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Synthesis method of amikacin

A technology of amikacin and kanamycin, which is applied in the field of medicine, can solve the problems of increasing the amount of reaction solvent used, increasing the production cost, and easy volatilization of the solvent, so as to simplify the production equipment, facilitate the production operation, and reduce the use of solvents Effect

Active Publication Date: 2018-12-11
PEKING UNIV FOUNDER GRP CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the active transesterification reaction, there is an independent unit reaction for preparing active ester, and the raw material N-hydroxyl-phthalimide (NOP) is used, which increases the amount of reaction solvent used, and the solvent in the process is easy to Volatilization, large loss, impact on the environment, increase production cost

Method used

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

Examples

Experimental program
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Embodiment 1

[0058] The present embodiment provides a method for synthesizing amikacin, comprising the steps of:

[0059] 1) Catalyzed silylation reaction: Put 600mL tetrahydrofuran into the silanization reaction bottle, add 0.1 billion kanamycin (KMA), add 190mL hexamethyldisilazane (HMDS), add catalyst triethylamine salt Salt 0.5g, start stirring, heat up to reflux, reflux reaction at 60-70°C for 130 minutes, vacuum distillation, vacuum degree ≤ -0.085Mpa, temperature 75-80°C until no solvent flows out, silanized product;

[0060] 2) Acylation reaction: add 1000mL tetrahydrofuran to the silylation product, start stirring, add 55g γ-N-phthalimide-α-hydroxybutyric acid (PHBA), add 48g N,N-dicyclohexyl Carbodiimide, control the temperature of the reactants at 25°C, and react for 120 minutes.

[0061] 3) Acidolysis reaction: After the acylation reaction is completed, start stirring, add 350ml of 4.0mol / L hydrochloric acid, make the pH of the feed solution 3.0, and acidify at room temperatur...

Embodiment 2

[0066] The present embodiment provides a method for synthesizing amikacin, comprising the steps of:

[0067] 1) Catalyzed silylation reaction: Put 600mL tetrahydrofuran into the silanization reaction bottle, add 0.1 billion kanamycin (KMA), add 200mL hexamethyldisilazane (HMDS), add catalyst diethylamine salt Salt 0.3g, start stirring, heat up to reflux, reflux at 60-70°C for 110 minutes, distill under reduced pressure, vacuum degree ≤ -0.085Mpa, temperature 75-80°C until no solvent flows out, and the silanized product;

[0068] 2) Acylation reaction: add 1000mL tetrahydrofuran to the silylation product, start stirring, add 60g γ-N-phthalimide-α-hydroxybutyric acid (PHBA), add 52g N,N-dicyclohexyl Carbodiimide, control the temperature of the reactants at 30°C, and react for 100 minutes.

[0069] 3) Acidolysis reaction: After the acylation reaction is completed, start stirring, add 360ml of 4.0mol / L hydrochloric acid, make the pH of the feed solution 3.5, and acidolyze at room...

Embodiment 3

[0074] This embodiment provides a method for synthesizing amikacin. The only difference from Example 1 is that in step 1), "catalyst triethylamine hydrochloride" is replaced by "triethylamine sulfate";

[0075] Obtain amikacin synthetic solution 1780ml, the content of amikacin is 2.1% (g / ml) and the synthesis yield of kanamycin A is 31.3%.

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Abstract

The invention relates to a synthesis method of amikacin, the synthesis method of amikacin comprises the following steps: 1) performing silanization on kanamycin A to form silanized kanamycin A; 2) taking the silanized kanamycin A and 4-phthalimido-2-hydroxy butyric acid as raw materials, N,N-bicyclohexyl carbodiimide as a condensing agent, performing acylation reaction, obtaining an acylated product; 3) sequentially performing acidolysis reaction and hydrazolysis reaction on the acylated product so as to obtain the amikacin. The synthesis method provided by the invention is simple in preparation, low in requirements for production equipment, mild in condition, simple and easy to operate, high in synthesis yield, and suitable for large-scale production, and is obvious in economic benefits.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing amikacin. Background technique [0002] Amikacin is a semi-synthetic aminoglycoside antibiotic, which has strong antibacterial power against a variety of bacteria; its sulfate has become the first-line anti-infective drug commonly used in clinical practice in the world; many companies are constantly developing new dosage forms and uses. [0003] Its sulfate: Amikacin sulfate is suitable for Pseudomonas aeruginosa and other Pseudomonas, Escherichia coli, Proteus, Klebsiella, Enterobacter, Serratia, Acinetobacter Severe infections caused by sensitive Gram-negative bacilli and Staphylococcus (methicillin-sensitive strains), such as bacteremia or sepsis, bacterial endocarditis, lower respiratory tract infection, bone and joint infection, biliary tract infection, abdominal infection , complicated urinary tract infection, skin and soft tissue inf...

Claims

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Application Information

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IPC IPC(8): C07H15/234C07H1/00
CPCC07H1/00C07H15/234
Inventor 李华德叶琤张葵
Owner PEKING UNIV FOUNDER GRP CO LTD
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