CN110066304A - The synthetic method of 1-N- ethyl micronomicin - Google Patents
The synthetic method of 1-N- ethyl micronomicin Download PDFInfo
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- C07H15/20—Carbocyclic rings
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- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
- C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
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Abstract
The present invention relates to a kind of synthetic method of 1-N- ethyl micronomicin, method includes the following steps: (1) to acetonitrile, in acetic anhydride and concentrated sulfuric acid mixed solution, is added 3; 2 ", 6 " ,-N, N; N- triacetyl gentamicinC2 b, after being heated to reflux, distills out acetonitrile；(2) reaction solution is cooled to 0~10 DEG C, and methylene chloride and acetaldehyde is added, reacts at 0~10 DEG C, and potassium borohydride, borate buffer is then added, and the reaction was continued, and normal heating is concentrated after reaction；(3) sodium hydroxide solution is added into concentrate, normal heating distillation steams partial solvent, and sodium hydroxide solution is being added, is being heated to reflux, end of reaction, system is down to room temperature, and filtrate is obtained by filtration；(4) pass through isolated target product 1-N- ethyl micronomicin after desalination.
Description
Technical field
The present invention relates to a kind of organic chemical synthesis methods, and specifically one kind is with 3,2 ", 6 " ,-N, N, N- triacetyl
The method of base gentamicinC2 b synthesis 1-N- ethyl micronomicin.
Background technique
Etimicin Sulfate (1-N-EthagentamycinC1a sulfate) is that China scientific research personnel voluntarily develops, and is possessed
Efficient, less toxic, antimicrobial agent the semi-synthetic aminoglycoside antibiotics of a new generation of independent intellectual property right is unique acquisition country
The anti-infectives of a kind of New Drug Certificate.Its preparation Etimicin Sulfate injection be suitable for its sensitive Escherichia coli, gram
Thunder Bai Shi pneumobacillus, Serratia category, citrobacter, Enterobacter, acinetobacter, Proteus, bloodthirsty stream
Feel various infection caused by bacillus, Pseudomonas aeruginosa and staphylococcus etc., clinical studies show this product is to below infected with preferable
Curative effect:
Respiratory tract infection: such as acute bronchitis, acute exacerbation of chronic bronchitis, community's pulmonary infection；
Kidney and urogenital infections: such as acute pyelonephritis, cystitis, chronic pyelonephritis or chronic cystitis
Acute attack etc.；
Skin soft tissue and other infection: such as skin and soft tissue infection, wound, wound and postpartum of performing the operation infection and its
He infects sensitive bacteria.
The adverse reaction that drug generates in clinical use has outside the Pass in addition to the pharmacological activity with drug itself, in drug
Existing impurity also has very big relationship.
Currently, Etimicin Sulfate preparation method mainly includes following documents:
1-N- ethyl micronomicin structural formula is as follows:
The compound is in H.Wang, ZJ.Zhang, F.Fei, Isolation and structure
characterization of related impurities in etimicin sulfate by LC/ESI-MSn and
NMR, Journal of Pharmaceutical and Biomedical Analysis [J] .55 (2011), 902-907. text
It is reported in offering, according to the document, 1-N- ethyl micronomicin is residual in Etimicin Sulfate bulk pharmaceutical chemicals and preparation
One of major impurity stayed, in the today for the technical standard being increasingly stringenter, 1-N- ethyl micronomicin has become and must give
With one of the impurity detected and controlled, but the prior art does not disclose the standard items of the 1-N- ethyl micronomicin of purity is high and goes out
It sells, also without corresponding preparation method document report.It improves and studies in the quality standard of Etimicin Sulfate bulk pharmaceutical chemicals and its preparation
In the process, it inevitably needs to use impurity reference substance.Therefore, a kind of preparation process of 1-N- ethyl micronomicin is developed
And to carry out purification process, to reach the requirement of standard items, for improve drug quality, improve clinical application safety tool
There is great meaning.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of 1-N- ethyl micronomicin.
Preparation method of the present invention, comprising the following steps:
(1) to acetonitrile, in acetic anhydride and concentrated sulfuric acid mixed solution, 3,2 are added ", 6 " ,-N, N, the celebrating of N- triacetyl is big mould
Plain C2b after being heated to reflux, distills out acetonitrile；
(2) reaction solution is cooled to 0~10 DEG C, and methylene chloride and acetaldehyde is added, reacts at 0~10 DEG C, boron is then added
Hydrofining, borate buffer, the reaction was continued, and normal heating is concentrated after reaction；
(3) sodium hydroxide solution is added into concentrate, normal heating distillation steams partial solvent, and hydroxide is being added
Sodium solution is heated to reflux, and end of reaction, system is down to room temperature, and filtrate is obtained by filtration；
(4) pass through isolated target product 1-N- ethyl micronomicin after desalination.
Wherein, the acetic anhydride and 3 in step (1), 2 ", 6 " ,-N, N, the molar ratio 2:1 of N- triacetyl gentamicinC2 b
~9:1；The concentrated sulfuric acid and 3,2 ", 6 " ,-N, N, molar ratio 0.05:1~1.5:1 of N- triacetyl gentamicinC2 b, heating temperature
Degree is in 80~100 DEG C of reflux 1-3h.Preferably, the acetic anhydride and 3 in step (1), 2 ", 6 " and ,-N, N, N- triacetyl are celebrated big mould
Molar ratio 4:1~8:1 of plain C2b；The concentrated sulfuric acid and 3,2 ", 6 " ,-N, N, the molar ratio 0.09 of N- triacetyl gentamicinC2 b:
1~1.2:1, heating temperature is in 90 DEG C of reflux 2h.
Wherein, the acetaldehyde and 3 in step (2), 2 ", 6 " ,-N, N, the molar ratio 1:1 of N- triacetyl gentamicinC2 b~
4:1, borate buffer solution adjust the pH value of solution to 8~11, potassium borohydride and 3,2 ", 6 " ,-N, N, and the celebrating of N- triacetyl is mould greatly
Molar ratio 4:1~8:1 of plain C2b.Preferably, the acetaldehyde and 3 in step (2), 2 ", 6 " ,-N, N, N- triacetyl gentamicin
The molar ratio 1.5:1 of C2b, borate buffer solution adjust the pH value of solution to 10, potassium borohydride and 3,2 ", 6 " ,-N, N, tri- second of N-
Molar ratio 5:1~6.5:1 of acyl group gentamicinC2 b.
Wherein, heating temperature is at 110~140 DEG C in step (3), and flow back 20~25h.Preferably, heating temperature in step (3)
Degree is at 125 DEG C, and reflux is for 24 hours.
Wherein, separation is to first pass through the preparation isolated 1-N- ethyl micronomicin of liquid phase in step (4).
Preferably, preparation method of the invention, comprising the following steps:
(1) in the dry round-bottomed flask of the 100mL equipped with the reflux condensing tube with drying tube, acetonitrile 8-16mL, second are put into
Acid anhydrides 0.65-2.9mL, concentrated sulfuric acid 0.01-0.04mL are added 3,2 after mixing evenly ", 6 " ,-N, N, N- triacetyl are celebrated big mould
Plain C2b 2g, is heated to flowing back, and reacts 2h., solvent acetonitrile is removed to be concentrated under reduced pressure；
(2) it is cooled to 0~10 DEG C, puts into methylene chloride 10-24mL, then under the conditions of 0~10 DEG C, acetaldehyde 0.2- is added dropwise
0.8mL stirs 0.5-2h, adds potassium borohydride 0.2-1g, reacts 0.2-1h, adds borate buffer 1-5mL, stirs 1-3h；
(3) 10% sodium hydroxide is added and stirs 0.5-2h, normal heating is distilled to 100 DEG C of liquid temperature, partial solvent is steamed,
20% sodium hydroxide solution 8-12mL is being added, is being heated to reflux 12-48h, is being cooled to room temperature, vacuum filtration obtains filtrate；
(4) filtrate is diluted with salt-free water, is passed through loading in chromatography column, washes column, 20-60% ethanol elution with purifying
Organic phase, concentration, concentrate add ammonium hydroxide to mix, and are passed through loading in chromatography column, collect effective component, concentration, and concentrate leads to
It crosses and prepares liquid phase process and separated, collect effective component, concentration.
The synthetic route of 1-N- ethyl micronomicin of the present invention, as follows:
Step 1
Step 2
The Chinese of the compound 1-5 occurred in said synthesis route:
Compound 1:3,2 ", 6 " ,-N, N, N- triacetyl gentamicinC2 b
Compound 2:2 ', 4 ', 5 "-triethyls -3,2 ", 6 ",-N, N, N- triacetyl gentamicinC2 b
Compound 3:2 ', 4 ', 5 "-triethyls -3,2 ", 6 ",-N, N, N- triacetyl -3- ethylidene gentamicinC2 b
Compound 4:2 ', 4 ', 5 "-triethyls -3,2 ", 6 ",-N, N, N- triacetyl -3- ethyl gentamicinC2 b
Compound 5:1-N- ethyl micronomicin
Above compound 1-5,1,5 be known compound (compound 1 "The 3,2 of a kind of high-purity ", 6 "-N, N, N- tri- Acetyl group gentamicinC2bUF membrane(CN103374047) " reported in document, compound 5 " H.Wang, ZJ.Zhang,
F.Fei,Isolation and structure characterization of related impurities in
etimicin sulfate by LC/ESI-MSn and NMR,Journal of Pharmaceutical and
Biomedical Analysis [J] .55 (2011) is reported in 902-907. " document), 2,3,4 be unknown compound.
Preparation method of the invention has the advantages that for existing technique
At present there is no the report of 1-N- ethyl micronomicin correlation synthesis technology, the present invention is small as unique 1-N- ethyl
The synthesis technology of promise mycin, synthetic route is simple, operates conveniently, and the used time is short, at low cost, and environmental pollution is small, by this hair
The 1-N- ethyl micronomicin that bright method is prepared have the characteristics that purity is high reach 98% and high income reach 80%, it is right
In improving drug quality, the safety for improving clinical application is of great significance.
Specific embodiment
By following specific embodiments, the present invention is further illustrated, but not as limitation of the invention
Embodiment 1,1-N- ethyl micronomicin
A, in the dry round-bottomed flask of the 100mL equipped with the reflux condensing tube with drying tube, acetonitrile 10mL, acetic anhydride are put into
2.5mL, concentrated sulfuric acid 0.04mL are added 3,2 after mixing evenly ", 6 " ,-N, N, N- triacetyl gentamicinC2 b 2.0g add
Heat reacts 2h to flowing back.It is changed to distilling apparatus normal heating and steams solvent ethylene glycol dimethyl ether.
B, it is cooled to 0~10 DEG C, puts into methylene chloride 9mL, then under the conditions of 0~10 DEG C, acetaldehyde 0.2mL is added dropwise, stirs
Mix 1h.Add potassium borohydride 0.5g, react 0.5h, add borate buffer 3mL (1.0g boric acid adds deionized water 3.0mL stirring and dissolving,
PH=10 is adjusted with sodium hydroxide), stir 1.5h.
C, 10% sodium hydroxide is added and stirs 0.5h, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent.It is added
20% sodium hydroxide solution 2mL, is heated to reflux for 24 hours, is cooled to room temperature, and vacuum filters to obtain filtrate.
D, filtrate is diluted with salt-free water, is passed through loading in chromatography column macroporous resin column, washes column, 40% second with purifying
Alcohol elutes organic phase, concentration.Concentrate is separated by preparation liquid phase according to the method that China Medicine University develops, and collection has
Ingredient is imitated, 1-N- ethyl micronomicin, purity 98%, yield 80% are concentrated to get.
Embodiment 2,1-N- ethyl micronomicin
A, in the dry round-bottomed flask of the 100mL equipped with the reflux condensing tube with drying tube, acetonitrile 10mL, acetic anhydride are put into
2.5mL, concentrated sulfuric acid 0.02mL are added 3,2 after mixing evenly ", 6 " ,-N, N, N- triacetyl gentamicinC2 b 2.0g add
Heat reacts 2h to flowing back.It is concentrated under reduced pressure and removes solvent ethylene glycol dimethyl ether.
B, it is cooled to 0~10 DEG C, puts into methylene chloride 9mL, then under the conditions of 0~10 DEG C, acetaldehyde 0.2mL is added dropwise, stirs
Mix 1h.Add potassium borohydride 0.5g, react 0.5h, add borate buffer 3mL (1.0g boric acid adds deionized water 3.0mL stirring and dissolving,
PH=10 is adjusted with sodium hydroxide), stir 1.5h.
C, 10% sodium hydroxide is added and stirs 0.5h, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent.It is added
20% sodium hydroxide solution 2mL, is heated to reflux for 24 hours, is cooled to room temperature, and vacuum filters to obtain filtrate.
D, filtrate is diluted with salt-free water, is passed through loading in chromatography column, washes column with purifying, 40% ethanol elution is organic
Phase, concentration.Concentrate is separated by preparation liquid phase according to the big method of medicine, is collected effective component, is concentrated to get 1-N- ethyl
Micronomicin, purity 98%, yield 40%.
The preparation of embodiment 3, high-purity standard items 1-N- ethyl micronomicin
A, in the dry round-bottomed flask of the 100mL equipped with the reflux condensing tube with drying tube, acetonitrile 10mL, acetic anhydride are put into
2.5mL, concentrated sulfuric acid 0.04mL are added 3,2 after mixing evenly ", 6 " ,-N, N, N- triacetyl gentamicinC2 b 2.0g add
Heat reacts 2h to flowing back.It is changed to distilling apparatus normal heating and steams solvent ethylene glycol dimethyl ether.
B, it is cooled to 0~10 DEG C, puts into methylene chloride 9mL, then under the conditions of 0~10 DEG C, acetaldehyde 0.2mL is added dropwise, stirs
Mix 1h.Add potassium borohydride 0.5g, react 0.5h, add borate buffer 3mL (1.0g boric acid adds deionized water 3.0mL stirring and dissolving,
PH=10 is adjusted with sodium hydroxide), stir 1.5h.
C, 10% sodium hydroxide is added and stirs 0.5h, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent.It is added
20% sodium hydroxide solution 2mL, is heated to reflux for 24 hours, is cooled to room temperature, and vacuum filters to obtain filtrate.
D, filtrate is diluted with salt-free water, is passed through loading in chromatography column macroporous resin column, washes column, 40% second with purifying
Alcohol elutes organic phase, concentration.
Salt concentrate is removed, is 10mg/ml with ultrapure water diluted concentration, the method for taking China Medicine University to develop carries out
Liquid phase separation is prepared, effective component is collected.
The method of China Medicine University's exploitation:
Chromatographic column: Gemini NX C18 (4.6mm × 150mm, 5 μm)；Mobile phase: A phase: water-ammonia water-glacial acetic acid (96:
3.6:0.4), B phase: methanol, gradient elution (program is shown in Tab.1)；Flow velocity: 0.8ml/min；Column temperature: 30 DEG C；Sample volume: 10 μ l；
ELSD parameter: drift tube temperature: 105 DEG C；Flow rate of carrier gas: 2.6L/min；Gain value: 1.
Tab.1 eluent gradient
The application example of embodiment 4,1-N- ethyl micronomicin,
The synthesis of Etimicin Sulfate bulk pharmaceutical chemicals:
A, in the dry round-bottomed flask of the 100mL equipped with the reflux condensing tube with drying tube, acetonitrile 10mL, acetic anhydride are put into
2.5mL, concentrated sulfuric acid 0.04mL are added 3,2 after mixing evenly ", 6 " ,-N, N, N- triacetyl gentamicinC2b2.0g, heating
To reflux, 2h is reacted.It is changed to distilling apparatus normal heating and steams solvent ethylene glycol dimethyl ether.
B, it is cooled to 0~10 DEG C, puts into methylene chloride 9mL, then under the conditions of 0~10 DEG C, acetaldehyde 0.2mL is added dropwise, stirs
Mix 1h.Add potassium borohydride 0.5g, react 0.5h, add borate buffer 3mL (1.0g boric acid adds deionized water 3.0mL stirring and dissolving,
PH=10 is adjusted with sodium hydroxide), stir 1.5h.
C, 10% sodium hydroxide is added and stirs 0.5h, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent.It is added
20% sodium hydroxide solution 2mL, is heated to reflux for 24 hours, is cooled to room temperature, and vacuum filters to obtain filtrate.
D, filtrate is diluted with salt-free water, is passed through loading in chromatography column macroporous resin column, washes column, 40% second with purifying
Alcohol elutes organic phase, concentration.Concentrate is separated by preparation liquid phase according to the method that China Medicine University develops, and collection has
Ingredient is imitated, 1-N- ethyl micronomicin, purity 98%, yield 80% are concentrated to get.
The detection method of Etimicin Sulfate bulk pharmaceutical chemicals:
The preparation of test solution:
It takes this product appropriate, adds flowing phased soln and dilute and be made in every 1ml containing about the solution of Etimicin 0.25mg, as
Test solution；
Precision measures test solution 1ml, sets in 100ml measuring bottle, is diluted to scale with mobile phase, shakes up, as control
Solution.
The preparation of standard solution:
It takes Etimicin reference substance and this product standard items each appropriate respectively, adds flowing phased soln and dilution is made in every 1ml
The respectively mixed solution containing about 0.025mg
Detection:
Test solution and control solution are injected into high performance liquid chromatograph, obtain chromatogram, are calculated according to chromatogram
The residual quantity of impurity 1-N- ethyl micronomicin in Etimicin bulk pharmaceutical chemicals.
It is exemplified below: weighing 1-N- ethyl micronomicin 6.56mg, be diluted to 25mL, take quantitative Etimicin Sulfate former
Material medicine is diluted to 25mL.Impurity 1-N- ethyl in Etimicin Sulfate bulk pharmaceutical chemicals can be calculated according to above data and peak area
The residual quantity of micronomicin.
Chromatographic condition is as follows:
It is filler (4.6mm × 250mm, 5 μm or the comparable chromatographic column of efficiency) with octadecylsilane chemically bonded silica, with
0.2mol/L trifluoroacetic acid (contains 0.05% 5 fluorine propionic acid, 50% sodium hydroxide of 1.5g/L anhydrous sodium sulfate, 0.8% (V/V) is molten
Liquid, adjusting pH value to 3.5)-acetonitrile (96:4) with 50% sodium hydroxide is mobile phase, and column temperature is 35 DEG C, and flow velocity is per minute
1.0ml is detected with integrated pulsed amperometric electrochemical detector, and detecting electrode is gold electrode (being recommended to use 3mm diameter), reference electricity
Extremely Ag/AgCl combination electrode, titanium alloy is to electrode, four waveforms detection current potentials, after column plus alkali (50% sodium hydroxide solution 1 →
25, recommend flow velocity 0.5ml per minute).
Claims (10)
1. a kind of synthetic method of 1-N- ethyl micronomicin, the described method comprises the following steps:
(1) to acetonitrile, in acetic anhydride and concentrated sulfuric acid mixed solution, 3,2 are added ", 6 " ,-N, N, N- triacetyl gentamicin
C2b after being heated to reflux, distills out acetonitrile；
(2) reaction solution is cooled to 0~10 DEG C, and methylene chloride and acetaldehyde is added, reacts at 0~10 DEG C, hydroboration is then added
Potassium, borate buffer, the reaction was continued, and normal heating is concentrated after reaction；
(3) sodium hydroxide solution is added into concentrate, normal heating distillation steams partial solvent, and sodium hydroxide is molten being added
Liquid is heated to reflux, and end of reaction, system is down to room temperature, and filtrate is obtained by filtration；
(4) pass through isolated target product 1-N- ethyl micronomicin after desalination.
2. the synthetic method of 1-N- ethyl micronomicin according to claim 1, it is characterised in that: the second in step (1)
Acid anhydrides and 3,2 ", 6 " ,-N, N, molar ratio 2:1~9:1 of N- triacetyl gentamicinC2 b；The concentrated sulfuric acid and 3,2 ", 6 " ,-N,
Molar ratio 0.05:1~1.5:1 of N, N- triacetyl gentamicinC2 b.
3. the synthetic method of 1-N- ethyl micronomicin according to claim 1, it is characterised in that: the second in step (1)
Acid anhydrides and 3,2 ", 6 " ,-N, N, molar ratio 4:1~8:1 of N- triacetyl gentamicinC2 b；The concentrated sulfuric acid and 3,2 ", 6 " ,-N,
Molar ratio 0.09:1~1.2:1 of N, N- triacetyl gentamicinC2 b.
4. the synthetic method of 1-N- ethyl micronomicin according to claim 1, it is characterised in that: temperature in step (1)
In 70~100 DEG C of reflux 2h.
5. the synthetic method of 1-N- ethyl micronomicin according to claim 1, it is characterised in that: temperature in step (1)
In 90 DEG C of 1.5~3h of reflux.
6. the synthetic method of 1-N- ethyl micronomicin according to claim 1, it is characterised in that: temperature in step (1)
In 90 DEG C of reflux 2h.
7. the synthetic method of 1-N- ethyl micronomicin according to claim 1, it is characterised in that: the second in step (2)
Aldehyde and 3,2 ", 6 " ,-N, N, molar ratio 1:1~4:1 of N- triacetyl gentamicinC2 b, the borate buffer in step (2) are molten
Liquid PH is adjusted to 8~11；Potassium borohydride and 3,2 ", 6 " ,-N, N, molar ratio 4:1~8:1 of N- triacetyl gentamicinC2 b.
8. the synthetic method of 1-N- ethyl micronomicin according to claim 1, it is characterised in that: the second in step (2)
Aldehyde and 3,2 ", 6 " ,-N, N, the molar ratio 1.5:1 of N- triacetyl gentamicinC2 b, the borate buffer solution PH in step (2)
It is adjusted to 10；Potassium borohydride and 3,2 ", 6 " ,-N, N, molar ratio 5:1~6.5:1 of N- triacetyl gentamicinC2 b.
9. the synthetic method of 1-N- ethyl micronomicin according to claim 1, it is characterised in that:；Temperature in step (3)
Separation is by preparing the isolated 1-N- ethyl micronomicin of liquid phase in 110~140 DEG C of 20~25h of reflux, step (3).
10. the synthetic method of 1-N- ethyl micronomicin according to claim 1, it is characterised in that: temperature in step (3)
It flows back for 24 hours at 125 DEG C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100467A (en) * | 1993-04-23 | 1995-03-22 | 江苏省微生物研究所 | 1-N-ethyl gentamicin derivative and its preparing method |
| CN1397562A (en) * | 2001-12-18 | 2003-02-19 | 国家药品监督管理局四川抗菌素工业研究所 | Derivative of micronomycine and its preparing process and medical application |
| CN101928311A (en) * | 2010-03-26 | 2010-12-29 | 常州方圆制药有限公司 | Preparation method of 1-N-ethyl gentamicin Cla |
| CN107652334A (en) * | 2017-09-13 | 2018-02-02 | 无锡济民可信山禾药业股份有限公司 | The synthetic method of 3 N ethyl Gentamicin C1as |
-
2019
- 2019-05-25 CN CN201910442380.7A patent/CN110066304B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100467A (en) * | 1993-04-23 | 1995-03-22 | 江苏省微生物研究所 | 1-N-ethyl gentamicin derivative and its preparing method |
| CN1397562A (en) * | 2001-12-18 | 2003-02-19 | 国家药品监督管理局四川抗菌素工业研究所 | Derivative of micronomycine and its preparing process and medical application |
| CN101928311A (en) * | 2010-03-26 | 2010-12-29 | 常州方圆制药有限公司 | Preparation method of 1-N-ethyl gentamicin Cla |
| CN107652334A (en) * | 2017-09-13 | 2018-02-02 | 无锡济民可信山禾药业股份有限公司 | The synthetic method of 3 N ethyl Gentamicin C1as |
Non-Patent Citations (1)
| Title |
|---|
| YUNING WU ET AL.: "Improved liquid chromatography combined with pulsed electrochemical detection for the analysis of etimicin sulfate", 《JOURNAL OF SEPARATION SCIENCE》 * |
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