CN114989169A - Preparation method of avibactam sodium - Google Patents
Preparation method of avibactam sodium Download PDFInfo
- Publication number
- CN114989169A CN114989169A CN202210786082.1A CN202210786082A CN114989169A CN 114989169 A CN114989169 A CN 114989169A CN 202210786082 A CN202210786082 A CN 202210786082A CN 114989169 A CN114989169 A CN 114989169A
- Authority
- CN
- China
- Prior art keywords
- compound
- sodium
- molar ratio
- structural formula
- chloroformate
- 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
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of abamectin sodium, which relates to the field of medicines and comprises the steps of cyclizing (2S,5R) -benzyloxypiperidine-2-ethyl formate oxalate starting raw materials in the presence of triphosgene organic solvent and alkali, sulfonating sulfur trioxide complex after hydrogenation reaction, and salifying with ammonium ion source to obtain a compound to prepare the abamectin sodium. The method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, simple operation, higher safety, high yield and good purity, and is suitable for large-scale chemical industry production. The invention is applied to the field of medicine preparation.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a preparation method of avibactam sodium.
Background
Avibatan sodium, British name, avibacam sodium, chemical name [ (1R,2S,5R) -2- (aminocarbonyl) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] sulfuric acid monosodium salt. The avibactam sodium belongs to a diazabicyclooctanone compound, does not have obvious antibacterial activity per se, and can inhibit beta-lactamases of A type (including ESBL and KPC) and C type. Therefore, when the antibacterial composition is used together with various cephalo-and carbapenem antibiotics, the antibacterial composition has broad-spectrum antibacterial activity, and particularly has remarkable activity on escherichia coli containing extended-spectrum beta-lactamase, klebsiella pneumoniae, escherichia coli containing excess AmpC enzyme and escherichia coli containing both AmpC and extended-spectrum beta-lactamase.
Ceftazidime and avibactam sodium for injection, which is a compound preparation consisting of the avibactam sodium and the ceftazidime according to a fixed proportioning dose, is a novel enzyme inhibitor compound preparation and can treat infection caused by drug-resistant gram-negative bacteria, including carbapenem drug-resistant enterobacteriaceae (CRE), multi-drug-resistant pseudomonas aeruginosa, ultra-broad-spectrum beta-lactamase (ESBLs) bacteria and the like. On 15 days 2 months 2015, FDA approved for marketing for the first time under the trade name of Avycaz (ceftazidime sodium for injection, 2.5g, european under the trade name of Zavicefta) for the treatment of adult complicated peritoneal and urinary tract infections.
Patent literature (CN103649051B) reports a preparation method of avibactam sodium as shown in scheme 1, which is complicated in reaction and operation process, uses a large amount of ammonia gas in the ammoniation process, causes environmental pollution, and has strong irritation, thus being not beneficial to industrial production. Expensive protective agent Fmoc-Cl and acylation reagent CDI are used in the cyclization process, and the two reagents are easy to degrade and difficult to store and are not suitable for large-scale industrial production.
Patent document (CN111777607A) reports a preparation method of avibactam sodium as shown in scheme 2, which requires pretreatment to remove oxalate, is easy to hydrolyze in the reaction process, and has poor product purity and low yield. Part of the unstable intermediate post-treatment process is easy to decompose to generate impurities. In the cyclization process, a more expensive protective agent Fmoc-CL and an acylation reagent CDI are used, the two reagents are easy to degrade and difficult to store, and the organic quaternary ammonium salt benzyltributylammonium chloride used in the patent is more expensive, increases the production cost and is not suitable for industrial large-scale production.
Patent literature (CN106866668B) reports a preparation method of avibactam sodium as shown in scheme 3, the preparation method of avibactam sodium adopts a one-pot method, a large amount of byproducts are accumulated in the reaction process, the product purity is poor, and the yield is low. Ammonium formate or hydrazine hydrate is used as a hydrogen donor, the conversion rate of the hydrogenation reaction is low, and the product yield is low.
Disclosure of Invention
The invention aims to solve the defects of the avibactam sodium synthesis method, and the method is characterized in that (2S,5R) -benzyloxyaminopiperidine-2-ethyl formate oxalate starting material is cyclized in the presence of triphosgene organic solvent and alkali, and after hydrogenation reaction, a sulfur trioxide complex is sulfonated and salified with an ammonium ion source to obtain the compound, namely the avibactam sodium. The method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, simple operation, higher safety, high yield and good purity, and is suitable for large-scale chemical industry production.
The synthesis route of the Abamebactam sodium is as follows:
the invention relates to a preparation method of abamectin sodium, which is carried out according to the following steps:
(1) compound I ((2S,5R) -5-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate) is prepared by adding triphosgene in the presence of an organic solvent and a base at a temperature of
Under (preferably) the conditions of
) Stirring the reaction until the reaction is finished to obtain a compound II ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [ 3.2.1)]Octane-2-carboxylic acid ethyl ester); wherein the molar ratio of the compound I to the base is
Preferably 1: 5-6; the molar ratio of the compound I to the triphosgene is
Preference is given to
The chemical structural formula of the compound I is
The chemical structural formula of the compound II is shown in the specification
(2) Directly adding an alkaline hydrolysis reagent into the solution of the compound II obtained in the step (1) at room temperature
Under (preferably) the conditions of
) The reaction was stirred to give Compound III ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1]Octane-2-carboxylic acid); wherein the molar ratio of the compound I to the alkaline hydrolysis reagent is 1:1 to 2, preferably 1:1.3 to 1.5;
the chemical structural formula of the compound III is
(3) The compound III in the step (2) (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1]Octane-2-carboxylic acid) solution is adjusted to acidity, then an extraction solvent is added to extract an organic phase, after drying, strong ammonia water is added in the presence of alkali and a carboxylic acid activating reagent at the temperature of
Stirring and reacting under the condition (preferably-15-5 ℃) until the reaction is finished, standing and layering, and crystallizing an organic phase to obtain a compound IV ((2S,5R) -5-benzyloxyaminopiperidine-2-formamide); the molar ratio of the compound I to the base is
Preferably 1: 1-1.2, and the molar ratio of the compound I to the carboxylic acid activating reagent is
Preferably 1: 1-1.2; the molar ratio of the compound I to the concentrated ammonia water is
Preference is given to
The chemical structural formula of the compound IV is
(4) The compound IV ((2S,5R) -5-benzyloxyaminopiperidine-2-formamide) is sulfonated with sulfur trioxide complex after hydrogenation, and then salified with ammonium ion source to obtain a compound V ((2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [ 3.2.1)]Octane-2-carboxamide); wherein the mass ratio of the compound IV to the catalyst in the hydrogenation reaction is
Preference is given to
More preferably
The molar ratio of the compound IV to the sulfur trioxide complex is
Preferably 1: 0.9-1.2(ii) a The molar ratio of the compound IV to the ammonium ion source is
Preferably 1: 1-2, more preferably 1: 1.2-1.5; the hydrogenation reaction temperature is
Preference is given to
The salt formation reaction temperature is
Preference is given to
The chemical structural formula of the compound V is
(5) Reacting the compound V with a sodium source in an organic solvent to obtain a compound abamectin sodium; the molar ratio of the compound V to the sodium source is
Preferably 1: 1.5-2; the temperature for treating the sodium source is 10-50 ℃, and the optimization is carried out
The chemical structural formula of the abamectin sodium is shown in the specification
Further, the organic solvent in step (1) and step (5) is one of methanol, ethanol, isopropanol, tetrahydrofuran and acetonitrile. Ethanol is preferred.
Further, the base in steps (1) and (3) is triethylamine, diisopropylamine, diisopropylethylamine, pyridine, lutidine or N-methylmorpholine. Pyridine or N-methylmorpholine are preferred.
Further, the alkaline hydrolysis reagent in the step (2) is sodium hydroxide, lithium hydroxide or potassium hydroxide. Lithium hydroxide is preferred.
Further, the extraction solvent in the step (3) is dichloromethane, trichloromethane, dichloroethane or diethyl ether. Preferably dichloromethane or trichloromethane; more preferably methylene chloride.
Further, the carboxylic acid activating reagent in the step (3) is methyl chloroformate, chloromethyl chloroformate, ethyl chloroformate, isobutyl chloroformate, tert-butyl chloroformate, n-butyl chloroformate or n-pentyl chloroformate. Preference is given to n-butyl chloroformate or n-pentyl chloroformate. More preferred is n-pentyl chloroformate.
Further, the crystallization solvent used in the step (3) is
The alkane or the mixed solvent of the above alkanes is preferably n-heptane.
Further, the catalyst in the step (4) is palladium carbon, palladium dichloride, palladium hydroxide carbon or palladium acetate. Palladium on carbon is preferred.
Further, the source of ammonium ions in step (4) is tetrabutylammonium hydroxide, tetrabutylammonium bromide or tetrabutylammonium acetate. Tetrabutylammonium acetate is preferred.
Further, in the step (5), the sodium source is C1-C10 sodium alkanoate. Sodium iso-octoate is preferred.
The invention is different from the prior art route, the invention uses (2S,5R) -benzyloxypiperidine-2-ethyl formate oxalate starting material, triphosgene organic solvent and alkali to perform cyclization, the starting material is hydrolyzed by alkaline hydrolysis reagent and then ammoniated, the product is directly crystallized in an organic phase to obtain a compound IV, and the compound IV is sulfonated by sulfur trioxide complex after hydrogenation reaction and salified with ammonium ion source to obtain the compound for preparing the avibactam sodium.
Compared with the prior art, the method has the advantages of cheap and easily obtained raw materials, avoidance of the use of expensive and easily decomposed protective reagent Fmoc-Cl and acylation reagent CDI, mild reaction conditions, simple operation and higher safety. The supported noble metal catalyst can be recycled by hydrogenation, the reaction conversion rate is high, the yield is high (the molar yield of the compound IV is 75-85%, the molar yield of the compound V is 80-85%, and the molar yield of the abamectin sodium is 90-95%), the product purity is good, and the method is suitable for large-scale industrial production.
Drawings
FIG. 1 is a test chart of substances of examples 1 to 3.
Detailed Description
For the purpose of promoting a clear understanding of the objects, aspects and advantages of the embodiments of the invention, reference will now be made in detail to the embodiments of the present disclosure, and it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the disclosure.
The exemplary embodiments of the present invention and the description thereof are provided to explain the present invention and not to limit the present invention.
Example 1: preparation of Compound IV
Adding 10g of compound I and 70mL of dichloromethane into a 500mL reaction bottle, adding 100mL of water and 5.7g of sodium bicarbonate, stirring for 30min, standing for layering, washing an aqueous phase with 35mL of dichloromethane, combining dichloromethane phases, drying by anhydrous sodium sulfate, performing suction filtration, washing, and performing vacuum distillation on an organic phase to obtain an oily substance. 120mL of tetrahydrofuran was added to the oil, and 10.2g of pyridine was added with stirring and the temperature was controlled
A solution of 5.8g of triphosgene in tetrahydrofuran (50ml) was added dropwise. And detecting by HPLC to obtain a solution of the compound II. And (3) heating to room temperature, dropwise adding a lithium hydroxide saturated solution, controlling the pH value of the feed liquid to be about 10, stirring for 1 hour, and detecting by HPLC (high performance liquid chromatography) to obtain a solution of a compound III. The reaction solution was made acidic with hydrochloric acid, and extracted with 100mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, washed, and 3.3g of N-methylmorpholine and 5.0g of n-pentyl chloroformate were added thereto under controlled temperature
And (3) dropwise adding 17mL of concentrated ammonia water, performing HPLC detection, adding 50mL of purified water after the reaction is finished, standing for layering, drying and filtering an organic layer by using anhydrous sodium sulfate, distilling under reduced pressure, dropwise adding 100mL of n-heptane at room temperature, growing crystals at 10 ℃ for 2h, filtering and drying to obtain a white-like solid, namely the compound IV.
The chemical structural formula of the compound I is
The chemical structural formula of the compound II is
The chemical structural formula of the compound III is
The chemical structural formula of the abamectin sodium is shown in the specification
Example 2: preparation of Compound V
Adding 10g of compound IV into a closed reactor, adding 5.7g of sulfur trioxide trimethylamine, 32g of isopropanol, 0.7g of triethylamine, 42mL of water and 0.3g of wet palladium-charcoal with the mass percentage of 10%, introducing hydrogen for reaction (40 ℃, 0.5MPa) after introducing nitrogen and discharging oxygen, releasing pressure and cooling after HPLC detection reaction is finished, taking out reaction liquid, and adjusting the pH value to be acidic by using acetic acid. Suction filtering, adding a solution of 14.5g tetrabutylammonium acetate, 0.2g acetic acid and 20mL water, stirring for 30min, adding 120mL dichloromethane, extracting, layering, drying the organic layer over anhydrous sodium sulfate, filtering, distilling under reduced pressure, adding 60mL methylThe presence of an isobutyl ketone in the reaction mixture,
cooling and growing crystal for 2h, filtering and drying to obtain white crystal.
Example 3: preparation of avibactam sodium
10g of the compound V is added into 60mL of absolute ethyl alcohol and stirred to be dissolved, the solution is heated to 35-40 ℃, and 60mL of absolute ethyl alcohol and 6.5g of sodium isooctanoate solution are added dropwise at the temperature of 35-40 ℃. After the dropwise addition is finished, solid is separated out and then the temperature is reduced to
Continuously stirring for growing the crystal for 2h, filtering and drying to obtain a white solid.
The content in the table refers to the content of effective components measured by using a reference substance with known content as an external standard, and the purity is related substance purity. The data in the table show that the avibactam sodium produced by the method has high reaction conversion rate, high yield, good product purity and high content. As shown in figure 1, the avibactam sodium produced by the method of the embodiment has good quality and high purity.
Claims (10)
1. The preparation method of the abamectin sodium is characterized by comprising the following steps of:
(1) adding triphosgene into the compound I in the presence of an organic solvent and a base at a temperature of-
Stirring and reacting under the condition (1) until the reaction is finished to obtain a solution of a compound II; wherein the molar ratio of the compound I to the base is
The molar ratio of the compound I to the triphosgene is
The chemical structural formula of the compound I is
The chemical structural formula of the compound II is
(2) Directly adding the solution of the compound II obtained in the step (1) into an alkaline hydrolysis reagent at room temperature
Stirring the mixture to react to generate a solution of a compound III; wherein the molar ratio of the compound I to the alkaline hydrolysis reagent is
The chemical structural formula of the compound III is
(3) Adjusting the solution of the compound III in the step (2) to acidity, adding an extraction solvent to extract an organic phase, drying, adding concentrated ammonia water in the presence of alkali and a carboxylic acid activating reagent, and reacting at the temperature of-
Stirring and reacting under the condition of (1) until the reaction is finished, standing and layering, distilling an organic phase under reduced pressure, and dropwise adding a crystallization solvent to separate out a white solid, namely a compound IV; whereinThe molar ratio of the compound I to the carboxylic acid activating reagent is
The molar ratio of the compound I to the concentrated ammonia water is
The chemical structural formula of the compound IV is
(4) Hydrogenating the compound IV, sulfonating the compound IV with a sulfur trioxide complex, and salifying the compound IV with an ammonium ion source to obtain a compound V; wherein the mass ratio of the compound IV to the catalyst in the hydrogenation reaction is
The molar ratio of the compound IV to the sulfur trioxide complex is
The molar ratio of the compound IV to the ammonium ion source is
The hydrogenation reaction temperature is
The salt formation reaction temperature is
The chemical structural formula of the compound V is
(5) Reacting the compound V with a sodium source in an organic solvent to obtain a compound abamectin sodium; compound V and sodiumThe molar ratio of the sources is
The temperature of sodium source treatment is 10-50 ℃;
the chemical structural formula of the abamectin sodium is
2. The method for preparing avibactam sodium according to claim 1, wherein the organic solvent in step (1) and step (5) is one of methanol, ethanol, isopropanol, tetrahydrofuran, and acetonitrile.
3. The method for preparing avibactam sodium according to claim 1, characterized in that the base in steps (1) and (3) is triethylamine, diisopropylamine, diisopropylethylamine, pyridine, lutidine or N-methylmorpholine.
4. The method for preparing avibactam sodium according to claim 1, characterized in that the alkaline hydrolysis reagent in step (2) is sodium hydroxide, lithium hydroxide or potassium hydroxide.
5. The method for preparing avibactam sodium according to claim 1, wherein the extraction solvent in step (3) is dichloromethane, trichloromethane, dichloroethane or diethyl ether.
6. The method according to claim 1, wherein the carboxylic acid activating reagent in step (3) is methyl chloroformate, chloromethyl chloroformate, ethyl chloroformate, isobutyl chloroformate, tert-butyl chloroformate, n-butyl chloroformate, or n-pentyl chloroformate.
7. The method for preparing avibactam sodium according to claim 1, wherein the crystallization solvent in step (3)The agent is
Or of alkyl or
A mixed solvent of several alkanes.
8. The method for preparing avibactam sodium according to claim 1, characterized in that the catalyst in step (4) is palladium carbon, palladium dichloride, palladium hydroxide carbon or palladium acetate.
9. The method for preparing abamectin sodium according to claim 1, wherein the source of ammonium ions in step (4) is tetrabutylammonium hydroxide, tetrabutylammonium bromide or tetrabutylammonium acetate.
10. The method for preparing abamectin sodium according to claim 1, characterized in that the sodium source in step (5) is sodium alkanoate of C1-C10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210786082.1A CN114989169A (en) | 2022-07-04 | 2022-07-04 | Preparation method of avibactam sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210786082.1A CN114989169A (en) | 2022-07-04 | 2022-07-04 | Preparation method of avibactam sodium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114989169A true CN114989169A (en) | 2022-09-02 |
Family
ID=83019692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210786082.1A Pending CN114989169A (en) | 2022-07-04 | 2022-07-04 | Preparation method of avibactam sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114989169A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100197928A1 (en) * | 2007-09-14 | 2010-08-05 | Novexel | Method for preparing disubstituted piperidine and intermediates |
| CN106866668A (en) * | 2017-01-23 | 2017-06-20 | 齐鲁天和惠世制药有限公司 | The method that one kettle way prepares AVM hereinafter Batan sodium |
| CN114685499A (en) * | 2020-12-29 | 2022-07-01 | 北京济美堂医药研究有限公司 | Preparation method of avibactam sodium |
-
2022
- 2022-07-04 CN CN202210786082.1A patent/CN114989169A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100197928A1 (en) * | 2007-09-14 | 2010-08-05 | Novexel | Method for preparing disubstituted piperidine and intermediates |
| CN106866668A (en) * | 2017-01-23 | 2017-06-20 | 齐鲁天和惠世制药有限公司 | The method that one kettle way prepares AVM hereinafter Batan sodium |
| CN114685499A (en) * | 2020-12-29 | 2022-07-01 | 北京济美堂医药研究有限公司 | Preparation method of avibactam sodium |
Non-Patent Citations (1)
| Title |
|---|
| 张睿: "新型β-内酰胺酶抑制剂阿维巴坦钠的合成工艺优化", 《中国优秀硕士学位论文全文数据库》, no. 03, pages 016 - 2083 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NZ566460A (en) | An improved process for the preparation of beta-lactam antibiotic | |
| NO140931B (en) | ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE ESTERS OF ALFA-AMINOBENZYLPENICILLINES | |
| CN108069998B (en) | Synthetic method of penem drug intermediate | |
| EP2401278A1 (en) | An improved process for the preparation of carbapenem antibiotic | |
| CN109485658B (en) | Preparation method of ceftezole acid | |
| US3316247A (en) | Process for the preparation of penicillins | |
| EP2892903A1 (en) | Process for the preparation of tazobactam | |
| CN114989169A (en) | Preparation method of avibactam sodium | |
| KR20020068518A (en) | Penicillin crystal and process for producing the same | |
| CN110128449A (en) | 7- phenylacetyl amido -3- desacetoxycephalosporanic acid salt and its preparation method and application | |
| CN101456869A (en) | Synthetic method of nafcillin sodium | |
| CN113025679B (en) | Enzymatic preparation process of cefcapene precursor acid of t-butyloxycarbonyl | |
| CN108299470B (en) | Preparation method of cefteram pivoxil | |
| CN101550089B (en) | Preparation method of L--dihydrophenyl glycine sodium salt | |
| CN115073458A (en) | Preparation method of avibactam sodium | |
| CN113387960A (en) | Refining method of latamoxef sodium intermediate | |
| EP0871632B1 (en) | Production of a crystalline salt of amoxicillin | |
| CN114685499A (en) | Preparation method of avibactam sodium | |
| CN108586517B (en) | Synthetic method of carbapenem antibiotic drug intermediate | |
| CN112358489A (en) | Production method of industrial penicillin sulfoxide product | |
| CN101508679A (en) | Synthesis of D(-)-alpha-(4-ethyl-2,3-dioxygen ethylene imine-1-formamido) p-hydroxybenzene acetic acid | |
| CN113929684B (en) | Meropenem intermediate and preparation method thereof | |
| CN110015969A (en) | A kind of synthetic method of Linezolid impurity | |
| CN103450182B (en) | Preparation and purification methods of Retapamulin | |
| CN110241167B (en) | Method for preparing cefamandole nafate derivative by enzyme method |
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 |