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Preparation method of 1-N-ethyl gentamicin Cla

A technology of ethyl gentamicin and gentamicin is applied in the field of preparation of medicinal raw materials, can solve the problem of low yield and the like, and achieves the advantages of avoiding alkylation side reactions, enhancing polarization and avoiding hydrolysis. Effect

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

The disadvantage of this method is that: 3,2',6'-tri-N-acetylgentamycin C 1a There are 3 hydroxyl groups, direct N-alkylation will lead to side reactions such as alkylation of hydroxyl groups, resulting in low yield

Method used

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  • Preparation method of 1-N-ethyl gentamicin Cla
  • Preparation method of 1-N-ethyl gentamicin Cla
  • Preparation method of 1-N-ethyl gentamicin Cla

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0029] ①Add 100mL of chloroform solvent, 20mL of 0.104mol hexamethyldisilazane and 0.05mL of catalytic concentrated sulfuric acid (98wt%) into the dried three-neck flask with reflux device, and then add 15g 0.026mol of 3,2',6'-tris-N-acetylgentamycin C 1a (I), heated to reflux to generate 3,2',6'-tri-N-acetyl-5,2",4"-tris(trimethylsilyl)gentamycin C 1a (Ⅱ) The silanization reaction, until the reaction is complete, the time of heating and reflux is 5h. Then, the chloroform solvent was evaporated to dryness to obtain 3,2',6'-tri-N-acetyl-5,2",4"-tris(trimethylsilyl)gentamycin C 1a (Ⅱ).

[0030] ②Reduce the temperature of the system in step ① to 20°C~25°C, add 100mL of dichloromethane, continue to cool down to 10°C, add 1.5mL of acetaldehyde, and generate 3,2',6'-tri-N- Acetyl-5,2",4"-tris(trimethylsilyl)ethylimine Gentamicin C 1a (Ⅲ) N-alkylation reaction for 1h. Then add 20mL of boric acid buffer solution with a pH of 9 to 10 (the boric acid buffer solution is composed of ...

Embodiment 2～ Embodiment 8）

[0035] The preparation method of each embodiment is basically the same as that of Example 1, except that the hexamethyldisilazane used in step ① and 3,2',6'-tri-N-acetylgentamycin C 1a The mol ratio, the mol ratio of each embodiment and the impact on reaction are shown in Table 1.

[0036] Table 1

[0037]

Hexamethyldisilazane and 3,2',6'-tri-N-acetylgentamycin C 1a molar ratio

3,2',6'-tri-N-acetylgentamycin C 1a conversion rate of

Example 1

4.0∶1

70.2%

Example 2

1.5∶1

43.8%

Example 3

2∶1

48.5%

Example 4

2.5∶1

53.2%

Example 5

3∶1

60.1%

Example 6

3.5∶1

69.7%

Example 7

4.5∶1

69.9%

Example 8

5∶1

68.4%

[0038] Theoretically, 1 mol of hexamethyldisilazane can silylate 2 mol of alcoholic hydroxyl groups, and every 1 molecule of 3,2',6'-tri-N-acetylgentamycin C 1a There are 3 alcoholic hydroxyl groups, therefore, hexamethyldisilazane and 3,2',6'-tri-N-...

Embodiment 9～ Embodiment 12）

[0041] The preparation method of each embodiment is basically the same as that of Example 1, except that the acetaldehyde used in step 2 and the 3,2',6'-tri-N-acetylgentamycin C used in step 1 1a The mol ratio, the mol ratio of each embodiment and the impact on reaction are shown in Table 2.

[0042] Table 2

[0043]

Acetaldehyde and 3,2',6'-tris-N-acetylgentamycin C 1a molar ratio

3,2',6'-tri-N-acetylgentamycin C 1a conversion rate of

ETM-1

ETM-2

Example 1

1∶1

70.2%

0.7%

1.5%

Example 9

0.8∶1

65.4%

0.4%

1.0%

Example 10

1.2∶1

70.3%

3.1%

8.2%

Example 11

1.5∶1

68.5%

4.2%

10.1%

Example 12

2∶1

69.5%

4.3%

13.4%

[0044] As can be seen from Table 2, increase the consumption of acetaldehyde, although the transformation rate improves slightly, two by-reaction products ETM-1 (3 "-N-ethylgentamycin C 1a ) and ETM-2 (1,3”-di-N-ethylgentamycin C 1a ) is also ...

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Abstract

The invention discloses a preparation method of 1-N-ethyl gentamicin Cla, which comprises the following steps of: reacting 3,2',6'-tri-N-acetyl gentamicin Cla with hexamethyldisilazane in a trichloromethane solvent under the catalysis of concentrated sulfuric acid to generate 3,2',6'-tri-N-acetyl-5,2'',4''-tri(trimethylsilyl) gentamicin Cla; carrying out N-alkylation reaction on the 3,2',6'-tri-N-acetyl-5,2'',4''-tri(trimethylsilyl) gentamicin Cla and acetaldehyde in a dichloromethane solvent at a temperature of 8-12 DEG C; carrying out reduction reaction with potassium borohydride; then hydrolyzing with an NaOH solution to obtain hydrolyzate of the 1-N-ethyl gentamicin Cla; and post-processing the hydrolyzate to obtain a finished product of the 1-N-ethyl gentamicin Cla. The method has the advantage of higher yield of the1-N-ethyl gentamicin Cla.

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 method of preparation. 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] 3,2',6'-tri-N-acetylgentamycin C 1a (I) Preparation of 1-N-ethyl gentamicin C 1a (Ⅴ) The method is: directly use acetaldehyde to 3,2',6'-tri-N-acetyl gentamicin C 1a N-alkylation followed by reduction with aqueous sodium borohydride affords 3,2',6'-tris-N-acetyl-1-N-ethylgentamycin C 1a , and then purified by YPR-Ⅱ macroporous resin column, and then hydrolyzed with sodium hydroxide to obtain 1-N-ethyl gentamicin C 1a The hydrolyzate, and finally after post-treatment to obtain 1-N-ethyl gentamicin C 1a (Ⅴ) The finished product. The disadvantage of this method is that: 3,2',6'-tri-N-acetylgentamy...

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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