid to the above-mentioned acylated product to adjust the pH to 2.34, stirring and reacting for 1 hour, and distilling off the solvent under reduced pressure to obtain a hydrolyzed product of kanamycin;

[0046] 4) Add a small amount of water to the above-mentioned feed liquid, control the optical rotation of the feed liquid to α=55.6, lowe...

Embodiment 2

[0048] 1) Weigh 48.5g (0.1mol) of kanamycin A, add 460ml of acetonitrile, 115ml of hexamethyldisilazane, 1ml of trimethylchlorosilane, reflux for 5.5 hours, and detect after the liquid becomes clear Density ρ=1.04g / ml, spray-dried to obtain 103.5g;

[0049] 2) Add the above-mentioned powdered silanized compound, 28.0g of PHBA, and 600ml of acetone into a 1000ml three-necked flask, stir for 30 minutes to clear the whole, cool down to 0°C, add 50ml of acetone solution containing 20.6g of DCC in 1 minute, and continue the reaction for 30 minutes to obtain Acylation products;

[0050] 3) adding concentrated hydrochloric acid to the above-mentioned acylated product to adjust the pH to 2.34, stirring and reacting for 1 hour, and distilling off the solvent under reduced pressure to obtain a hydrolyzed product of kanamycin A;

[0051] 4) Add a small amount of water to the above-mentioned feed liquid, control the optical rotation of the feed liquid to α=55.6, lower the temperature to ...

Embodiment 3

[0053] 1) Weigh 48.5g (0.1mol) of kanamycin A, add 460ml of acetonitrile, 115ml of hexamethyldisilazane, 1ml of trimethylchlorosilane, reflux for 5 hours, and detect after the liquid becomes clear Density ρ=1.02g / ml, spray-dried to get 101.0g;

[0054] 2) Add the above-mentioned powdered silanized compound, 27.4g of PHBA, and 600ml of acetone to a 1000ml three-necked flask, stir for 30 minutes to clear the whole, cool down to -20°C, add 50ml of acetone solution containing 19.4g of DCC in 1 minute, and continue the reaction for 30 minutes Acylated products are obtained;

[0055] 3) adding concentrated hydrochloric acid to the acylated product to adjust the pH to 2.34, stirring for 1 hour, and distilling off the solvent under reduced pressure to obtain a hydrolyzed product of kanamycin A;

[0056] 4) Add a small amount of water to the above-mentioned feed liquid, control the optical rotation of the feed liquid α=55.6, lower the temperature to 20°C, add 20.2g of 80% hydrazine hy...

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Abstract

The invention discloses a synthesis method of amikacin. The synthesis method comprises following steps: firstly, a partially silanization protection product of kanamycin A is prepared; dehydration of the partially silanization protection product with PHBA under the action of DCC is carried out so as to obtain a acylated product; the acylated product is subjected to hydrolysis, nitrilase, and column chromatography purification so as to obtain amikacin. According to the synthesis method, NOP is not used, synthesis of an active ester via esterification is avoided, damage on the health of workers is reduced greatly, solid waste generated in production process is reduced greatly, product yield is increased, and the synthesis method is especially suitable for industrialized production.

Description

technical field [0001] The invention relates to a synthesis method of amikacin, which belongs to the field of medicine. Background technique [0002] Amikacin acid is a semi-synthetic aminoglycoside antibiotic with a broad antibacterial spectrum and strong antibacterial ability against a variety of bacteria. Since its launch in the 1970s, amikacin sulfate has been widely used due to its definite curative effect, and has become the first-line anti-infective drug commonly used clinically in the world. In my country, Amikacin Sulfate has been included in the National Essential Drug List, and also included in the Class A drug in the "National Basic Medical Insurance and Work Injury Insurance Drug List". [0003] Amikacin, also known as amikacin. The most commonly used in the existing amikacin synthesis route is the silylation protection route, which comprises: (1) taking kanamycin A as raw material to obtain the silylation protection product of kanamycin A through silylation p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/234C07H1/00
CPCC07H1/00C07H15/234
Inventor 王仕川张坤蔡成伟褚杰孙政军布彬彬孙星星王凤银
Owner 山东安信制药有限公司
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