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A kind of method that improves the yield of preparing amikacin

A technology of star yield and amikacin, applied in the field of amikacin preparation, can solve the problems of low acylation reaction selectivity, many reaction steps, complicated post-processing methods, etc., so as to improve synthesis yield and reduce material degradation. , the effect of reducing operation time

Active Publication Date: 2017-05-24
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

[0014] The above-mentioned synthetic route has many reaction steps, complex post-treatment methods, low selectivity of acylation reaction, etc.

Method used

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  • A kind of method that improves the yield of preparing amikacin
  • A kind of method that improves the yield of preparing amikacin
  • A kind of method that improves the yield of preparing amikacin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] (1) Weigh 5.96g of AHBA (50.0 millimoles), add 300ml of acetone, add 12.94g of fluorenyl methoxycarbonyl chloride (50.0 millimoles) dropwise, reflux with nitrogen and react for 2 hours. After the plate reaction is complete, place it for later use ;

[0042] (2) Add 8.16g of NOP (50.0 millimoles) and 8.26g of DCC (50.0 millimoles) to the above reaction solution, and react at 20-25°C for 2 hours, and then cool to room temperature after the plate is finished;

[0043] (3) Add 63.93g of kanamycin A silanide (50.0 millimoles) to the above reaction solution, and react at 10-15°C for 2 hours. The plate reaction is complete and ready for use;

[0044] (4) Add 40% hydrobromic acid in the previous step to adjust the pH to 2.0-3.0; remove the solid impurities by suction filtration, and evaporate the solvent under reduced pressure; add concentrated ammonia water to adjust the pH to 7-8, and separate on the CD180 resin column. -3.0mol / L ammonia water was subjected to gradient release to o...

Embodiment 2

[0045] (1) Weigh 5.96g of AHBA, add 300ml of acetone, add 13.00g of fluorenyl methoxycarbonyl chloride dropwise, and react under reflux with nitrogen for 2 hours. After the plate reaction is complete, place it for use;

[0046] (2) Add 8.20g NOP and 8.30g DCC to the above reaction solution, control the temperature at 25-30°C and react for 1.5 hours, and then cool to room temperature after the plate is finished;

[0047] (3) Add 63.93g of kanamycin A silanide to the above reaction solution, control the temperature at 15-20°C and react for 1.5 hours, the spotting reaction is complete and ready for use;

[0048] (4) Add 40% hydrobromic acid in the previous step to adjust the pH to 2.0-3.0; remove the solid impurities by suction filtration, and evaporate the solvent under reduced pressure; add concentrated ammonia water to adjust the pH to 7-8, and separate on the CD180 resin column. -3.0mol / L ammonia water was subjected to gradient release to obtain pure amikacin feed liquid, concentrat...

Embodiment 3

[0049] (1) Weigh 5.96g AHBA, add 200ml acetone, add 13.58g fluorenyl methoxycarbonyl chloride dropwise, and reflux with nitrogen for 1.5 hours. After the plate reaction is complete, place it for later use;

[0050] (2) Add 8.56g NOP and 10.83g DCC to the above reaction solution, control the temperature at 20-25°C and react for 2 hours, and then cool to room temperature after the plate is finished;

[0051] (3) Add 63.93g of kanamycin A silanide to the above reaction solution, control the temperature at 10-15°C and react for 2 hours, the spotting reaction is complete and ready for use;

[0052] (4) Add 35% hydrobromic acid in the previous step to adjust the pH to 2.0-3.0; remove the solid impurities by suction and evaporate the solvent under reduced pressure; add concentrated ammonia water to adjust the pH to 7-8, and separate on the CD180 resin column to 0.1 -3.0mol / L ammonia water was subjected to gradient release to obtain pure amikacin material liquid, concentrated to 30° of optic...

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Abstract

The invention discloses a method for increasing yield of amikacin. The method for increasing yield of amikacin comprises the following steps: heating, refluxing and carrying out reaction on gamma-amino-alpha-hydroxybutyric acid and fluorenylmethyl chloroformate, so as to generate a reaction liquid containing gamma-amino-alpha-hydroxybutyric acid; directly adding N-hydroxyl phthalimide and N,N-dicyclohexylcarbodiimide into the reaction liquid, and carrying out reaction to generate a reaction liquid containing active ester; directly adding a kanamycin A silanization compound into the reaction liquid containing the active ester for carrying out acylation reaction, after complete reaction is finished, adding an HBr aqueous solution until the pH is adjusted to be 2-3, and carrying out suction filtration to remove solid impurities; and then carrying out reduced pressure distillation for removing the solvent, adjusting the pH to be 7-8 with concentrated liquor, purifying by virtue of a CD180 macroporous resin column, concentrating, and carrying out freeze drying, so that amikacin solid is obtained. The active ester causes selectivity of the acylation reaction to be greatly improved due to enlargement of a protective group, and a follow-up processing step is also greatly simplified, so that the amikacin synthesis yield is increased.

Description

Technical field [0001] The invention relates to a preparation method of 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 ability against a variety of bacteria. Amikacin sulfate has been widely used since its market in the 1970s, and has become a first-line anti-infective drug commonly used clinically 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 currently commonly used synthetic route of amikacin is the silylation protection route, which includes: (1) AHBA protection: γ-amino-α-hydroxybutyric acid (abbreviated as AHBA) reacts with phthalic anhydride to form γ- Phthalimido-α-hydroxybutyric acid (PHBA); (2)...

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 蔡成伟褚杰孙政军王仕川顾宗帅李保勇吴柯樊长莹张兆珍董廷华
Owner 山东安信制药有限公司