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New synthesis method of Etimicin sulfate intermediate 3, 2', 6'-tri-N-acetyl gentamicin Cla

A technology for etimicin sulfate and gentamicin, which is applied in the field of preparation of medical API intermediates, can solve the problems of containing, complicated operation, and multi-zinc ions, thereby reducing the consumption of organic solvents and improving the complexation efficiency. , the effect of shortening the purification time

Active Publication Date: 2014-07-30
CHANGZHOU FANGYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the patent CN101928309A, when purifying 3,2',6'-tri-N-acetylgentamycin Cla, a large amount of organic solvents were used, and collected according to the optical rotation of the effluent, which would cause the collected liquid to contain more Zinc ions
In patent CN101928310A, when purifying 3,2',6'-tri-N-acetylgentamycin Cla, sodium filtration membrane is used to remove divalent zinc ions, and the operation is relatively cumbersome

Method used

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  • New synthesis method of Etimicin sulfate intermediate 3, 2', 6'-tri-N-acetyl gentamicin Cla

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] A kind of etimicin sulfate intermediate 3,2 ', the synthetic method of 6 '-three-N-acetyl gentamycin Cla, comprises the steps:

[0017] a, temperature is 60 DEG C, and stirring time is under the stirring condition of 4 hours, 60Kg gentamicin Cla and 67Kg zinc acetate are reacted to generate Cla-Zn complex in the methanol solvent of 660L;

[0018] b. Lower the temperature of the above reaction system to 0°C to 10°C, add 93L triethylamine, dropwise add 53Kg acetic anhydride in tetrahydrofuran solution for reaction, add sodium oxalate solution (54Kg sodium oxalate plus 1600L water) after the reaction, filter zinc oxalate precipitated filtrate;

[0019] C. Put the sulfonic acid type D113 resin on the filtrate, wash it with pure water first, the flow rate is 40L / hour, then analyze with the hydrochloric acid solution of pH=0.24, the flow rate is 50L / hour, after the acid analysis solution is adjusted to pH=9, concentrate, add The solid was precipitated by ethanol, filtered, a...

Embodiment 2～ Embodiment 4

[0021] The preparation method of this example is basically the same as that of Example 1, except for the complexation temperature of gentamicin Cla and zinc acetate in step (1). The effect of different complexation temperature on the reaction is shown in Table 1.

[0022] Table 1 Effect of complexation temperature on yield

[0023] complexation temperature 3,2', 6'-tri-N-acetyl gentamycin Cla yield Example 1 60℃ 95.2% Example 2 50℃ 92.3% Example 3 40℃ 91.5% Example 4 30℃ 90.2%

[0024] Increasing the complexation temperature improves the complexation ability of zinc ions and Cla, and shortens the complexation reaction time. Since the solvent used is methanol, in order to reduce the volatilization of the solvent, we choose the temperature to be 60°C.

Embodiment 5～ Embodiment 6

[0026] The preparation method of this example is basically the same as that of Example 1, the difference lies in: the flow rate when using hydrochloric acid solution with pH=0.24 in step (3) for analysis. The effect of different flow rates on the reaction is shown in Table 2.

[0027] Table 2 Effect of flow rate of analyte on yield

[0028] Flow rate of hydrochloric acid solution 3,2', 6'-tri-N-acetyl gentamycin Cla yield Example 1 50L / hour 95.2% Example 5 40L / hour 94.8% Example 6 60L / hour 90.1%

[0029] When washing the column with the hydrochloric acid analysis solution of 50L / hour and 40L / hour flow velocity, 3,2', the yield difference of 6'-tri-N-acetylgentamycin Cla is little, but because with 40L / hour During analysis, the flow rate is slow, which requires a long time for elution, which prolongs the production cycle; when flushing the column with 60L / hour hydrochloric acid analysis solution, due to the fast flow rate, some ...

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Abstract

The invention relates to a method for synthesis of Etimicin sulfate intermediate 3, 2', 6'-tri-N-acetyl gentamicin Cla. The method consists of the following steps of: under certain temperature, reacting gentamicin Cla with zinc acetate in a methanol solvent to generate a complex, cooling the reaction solution and adding triethylamine, adding a tetrahydrofuran solution of acetic anhydride dropwisely for an acylation reaction, carrying out liquid phase tracking, and adding a sodium oxalate solution after completion of the reaction, filtering a zinc oxalate precipitate, delivering the filtrate to ion exchange resin, first conducting washing with pure water, then conducting washing with acid of certain concentration, adjusting the pH of the acid washed liquid to 9, performing concentration, adding ethanol to separate out a solid, implementing filtration, and freeze-drying the filtrate, thus obtaining the 3, 2', 6'-tri-N-acetyl gentamicin Cla.

Description

technical field [0001] The present invention relates to a kind of preparation method of medical crude drug intermediate, be specifically related to a kind of etimicin sulfate intermediate 3,2 ', the new synthetic method of 6'-tri-N-acetyl gentamycin Cla. Background technique [0002] 3,2',6'-tri-N-acetyl gentamycin Cla is an important intermediate for the synthesis of national first-class new drug etimicin sulfate. The synthesis method of etimicin sulfate is to use gentamicin Cla as the starting raw material, adopt transition metal Zn complexation to protect part of the amino groups in gentamicin Cla, and react with acetic anhydride to obtain intermediate 3, 2', 6' - Tri-N-acetyl gentamycin Cla, after silanization hydroxyl protection, acetaldehyde condensation, potassium borohydride reduction, sodium hydroxide hydrolysis, purified to obtain 1-N-ethyl gentamycin Cla, and sulfuric acid After salting, etimicin sulfate was obtained. Chinese patent documents CN101928309A (appli...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/236C07H1/00
Inventor 姜艳封成军周长清李兴刚谢立成
Owner CHANGZHOU FANGYUAN PHARMA
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