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Preparation method of 1-N-ethyl gentamicin Cla

A technology of ethyl gentamycin and ethyl gentamycin, which is applied in the field of preparation of medicinal raw materials, can solve the problems of low yield, avoid side reactions of alkylation, enhance polarization, and avoid hydrolysis Effect

Active Publication Date: 2012-09-05
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）

[0028] ①Add 100mL of chloroform solvent, 20mL of 0.104mol hexamethyldisilazane and 0.05mL of catalytic concentrated sulfuric acid (98wt%) into the dried three-necked flask with reflux device, and then add 15g 0.026mol of 3,2',6'-tris-N-acetyl gentamicin C 1a (Ⅰ), heating to reflux and generating 3,2',6'-tris-N-acetyl-5,2”,4”-tris(trimethylsilyl)gentamicin C 1a (II) The silanization reaction, until the reaction is complete, the heating reflux time is 5h. Then, evaporate the chloroform solvent to obtain 3,2',6'-tris-N-acetyl-5,2”,4”-tris(trimethylsilyl)gentamicin C 1a (II).

[0029] ②Cool the system of step ① to 20℃~25℃, add 100mL of dichloromethane, continue to cool down to 10℃, add 1.5mL of acetaldehyde, and generate 3,2',6'-tri-N- under stirring Acetyl-5,2”,4”-tris(trimethylsilyl)ethylimine gentamicin C 1a (Ⅲ) N-alkylation reaction for 1h. Then add 20mL of boric acid buffer with a pH of 9~10 (the boric acid buffer is composed of 0.6g of boric acid, 15mL of water and 5ml of NaOH...

Embodiment 2～ Embodiment 8）

[0033] The preparation method of each embodiment is basically the same as that of embodiment 1, the difference is: the hexamethyldisilazane used in step ① and 3,2',6'-tri-N-acetylgentamicin C 1a The molar ratio of, the molar ratio of each embodiment and the effect on the reaction are shown in Table 1.

[0034] Table 1

[0035] Hexamethyldisilazane and 3,2',6'-tris-N-acetyl gentamicin C 1a Molar ratio 3,2',6'-tris-N-acetyl gentamicin C 1a Conversion rate 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%

[0036] Theoretically, 1mol of hexamethyldisilazane can silylate 2mol of alcoholic hydroxyl groups, and every molecule of 3,2',6'-tri-N-acetylgentamycin C 1a There are 3 alcoholic hydroxyl groups, therefore, hexamethyldisilazane and 3,2',6'-tris-N-acetyl gentamicin C 1a The theoretical molar ratio is 1.5:1. However, it can be seen from Table 1 that the t...

Embodiment 9～ Embodiment 12）

[0038] The preparation method of each embodiment is basically the same as that of embodiment 1, except that: the acetaldehyde used in step ② is the same as the 3,2',6'-tris-N-acetylgentamicin C used in step ① 1a The molar ratio of, the molar ratio of each embodiment and the effect on the reaction are shown in Table 2.

[0039] Table 2

[0040] Acetaldehyde and 3,2',6'-tris-N-acetyl gentamicin C 1a Molar ratio 3,2',6'-tris-N-acetyl gentamicin C 1a Conversion rate 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%

[0041] It can be seen from Table 2 that increasing the amount of acetaldehyde, although the conversion rate is slightly improved, but the two side reaction products ETM-1 (3"-N-ethyl gentamicin C 1a ) And ETM-2 (1,3”-di-N-ethyl gentamicin C 1a ) Is also significantly increased, and these two side reaction products are difficult to remove in the ...

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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 medicinal raw materials, in particular to a kind of 1-N-ethyl gentamicin C 1a The preparation method. Background technique [0002] Chinese patent document CN1040177C (application number 93112412. 3) discloses a method containing 1-N-ethyl gentamicin C 1a Or its salt medicinal preparation and preparation method. [0003] Among them is 3,2',6'-tris-N-acetyl gentamicin 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 Carry out N-alkylation, then reduce with sodium borohydride aqueous solution to obtain 3,2',6'-tris-N-acetyl-1-N-ethylgentamycin C 1a , Then purified with YPR-Ⅱ macroporous resin column, and then hydrolyzed with sodium hydroxide to obtain 1-N-ethyl gentamicin C 1a Hydrolyzed liquid, and finally after treatment to obtain 1-N-ethyl gentamicin C 1a (Ⅴ) The finished product. The disadvantage of this method is: 3,2',6'-t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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