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Preparation method of 1-N-ethyl gentamicin C1a sulfate

The technology of ethyl gentamicin and gentamicin is applied in the field of preparation of medicinal raw materials, which can solve the problems of high requirements, complicated operation and the like, and achieve the effect of improving the yield

Active Publication Date: 2010-12-29
CHANGZHOU FANGYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This step is to first obtain 1-N-ethyl gentamicin C 1a Sulfate filtrate, then the filtrate is lyophilized to obtain 1-N-ethyl gentamicin C 1a Sulphate, so the operation is more complicated and the requirements are higher

Method used

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  • Preparation method of 1-N-ethyl gentamicin C1a sulfate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0037] ①Add 1000mL of methanol solvent and 90g of gentamicin C 1a (0.2mol) and 110g of zinc acetate, stirred to fully dissolve, gentamicin C 1a (I) Coordination reaction with zinc acetate to obtain gentamicin C 1a -Zn complexes.

[0038] ②Reduce the temperature of the system in step ① to 0°C to 10°C, add dropwise a mixture of 85mL acetic anhydride (0.9mol), 350mL triethylamine and 150mL tetrahydrofuran to the system in step ① under stirring, and generate 3,2',6'-tri-N-acetylgentamycin C 1a For the acylation reaction of the Zn complex, continue stirring and insulated reaction for 1 h after the dropwise completion. Then add 300mL of purified water to the reacted material, then place it in a rotary evaporator and distill under vacuum and reduced pressure at a temperature of 60°C to obtain 3,2',6'-tri-N-acetyl genta Mycin C 1a -300 mL of the concentrated solution of the Zn complex, and then cooled to 30°C.

[0039] ③Post-treatment the concentrated solution obtained in step ②...

Embodiment 2）

[0048] The rest of this embodiment is the same as in Example 1, except that step 3.: dilute the concentrated solution obtained in step 2. with water to 2000mL, and then use the DL8040 nanofiltration membrane produced by DE Company of the United States to carry out nanofiltration treatment on the diluted solution until The concentration of zinc ions in the diluent is ≤10ug / mL, and then the nanofiltrate is placed in a rotary evaporator and vacuum-reduced at a temperature of 60°C to obtain a 50mL concentrated solution, and finally the concentrated solution is spray-dried to obtain 110g of powdered 3,2 ',6'-tri-N-acetylgentamycin C 1a , the yield reached 94.9%, and the purity reached 92%.

[0049]

Embodiment 3～ Embodiment 6）

[0051] The preparation method of each embodiment is basically the same as that of Example 1, and the difference is that the acetic anhydride used in step 2. and gentamicin C1a The molar ratio of different, the influence of acetic anhydride dosage on the reaction yield is shown in Table 1.

[0052] Table 1

[0053]

Acetic anhydride and gentamicin C 1a molar ratio

yield

Example 1

4.5∶1

93.9%

Example 3

5∶1

93.6%

Example 4

4∶1

90.2%

Example 5

3.5∶1

87.9%

Example 6

3∶1

85.4%

[0054] As can be seen from Table 1, increasing the amount of acetic anhydride increases the reaction yield, and when the molar ratio reaches 4.5:1, the yield decreases instead when the amount of acetic anhydride is increased. Therefore, acetic anhydride and Qing Damycin C 1a The optimum molar ratio is 4.5:1.

[0055]

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Abstract

The invention discloses a preparation method of 1-N-ethyl gentamicin C1a sulfate. The method comprises the following steps of: carrying out a complexation reaction on gentamicin C1a and zinc acetate in a methanol solvent; then, dropping a mixed solution of acetic anhydride, triethylamine and tetrahydrofuran to carry out an acylation reaction and obtaining 3,2',6'-3-N-acetyl-gentamicin C1a by post-treatment; then, carrying out a silylation reaction with hexamethyl disilazane in a chloroform solvent; carrying out an N-alkylation reaction with acetaldehyde in a carrene solvent; then, carrying out a reduction reaction with potassium borohydride; hydrolyzing with an NaOH solution; obtaining 1-N-ethyl gentamicin C1a by post-treatment; adding the 1-N-ethyl gentamicin C1a to anhydrous ethanol or anhydrous methanol for stirring or dissolving; then, dropping concentrated sulfuric acid; and obtaining 1-N-ethyl gentamicin C1a sulfate by post-treatment. The method of the invention has higher yield.

Description

technical field [0001] The invention relates to a preparation method of a medicinal raw material, in particular to a 1-N-ethyl gentamicin C 1a Preparation method of sulphate. Background technique [0002] Chinese patent document CN1040177C (application number 93112412.3) discloses a 1-N-ethyl gentamicin C 1a Pharmaceutical formulations and preparation methods of salts thereof. [0003] First, by gentamicin C 1a Preparation of 3,2',6'-tris-N-acetylgentamycin C 1a , that is, at room temperature, the gentamicin C 1a Dissolve in water and non-protic polar organic solvents (such as dimethylformamide, dimethyl sulfoxide, etc.), then add cobalt acetate, and then add dropwise the THF solution of acetic anhydride until the reaction is completed. The post-treatment is: dilute the reaction solution with water, and then pass through the strongly acidic 732 (H + ) resin column adsorption, followed by water washing, ammonia water analysis, and concentration under reduced pressure, t...

Claims

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Application Information

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IPC IPC(8): C07H15/236C07H1/00
Inventor 封成军李兴刚胡东辉毕晓明苏晓春狄绍炎
Owner CHANGZHOU FANGYUAN PHARMA
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