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Synthetic method of environment-friendly amikacin

A technology of amikacin and a synthesis method, applied in the field of medicine, can solve the problems of high environmental harm, environmental harm, poor purity, etc., and achieve the effects of shortening the synthesis route, reducing waste water and solid waste, and reducing the harm to the environment

Active Publication Date: 2016-01-20
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

On the one hand, the by-product has low reuse value due to poor purity
On the other hand, this by-product is not easy to biodegrade and is very harmful to the environment. The general treatment method is incineration, but it still causes certain harm to the environment.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] (1) Weigh 16.2g (0.11mol) of compound A (2(S)-2-hydroxy-4-carbamoylbutyric acid), 26.7g of N-hydroxyphthalimide, add 500ml of acetone, and heat up Dissolve; lower the temperature to 30°C, add 45.3g DCC, react for 60 minutes; filter to remove the white precipitate; rinse the filter cake twice with 50ml acetone, and combine the filtrate to obtain an active ester / acetone solution for use;

[0049] (2) Weigh 127.8g (0.1mol) of kanamycin A silanide (calculated as full protection), dissolve it with 500ml of acetone, add the above active ester, and react at 5°C for 2 hours to obtain an acylated product;

[0050] (3) Add concentrated hydrochloric acid to the above acylated product to adjust the pH to 2.34, stir for 1 hour, distill under reduced pressure to remove the solvent, add a small amount of water to the above material liquid, and control the material liquid concentration to 82.6g / L;

[0051] (4) Cool down to -10°C, add 60ml of 30% liquid caustic soda, and control the temperatur...

Embodiment 2

[0054] (1) Weigh 16.2g (0.11mol) of compound A (2(S)-2-hydroxy-4-carbamoylbutyric acid), 26.5g of N-hydroxyphthalimide, add 500ml of acetone, and heat up Dissolve; cool to 30°C, add 45.0g DCC, react for 65 minutes; filter to remove the white precipitate; rinse the filter cake twice with 50ml of acetone, combine the filtrate to obtain an active ester / acetone solution for use;

[0055] (2) Weigh 127.8g (0.1mol) of kanamycin A silanide (calculated as full protection), dissolve it with 500ml of acetone, add the above active ester, and react at 5°C for 2 hours to obtain an acylated product;

[0056] (3) Add concentrated hydrochloric acid to the above acylated product to adjust the pH=2.54, stir for 1 hour, distill under reduced pressure to remove the solvent, add a small amount of water to the above material liquid, and control the material liquid concentration to 82.0g / L;

[0057] (4) Cool down to -15°C, add 58ml of 30% liquid caustic soda, control the temperature of the material liquid ...

Embodiment 3

[0060] (1) Weigh 16.2g (0.11mol) of compound A (2(S)-2-hydroxy-4-carbamoylbutyric acid), 27.0g of N-hydroxyphthalimide, add 500ml of acetone, and heat up Dissolve; Cool down to 30°C, add 45.5g DCC, react for 55 minutes; filter to remove the white precipitate; rinse the filter cake twice with 50ml acetone, combine the filtrate to obtain the active ester / acetone solution for use;

[0061] (2) Weigh 127.8g (0.1mol) of kanamycin A silanide (calculated as full protection), dissolve it with 500ml of acetone, add the above active ester, and react at 5°C for 2 hours to obtain an acylated product;

[0062] (3) Add concentrated hydrochloric acid to the above acylated product to adjust the pH=2.76, stir for 1 hour, distill under reduced pressure to remove the solvent, add a small amount of water to the above feed liquid, and control the feed liquid concentration to 80.6g / L;

[0063] (4) Cool down to -10°C, add 62ml of 30% liquid caustic soda, control the temperature of the material liquid to -1...

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Abstract

The invention discloses a synthetic method of environment-friendly amikacin. The synthetic method comprises synthesis of active ester, synthesis of a kanamycin A silylation substance, an acylation reaction, a hydrolysis reaction and a degradation reaction, wherein a synthetic method of the active ester comprises the following step: 2(S)-2-hydroxyl-4-carbamoyl butyric acid and N-hydroxyphthalimide have the acylation reaction in the presence of N,N-dicyclohexylcarbodiimide, and the active ester is generated; a method for the degradation reaction comprises steps as follows: a hydrolysis reaction product is degraded by sodium hypochlorite under an alkaline condition, and amikacin is obtained. With adoption of the synthetic method, phthalyl protecting groups of amino groups on side chains are omitted, generation of phthalylhydrazine solid waste can be avoided, harm to the environment is reduced, the synthesis is shortened to 5 steps from the original 7 steps, and wastewater and solid waste generated in a synthetic process are reduced greatly.

Description

Technical field [0001] The invention relates to a method for synthesizing amikacin and belongs to the field of medicine. Background technique [0002] Amikacin sulfate is a semi-synthetic aminoglycoside antibiotic with a broad antibacterial spectrum and strong antibacterial ability against a variety of bacteria. Amikacin sulfate has been widely used since its market in the 1970s, and has become the first-line anti-infective drug commonly used in clinical practice in the world. In my country, amikacin sulfate has been included in the National Essential Drug List, and has also been included in the "National Basic Medical Insurance and Work Injury Insurance Drug List" as a Class A drug. [0003] Amikacin, also known as amikacin. The most commonly used synthetic route for amikacin is the silanization protection route, which includes: [0004] 1. Preparation of AHBA: Compound A (2(S)-2-hydroxy-4-carbamoylbutyric acid) is degraded by hoffman to form 2(S)-4-amino-2-hydroxybutyric acid (A...

Claims

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Application Information

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IPC IPC(8): C07H15/234C07H1/00
CPCY02P20/55
Inventor 王仕川褚杰蔡成伟孙政军孙星星顾宗帅李志鹏
Owner 山东安信制药有限公司
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