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A synthetic method of amikacin

A synthetic method, amikacin technology, 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, and achieve the effects of simplifying production equipment, improving selectivity, and ensuring synthesis yield

Inactive Publication Date: 2016-03-30
CHONGQING DAXIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the use of active transesterification, a large excess of reactant active ester is required to increase the reaction yield, and there is an independent unit reaction for preparing active ester, and the raw material N-hydroxyl-phthalimide is used (NOP), increased the amount of reaction solvent used, the solvent in the process is volatile, the loss is relatively large, affects the environment, and increases production costs

Method used

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  • A synthetic method of amikacin
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  • A synthetic method of amikacin

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Put 600mL of acetonitrile into the silanization reaction bottle, put in 0.1 billion kanamycin A (KMA), close the feeding port and start stirring for 10 minutes, add 400mL of hexamethyldisilazane (HMDS), heat up to reflux , Reflux reaction at 75-80°C for 7hr. Use drinking water to cool down outside the reaction bottle to lower the temperature to below 35°C, let it stand still, and naturally stratify. The lower layer was separated and collected to obtain a silyl-protected product.

[0047] Add 1000mL of acetone to the silyl-protected product, start stirring, add 60g of γ-N-phthalimide-α-hydroxybutyric acid (PHBA), and then add 2.5g of catalyst 4-N,N-dimethyl Pyridine (DMAP), lower the temperature to -15~-10°C.

[0048]Dissolve 60g of N,N-dicyclohexylcarbodiimide in 300mL of acetone, and add it to the above reactant, control the flow rate at 5mL / min, and control the temperature of the reactant at -15~-10°C; continue the reaction for 1 hour after the addition is complete ...

Embodiment 2

[0053] Put 600mL of acetonitrile into the silanization reaction bottle, put in 0.1 billion kanamycin A (KMA), close the feeding port and start stirring for 10 minutes, then add 500mL of hexamethyldisilazane (HMDS), heat up to reflux , Reflux at 75-80°C for 8 hours. After the reaction is completed, the temperature is cooled to 40°C with drinking water and left to stand, and the layers are separated naturally. The lower layer was separated and collected to obtain a silyl-protected product.

[0054] Add 1000mL of acetone to the silyl-protected product, start stirring, add 70g of γ-N-phthalimide-α-hydroxybutyric acid (PHBA), and then add 3.0g of catalyst 1-hydroxybenzotriazole ( HOBT), after the material is dissolved, cool down to -15~-10°C.

[0055] Dissolve 70g of N,N-dicyclohexylcarbodiimide in 300mL of acetone, and add it to the above reactant, control the flow rate at 6mL / min, and control the temperature of the reactant at -15~-10°C; continue the reaction for 1.5 hours afte...

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Abstract

A synthetic method of amikacin is disclosed. Gamma-4-phthalimido-2-hydroxy butyric acid is adopted as a raw material for direct acylation. 4-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBT) is adopted as a catalyst. N,N'-dicyclohexylcarbodiimide is adopted as a condensing agent. Silyl kanamycin A is directly acylated to obtain an acylation product and the acylation product is subjected to acidolysis and hydrazinolysis to obtain the amikacin. A production operation for specially preparing active ester for acylation is not needed in the method, thus simplifying operation steps and production equipment. N-hydroxyphthalimide for preparing the active ester is not used in the direct acylation, thus reducing the production cost. By optimization of acylation conditions, selectivity of the acylation is improved, the synthesis yield is ensured, contents of impurities is lowered, and beneficial conditions for subsequent purification of the amikacin are provided.

Description

technical field [0001] The invention relates to a synthesis method of amikacin, which belongs to the technical field of medicine. Background technique [0002] Amikacin is a semi-synthetic aminoglycoside antibiotic with a wide antibacterial spectrum and 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, and new ones are constantly being developed Dosage forms and uses. [0003] Amikacin sulfate is suitable for sensitive leather such as Pseudomonas aeruginosa and other Pseudomonas, Escherichia coli, Proteus, Klebsiella, Enterobacter, Serratia, and Acinetobacter Severe infections caused by blue-negative bacilli and staphylococci (methicillin-susceptible strains), such as bacteremia or sepsis, bacterial endocarditis, lower respiratory tract infections, bone and joint infections, biliary tract infections, abdominal infections, complicated urinary tract infections R...

Claims

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Application Information

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IPC IPC(8): C07H15/234C07H1/00
Inventor 李华德廖秀兰徐红谢云张洪兰
Owner CHONGQING DAXIN PHARMA
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