CN111057118A - Preparation method of erythromycin impurity D - Google Patents
Preparation method of erythromycin impurity D Download PDFInfo
- Publication number
- CN111057118A CN111057118A CN201911343134.2A CN201911343134A CN111057118A CN 111057118 A CN111057118 A CN 111057118A CN 201911343134 A CN201911343134 A CN 201911343134A CN 111057118 A CN111057118 A CN 111057118A
- Authority
- CN
- China
- Prior art keywords
- erythromycin
- impurity
- erythromycin impurity
- reaction solution
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- YKAVHPRGGAUFDN-JTQLBUQXSA-N 24464-30-0 Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]2(C)O[C@]3([C@@H]([C@H]2O)C)[C@H](C)C[C@](O3)(C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 YKAVHPRGGAUFDN-JTQLBUQXSA-N 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims abstract description 32
- 238000003756 stirring Methods 0.000 claims abstract description 17
- 229960003276 erythromycin Drugs 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 10
- 230000002378 acidificating effect Effects 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 1
- 238000011020 pilot scale process Methods 0.000 abstract description 3
- 230000006872 improvement Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 29
- 239000012535 impurity Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000004881 Amebiasis Diseases 0.000 description 1
- 206010001980 Amoebiasis Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000606125 Bacteroides Species 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 241000589562 Brucella Species 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241000187654 Nocardia Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000606701 Rickettsia Species 0.000 description 1
- 241000589970 Spirochaetales Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 241001312524 Streptococcus viridans Species 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a preparation method of an erythromycin impurity D, which comprises the following steps: adding water into erythromycin, stirring and reacting at 25-30 ℃ under an acidic condition, and then separating and purifying a reaction solution to obtain an erythromycin impurity D; the preparation method of the erythromycin impurity D has mild reaction conditions, does not relate to ultralow temperature reaction, reduces the process steps, and is suitable for pilot scale of laboratories; the purity of the prepared erythromycin impurity D reaches over 90 percent, the quality research requirement can be met, and meanwhile, a technical basis is provided for the national quality standard improvement of erythromycin.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of an erythromycin impurity D.
Background
Erythromycin (Erythromycin) belongs to macrolide antibiotics, is a fermentation antibiotic, and has been widely developed and applied in the medical field. The antibacterial spectrum is similar to that of penicillin, and has strong inhibiting effect on gram-positive bacteria such as staphylococcus, streptococcus pyogenes, streptococcus viridans, streptococcus pneumoniae, streptococcus faecalis, hemolytic streptococcus, clostridium, diphtheria bacillus, bacillus anthracis and the like. It also has certain inhibitory effect on gram-negative bacteria such as gonococcus, helicobacter, Bordetella pertussis, Brucella, Legionella, meningococcus, Haemophilus influenzae, Bacteroides, partial dysentery bacillus, and Escherichia coli. In addition, it has inhibitory effect on mycoplasma, actinomycetes, spirochetes, rickettsia, chlamydia, nocardia, a few mycobacteria and amebiasis.
The erythromycin impurity is a component without any pharmacodynamic action in the medicine, and part of the impurity has carcinogenicity and teratogenicity, and the impurity has adverse reaction, thereby seriously influencing the medication safety and bringing immeasurable risk to the user.
The domestic preparation process of the imitation drugs is various, so that the generated impurities are different, and different from the process of the original research drugs, the content and the types of the impurities also have different, but the domestic generation mechanism, synthesis preparation, separation and purification and pharmacology of the impurities cannot be systematically and comprehensively researched, and some impurities have a plurality of tautomers, are limited by the fact that monomer impurities are difficult to obtain by a separation and purification technology, cannot be systematically researched, and cause the quality of the imitation drugs to be obviously inferior to the quality of the original research drugs. Therefore, the research on impurities is particularly important, and the synthesis and separation of the impurity monomer are essential to the research on the structure, toxicity and quality control of the impurity monomer, and have important significance for improving the quality of domestic medicines.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides the preparation method of the erythromycin impurity D, which has mild reaction conditions, does not relate to ultralow temperature reaction, has few process steps and is suitable for pilot scale test in a laboratory.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of erythromycin impurity D comprises the following steps: adding water into erythromycin, stirring and reacting at 25-30 ℃ under an acidic condition, and then separating and purifying a reaction solution to obtain an erythromycin impurity D; the chemical structural formula of the erythromycin impurity D is as follows:
the chemical structural formula of the erythromycin impurity D is as follows: c37H65NO12The molecular formula is 715, and the reaction process of the preparation method is as follows:
preferably, the preparation method of the erythromycin impurity D comprises the following steps:
(1) adding water into erythromycin, slowly dropwise adding an acid while stirring at room temperature, keeping the pH of the reaction solution at 1-2, and stirring for reaction to obtain a reaction solution;
(2) adjusting the pH of the reaction liquid to 8-9 by using alkali to obtain an erythromycin impurity D reaction liquid;
(3) and (3) adding methanol into the erythromycin impurity D reaction solution for dissolving, separating by using a C18 column, sequentially eluting by using acetonitrile water solutions with different concentrations, and freeze-drying to obtain an erythromycin impurity D pure product with the purity of over 90%.
Preferably, in the step (1), the amount of water is 20-30 mL per gram of erythromycin.
Preferably, the acid in step (1) is concentrated hydrochloric acid.
Preferably, the alkali in the step (2) is sodium hydroxide with the concentration of 0.5-1.5 mol/L.
Preferably, in the step (1), the stirring reaction time is 0.5-1 h.
Preferably, in the step (3), the mixture is separated by an upper 600mL C18 column, and is sequentially treated by a volume ratio of 40: 60. 50: 50. 60: and eluting 1.5L of acetonitrile and water solution of 40 parts respectively to obtain pure erythromycin impurity D, and freeze-drying to obtain pure erythromycin impurity D.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method of the erythromycin impurity D has mild reaction conditions, does not relate to ultralow temperature reaction, reduces the process steps, and is suitable for pilot scale of laboratories; the purity of the prepared erythromycin impurity D reaches over 90 percent, the quality research requirement can be met, and meanwhile, a technical basis is provided for the national quality standard improvement of erythromycin.
Drawings
FIG. 1 is an HPLC detection spectrum (chromatographic conditions: European pharmacopoeia 9.0) of erythromycin impurity D prepared by the preparation method of the present invention;
FIG. 2 is a HPLC detection profile of a blank control (chromatographic conditions: European pharmacopoeia 9.0);
FIG. 3 is a HNMR map of erythromycin impurity D prepared by the preparation method of the present invention;
FIG. 4 is a C13NMR spectrum of erythromycin impurity D prepared by the preparation method of the present invention;
FIG. 5 is an ESI-MS spectrum of erythromycin impurity D prepared by the preparation method of the present invention.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.
Example 1
The preparation method of the erythromycin impurity D comprises the following steps:
(1) weighing 5g of erythromycin, adding 100mL of water, slowly dropwise adding concentrated hydrochloric acid while stirring at room temperature, keeping the pH of the reaction solution at 1.0, and stirring for reacting for 0.5h to obtain a reaction solution;
(2) adjusting the pH of the reaction solution to 8-9 by using 1mol/L sodium hydroxide to obtain an erythromycin impurity D reaction solution;
(3) dissolving the erythromycin impurity D reaction solution in methanol, separating by a 600mL C18 column, and purifying by acetonitrile: aqueous solution 40: 60(V/V), 50: 50(V/V), 60: and eluting 1.5L of the raw materials respectively to obtain pure erythromycin impurity D, and freeze-drying to obtain pure erythromycin impurity D with purity of over 90% and yield of 15.7%.
Example 2
The preparation method of the erythromycin impurity D comprises the following steps:
(1) weighing 5g of erythromycin, adding 125mL of water, slowly dropwise adding concentrated hydrochloric acid while stirring at room temperature, keeping the pH of the reaction solution at 1.5, and stirring for reacting for 0.7h to obtain a reaction solution;
(2) adjusting the pH of the reaction solution to 8-9 by using 1mol/L sodium hydroxide to obtain an erythromycin impurity D reaction solution;
(3) dissolving the erythromycin impurity D reaction solution in methanol, separating by a 600mL C18 column, and purifying by acetonitrile: aqueous solution 40: 60(V/V), 50: 50(V/V), 60: eluting 1.5L of each component 40(V/V) to obtain pure erythromycin impurity D, and freeze-drying to obtain pure erythromycin impurity D with purity over 90% and yield of 12.6%.
Example 3
The preparation method of the erythromycin impurity D comprises the following steps:
(1) weighing 5g of erythromycin, adding 150mL of water, slowly dropwise adding concentrated hydrochloric acid while stirring at room temperature, keeping the pH of the reaction solution at 2.0, and stirring for reacting for 1h to obtain a reaction solution;
(2) adjusting the pH of the reaction solution to 8-9 by using 0.5mol/L sodium hydroxide to obtain an erythromycin impurity D reaction solution;
(3) dissolving the erythromycin impurity D reaction solution in methanol, separating by a 600mL C18 column, and purifying by acetonitrile: aqueous solution 40: 60(V/V), 50: 50(V/V), 60: eluting 1.5L of each component 40(V/V) to obtain pure erythromycin impurity D, and freeze-drying to obtain pure erythromycin impurity D with purity over 90% and yield of 11.3%.
Example 4
The preparation method of the erythromycin impurity D comprises the following steps:
(1) weighing 5g of erythromycin, adding 100mL of water, slowly dropwise adding concentrated hydrochloric acid while stirring at room temperature, keeping the pH of the reaction solution at 2.0, and stirring for reacting for 1h to obtain a reaction solution;
(2) adjusting the pH of the reaction solution to 8-9 by using 1.5mol/L sodium hydroxide to obtain an erythromycin impurity D reaction solution;
(3) dissolving the erythromycin impurity D reaction solution in methanol, separating by a 600mL C18 column, and purifying by acetonitrile: aqueous solution 40: 60(V/V), 50: 50(V/V), 60: eluting 1.5L of each component 40(V/V) to obtain pure erythromycin impurity D, and freeze-drying to obtain pure erythromycin impurity D with purity of over 90% and yield of 10.1%.
An HPLC detection spectrum of the erythromycin impurity D prepared in the embodiments 1-4 is shown in figure 1, an HPLC detection spectrum of a blank control is shown in figure 2, and a structure identification HNMR spectrum, a C13NMR spectrum and an ESI-MS spectrum are respectively shown in figures 3, 4 and 5; the structure of the prepared erythromycin impurity D is as follows:
finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (7)
1. A preparation method of erythromycin impurity D is characterized by comprising the following steps: adding water into erythromycin, stirring and reacting at 25-30 ℃ under an acidic condition, and then separating and purifying a reaction solution to obtain an erythromycin impurity D; the chemical structural formula of the erythromycin impurity D is as follows:
2. the method of preparing erythromycin impurity D according to claim 1, comprising the steps of:
(1) adding water into erythromycin, slowly dropwise adding an acid while stirring at room temperature, keeping the pH of the reaction solution at 1-2, and stirring for reaction to obtain a reaction solution;
(2) adjusting the pH of the reaction liquid to 8-9 by using alkali to obtain an erythromycin impurity D reaction liquid;
(3) and (3) adding methanol into the erythromycin impurity D reaction solution for dissolving, separating by using a C18 column, sequentially eluting by using acetonitrile water solutions with different concentrations, and freeze-drying to obtain an erythromycin impurity D pure product with the purity of over 90%.
3. The method for preparing erythromycin impurity D according to claim 2, wherein in the step (1), the amount of water is 20-30 mL per gram of erythromycin.
4. The process of claim 2, wherein the acid of step (1) is concentrated hydrochloric acid.
5. The method for preparing erythromycin impurity D according to claim 2, wherein the alkali in the step (2) is sodium hydroxide with a concentration of 0.5-1.5 mol/L.
6. The method for preparing erythromycin impurity D according to claim 2, wherein in the step (1), the stirring reaction time is 0.5-1 h.
7. The process for the preparation of erythromycin impurity D as described in claim 2, wherein in the step (3), the separation is carried out on 600mLC18 column, and the separation is carried out sequentially by using a solvent having a volume ratio of 40: 60. 50: 50. 60: and eluting 1.5L of acetonitrile and water solution of 40 parts respectively to obtain pure erythromycin impurity D, and freeze-drying to obtain pure erythromycin impurity D.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911343134.2A CN111057118A (en) | 2019-12-23 | 2019-12-23 | Preparation method of erythromycin impurity D |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911343134.2A CN111057118A (en) | 2019-12-23 | 2019-12-23 | Preparation method of erythromycin impurity D |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111057118A true CN111057118A (en) | 2020-04-24 |
Family
ID=70302670
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911343134.2A Pending CN111057118A (en) | 2019-12-23 | 2019-12-23 | Preparation method of erythromycin impurity D |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111057118A (en) |
-
2019
- 2019-12-23 CN CN201911343134.2A patent/CN111057118A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| ABDOLREZA HASSANZADEH ET AL.: "Pediatric Erythromycins:a Comparison of the Properties of Erythromycins A and B 2"-Ethyl Succinates", 《J. MED. CHEM.》 * |
| ADDOLREZA HASSANZADEH ET AL.: "Determination of the stereochemistry of anhydroerythromycin A, the principal degradation product of the antibiotic erythromycin A", 《ORG. BIOMOL. CHEM.》 * |
| ZHILING CAO ET AL.: "A Validated RP-LC Method for the Determination of Erythromycin an Oxime and Related Substances", 《ADVANCE JOURNAL OF FOOD SCIENCE AND TECHNOLOGY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK2125850T3 (en) | MACROCYCLIC POLYMORPHS, COMPOSITIONS INCLUDING SUCH POLYMORPHS, PROCEDURES FOR PREPARING AND USING THEREOF | |
| Fajdetić et al. | 4 ″-O-(ω-Quinolylamino-alkylamino) propionyl derivatives of selected macrolides with the activity against the key erythromycin resistant respiratory pathogens | |
| CN113173956B (en) | Preparation method of clarithromycin lactobionate | |
| CN111057118A (en) | Preparation method of erythromycin impurity D | |
| CN111040009A (en) | Preparation method of erythromycin impurity E | |
| KR100402560B1 (en) | Hygromycin a derivatives | |
| CN109053638B (en) | Extraction and purification method of fumagillin | |
| CN111087410A (en) | Preparation method of amoxicillin impurity G | |
| CN107683284A (en) | The manufacture method of epirubicin and its new manufacture intermediate | |
| CN110790774A (en) | Preparation method of cefdinir impurity D | |
| CN111040007B (en) | Synthetic method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a | |
| CN110922435A (en) | Preparation method of erythromycin A-6,9 imino ether impurity | |
| CN1205218C (en) | Cost effective method for selective methylation of erythromycin A derivatives | |
| CN102127093B (en) | Refining process for Cefotiam hexetil hydrochloride | |
| CN110964003A (en) | Preparation method of amoxicillin impurity C | |
| CN110759933A (en) | Preparation method of cefdinir impurity G | |
| CN110776520B (en) | Preparation method of cefazolin sodium impurity G | |
| CN106146579B (en) | Method for purifying avilamycin | |
| CN111018804A (en) | Preparation method of amoxicillin impurity E | |
| CN103030650A (en) | Method for preparing cefotiam hexetil and method for preparing cefotiam hexetil dihydrochloride | |
| CN116284051B (en) | Cefodinic acid derivative and preparation method and application thereof | |
| CN108299468B (en) | Refining method of cefprozil | |
| CN113429425B (en) | Preparation method of cefditoren pivoxil ring-opening dimer | |
| CN112521435B (en) | Application of roxithromycin analogue in preparation of antibacterial drugs | |
| CN110627815A (en) | Preparation method of cefdinir impurity B |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200424 |
|
| RJ01 | Rejection of invention patent application after publication |