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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 increasing the amount of reaction solvent used, increasing the production cost, volatile solvents, etc., and achieve the effects of simplifying production equipment, improving selectivity, and ensuring synthesis yield.

Inactive Publication Date: 2018-03-09
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 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

[0046] Put 600 mL of acetonitrile into the silanization reaction flask, put in 0.1 billion kanamycin A (KMA), close the feeding port and stir for 10 minutes, add 400 mL of hexamethyldisilazane (HMDS), and heat to reflux Reflux for 7hrs at 75~80℃. Use drinking water to cool the outside of the reaction flask to lower the temperature to below 35°C, let it stand for natural layering. Separate and collect the lower layer to obtain a silyl group protected product.

[0047] Add 1000mL of acetone to the silyl group protection product, start stirring, add 60g of γ-N-phthalimido-α-hydroxybutyric acid (PHBA), and then add 2.5g of catalyst 4-N,N-dimethyl Pyridine (DMAP), cooling to -15~-10℃.

[0048] Dissolve 60g of N,N-bicyclohexylcarbodiimide with 300mL of acetone, add its flow to the above reactants, control the flow rate at 5mL / min, and control the temperature of the reactants at -15~-10℃; continue to react for 1 hour after the flow is added .

[0049] After the acylation reaction is com...

Embodiment 2

[0053] Put 600 mL of acetonitrile into the silanization reaction flask, put in 0.1 billion kanamycin A (KMA), close the feeding port and stir for 10 minutes, add 500 mL of hexamethyldisilazane (HMDS), and heat to reflux Reflux the reaction at 75~80℃ for 8hr. After the reaction is completed, cool down to 40°C with drinking water and let it stand for natural layering. Separate and collect the lower layer to obtain a silyl group protected product.

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

[0055] Dissolve 70g of N,N-bicyclohexylcarbodiimide with 300mL of acetone, add its flow to the above reactants, control the flow rate of 6mL / min, and control the temperature of the reactants from -15 to -10°C; continue the reaction for 1.5 hours after the flow is added .

[0056] After the ...

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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 method for synthesizing amikacin and belongs to the technical field of medicine. Background technique [0002] Amikacin is a semi-synthetic aminoglycoside antibiotic with a broad antibacterial spectrum and strong antibacterial power against a variety of bacteria; its sulfate has become a clinically commonly used first-line anti-infective drug in the world, and new ones are constantly being developed Formulation and use. [0003] Amikacin sulfate is suitable for sensitive leather such as Pseudomonas aeruginosa and other Pseudomonas, Escherichia coli, Proteus, Klebsiella, Enterobacter, Serratia, Acinetobacter, etc. Severe infections caused by blue-negative bacilli and Staphylococcus (methicillin-sensitive strains), such as bacteremia or sepsis, bacterial endocarditis, lower respiratory tract infections, bone and joint infections, biliary tract infections, abdominal infections, and complicated urine Road infections, skin and soft tis...

Claims

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Application Information

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