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Synthesis method of 6''-N-ethyl gentamicin C1a

A technology of ethyl gentamicin and triacetyl gentamicin, which is applied in the field of synthesis of intermediate products of pharmaceutical compounds, can solve problems such as difficulty in obtaining, and achieve less side reactions, high synthesis yield, and easy purification and separation Effect

Active Publication Date: 2019-11-26
WUXI JIYU SHANHE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Its chemical name is: 6”-N-ethyl gentamycin C1a. The compound was first reported in the patent “An Aminoglycoside Compound and Its Extraction and Separation Method”. According to the report, 6”-N-ethyl Gentamicin C1a is one of the main impurities remaining in etimicin sulfate raw materials and preparations, and it is also the most difficult to obtain. There is no standard product of 6”-N-ethyl gentamicin C1a for sale at home and abroad There is no relevant literature report

Method used

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  • Synthesis method of 6''-N-ethyl gentamicin C1a
  • Synthesis method of 6''-N-ethyl gentamicin C1a
  • Synthesis method of 6''-N-ethyl gentamicin C1a

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment 1, 6 "-N-ethyl gentamycin C1a

[0056] 1. Dissolve gentamicin C1a (5g) in tetrahydrofuran / triethylamine / water (25mL / 25mL / 25mL), and cool to -5~0°C. Add BOC-ON (2-tert-butoxycarbonyliminophenylacetonitrile) (1.0eq) and stir for 1-2 hours. Add 50mL of water and 50mL of ethyl acetate, separate the layers, take the aqueous phase and concentrate.

[0057] 2. Dissolve the concentrate in 50mL of methanol, add 10mL of triethylamine, cool to 0-10°C, add acetic anhydride (4-5eq), and stir for 0.5-1 hour. Concentrate to remove solvent.

[0058] 3. Add 50-75 mL of 3 mol / L hydrochloric acid to the concentrated solution, and stir at room temperature for 1-3 hours. Adjust the pH to 8~9 with sodium hydroxide solution, concentrate, and purify and separate 1,3,2"-N,N,N-triacetylgentamycin C1a with silica gel column. Among them, the specific packing type and size of silica gel column , the elution method and other conditions are as follows:

[0059] Silica gel column model...

Embodiment 2

[0065] Embodiment 2, 6 "-N-ethyl gentamycin C1a

[0066] 1. Dissolve gentamicin C1a (5g) in tetrahydrofuran / triethylamine / water (25mL / 25mL / 25mL), and cool to -5~0°C. Add BOC-ON (2-tert-butoxycarbonyliminophenylacetonitrile) (1.0eq) and stir for 1-2 hours. Add 50mL of water and 50mL of ethyl acetate, separate the layers, take the aqueous phase and concentrate.

[0067] 2. Dissolve the concentrate in 50mL of methanol, add 10mL of triethylamine, cool to 0-10°C, add acetic anhydride (4-5eq), and stir for 0.5-1 hour. Concentrate to remove solvent.

[0068] 3. Add 50-75 mL of 3 mol / L hydrochloric acid to the concentrated solution, and stir at room temperature for 1-3 hours. Adjust the pH to 8~9 with sodium hydroxide solution, concentrate, and purify and separate 1,3,2”-N,N,N-triacetylgentamycin C1a with silica gel column. Among them, the specific packing type and size of the silica gel column , the elution method and other conditions are as follows:

[0069] Silica gel column m...

Embodiment 3

[0078] Embodiment 3, 6 "-N-ethyl gentamycin C1a

[0079] 1. Dissolve gentamicin C1a (5g) in tetrahydrofuran / triethylamine / water (25mL / 25mL / 25mL), and cool to -5~0°C. Add BOC-ON (2-tert-butoxycarbonyliminophenylacetonitrile) (1.0eq) and stir for 1-2 hours. Add 50mL of water and 50mL of ethyl acetate, separate the layers, take the aqueous phase and concentrate.

[0080] 2. Dissolve the concentrate in 50mL of methanol, add 10mL of triethylamine, cool to 0-10°C, add acetic anhydride (4-5eq), and stir for 0.5-1 hour. Concentrate to remove solvent.

[0081] 3. Add 50-75 mL of 3 mol / L hydrochloric acid to the concentrated solution, and stir at room temperature for 1-3 hours. Adjust the pH to 8-9 with sodium hydroxide solution, concentrate, and purify with silica gel column to separate 1,3,2"-N,N,N-triacetylgentamycin C1a.

[0082] Among them, the specific filler type, size, and elution method of the silica gel column are as follows:

[0083] Silica gel column model: ZCX Ⅱ, reage...

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Abstract

The invention relates to a synthesis method of 6''-N-ethyl gentamicin C1a. The synthesis method of the 6''-N-ethyl gentamicin C1a comprises the following steps that (1) a compound 1 gentamicin C1a isdissolved in a solvent for cooling, BOC-ON is added and stirred, and water and ethyl acetate are added to be subjected to liquid separating, water phase taking, and condensing to obtain a compound 2;(2) a concentrated solution is dissolved by methanol, triethylamine is added for cooling, and acetic anhydride is added, stirred and condensed to remove a solvent; (3) hydrochloric acid is added to aconcentrated solution, and stirred at the room temperature, pH is adjusted by a sodium hydroxide solution for concentration, and a compound 3, namely 1,3,2''-N,N,N-triacetyl gentamicin C1a is obtainedby purification and separation through a silica gel column; and (4) after the 1,3,2''-N,N,N-tracetyl gentamicin C1a, glycol dimethyl ether, hexamethyldisilazane and a concentrated sulfuric acid are mixed and heated until refluxing and dissolving, stirring and concentrating continue to be conducted to remove the solvent so as to obtain a compound 4, dichloromethane is added for cooling, acetaldehyde is added to be stirred, potassium borohydride is added to be stirred, a borate buffer solution is added to be stirred, sodium hydroxide is added for condensing and removing the dichloromethane, thesodium hydroxide is added for heating and refluxing, and macroporous resin is subjected to desalination and separation to obtain a compound 5, namely 6''-N- ethyl gentamicin C1a.

Description

technical field [0001] The invention relates to a method for synthesizing intermediate products of pharmaceutical compounds, in particular to a method for synthesizing 6"-N-ethyl gentamycin C1a. Background technique [0002] Etimicin sulfate is a new generation of semi-synthetic water-soluble antibiotics developed by Chinese researchers with independent intellectual property rights, high efficiency, low toxicity, and resistance to drug-resistant bacteria. It belongs to aminoglycosides. Its mechanism of action is to inhibit the normal It is the only anti-infective drug that has obtained the national first-class new drug certificate. It has a good antibacterial effect on most G+ and G- bacteria, especially Escherichia coli, Klebsiella pneumoniae, Serratia, Proteus mirabilis, Salmonella, Haemophilus influenzae and Staphylococcus. High antibacterial activity, it has certain antibacterial activity against some Pseudomonas aeruginosa, Acinetobacter, etc., and it is resistant to s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/236C07H1/00C07H1/06
CPCC07H15/236C07H1/00C07H1/06
Inventor 华梦丹於江华吴凌云王晓霞彭帅
Owner WUXI JIYU SHANHE PHARM CO LTD
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