CN112961156A - Preparation process of antibiotic drug panipenem - Google Patents
Preparation process of antibiotic drug panipenem Download PDFInfo
- Publication number
- CN112961156A CN112961156A CN202110165379.1A CN202110165379A CN112961156A CN 112961156 A CN112961156 A CN 112961156A CN 202110165379 A CN202110165379 A CN 202110165379A CN 112961156 A CN112961156 A CN 112961156A
- Authority
- CN
- China
- Prior art keywords
- panipenem
- product
- reaction
- acid
- antibiotic drug
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/04—Preparation by forming the ring or condensed ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation process of an antibiotic drug panipenem, which adopts a unique synthetic method to prepare. The invention solves the problems of expensive raw materials, long production process period, low yield, low purity and the like in the preparation of the conventional antibiotic drug panipenem. The invention provides a preparation process with high efficiency, high yield, high purity, short period and low production cost for the synthesis of panipenem.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation process of an antibiotic drug panipenem.
Background
Panipenem (Panipenem, 1), chemically (5R, 6S) -2- [ (3S) -1- (acetyliminopyrrolidin-3-yl) thio ] -6[ (1R) -1-hydroxyethyl ] -2-carbapenem-3-carboxylic acid, is a carbapenem antibiotic developed by the japan triple co-company, first marketed in japan in 1993 [ ]. The betamipron inhibitor is clinically used in an equivalent way with an organic cation delivery system inhibitor, has strong antibacterial activity on gram-positive bacteria, gram-negative bacteria, aerobic bacteria and anaerobic bacteria, and has low adverse reaction incidence and good organism tolerance. The traditional Chinese medicine composition is clinically used for septicemia, osteomyelitis, lung infection, empyema, biliary tract infection, abdominal cavity infection, meningitis and the like caused by sensitive bacteria, has the effective rate of over 80 percent on penicillin, cephalosporin and aminoglycoside treatment ineffective patients, and has definite curative effect on bacterial infection of severe lower respiratory tract, urinary tract, abdominal cavity and other parts.
The synthesis method of panipenem comprises the following steps: both USP4552873 and EPO161546 describe the condensation docking of a parent nucleus of panipenem with its imidized side chain, followed by deprotection to afford panipenem, with the following disadvantages: the imidization yield is low, the side reaction is more, the yield of panipenem is low, and the production cost is high; tesuo, m.; yulio, s.; toshihiko, h.; et al.Systhesis and in vitro activity of new carbapenem RS-533[ J ]. The Journal of Antibiotics, 1983, 36 (8): 1034-1039, it is described that Shinichi's topic group synthesizes panipenem mother nucleus and its non-imidized side chain by using 4-acetoxy-3- [1- (tert-butyldimethylsilyloxy) ethyl ] azetidinone as starting material, then obtains panipenem through deprotection and imidization, the method has less reaction steps in synthesizing panipenem mother nucleus, but the total yield is only about 24.5%, and needs special reagents such as butyl lithium and diethylaluminum chloride, etc., the reaction anhydrous condition is higher, the reaction temperature is-60 ℃, and it can be reached in liquid nitrogen or dry ice, the production cost is high, and it is not suitable for industrial production.
The other method is that a phosphorylated mother nucleus II reacts with an imine ethylated side chain V to generate panipenem VI with double protecting groups (also called double-protection panipenem or a double-protection intermediate), and then panipenem is obtained by catalytic hydrogenation reduction. Wherein R in USRE34960 and EP0161546 is benzyl or substituted benzyl; CN200710041209 discloses a method for replacing a protecting group R with allyl or substituted allyl. When R is allyl or substituted allyl, most intermediates are oily substances, which brings difficulty to separation and purification; when R is benzyl or substituted benzyl, the solubility of the double-protection Intermediate (IV) in a solvent system (acetonitrile, dichloromethane, ethyl acetate, trichloromethane, tetrahydrofuran and acetone) reported by the patent is poor, slurry is often formed in a reaction system, and separation and purification are difficult; meanwhile, the poor solubility of the intermediate ensures that the intermediate can be dissolved only by heating to more than 40 ℃ in the subsequent hydrogenation process, so that the decomposition rate of the product generated in the system is greatly increased, and the yield and the quality of the product are reduced.
Disclosure of Invention
Aiming at the defects in the prior art, the invention solves the problems of expensive raw materials, long production process period, low yield, low purity and the like in the preparation of the existing antibiotic drug panipenem. The invention provides a preparation process with high efficiency, high yield, high purity, short period and low production cost for the synthesis of panipenem.
The invention provides the following technical scheme, a preparation process of an antibiotic drug panipenem, which comprises the following specific reaction steps:
s1, adding 2-diazo-acetoacetic acid p-nitrobenzyl ester, sodium iodide, toluene, triethylamine and hexamethyldisilazane into a reaction bottle, heating to 40-50 ℃, and stirring; diluting with toluene, concentrating at 45 deg.C under reduced pressure, and cooling to below 10 deg.C; filtering, adding azacyclo-ketone and anhydrous zinc bromide into the filtrate under the protection of nitrogen, after complete reaction, concentrating under reduced pressure, adding methanol and methanesulfonic acid, stirring, filtering, washing a filter cake with toluene and acetone in sequence, and drying under reduced pressure to obtain a product;
s2, adding the product obtained in the step S1 and ethanol into a reaction bottle, dropwise adding p-toluenesulfonic acid, reacting completely, concentrating under reduced pressure, and recrystallizing with ethyl acetate to obtain a product;
s3: adding the product obtained in the step S2 and diphenoxy phosphoryl chloride into a reaction bottle, cooling, dropwise adding diisopropylethylamine under the protection of nitrogen, and reacting for 30min at the temperature; adding diphenoxy phosphoryl chloride and (3S) -3-acetylthio-1-p-nitrobenzyloxycarbonyl pyrrolidine, reacting for 40-60 min after the dropwise addition is finished, monitoring by TLC to complete the reaction, filtering the precipitated solid, and washing with ethyl acetate to obtain a product;
s4, dissolving the product obtained in the step S3 in a phosphoric acid buffer solution, adjusting the pH value to 8.5 by using sodium bicarbonate, adding ethylidene acid ethyl ester hydrochloride, stirring at room temperature, eluting a reaction solution by using an aqueous solution containing acetone, collecting an effluent containing panipenem, freezing and drying to obtain white solid powder, and recrystallizing the obtained crude product by using water-ethanol to obtain white crystalline powder.
In order to further supplement the technical scheme, in the step S1, the mass ratio of the 2-diazoacetoacetic acid p-nitrobenzyl ester to the hexamethyldisilazane is 4: 1-6: 1; the molar ratio of the azacyclic ketone to the hexamethyldisilazane is 1.5:1 to 2: 1.
In order to further supplement the technical scheme, in the step S2, the mass ratio of ethanol to p-toluenesulfonic acid is 5: 1-7: 1, and the molar ratio of the product in the step S1 to p-toluenesulfonic acid is 1.2: 1-2: 1.
In order to further supplement the technical scheme, in the step S3, the mass ratio of diisopropylethylamine to the product in the step S2 is 6: 1-8: 1; the molar ratio of the diisopropylethylamine to the diphenoxyphosphoryl chloride is 1.25: 1-1.4: 1.
Has the advantages that: the invention solves the problems of expensive raw materials, long production process period, low yield, low purity and the like in the preparation of the conventional antibiotic drug panipenem. The invention provides a preparation process with high efficiency, high yield, high purity, short period and low production cost for the synthesis of panipenem.
Detailed Description
The invention is described in detail below, and a preparation process of an antibiotic drug panipenem comprises the following specific reaction steps:
a preparation process of an antibiotic drug panipenem comprises the following specific reaction steps:
s1, adding 2-diazo-acetoacetic acid p-nitrobenzyl ester, sodium iodide, toluene, triethylamine and hexamethyldisilazane into a reaction bottle, heating to 40-50 ℃, and stirring; diluting with toluene, concentrating at 45 deg.C under reduced pressure, and cooling to below 10 deg.C; filtering, adding azacyclo-ketone and anhydrous zinc bromide into the filtrate under the protection of nitrogen, after complete reaction, concentrating under reduced pressure, adding methanol and methanesulfonic acid, stirring, filtering, washing a filter cake with toluene and acetone in sequence, and drying under reduced pressure to obtain a product;
s2, adding the product obtained in the step S1 and ethanol into a reaction bottle, dropwise adding p-toluenesulfonic acid, reacting completely, concentrating under reduced pressure, and recrystallizing with ethyl acetate to obtain a product;
s3: adding the product obtained in the step S2 and diphenoxy phosphoryl chloride into a reaction bottle, cooling, dropwise adding diisopropylethylamine under the protection of nitrogen, and reacting for 30min at the temperature; adding diphenoxy phosphoryl chloride and (3S) -3-acetylthio-1-p-nitrobenzyloxycarbonyl pyrrolidine, reacting for 40-60 min after the dropwise addition is finished, monitoring by TLC to complete the reaction, filtering the precipitated solid, and washing with ethyl acetate to obtain a product;
s4, dissolving the product obtained in the step S3 in a phosphoric acid buffer solution, adjusting the pH value to 8.5 by using sodium bicarbonate, adding ethylidene acid ethyl ester hydrochloride, stirring at room temperature, eluting a reaction solution by using an aqueous solution containing acetone, collecting an effluent containing panipenem, freezing and drying to obtain white solid powder, and recrystallizing the obtained crude product by using water-ethanol to obtain white crystalline powder.
In the step S1, the mass ratio of 2-diazoacetoacetic acid p-nitrobenzyl ester to hexamethyldisilazane is 4: 1-6: 1; the molar ratio of the azacyclic ketone to the hexamethyldisilazane is 1.5:1 to 2: 1.
In the step S2, the mass ratio of ethanol to p-toluenesulfonic acid is 5: 1-7: 1, and the molar ratio of the product in the step S1 to p-toluenesulfonic acid is 1.2: 1-2: 1.
In the step S3, the mass ratio of diisopropylethylamine to the product in the step S2 is 6: 1-8: 1; the molar ratio of the diisopropylethylamine to the diphenoxyphosphoryl chloride is 1.25: 1-1.4: 1.
Example 1
A preparation process of an antibiotic drug panipenem comprises the following specific reaction steps:
s1, adding 2-diazo-p-nitrobenzyl acetoacetate (0.33Kg, 3.4mol), sodium iodide, toluene, triethylamine and hexamethyldisilazane (0.2Kg, 2.8mol) into a reaction bottle, heating to 40-50 ℃ and stirring; diluting with toluene, concentrating at 45 deg.C under reduced pressure, and cooling to below 10 deg.C; filtering, adding azacyclo-ketone (250g, 2.1mol) and anhydrous zinc bromide into the filtrate under the protection of nitrogen, after complete reaction, concentrating under reduced pressure, adding methanol and methanesulfonic acid, stirring, filtering, washing a filter cake with toluene and acetone in sequence, and drying under reduced pressure to obtain a product; the yield is 85.3 percent, and the purity is 91.2 percent.
S2, adding the product (770g, 3.25mol) obtained in the S1 step and ethanol (550g, 3.03mol) into a reaction bottle, dropwise adding p-toluenesulfonic acid (770g, 1.8mol), reacting completely, concentrating under reduced pressure, and then recrystallizing with ethyl acetate to obtain the product; the yield was 79.6% and the purity was 90.7%.
S3: adding the product (880g, 3.25mol) in the S2 step and diphenoxy phosphoryl chloride (680g, 3.64mol) into a reaction bottle, cooling, dropwise adding diisopropylethylamine (540g, 3.25mol) under the protection of nitrogen, and reacting at the temperature for 30 min; adding diphenoxy phosphoryl chloride and (3S) -3-acetylthio-1-p-nitrobenzyloxycarbonyl pyrrolidine, reacting for 40-60 min after the dropwise addition is finished, monitoring by TLC to complete the reaction, filtering the precipitated solid, and washing with ethyl acetate to obtain a product; the yield was 82.8% and the purity was 93.6%.
S4, dissolving the product obtained in the step S3 in a phosphoric acid buffer solution, adjusting the pH value to 8.5 by using sodium bicarbonate, adding ethylidene acid ethyl ester hydrochloride, stirring at room temperature, eluting a reaction solution by using an aqueous solution containing acetone, collecting an effluent containing panipenem, freezing and drying to obtain white solid powder, and recrystallizing the obtained crude product by using water-ethanol to obtain white crystalline powder. The yield was 89.4% and the purity was 95.2%.
Example 2
A preparation process of an antibiotic drug panipenem comprises the following specific reaction steps:
s1, adding 2-diazo-p-nitrobenzyl acetoacetate (400g, 3.25mol), sodium iodide, toluene, triethylamine and hexamethyldisilazane (600g, 3.14mol) into a reaction bottle, heating to 40-50 ℃, and stirring; diluting with toluene, concentrating at 45 deg.C under reduced pressure, and cooling to below 10 deg.C; filtering, adding azacyclo-ketone (550g, 2.5mol) and anhydrous zinc bromide into the filtrate under the protection of nitrogen, after complete reaction, concentrating under reduced pressure, adding methanol and methanesulfonic acid, stirring, filtering, washing a filter cake with toluene and acetone in sequence, and drying under reduced pressure to obtain a product; the yield was 87.4% and the purity was 89.2%.
S2, adding the product (600g, 1.95mol) obtained in the S1 step and ethanol (415g, 2.85mol) into a reaction bottle, dropwise adding p-toluenesulfonic acid (580g, 3.25mol), completely reacting, concentrating under reduced pressure, and then recrystallizing with ethyl acetate to obtain the product; the yield was 88.5% and the purity was 91.2%.
S3: adding the product (412.5g, 2.625mol) in the S2 step and diphenoxy phosphoryl chloride (770g, 3.4mol) into a reaction bottle, cooling, dropwise adding diisopropylethylamine (550g, 3.03mol) under the protection of nitrogen, and reacting at the temperature for 30 min; adding diphenoxy phosphoryl chloride and (3S) -3-acetylthio-1-p-nitrobenzyloxycarbonyl pyrrolidine, reacting for 40-60 min after the dropwise addition is finished, monitoring by TLC to complete the reaction, filtering the precipitated solid, and washing with ethyl acetate to obtain a product; the yield was 84.8%, and the purity was 91.2%.
S4, dissolving the product obtained in the step S3 in a phosphoric acid buffer solution, adjusting the pH value to 8.5 by using sodium bicarbonate, adding ethylidene acid ethyl ester hydrochloride, stirring at room temperature, eluting a reaction solution by using an aqueous solution containing acetone, collecting an effluent containing panipenem, freezing and drying to obtain white solid powder, and recrystallizing the obtained crude product by using water-ethanol to obtain white crystalline powder. The yield was 88.9%, and the purity was 97.4%.
Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the invention as defined by the appended claims. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. A preparation process of an antibiotic drug panipenem is characterized by comprising the following steps: the specific reaction steps are as follows:
s1, adding 2-diazo-acetoacetic acid p-nitrobenzyl ester, sodium iodide, toluene, triethylamine and hexamethyldisilazane into a reaction bottle, heating to 40-50 ℃, and stirring; diluting with toluene, concentrating at 45 deg.C under reduced pressure, and cooling to below 10 deg.C; filtering, adding azacyclo-ketone and anhydrous zinc bromide into the filtrate under the protection of nitrogen, after complete reaction, concentrating under reduced pressure, adding methanol and methanesulfonic acid, stirring, filtering, washing a filter cake with toluene and acetone in sequence, and drying under reduced pressure to obtain a product;
s2, adding the product obtained in the step S1 and ethanol into a reaction bottle, dropwise adding p-toluenesulfonic acid, reacting completely, concentrating under reduced pressure, and recrystallizing with ethyl acetate to obtain a product;
s3: adding the product obtained in the step S2 and diphenoxy phosphoryl chloride into a reaction bottle, cooling, dropwise adding diisopropylethylamine under the protection of nitrogen, and reacting for 30min at the temperature; adding diphenoxy phosphoryl chloride and (3S) -3-acetylthio-1-p-nitrobenzyloxycarbonyl pyrrolidine, reacting for 40-60 min after the dropwise addition is finished, monitoring by TLC to complete the reaction, filtering the precipitated solid, and washing with ethyl acetate to obtain a product;
s4, dissolving the product obtained in the step S3 in a phosphoric acid buffer solution, adjusting the pH value to 8.5 by using sodium bicarbonate, adding ethylidene acid ethyl ester hydrochloride, stirring at room temperature, eluting a reaction solution by using an aqueous solution containing acetone, collecting an effluent containing panipenem, freezing and drying to obtain white solid powder, and recrystallizing the obtained crude product by using water-ethanol to obtain white crystalline powder.
2. The process for preparing panipenem, an antibiotic drug, according to claim 1, characterized in that: in the step S1, the mass ratio of 2-diazoacetoacetic acid p-nitrobenzyl ester to hexamethyldisilazane is 4: 1-6: 1; the molar ratio of the azacyclic ketone to the hexamethyldisilazane is 1.5:1 to 2: 1.
3. The process for preparing panipenem, an antibiotic drug, according to claim 1, characterized in that in the step S2, the mass ratio of ethanol to p-toluenesulfonic acid is 5: 1-7: 1, and the molar ratio of the product in the step S1 to p-toluenesulfonic acid is 1.2: 1-2: 1.
4. The preparation process of the antibiotic drug panipenem as claimed in claim 1, wherein in the step S3, the mass ratio of diisopropylethylamine to the product in the step S2 is 6: 1-8: 1; the molar ratio of the diisopropylethylamine to the diphenoxyphosphoryl chloride is 1.25: 1-1.4: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110165379.1A CN112961156A (en) | 2021-02-06 | 2021-02-06 | Preparation process of antibiotic drug panipenem |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110165379.1A CN112961156A (en) | 2021-02-06 | 2021-02-06 | Preparation process of antibiotic drug panipenem |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112961156A true CN112961156A (en) | 2021-06-15 |
Family
ID=76274842
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110165379.1A Pending CN112961156A (en) | 2021-02-06 | 2021-02-06 | Preparation process of antibiotic drug panipenem |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112961156A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5071843A (en) * | 1978-07-24 | 1991-12-10 | Merck & Co., Inc. | Combination of 2-substituted carbapenems with dipeptidase inhibitors |
| CN101570537A (en) * | 2009-06-18 | 2009-11-04 | 浙江师范大学 | Preparation method of panipenem |
| CN101885727A (en) * | 2010-07-02 | 2010-11-17 | 深圳市海滨制药有限公司 | Method for preparing penipenem |
-
2021
- 2021-02-06 CN CN202110165379.1A patent/CN112961156A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5071843A (en) * | 1978-07-24 | 1991-12-10 | Merck & Co., Inc. | Combination of 2-substituted carbapenems with dipeptidase inhibitors |
| CN101570537A (en) * | 2009-06-18 | 2009-11-04 | 浙江师范大学 | Preparation method of panipenem |
| CN101885727A (en) * | 2010-07-02 | 2010-11-17 | 深圳市海滨制药有限公司 | Method for preparing penipenem |
Non-Patent Citations (5)
| Title |
|---|
| 张玲等: "帕尼培南的合成", 《化学试剂》 * |
| 方惠珍等: "帕尼培南的合成工艺改进", 《中国药物化学杂志》 * |
| 王其军: "《浙江师范大学2009年硕士论文》", 31 December 2009 * |
| 王其军等: "帕尼培南-倍他米隆的合成研究", 《浙江化工》 * |
| 陈晓芳等: "帕尼培南关键中间体2-酮碳青霉烷-3-羧酸对硝基苄酯的合成改进", 《中国药物化学杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8729260B2 (en) | Process for the preparation of carbapenem using cabapenem intermediates and recovery of cabapenem | |
| NZ566460A (en) | An improved process for the preparation of beta-lactam antibiotic | |
| CN101544660A (en) | Cefixime compound and preparation method thereof | |
| CN101875665B (en) | Ertapenem intermediate, composite containing same and preparation method thereof | |
| WO2011141847A1 (en) | An improved process for the preparation of meropenem | |
| US20110118229A1 (en) | 2-arylmethylazetidine-carbapenem-3-carboxylic acid ester derivative or its salt, process for the preparation thereof and pharmaceutical composition comprising the same | |
| EP2401278A1 (en) | An improved process for the preparation of carbapenem antibiotic | |
| CN104447800B (en) | A kind of synthetic technology of cefoxitin acid | |
| JP4480396B2 (en) | Method for producing carbapenem compounds | |
| CN102153566A (en) | Method for preparing cefdinir | |
| CN112961156A (en) | Preparation process of antibiotic drug panipenem | |
| CA1300604C (en) | Methoxymethyl compounds | |
| CN113387960B (en) | Refining method of latamoxef sodium intermediate | |
| US20110288289A1 (en) | Preparation of Carbapenem Intermediate and Their Use | |
| CN113185538B (en) | Preparation method of cefpodoxime acid | |
| CN108299470B (en) | Preparation method of cefteram pivoxil | |
| GB1570990A (en) | Derivatives of thienamycin and its isomers | |
| CN102731503B (en) | A kind of preparation method of tebipenem | |
| GB1570987A (en) | Thienamycin derivatives | |
| US5506225A (en) | Antibacterial penem compounds | |
| SE460197B (en) | NEW CARBAPENE MEMBER DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF | |
| JP2934283B2 (en) | Carbapenem derivatives | |
| CN113929684B (en) | Meropenem intermediate and preparation method thereof | |
| JP2003183282A (en) | Carbapenem compound | |
| CN110698480B (en) | Synthesis and purification method of ertapenem intermediate |
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: 20210615 |
|
| RJ01 | Rejection of invention patent application after publication |