CN113214186A - Refining method of cefdinir active ester - Google Patents
Refining method of cefdinir active ester Download PDFInfo
- Publication number
- CN113214186A CN113214186A CN202110542143.5A CN202110542143A CN113214186A CN 113214186 A CN113214186 A CN 113214186A CN 202110542143 A CN202110542143 A CN 202110542143A CN 113214186 A CN113214186 A CN 113214186A
- Authority
- CN
- China
- Prior art keywords
- active ester
- cefdinir
- cefdinir active
- stirring
- refining
- 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
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 title claims abstract description 56
- 229960003719 cefdinir Drugs 0.000 title claims abstract description 55
- 150000002148 esters Chemical class 0.000 title claims abstract description 54
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000007670 refining Methods 0.000 title claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 24
- 238000003756 stirring Methods 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000001816 cooling Methods 0.000 claims abstract description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012044 organic layer Substances 0.000 claims abstract description 10
- 239000008213 purified water Substances 0.000 claims abstract description 10
- 238000000967 suction filtration Methods 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000706 filtrate Substances 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- 238000004537 pulping Methods 0.000 claims description 7
- KVKDHRUVQQPKCW-HYARGMPZSA-N tert-butyl 2-[(e)-[1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino]oxyacetate Chemical compound N=1C2=CC=CC=C2SC=1SC(=O)/C(=N/OCC(=O)OC(C)(C)C)C1=CSC(N)=N1 KVKDHRUVQQPKCW-HYARGMPZSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 11
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000006872 improvement Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229940124588 oral cephalosporin Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- IWGDHEBGOWLLFP-YHYXMXQVSA-N (2Z)-2-acetyloxyimino-2-(2-amino-1,3-thiazol-4-yl)ethanethioic S-acid Chemical group CC(=O)O\N=C(/C(O)=S)C1=CSC(N)=N1 IWGDHEBGOWLLFP-YHYXMXQVSA-N 0.000 description 1
- -1 (Z) -2- (2-aminothiazole-4-yl) -2-trityloxyiminoacetic acid (2-mercaptobenzothiazole) Chemical group 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- AFZSMODLJJCVPP-UHFFFAOYSA-N dibenzothiazol-2-yl disulfide Chemical compound C1=CC=C2SC(SSC=3SC4=CC=CC=C4N=3)=NC2=C1 AFZSMODLJJCVPP-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/70—Sulfur atoms
- C07D277/74—Sulfur atoms substituted by carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention provides a method for refining cefdinir active ester, which comprises the following steps: adding a solvent into the unqualified cefdinir active ester, heating, and stirring for dissolving; adding active carbon for decoloring and filtering; cooling the filtrate to room temperature, adding a solvent, and stirring at room temperature; adding purified water, stirring for 0.5 hour, standing and layering; and cooling and crystallizing the organic layer, and performing suction filtration to obtain a pure cefdinir active ester product. The method has the advantages of simple process, convenient operation, effective improvement of the purity of the cefdinir active ester, capability of meeting the market demand, high yield, low cost and suitability for industrial production, and the total impurities of the refined cefdinir active ester are below 0.5 percent and the maximum single impurity is below 0.2 percent.
Description
Technical Field
The invention belongs to the field of preparation of medical intermediates, and particularly relates to a method for refining cefdinir active ester.
Background
Cefdinir (cefdinir), a third-generation oral cephalosporin developed by Japan Tengze pharmaceutical industry Co., Ltd, is obtained by carrying out structural modification on cefixime, maintains high stability to beta-lactamase, improves the action on gram-positive bacteria, improves the pharmacokinetic property, has the characteristics of strong bactericidal power, wide antibacterial spectrum, high curative effect, low toxicity and the like, is widely applied clinically, and is an excellent oral cephalosporin medicament variety.
The cefdinir active ester is a key intermediate for synthesizing cefdinir. At present, the cefdinir active ester on the market has 2 kinds, the 1 st kind is that oxime hydroxyl is protected by trityl, the chemical name is (Z) -2- (2-aminothiazole-4-yl) -2-trityloxyiminoacetic acid (2-mercaptobenzothiazole), BAEM for short; the 2 nd is oxime hydroxy protected by acetyl, and the chemical name is (Z) -2- (2-aminothiazole-4-yl) -2-acetoxyiminothioacetic acid (S-2-benzothiazole) ester, which is called CAEM for short.
In recent years, the requirements of the market and the country on the quality of raw material medicines and medicines are increasingly increased, and the requirement of the market on the purity of cefdinir active ester is also increasingly high. Because the cefdinir active ester has poor solubility in most solvents, the degradation impurities generated in the production process and brought in the storage and transportation processes are difficult to remove, the quality of the cefdinir active ester is directly influenced, and the quality and the cost of the cefdinir medicament are further influenced.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for refining cefdinir active ester. The method has the advantages of simple process, convenient operation, high yield and low cost, can effectively improve the purity of the cefdinir active ester, optimizes the product quality, and is suitable for industrial production.
In order to solve the technical problems, the invention adopts the following technical scheme:
the refining method of cefdinir active ester comprises the following steps:
(1) adding a solvent into the unqualified cefdinir active ester, heating, and stirring for dissolving;
(2) adding active carbon for decoloring and filtering;
(3) cooling the filtrate to room temperature, adding a solvent, and stirring at room temperature;
(4) adding purified water, stirring for 0.5 hour, standing and layering;
(5) and cooling and crystallizing the organic layer, and performing suction filtration to obtain a pure cefdinir active ester product.
Further, the cefdinir active ester comprises two active esters, i.e. BAEM and CAEM.
Further, the solvent in the step (1) is N, N-Dimethylformamide (DMF), and the mass usage of the solvent is 2-5 times of the mass usage of unqualified cefdinir active ester.
Further, the temperature in the step (1) is raised to 40-50 ℃.
Further, the solvent in the step (3) is dichloromethane, and the mass usage amount of the solvent is 5-10 times of that of unqualified cefdinir active ester.
Further, the stirring time at room temperature in the step (3) is 0.5-1 hour.
Further, the mass usage amount of the purified water in the step (4) is 5-15 times of the mass usage amount of unqualified cefdinir active ester.
Further, the crystallization process in the step (5) comprises the steps of cooling the organic layer to 0-5 ℃, preserving heat, stirring for 1-1.5 hours, carrying out suction filtration to obtain a wet product, and pulping the wet product with methanol to obtain a pure cefdinir active ester product.
In conclusion, the invention has the following beneficial effects:
the invention provides a method for refining cefdinir active ester, which has the advantages of simple process, convenient operation, effective improvement of the purity of the cefdinir active ester, capability of meeting the market demand, high yield, low cost and suitability for industrial production, and the total impurities of the refined cefdinir active ester are below 0.5 percent and the maximum single impurity is below 0.2 percent.
Detailed Description
The present invention will be described in further detail with reference to examples.
The unqualified cefdinir active ester is an unqualified product containing single impurities and side reaction products, trans-form or precursor cefdinir side chain acid, 2-mercaptobenzothiazole (M) and 2,2' -Dithiodibenzothiazole (DM).
Example 1
100g of DMF (dimethyl formamide) is added into a reaction bottle containing 40g of unqualified cefdinir active ester (with the purity of 98.19 percent), the temperature is raised to 45 ℃, and the mixture is stirred and dissolved. After dissolving, adding 2g of activated carbon, decoloring for 30 minutes, and filtering; after the filtrate was cooled to room temperature, 280g of methylene chloride was added thereto, and the mixture was stirred at room temperature for 0.5 hour. Adding purified water 400g, stirring for 0.5 hr, standing, and layering. And cooling the organic layer to 0-5 ℃, preserving heat, stirring for 1.5 hours, performing suction filtration to obtain a wet product, pulping the wet product by using methanol, and drying to obtain 37.2g of a pure cefdinir active ester product with the purity of 99.75% and the maximum single impurity content of 0.06%.
Example 2
160g of DMF (dimethyl formamide) is added into a reaction bottle containing 40g of unqualified cefdinir active ester (with the purity of 97.24 percent), the temperature is raised to 40 ℃, and the mixture is stirred and dissolved. After dissolving, adding 2g of activated carbon, decoloring for 30 minutes, and filtering; after the filtrate was cooled to room temperature, 360g of methylene chloride was added thereto, and the mixture was stirred at room temperature for 0.5 hour. Adding 500g of purified water, stirring for 0.5 hour, standing and demixing. And cooling the organic layer to 0-5 ℃, keeping the temperature and stirring for 1.5 hours, performing suction filtration to obtain a wet product, pulping the wet product by using methanol, and drying to obtain 36.8g of a pure cefdinir active ester product with the purity of 99.68% and the maximum single impurity content of 0.11%.
Example 3
200g of DMF was added to a reaction flask containing 40g (purity: 96.26%) of unqualified cefdinir active ester, and the mixture was heated to 45 ℃ and dissolved by stirring. After dissolving, adding 3g of active carbon, decoloring for 30 minutes, and filtering; after the filtrate was cooled to room temperature, 400g of methylene chloride was added thereto, and the mixture was stirred at room temperature for 1 hour. 600g of purified water was added thereto, and the mixture was stirred for 0.5 hour, allowed to stand, and then the layers were separated. And cooling the organic layer to 0-5 ℃, keeping the temperature and stirring for 1.5 hours, performing suction filtration to obtain a wet product, pulping the wet product by using methanol, and drying to obtain 35.6g of a pure cefdinir active ester product with the purity of 99.63 percent and the maximum single impurity content of 0.10 percent.
Example 4
120g of DMF was added to a reaction flask containing 40g of unqualified cefdinir active ester (purity 95.87%), the temperature was raised to 50 ℃ and the mixture was dissolved by stirring. After dissolving, adding 3g of active carbon, decoloring for 30 minutes, and filtering; after the filtrate was cooled to room temperature, 350g of methylene chloride was added thereto, and the mixture was stirred at room temperature for 1 hour. Adding 500g of purified water, stirring for 0.5 hour, standing and demixing. And cooling the organic layer to 0-5 ℃, preserving heat, stirring for 1.5 hours, performing suction filtration to obtain a wet product, pulping the wet product by using methanol, and drying to obtain 36.5g of a pure cefdinir active ester product with the purity of 99.70% and the maximum single impurity content of 0.09%.
Example 5
80g of DMF (dimethyl formamide) is added into a reaction bottle containing 40g of unqualified cefdinir active ester (with the purity of 98.07 percent), the temperature is raised to 50 ℃, and the mixture is stirred and dissolved. After dissolving, adding 2g of activated carbon, decoloring for 30 minutes, and filtering; after the filtrate was cooled to room temperature, 250g of methylene chloride was added thereto, and the mixture was stirred at room temperature for 1 hour. Adding purified water 400g, stirring for 0.5 hr, standing, and layering. And cooling the organic layer to 0-5 ℃, preserving heat, stirring for 1 hour, performing suction filtration to obtain a wet product, pulping the wet product by using methanol, and drying to obtain 37.8g of the pure cefdinir active ester, wherein the purity is 99.72%, and the maximum single impurity content is 0.08%.
The present embodiment is only for explaining the present invention, and it is not limited to the present invention, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present invention.
Claims (8)
1. The method for refining cefdinir active ester is characterized by comprising the following steps:
(1) adding a solvent into the unqualified cefdinir active ester, heating, and stirring for dissolving;
(2) adding active carbon for decoloring and filtering;
(3) cooling the filtrate to room temperature, adding a solvent, and stirring at room temperature;
(4) adding purified water, stirring for 0.5 hour, standing and layering;
(5) and cooling and crystallizing the organic layer, and performing suction filtration to obtain a pure cefdinir active ester product.
2. The method of claim 1, wherein the cefdinir active ester comprises BAEM and CAEM active esters.
3. The method for refining cefdinir active ester according to claim 1, wherein the solvent in step (1) is N, N-Dimethylformamide (DMF), and the mass amount of the solvent is 2-5 times of the mass amount of unqualified cefdinir active ester.
4. The method for refining cefdinir active ester according to claim 1, wherein the temperature in step (1) is raised to 40-50 ℃.
5. The method for refining cefdinir active ester according to claim 1, wherein the solvent in step (3) is dichloromethane, and the mass amount of the solvent is 5-10 times of the mass amount of unqualified cefdinir active ester.
6. The method for refining cefdinir active ester according to claim 1, wherein the stirring time at room temperature in step (3) is 0.5 to 1 hour.
7. The method for refining cefdinir active ester according to claim 1, wherein the mass amount of the purified water in the step (4) is 5-15 times of the mass amount of unqualified cefdinir active ester.
8. The refining method of cefdinir active ester according to claim 1, wherein the crystallization process in the step (5) comprises cooling the organic layer to 0-5 ℃, stirring for 1-1.5 hours under heat preservation, performing suction filtration to obtain a wet product, and pulping the wet product with methanol to obtain a pure cefdinir active ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110542143.5A CN113214186A (en) | 2021-05-18 | 2021-05-18 | Refining method of cefdinir active ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110542143.5A CN113214186A (en) | 2021-05-18 | 2021-05-18 | Refining method of cefdinir active ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113214186A true CN113214186A (en) | 2021-08-06 |
Family
ID=77092772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110542143.5A Pending CN113214186A (en) | 2021-05-18 | 2021-05-18 | Refining method of cefdinir active ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113214186A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060025586A1 (en) * | 2002-08-13 | 2006-02-02 | Peter Kremminger | Cefdinir intermediate |
| US20080287673A1 (en) * | 2005-06-15 | 2008-11-20 | Parthasaradhi Reddy Bandk | Cefdinir process |
| CN102977089A (en) * | 2012-12-06 | 2013-03-20 | 山东优胜美特医药有限公司 | Method for preparing high-purity cefdinir antibiotic 7-side chain synthesis critical material |
| CN110330466A (en) * | 2019-07-25 | 2019-10-15 | 山东金城医药化工有限公司 | The method of curing di-mercaptobenzothiazolby is recycled from cephalo active ester production mother liquor |
| CN112661723A (en) * | 2020-12-28 | 2021-04-16 | 山东金城柯瑞化学有限公司 | Method for producing cefdinir active ester |
-
2021
- 2021-05-18 CN CN202110542143.5A patent/CN113214186A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060025586A1 (en) * | 2002-08-13 | 2006-02-02 | Peter Kremminger | Cefdinir intermediate |
| US20080287673A1 (en) * | 2005-06-15 | 2008-11-20 | Parthasaradhi Reddy Bandk | Cefdinir process |
| CN102977089A (en) * | 2012-12-06 | 2013-03-20 | 山东优胜美特医药有限公司 | Method for preparing high-purity cefdinir antibiotic 7-side chain synthesis critical material |
| CN110330466A (en) * | 2019-07-25 | 2019-10-15 | 山东金城医药化工有限公司 | The method of curing di-mercaptobenzothiazolby is recycled from cephalo active ester production mother liquor |
| CN112661723A (en) * | 2020-12-28 | 2021-04-16 | 山东金城柯瑞化学有限公司 | Method for producing cefdinir active ester |
Non-Patent Citations (2)
| Title |
|---|
| DEFOSSA, ELISABETH等: ""Synthesis of HR 916 K. An efficient route to the pure diastereomers of the 1-(pivaloyloxy)ethyl esters of cephalosporins"", 《LIEBIGS ANNALEN》 * |
| 张静等: ""活性硫酯法制备头孢地尼新工艺"", 《中国抗生素杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101486719A (en) | Method for converting cefotaxime acid into sodium salt crystal | |
| CN107216289B (en) | Preparation method of edaravone | |
| CN101941969A (en) | Preparation method of moxifloxacin hydrochloride | |
| CN104513256A (en) | Preparation method of cefditoren pivoxil | |
| CN103288853A (en) | Novel preparation technology of cefotiam hexetil hydrochloride | |
| SK14672001A3 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
| CN113214186A (en) | Refining method of cefdinir active ester | |
| CN111004293B (en) | Purification method of clindamycin phosphate | |
| CN101863904A (en) | Preparation method of high-purity Levofloxacin semihydrate | |
| NO151748B (en) | PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL ACCEPTABLE, NON-SOLVATED, WATER-FREE, GAMMA CRYSTALLINIC FORM OF SODRIM-7- (D-ALFA-FORMYLOXY-ALFA-PHENYLACETAMIDO) -3- (1-METHYL-METHYL-YL-METHYL-H-METHYL-YL-METHYL-1-METHYL-METHYL-METHYL) 3-cephem-4-carboxylate | |
| CN108690050B (en) | A kind of purification process of sulbactam | |
| CN104031043A (en) | Novel synthesis method of moxifloxacin hydrochloride | |
| CN114213260B (en) | Preparation method of prionamine iodide | |
| CN104447758A (en) | Synthesis process of pyrazolo[3,4-d]pyrimidine compounds | |
| CN103755726A (en) | Cefalonium refinement purification method | |
| CN113387960A (en) | Refining method of latamoxef sodium intermediate | |
| KR101485418B1 (en) | A synthetic method of high purity mirtazapine | |
| CN108840877B (en) | Preparation method of oxygen cephalosporin intermediate | |
| CN112745246A (en) | Purification method of shakubiqu intermediate | |
| CN106187864A (en) | A kind of method being prepared high-purity bupivacaine alkali by bupivacaine hydrochloride | |
| CN114195761B (en) | Preparation method of high-purity sitafloxacin hydrate 3/2 | |
| CN108586517B (en) | Synthetic method of carbapenem antibiotic drug intermediate | |
| CN115536658B (en) | Preparation method of moxifloxacin hydrochloride monohydrate | |
| KR100781821B1 (en) | Process for preparing carbapenem compound | |
| CN102977102A (en) | Preparation method of meropenem trihydrate crystal |
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: 20210806 |
|
| RJ01 | Rejection of invention patent application after publication |