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A kind of synthetic method of amikacin

A synthesis method and technology of amikacin, applied in the field of medicine, can solve the problems of high environmental hazard, environmental hazard, difficult biodegradation, etc., and achieve the effects of shortening the synthesis route, reducing the environmental hazard, and reducing the waste water and solid waste.

Active Publication Date: 2018-06-19
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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  • A kind of synthetic method of amikacin
  • A kind of synthetic method of amikacin
  • A kind of synthetic method of amikacin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] (1) Weigh compound A (2(S)-2-hydroxy-4-carbamoylbutyric acid) 16.2g (0.11mol), N-hydroxyphthalimide 26.7g, add 500ml acetone, heat up Dissolve; cool to 30°C, add 45.3g DCC, react for 60 minutes; filter to remove white precipitate; rinse the filter cake twice with 50ml acetone, and combine the filtrates to obtain an active ester / acetone solution for later use;

[0048] (2) Weigh 127.8g (0.1mol) of kanamycin A silanide (calculated by full protection), dissolve it with 500ml acetone, add the above-mentioned active ester, and react at 5°C for 2 hours to obtain an acylated product;

[0049] (3) add concentrated hydrochloric acid to above-mentioned acylation product and adjust pH=2.34, stir for 1 hour, remove solvent under reduced pressure distillation, add above-mentioned feed liquid to a small amount of water, control feed liquid concentration 82.6g / L;

[0050] (4) Cool down to -10°C, add 60ml of 30% liquid caustic soda, and control the temperature of the feed liquid to -12...

Embodiment 2

[0053] (1) Weigh compound A (2(S)-2-hydroxy-4-carbamoylbutyric acid) 16.2g (0.11mol), N-hydroxyphthalimide 26.5g, add 500ml acetone, heat up Dissolve; cool to 30°C, add 45.0g DCC, react for 65 minutes; filter to remove white precipitate; rinse the filter cake twice with 50ml acetone, and combine the filtrates to obtain an active ester / acetone solution for later use;

[0054] (2) Weigh 127.8g (0.1mol) of kanamycin A silanide (calculated by full protection), dissolve it with 500ml acetone, add the above-mentioned active ester, and react at 5°C for 2 hours to obtain an acylated product;

[0055] (3) add concentrated hydrochloric acid to above-mentioned acylation product and adjust pH=2.54, stir for 1 hour, remove solvent under reduced pressure, add above-mentioned feed liquid to a small amount of water, control feed liquid concentration 82.0g / L;

[0056] (4) be cooled to -15 ℃, add 58ml of 30% liquid caustic soda, control the temperature of the feed liquid to -16 ℃, start to drip...

Embodiment 3

[0059] (1) Weigh compound A (2(S)-2-hydroxy-4-carbamoylbutyric acid) 16.2g (0.11mol), N-hydroxyphthalimide 27.0g, add 500ml acetone, heat up Dissolve; cool to 30°C, add 45.5g DCC, react for 55 minutes; filter to remove white precipitate; rinse the filter cake twice with 50ml acetone, and combine the filtrates to obtain an active ester / acetone solution for later use;

[0060] (2) Weigh 127.8g (0.1mol) of kanamycin A silanide (calculated by full protection), dissolve it with 500ml acetone, add the above-mentioned active ester, and react at 5°C for 2 hours to obtain an acylated product;

[0061] (3) add concentrated hydrochloric acid to the above-mentioned acylation product and adjust pH=2.76, stir for 1 hour, remove the solvent by distillation under reduced pressure, add a small amount of water to the above-mentioned feed liquid, and control the feed liquid concentration 80.6g / L;

[0062] (4) be cooled to -10 ℃, add 62ml of 30% liquid caustic soda, control the temperature of the...

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Abstract

The invention discloses a synthesis method of amikacin. It includes the synthesis of active ester, the synthesis of kanamycin A silyl compound, acylation reaction, hydrolysis reaction and degradation reaction, wherein the synthesis method of active ester is: 2(S)‑2‑hydroxy‑4‑carbamoylbutyl Acid and N-hydroxyphthalimide, in the presence of N, N-dicyclohexylcarbodiimide, carry out esterification reaction to generate active ester; degradation reaction method is: hydrolysis reaction product under alkaline conditions , using sodium hypochlorite to degrade to obtain amikacin. By adopting the synthetic method of the present invention, the phthaloyl protecting group of the amino group on the side chain is omitted, the solid waste of phthalic hydrazide can be avoided, the harm to the environment is reduced, and the synthetic steps are changed from the original 7 steps at the same time. It is shortened to 5 steps, which greatly reduces the waste water and solid waste generated in the synthesis process.

Description

technical field [0001] The invention relates to a method for synthesizing amikacin, which 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 activity against a variety of bacteria. Since its launch in the 1970s, amikacin sulfate has been widely used due to its exact curative effect and has become a commonly used first-line anti-infective drug in the world. In my country, amikacin sulfate has been included in the National Essential Drug List, and has also been included in the Class A drug of the National Basic Medical Insurance and Industrial Injury Insurance Drug List. [0003] Amikacin, also known as amikacin. The most commonly used amikacin synthesis route is the silanization protection route, which includes: [0004] 1. Preparation of AHBA: Compound A (2(S)-2-hydroxy-4-carbamoylbutyric acid) was degraded by hoffman to form 2(S)-4-amin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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