CN110066304B - Synthesis method of 1-N-ethyl micronomicin - Google Patents
Synthesis method of 1-N-ethyl micronomicin Download PDFInfo
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- CN110066304B CN110066304B CN201910442380.7A CN201910442380A CN110066304B CN 110066304 B CN110066304 B CN 110066304B CN 201910442380 A CN201910442380 A CN 201910442380A CN 110066304 B CN110066304 B CN 110066304B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a synthesis method of 1-N-ethyl micronomicin, which comprises the following steps: (1) adding 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b into the mixed solution of acetonitrile, acetic anhydride and concentrated sulfuric acid, heating and refluxing, and distilling out acetonitrile; (2) cooling the reaction liquid to 0-10 ℃, adding dichloromethane and acetaldehyde, reacting at 0-10 ℃, then adding potassium borohydride and boric acid buffer solution, continuing the reaction, and heating and concentrating under normal pressure after the reaction; (3) adding a sodium hydroxide solution into the concentrated solution, heating and distilling at normal pressure to evaporate part of the solvent, adding the sodium hydroxide solution, heating and refluxing, cooling the system to room temperature after the reaction is finished, and filtering to obtain a filtrate; (4) and after desalting, separating to obtain the target product 1-N-ethyl micronomicin.
Description
Technical Field
The invention relates to an organic chemical synthesis method, in particular to a method for synthesizing 1-N-ethyl micronomicin by using 3,2 ', 6', -N, N, N-triacetyl gentamicin C2 b.
Background
Etimicin sulfate (1-N-ethyl gentamicin C1a sulfate) is a new-generation semisynthetic aminoglycoside antibiotic with high efficiency, low toxicity and drug-resistant bacteria, which is self-developed by Chinese researchers, has independent intellectual property rights and is the only anti-infective drug for obtaining a new drug certificate in China. The etimicin sulfate injection is suitable for various infections caused by sensitive escherichia coli, klebsiella pneumoniae, serratia, citrobacter, enterobacter, acinetobacter, proteus, hemophilus influenza bacillus, pseudomonas aeruginosa, staphylococcus and the like, and clinical researches show that the product has better curative effects on the following infections:
respiratory tract infection: such as acute bronchitis, acute attack of chronic bronchitis, community lung infection, etc.;
kidney and urogenital infections: such as acute pyelonephritis, cystitis, chronic pyelonephritis or chronic cystitis acute attack;
cutaneous soft tissue and other infections: such as skin and soft tissue infections, infections after trauma, trauma and surgery and other sensitive bacterial infections.
The adverse reaction generated in clinical use of the medicine is not only related to the pharmacological activity of the medicine, but also has a great relationship with impurities in the medicine.
At present, the preparation method of etimicin sulfate mainly comprises the following documents:
the structural formula of the 1-N-ethyl micronomicin is as follows:
the compound is reported in H.Wang, ZJ.Zhang, F.Fei, Isolation and structure characterization of related expressed in the experimental amino sulfate by LC/ESI-MSn and NMR, Journal of Pharmaceutical and biological Analysis [ J ].55(2011), 902-. In the research process of improving the quality standard of etimicin sulfate bulk drugs and preparations thereof, an impurity reference substance is inevitably required to be used. Therefore, the preparation process of the 1-N-ethyl micronomicin is developed and purified to meet the requirements of the standard substance, and has great significance for improving the quality of the medicine and the safety of clinical medication.
Disclosure of Invention
The invention aims to provide a preparation method of 1-N-ethyl micronomicin.
The preparation method comprises the following steps:
(1) adding 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b into the mixed solution of acetonitrile, acetic anhydride and concentrated sulfuric acid, heating and refluxing, and distilling out acetonitrile;
(2) cooling the reaction liquid to 0-10 ℃, adding dichloromethane and acetaldehyde, reacting at 0-10 ℃, then adding potassium borohydride and boric acid buffer solution, continuing the reaction, and heating and concentrating under normal pressure after the reaction;
(3) adding a sodium hydroxide solution into the concentrated solution, heating and distilling at normal pressure to evaporate part of the solvent, adding the sodium hydroxide solution, heating and refluxing, cooling the system to room temperature after the reaction is finished, and filtering to obtain a filtrate;
(4) and after desalting, separating to obtain the target product 1-N-ethyl micronomicin.
Wherein the molar ratio of acetic anhydride to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b in the step (1) is 2: 1-9: 1; the molar ratio of concentrated sulfuric acid to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b is 0.05: 1-1.5: 1, and the heating temperature is 80-100 ℃ for refluxing for 1-3 h. Preferably, the molar ratio of acetic anhydride to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b in the step (1) is 4: 1-8: 1; the molar ratio of concentrated sulfuric acid to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b is 0.09: 1-1.2: 1, and the heating temperature is 90 ℃ for refluxing for 2 h.
Wherein the molar ratio of acetaldehyde to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b in the step (2) is 1: 1-4: 1, the pH value of the solution is adjusted to 8-11 by using a boric acid buffer solution, and the molar ratio of potassium borohydride to 3,2 ', 6', -N, N-triacetyl gentamicin C2b is 4: 1-8: 1. Preferably, the molar ratio of acetaldehyde to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b in the step (2) is 1.5:1, the pH value of the solution is adjusted to 10 by boric acid buffer solution, and the molar ratio of potassium borohydride to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b is 5: 1-6.5: 1.
Wherein the heating temperature in the step (3) is 110-140 ℃, and the reflux is carried out for 20-25 h. Preferably, the heating temperature in step (3) is 125 ℃, and the reflux is carried out for 24 h.
Wherein, the separation in the step (4) is to obtain the 1-N-ethyl micronomicin by preparative liquid phase separation.
Preferably, the preparation method comprises the following steps:
(1) in a 100mL dry round bottom flask equipped with a reflux condenser with a drying tube, 8-16mL acetonitrile, 0.65-2.9mL acetic anhydride and 0.01-0.04mL concentrated sulfuric acid are added, and after stirring uniformly, 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b 2g is added, and the mixture is heated to reflux and reacted for 2 h. Removing the solvent acetonitrile by vacuum concentration;
(2) cooling to 0-10 ℃, adding 10-24mL of dichloromethane, then dropwise adding 0.2-0.8mL of acetaldehyde at 0-10 ℃, stirring for 0.5-2h, adding 0.2-1g of potassium borohydride, reacting for 0.2-1h, adding 1-5mL of boric acid buffer solution, and stirring for 1-3 h;
(3) adding 10% sodium hydroxide, stirring for 0.5-2h, distilling under normal pressure to 100 deg.C, distilling off part of solvent, adding 8-12mL 20% sodium hydroxide solution, heating and refluxing for 12-48h, cooling to room temperature, and vacuum filtering to obtain filtrate;
(4) diluting the filtrate with salt-free water, introducing into chromatographic separation column, eluting with purified water, eluting with 20-60% ethanol to obtain organic phase, concentrating, mixing the concentrated solution with ammonia water, introducing into chromatographic separation column, collecting effective components, concentrating, separating the concentrated solution by liquid phase preparation method, collecting effective components, and concentrating.
The synthetic route of the 1-N-ethyl micronomicin is as follows:
step 1
Step 2
The chinese names of compounds 1-5 appearing in the above synthetic route:
compound 1: 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b
Compound 2: 2 ', 4', 5 "-triethyl ester-3, 2", 6 "-N, N, N-triacetyl gentamicin C2b
Compound 3: 2 ', 4', 5 "-triethyl ester-3, 2", 6 "-N, N, N-triacetyl-3-ethylene gentamicin C2b
Compound 4: 2 ', 4', 5 "-triethyl ester-3, 2", 6 "-N, N, N-triacetyl-3-ethyl gentamicin C2b
Compound 5: 1-N-Ethyl micronomicin
The above-mentioned compounds 1-5, 1,5 are known compounds (Compound 1 is "High-purity 3,2 ', 6' -N, N, N-tris 2b Membrane separation of acetyl gentamicin C(CN103374047) "document reports that Compound 5 is produced by" H.Wang, ZJ.Zhang, F.Fei, Isolation and structure characterization of related assays in animal proteins sulfate by LC/ESI-MSn and NMR, Journal of Pharmaceutical and biological Analysis [ J.]55(2011), 902-.
Compared with the prior art, the preparation method of the invention has the following beneficial effects:
at present, no report of a relevant synthesis process of the 1-N-ethyl micronomicin exists, the only synthesis process of the 1-N-ethyl micronomicin is provided by the invention, the synthesis route is simple, the operation is convenient, the time consumption is short, the cost is low, and the environmental pollution is small, and the 1-N-ethyl micronomicin prepared by the method has the characteristics of high purity of 98%, high yield of 80% and the like, and has great significance for improving the medicine quality and improving the safety of clinical medication.
Detailed description of the preferred embodiments
The invention is further illustrated by the following specific examples, which are not to be construed as limiting the invention
Example 1, 1-N-Ethyl micronomicin
a. In a 100mL dry round bottom flask equipped with a reflux condenser with a drying tube, 10mL acetonitrile, 2.5mL acetic anhydride and 0.04mL concentrated sulfuric acid were added, and after stirring well, 2.0g of 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b 2.0 was added, and the mixture was heated to reflux and reacted for 2 hours. The distillation device is changed to heat at normal pressure to evaporate the solvent glycol dimethyl ether.
b. Cooling to 0-10 ℃, adding 9mL of dichloromethane, then dropwise adding 0.2mL of acetaldehyde at 0-10 ℃, and stirring for 1 h. Potassium borohydride (0.5 g) was added thereto, the reaction was carried out for 0.5h, and 3mL of a boric acid buffer (3.0 mL of deionized water to 1.0g of boric acid was added thereto and dissolved by stirring, and the pH was adjusted to 10 with sodium hydroxide) was added thereto and stirred for 1.5 h.
c. Adding 10% sodium hydroxide, stirring for 0.5 hr, distilling at normal pressure to 100 deg.C, and distilling off part of solvent. Adding 2mL of 20% sodium hydroxide solution, heating and refluxing for 24h, cooling to room temperature, and performing vacuum filtration to obtain a filtrate.
d. Diluting the filtrate with salt-free water, introducing into macroporous resin column of chromatographic separation column, washing the column with purified water, eluting organic phase with 40% ethanol, and concentrating. Separating the concentrated solution by preparative liquid phase according to the method developed by university of Chinese pharmacy, collecting effective components, and concentrating to obtain 1-N-ethyl micronomicin with purity of 98% and yield of 80%.
Example 2, 1-N-Ethyl-micronomicin
a. In a 100mL dry round bottom flask equipped with a reflux condenser with a drying tube, 10mL acetonitrile, 2.5mL acetic anhydride and 0.02mL concentrated sulfuric acid were added, and after stirring well, 2.0g of 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b 2.0 was added, and the mixture was heated to reflux and reacted for 2 hours. Concentrating under reduced pressure to remove the solvent glycol dimethyl ether.
b. Cooling to 0-10 ℃, adding 9mL of dichloromethane, then dropwise adding 0.2mL of acetaldehyde at 0-10 ℃, and stirring for 1 h. Potassium borohydride (0.5 g) is added to react for 0.5h, and then 3mL of boric acid buffer (3.0 mL of deionized water added to 1.0g of boric acid is dissolved by stirring, and the pH value is adjusted to 10 by sodium hydroxide), and the mixture is stirred for 1.5 h.
c. Adding 10% sodium hydroxide, stirring for 0.5 hr, distilling at normal pressure to 100 deg.C, and distilling off part of solvent. Adding 2mL of 20% sodium hydroxide solution, heating and refluxing for 24h, cooling to room temperature, and vacuum-filtering to obtain a filtrate.
d. Diluting the filtrate with salt-free water, introducing into chromatographic separation column, loading, washing the column with purified water, eluting the organic phase with 40% ethanol, and concentrating. Separating the concentrated solution by a preparation liquid phase according to a pharmaceutical preparation method, collecting effective components, and concentrating to obtain the 1-N-ethyl micronomicin with the purity of 98% and the yield of 40%.
Example 3 preparation of high purity Standard 1-N-Ethyl micronomicin
a. In a 100mL dry round bottom flask equipped with a reflux condenser with a drying tube, 10mL acetonitrile, 2.5mL acetic anhydride and 0.04mL concentrated sulfuric acid were added, and after stirring well, 2.0g of 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b 2.0 was added, and the mixture was heated to reflux and reacted for 2 hours. The distillation device is changed to heat at normal pressure to evaporate the solvent glycol dimethyl ether.
b. Cooling to 0-10 ℃, adding 9mL of dichloromethane, then dropwise adding 0.2mL of acetaldehyde at 0-10 ℃, and stirring for 1 h. Potassium borohydride (0.5 g) was added thereto, the reaction was carried out for 0.5h, and 3mL of a boric acid buffer (3.0 mL of deionized water to 1.0g of boric acid was added thereto and dissolved by stirring, and the pH was adjusted to 10 with sodium hydroxide) was added thereto and stirred for 1.5 h.
c. Adding 10% sodium hydroxide, stirring for 0.5 hr, distilling at normal pressure to 100 deg.C, and distilling off part of solvent. Adding 2mL of 20% sodium hydroxide solution, heating and refluxing for 24h, cooling to room temperature, and vacuum-filtering to obtain a filtrate.
d. Diluting the filtrate with salt-free water, introducing into macroporous resin column of chromatographic separation column, washing the column with purified water, eluting organic phase with 40% ethanol, and concentrating.
Diluting the desalted concentrated solution with ultrapure water to 10mg/ml, separating the prepared liquid phase by the method developed by Chinese pharmaceutical university, and collecting the effective components.
The method developed by the university of Chinese pharmacy comprises the following steps:
a chromatographic column: gemini NX C18(4.6 mm. times.150 mm, 5 μm); mobile phase: phase A: water-ammonia-glacial acetic acid (96: 3.6: 0.4), phase B: methanol, gradient elution (procedure see tab.1); flow rate: 0.8 ml/min; column temperature: 30 ℃; sample introduction amount: 10 mu l of the mixture; ELSD parameters: temperature of the drift tube: 105 ℃; flow rate of carrier gas: 2.6L/min; gain value: 1.
tab.1 mobile phase gradient
Example 4, an example of the use of 1-N-ethyl micronomicin,
synthesizing etimicin sulfate raw material medicine:
a. in a 100mL dry round-bottom flask equipped with a reflux condenser tube with a drying tube, 10mL acetonitrile, 2.5mL acetic anhydride and 0.04mL concentrated sulfuric acid were added, and after stirring well, 3,2 ', 6', -N, N, N-triacetyl gentamicin C was added 2b 2.0g, heated to reflux and reacted for 2 h. The distillation device is changed to heat at normal pressure to evaporate the solvent glycol dimethyl ether.
b. Cooling to 0-10 ℃, adding 9mL of dichloromethane, then dropwise adding 0.2mL of acetaldehyde at 0-10 ℃, and stirring for 1 h. Potassium borohydride (0.5 g) was added thereto, the reaction was carried out for 0.5h, and 3mL of a boric acid buffer (3.0 mL of deionized water to 1.0g of boric acid was added thereto and dissolved by stirring, and the pH was adjusted to 10 with sodium hydroxide) was added thereto and stirred for 1.5 h.
c. Adding 10% sodium hydroxide, stirring for 0.5 hr, distilling at normal pressure to 100 deg.C, and distilling off part of solvent. Adding 2mL of 20% sodium hydroxide solution, heating and refluxing for 24h, cooling to room temperature, and vacuum-filtering to obtain a filtrate.
d. Diluting the filtrate with salt-free water, introducing into macroporous resin column of chromatographic separation column, washing the column with purified water, eluting organic phase with 40% ethanol, and concentrating. Separating the concentrated solution by preparative liquid phase according to the method developed by Chinese pharmaceutical university, collecting effective components, and concentrating to obtain 1-N-ethyl micronomicin with purity of 98% and yield of 80%.
The detection method of the etimicin sulfate raw material medicine comprises the following steps:
preparing a test solution:
dissolving appropriate amount of the product with mobile phase, and diluting to obtain solution containing etimicin 0.25mg per 1ml as test solution;
precisely measuring 1ml of the test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a control solution.
Preparing a standard solution:
respectively taking appropriate amount of etimicin reference substance and standard substance, dissolving with mobile phase, and diluting to obtain mixed solution containing 0.025mg of etimicin per 1ml
And (3) detection:
injecting the test solution and the reference solution into a high performance liquid chromatograph to obtain a chromatogram, and calculating the residual amount of the impurity 1-N-ethyl micronomicin in the etimicin raw material drug according to the chromatogram.
Examples are as follows: weighing 6.56mg of 1-N-ethyl micronomicin, diluting to 25mL, and taking a certain amount of etimicin sulfate raw material medicine to dilute to 25 mL. According to the data and the peak area, the residual amount of the 1-N-ethyl micronomicin as the impurity in the etimicin sulfate bulk drug can be calculated.
The chromatographic conditions were as follows:
octadecylsilane chemically bonded silica was used as a filler (4.6 mm. times.250 mm, 5 μm or equivalent performance column), 0.2mol/L trifluoroacetic acid (containing 0.05% pentafluoropropionic acid, 1.5g/L anhydrous sodium sulfate, 0.8% (V/V) 50% sodium hydroxide solution, pH adjusted to 3.5 with 50% sodium hydroxide) -acetonitrile (96:4) was used as a mobile phase, the column temperature was 35 ℃ and the flow rate was 1.0ml per minute, and detection was performed with an integrated pulse amperometric electrochemical detector, the detection electrode was a gold electrode (3 mm diameter is recommended), the reference electrode was a Ag/AgCl composite electrode, a titanium alloy counter electrode, a four-wave detection potential, and base was added after the column (50% sodium hydroxide solution 1 → 25, 0.5ml per minute).
Claims (3)
1. A method for synthesizing 1-N-ethyl micronomicin, comprising the steps of:
(1) adding 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b into the mixed solution of acetonitrile, acetic anhydride and concentrated sulfuric acid, heating and refluxing, and distilling out acetonitrile;
(2) cooling the reaction liquid to 0-10 ℃, adding dichloromethane and acetaldehyde, reacting at 0-10 ℃, then adding potassium borohydride and boric acid buffer solution, continuing the reaction, and heating and concentrating under normal pressure after the reaction;
(3) adding a sodium hydroxide solution into the concentrated solution, heating and distilling at normal pressure to evaporate part of the solvent, then adding the sodium hydroxide solution, heating and refluxing, cooling the system to room temperature after the reaction is finished, and filtering to obtain a filtrate;
(4) after desalting, separating to obtain a target product 1-N-ethyl micronomicin;
wherein the molar ratio of acetic anhydride to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b in the step (1) is 2: 1-9: 1; the molar ratio of concentrated sulfuric acid to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b is 0.05: 1-1.5: 1; refluxing for 2h at 70-100 ℃; the molar ratio of acetaldehyde to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b in the step (2) is 1: 1-4: 1, and the pH value of a boric acid buffer solution is adjusted to 8-11; the molar ratio of potassium borohydride to 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b is 4: 1-8: 1, the temperature in the step (3) is 110-140 ℃ for refluxing for 20-25 h, the separation in the step (3) is to obtain 1-N-ethyl micronomicin through preparation liquid phase separation, and the temperature in the step (3) is 125 ℃ for refluxing for 24 h.
2. The method of synthesizing 1-N-ethyl micronomicin according to claim 1, characterized in that: in the step (1), the temperature is refluxed for 2 hours at 90 ℃.
3. The method of synthesizing 1-N-ethyl micronomicin according to claim 1, characterized in that: adjusting the pH value of the boric acid buffer solution in the step (2) to 10; the molar ratio of the potassium borohydride to the 3,2 ', 6', -N, N, N-triacetyl gentamicin C2b is 5: 1-6.5: 1.
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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 |
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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 |
|---|
| Improved liquid chromatography combined with pulsed electrochemical detection for the analysis of etimicin sulfate;Yuning Wu et al.;《JOURNAL OF SEPARATION SCIENCE》;20161231;第39卷;第1471-1479页 * |
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