CN109232609A - A method of preparing high-purity Cefpodoxime Proxetil - Google Patents
A method of preparing high-purity Cefpodoxime Proxetil Download PDFInfo
- Publication number
- CN109232609A CN109232609A CN201811135618.3A CN201811135618A CN109232609A CN 109232609 A CN109232609 A CN 109232609A CN 201811135618 A CN201811135618 A CN 201811135618A CN 109232609 A CN109232609 A CN 109232609A
- Authority
- CN
- China
- Prior art keywords
- cefpodoxime
- carbonate
- ionic liquid
- ester
- alcohol
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
Abstract
The invention discloses a kind of methods for preparing high-purity Cefpodoxime Proxetil, comprising: under the action of carbonate and alkali ionic liquid, cefpodoxime acid reacts in organic solvent with iodo-ester, obtains the Cefpodoxime Proxetil after post treatment after reaction.Method of the invention obtains Cefpodoxime ester products total impurities less than 3%, Δ3(EP7.0 provides that total impurities provide total impurities less than 6%) less than 4%, USP35 to 1.5% or less isomers, and product stability is good, molar yield 78.3%~83.7%, high income, suitable industrialized production easy to operate.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of to prepare height by raw material one-step method of cefpodoxime acid
The method of pure cefditoren pool oxime ester.
Background technique
Cefpodoxime Proxetil Cefpodoxime Proxetil, CPDX-PR, (6R, 7R) -7- [2- (thiazolamine -4-
Base) -2- (z)-(methoxyimino)-acetamido] -3- methoxyl methyl -8- oxo -5- sulphur -1- azabicyclo-[4.2.0] octyl-
2- alkene -2- formic acid isopropyl oxygen carbonyl oxygen ethyl ester is a kind of cephalosporin ester prodrugs shown in structure such as formula (I), is given when oral
When, by the esterase being present in intestinal wall, fast hydrolyzing and be converted into Cefpodoxime, Cefpodoxime is a kind of antibacterial agent.
Cefpodoxime shows resisting gram-positive and negative bacterium, for example, staphylococcus aureus, golden yellow streptococcus, Escherichia coli,
The wide antibacterial activity range of bacillus canalis capsulatus and proteus vulgaris, while also having highly stable to beta-lactamase
Property.Cefpodoxime Proxetil belongs to third generation oral cephalosporin drug.
Document (J.of Antibiotics, Vol40,370 (1987)) report, by making cefpodoxime acid (structure such as formula
Shown in II) it is reacted in the presence of strong organic base such as dicyclohexyl amine with iodo-ester (structure is as shown in formula III) and prepares Cefpodoxime
Ester.The product that this method obtains, by-product especially isomers Δ3It is relatively high, generally 3% or more.Due to structure
Similitude is difficult to separate this undesirable by-product with product.It once attempted isomers Δ3It is opposite to be converted into body Δ2It is different
Structure body, but this method needs a series of reaction, therefore is not economically feasible.
Chinese patent (CN1305876C) discloses a kind of method of one-step method preparation high-purity Cefpodoxime Proxetil, with cephalo
Mooring oxime (acid) is raw material, is the organic weak bases such as sodium acetate, sodium propionate, sodium iso-octoate, potassium acetate, potassium propionate or isooctyl acid potassium
After reactant salt, iodo-ester is added, Cefpodoxime Proxetil is made, product yield 70%~75% is repeating Chinese patent
(CN1305876C) it finds to obtain Cefpodoxime Proxetil product cis-trans-isomer R/ (R+S) < 0.5 when and does not meet States Pharmacopoeia specifications.(medicine
Allusion quotation provides: in the test solution chromatogram recorded under content determination item, Cefpodoxime Proxetil B isomer peak area and cephalo are moored
Oxime ester A, B isomer peak area and the ratio between should be 0.50~0.60).
The patent application of Publication No. WO01/34611, which is disclosed, makees catalyst using crown ether, prepares head from cefpoxime proxetil
Spore moors oxime ester.Firstly, it is necessary to prepare Cefpodoxime Proxetil using crown ether, not only higher cost, and also the toxicity of crown ether is for last
It is unfavorable for preparing finished product, meanwhile, if not having to crown ether, the isomers of formation is up to 6-8% (weight) range, therefore is preparing
On it is still defective.
United States Patent (USP) 5,498,787 is disclosed with quaternary ammonium salt phase transfer catalyst, such as 4-butyl ammonium hydrogen sulfate, is moored from cephalo
The method that oximate prepares Cefpodoxime Proxetil, is based on Cefpodoxime, and the amount of quaternary ammonium salt phase transfer catalyst (is rubbed for 35 to 120%
You).This method can effectively inhibit isomers Δ3Formation, but the problem for having the yield of desired product low, yield exist
In the range of 50%-60%, and need using expensive quaternary ammonium salt.
In addition, according to South Korea No.99-54751 is disclosed disclosed in method, by make the cephem compounds of Cefpodoxime with
Alkyl carbonate reaction obtains ester, then acylated with the active ester form of aminothiazole guanidine-acetic acid in the presence of a large amount of quaternary ammonium salts
Ester obtained and prepare Cefpodoxime Proxetil.This method is also needed using expensive quaternary ammonium salt, and due to needing about 3 days
Long reaction process and cause low yield.
Summary of the invention
Technical problems to be solved needed for the present invention are to overcome above-mentioned shortcoming, and it is high-purity to provide a kind of preparing for simplicity
The method of Cefpodoxime Proxetil is spent, and product stability is good.
A method of preparing high-purity Cefpodoxime Proxetil, comprising:
Under the action of carbonate and alkali ionic liquid, cefpodoxime acid and iodo-ester occur instead in organic solvent
It answers, obtains the Cefpodoxime Proxetil after post treatment after reaction；
The cation of the carbonate is selected from alkali metal ion or alkaline-earth metal ions；
The alkali ionic liquid is hydroxide 1- butyl -3- methylimidazole salt ([bmlm] OH).
Synthetic route is as follows:
The purity is high of the Cefpodoxime Proxetil made from the method for the present invention, the HPLC method detection through European Pharmacopoeia EP7.0 is wherein
Δ3Isomers 1.5% hereinafter, total impurities less than 3%, and European Pharmacopoeia EP7.0 provide total impurities less than 4%, United States Pharmacopeia
USP35 provides total impurities less than 6%, illustrates product made from the method for the present invention better than European standard and Unite States Standard.
In the present invention, the weight ratio of alkali ionic liquid and carbonate is 0.001~1.0:1, preferably 0.2:1.
In the present invention, used alkali ionic liquid dosage is 0.001~0.2 times of the weight of cefpodoxime acid.Instead
Answering temperature is -20 DEG C~-5 DEG C, and relatively good temperature range is -20 DEG C~-10 DEG C.Reaction time is 0.5 to 2.5 hour, excellent
It selects 0.5 to 1.5 hour.
In the present invention, used organic solvent is selected from acetonitrile, tetrahydrofuran, n,N-Dimethylformamide, N, N- dimethyl
Sulfoxide, DMAC N,N' dimethyl acetamide and their mixture；Preferably DMAC N,N' dimethyl acetamide.
Preferably, the carbonate is potassium carbonate or sodium carbonate.
In the present invention, the amount based on cefpodoxime acid, the amount of used iodo-ester is 1 to 3 molar equivalent, preferably 1
To 1.2 equivalents.When the amount of iodo-ester increases, the rising of impurity or the increase of cost will cause.
Preferably, the post-processing includes: by the active carbon decoloring of reaction solution, filtering, alcohol and water is added in filtrate
It is crystallized in mixed solution, the high-purity Cefpodoxime Proxetil is obtained after the completion of crystallization.As a further preference, described
Mixed solution in, the weight ratio of alcohol and water is 0.01-0.1:1；
The alcohol is methanol or ethyl alcohol.
Compared with the existing technology, the beneficial effects of the present invention are embodied in:
Method of the invention obtains Cefpodoxime ester products total impurities less than 3%, Δ31.5% or less (EP7.0 of isomers
Providing that total impurities provide total impurities less than 6%) less than 4%, USP35, product stability is good, molar yield 78.3%~
83.7%, high income, suitable industrialized production easy to operate.
Specific embodiment
Further illustrate that the present invention, following embodiment are for illustration purposes only combined with specific embodiments below, without trying
Figure limits the scope of the invention.
Embodiment 1
By 10g (0.0234moL) cefpodoxime acid B under the reaction flask of 250ml, nitrogen protection, 50ml DMAc is put into
In (n,N-dimethylacetamide), stirring cools to -20 DEG C of dissolutions, and [bmlm] OH0.05g, potassium carbonate 3.5g, stirring 20 is added
Minute.It being added dropwise alpha-iodine ethyl oxygen propylene carbonate 6.5g (0.0253mol), temperature control is at -18 DEG C~-19 DEG C, after reaction 30 minutes,
HPLC controls raw material cefpodoxime acid B≤0.5%, and esterification terminates, and the decoloration of 1g medical active carbon is added, and decoloration finishes slowly
Reactant of esterification be pressed into pre-cool to 5 DEG C containing in 1% methanol/purification of aqueous solutions 400ml, filters pressing finishes continues to stir
It mixes 30 minutes, rejection filter, purified water 50mL cleaning product, is dried in vacuo, obtains white powder solid 10.5g (molar yield
80.6%).
Product (R+S) HPLC=99.2%, R/ (R+S)=0.51, Δ3=0.35%.
Embodiment 2
By 10g (0.0234moL) cefpodoxime acid B under the reaction flask of 250ml, nitrogen protection, 50ml DMAc is put into
In, stirring cools to -20 DEG C of dissolutions, and [bmlm] OH0.1g is added, and sodium carbonate 3.1g is stirred 20 minutes.Alpha-iodine ethyl oxygen carbon is added dropwise
Isopropyl propionate 6.5g0.0253mol), temperature control is at -18 DEG C~-19 DEG C, after reaction 30 minutes,
HPLC controls raw material cefpodoxime acid B≤0.5%, and esterification terminates, and the decoloration of 1g medical active carbon, decoloration is added
It finishes slowly to be pressed into reactant of esterification and pre-cool to 5 DEG C containing in 1% methanol/purification of aqueous solutions 400ml, filters pressing is complete
Bi Jixu stir 30 minutes, rejection filter, purified water 50mL cleaning product, vacuum drying, obtain white powder solid 10.2g (mole
Yield=78.3%).
Product (R+S) HPLC=99.1%, R/ (R+S)=0.53, Δ 3=0.36%.
Embodiment 3
By 20g (0.0468moL) cefpodoxime acid B under the four-hole bottle of 250ml, nitrogen protection, 100mlDMF is put into
In, stirring cools to -15 DEG C~-18 DEG C dissolutions, and [bmlm] OH0.2g, potassium carbonate 6.3g is added, and stirs 20 minutes.Alpha-iodine is added dropwise
Ethyl oxygen propylene carbonate 13g (0.0505mol), after insulation reaction 30 minutes, HPLC control raw material cefpodoxime acid B≤
0.5%, esterification terminates, and the decoloration of 2g medical active carbon is added, and decoloration, which finishes, is slowly pressed into reactant of esterification in advance
Be cooled to 5 DEG C containing in 2% ethyl alcohol/purification of aqueous solutions 800ml, filters pressing finishes precipitation solid, continues stirring 30 minutes.Rejection filter,
Purified water 50mL washing, vacuum drying obtain white powder solid 18.9g (weight yield=94.5%).
Product (R+S) HPLC=99.2%, R/ (R+S)=0.51, Δ3=0.37%.
Embodiment 4
By 10g (0.0234moL) cefpodoxime acid B under the reaction flask of 250ml, nitrogen protection, 50ml DMAc is put into
In, stirring cools to -19 DEG C~-20 DEG C dissolutions, and [bmlm] OH 1.5g, sodium carbonate 3.0g is added, and stirs 20 minutes.α-is added dropwise
Iodine ethyl oxygen propylene carbonate 6.5g (0.0253mol), temperature control is at -17 DEG C~-19 DEG C, and after reaction 30 minutes, HPLC control is former
Expect cefpodoxime acid B≤0.5%, esterification terminates, and addition 1g medical active carbon decolourizes, and decoloration, which finishes, will slowly be esterified instead
Object is answered to be pressed into pre-cool to 5 DEG C and continues stirring 30 minutes containing in 1% ethyl alcohol/purification of aqueous solutions 400ml, filters pressing is finished,
Rejection filter, purified water 50mg cleaning product, vacuum drying obtain white powder solid 10.9g (molar yield=83.7%).
Product (R+S) HPLC=99.1%, R/ (R+S)=0.53, Δ3=0.36%.
Embodiment 5
By 20g (0.0468moL) cefpodoxime acid B under the four-hole bottle of 250ml, nitrogen protection, 100mlDMF is put into
In, stirring cools to -18 DEG C~-15 DEG C dissolutions, and [bmlm] OH 1.1g is added, and potassium carbonate 5.5g is stirred 20 minutes.Alpha-iodine is added dropwise
Ethyl oxygen propylene carbonate 13.3g (0.0517mol), after insulation reaction 30 minutes, HPLC control raw material cefpodoxime acid B≤
0.5%, esterification terminates, and the decoloration of 2g medical active carbon is added, and decoloration, which finishes, is slowly pressed into reactant of esterification in advance
Be cooled to 5 DEG C containing in 2% ethyl alcohol/purification of aqueous solutions 800ml, filters pressing finishes precipitation solid, continues stirring 30 minutes.Rejection filter,
Purified water 50mL washing, vacuum drying obtain white powder solid 21.4g (molar yield 82.2%).
Product (R+S) HPLC=99.2%, R/ (R+S)=0.52, Δ3=0.38%.
Embodiment 6
By 10g (0.0234moL) cefpodoxime acid B under the reaction flask of 250ml, nitrogen protection, 50ml DMAc is put into
In, stirring cools to -20 DEG C of dissolutions, and [bmlm] OH0.9g is added, and sodium carbonate 2.5g is stirred 20 minutes.Alpha-iodine ethyl oxygen carbon is added dropwise
Isopropyl propionate 6.5g (0.0253mol), temperature control is at -18 DEG C~-17 DEG C, and after reaction 30 minutes, HPLC controls raw material Cefpodoxime
Sour B≤0.5%, esterification terminate, and the decoloration of 1g medical active carbon is added, and decoloration, which finishes, is slowly pressed into reactant of esterification
In advanceIt is cooled to5 DEG C are continued stirring 30 minutes, rejection filter, purified water containing in 1% ethyl alcohol/purification of aqueous solutions 400ml, filters pressing is finished
50mL cleaning product, vacuum drying obtain white powder solid 10.4g (, molar yield 80.0%).
Product (R+S) HPLC=99.2%, R/ (R+S)=0.54, Δ3=0.38%.
Comparative example 7 (refers to CN1305876C document)
20g (0.0468moL) cefpodoxime acid B is put into 120ml DMAc in the reaction flask of 250ml, stirring drop
Dissolution is added anhydrous sodium acetate 4.6g and 1g water, is stirred at room temperature 30 minutes.It is cooled to 5 DEG C, alpha-iodine ethyl oxygen propylene carbonate is added
15g (0.0584mol), 5 DEG C~10 DEG C are reacted 1.5 hours.Esterification terminates, and pours into 200ml ethyl acetate and 100 5%
In NaHCO3 mixed liquor, stirring separates organic phase, and water phase is extracted with 100ml ethyl acetate, merges organic phase, uses saturated common salt
Water washing is twice, organic to be added to 10g anhydrous magnesium sulfate and 10g activity carbon decoloring 30min, and filtering is concentrated under reduced pressure into 80g, fastly
500ml isopropyl ether is added in speed, filters after high degree of agitation, is dried in vacuo, obtain it is white to off-white powder 18.8g (weight yield=
94.0%.Molar yield 72.2%).With European Pharmacopoeia EP7.0HPLC testing result: product (R+S) HPLC=96.23%, R/
(R+S)=0.497 < 0.5 (not meeting pharmacopoeial requirements 0.5~0.6), Δ 3=0.54%.
The product of embodiment 1,3 and 7 is subjected to stability test, the results are shown in Table 1:
The stability test result of the different embodiment products of table 1
Claims (9)
1. a kind of method for preparing high-purity Cefpodoxime Proxetil characterized by comprising
Under the action of carbonate and alkali ionic liquid, cefpodoxime acid reacts in organic solvent with iodo-ester, instead
The Cefpodoxime Proxetil is obtained after answering after post treatment；
The cation of the carbonate is selected from alkali metal ion or alkaline-earth metal ions；
The alkali ionic liquid is hydroxide 1- butyl -3- methylimidazole salt.
2. the method according to claim 1, wherein the carbonate is potassium carbonate or sodium carbonate.
3. the method according to claim 1, wherein the weight ratio of the alkali ionic liquid and carbonate is
0.001~1.0:1.
4. the method according to claim 1, wherein the weight of the alkali ionic liquid and cefpodoxime acid
Than 0.01~0.2:1.
5. the method according to claim 1, wherein reaction temperature is -20 DEG C~-5 DEG C.
6. according to the method described in claim 5, it is characterized in that, reaction temperature is -20 DEG C~-10 DEG C.
7. the method according to claim 1, wherein the organic solvent is selected from acetonitrile, tetrahydrofuran, N, N-
Dimethylformamide, N, N- dimethyl sulfoxide, DMAC N,N' dimethyl acetamide and their mixture.
8. the method according to claim 1, wherein the post-processing includes: to take off reaction solution with active carbon
Color, filtering, filtrate are added in the mixed solution of alcohol and water and are crystallized, and the high-purity Cefpodoxime is obtained after the completion of crystallization
Ester.
9. according to the method described in claim 8, it is characterized in that, in the mixed solution, the weight ratio of alcohol and water is
0.01~0.1:1；
The alcohol is methanol or ethyl alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811135618.3A CN109232609B (en) | 2018-09-27 | 2018-09-27 | Method for preparing high-purity cefpodoxime proxetil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811135618.3A CN109232609B (en) | 2018-09-27 | 2018-09-27 | Method for preparing high-purity cefpodoxime proxetil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109232609A true CN109232609A (en) | 2019-01-18 |
| CN109232609B CN109232609B (en) | 2021-07-02 |
Family
ID=65057348
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811135618.3A Active CN109232609B (en) | 2018-09-27 | 2018-09-27 | Method for preparing high-purity cefpodoxime proxetil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109232609B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999252A (en) * | 2021-12-03 | 2022-02-01 | 浙江东邦药业有限公司 | Cefpodoxime proxetil impurity cefpodoxime dippivoxil and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5498787A (en) * | 1994-04-20 | 1996-03-12 | Standard Chemical & Pharmaceutical Co., Ltd. | Method for preparing cephalosporin derivatives |
| CN1288466A (en) * | 1998-01-09 | 2001-03-21 | 生物化学有限公司 | Process for prepn. of sefpodoxime proxetil diastereoisomers |
| CN1160361C (en) * | 1999-11-08 | 2004-08-04 | 韩美药品工业株式会社 | Method for prepairng highly purity cefpodoxime proxetil |
| US20080255200A1 (en) * | 2007-04-11 | 2008-10-16 | Auspex Pharmaceuticals, Inc. | Substituted benzimidazoles |
| WO2010097675A1 (en) * | 2009-02-27 | 2010-09-02 | Dhanuka Laboratories Ltd. | An improved preparation process for cefpodoxime proxetil |
| CN101843599A (en) * | 2009-03-23 | 2010-09-29 | 杭州锐思医药科技有限公司 | Oral cephalosporin ester capsule |
-
2018
- 2018-09-27 CN CN201811135618.3A patent/CN109232609B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5498787A (en) * | 1994-04-20 | 1996-03-12 | Standard Chemical & Pharmaceutical Co., Ltd. | Method for preparing cephalosporin derivatives |
| CN1288466A (en) * | 1998-01-09 | 2001-03-21 | 生物化学有限公司 | Process for prepn. of sefpodoxime proxetil diastereoisomers |
| CN1160361C (en) * | 1999-11-08 | 2004-08-04 | 韩美药品工业株式会社 | Method for prepairng highly purity cefpodoxime proxetil |
| US20080255200A1 (en) * | 2007-04-11 | 2008-10-16 | Auspex Pharmaceuticals, Inc. | Substituted benzimidazoles |
| WO2010097675A1 (en) * | 2009-02-27 | 2010-09-02 | Dhanuka Laboratories Ltd. | An improved preparation process for cefpodoxime proxetil |
| CN101843599A (en) * | 2009-03-23 | 2010-09-29 | 杭州锐思医药科技有限公司 | Oral cephalosporin ester capsule |
Non-Patent Citations (2)
| Title |
|---|
| HONG WOO LEE等，: ""Preparation Of Ceph-3-Em Esters Unaccompanied By δ3 To δ2 Isomerization Of The Cephalosporin Derivatives"", 《SYNTHETIC COMMUNICATIONS》 * |
| 杨涛，: ""功能化离子液体的制备及其在头孢托仑酯合成中的应用"", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999252A (en) * | 2021-12-03 | 2022-02-01 | 浙江东邦药业有限公司 | Cefpodoxime proxetil impurity cefpodoxime dippivoxil and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109232609B (en) | 2021-07-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2281685T3 (en) | SALTS OF CEFDINIR CRYSTALS. | |
| BR102012032754A2 (en) | CONTINUOUS PROCESS FOR THE ALKYLATION OF CYCLIC TERTIARY AMINES | |
| CN109232609A (en) | A method of preparing high-purity Cefpodoxime Proxetil | |
| KR101577488B1 (en) | Cefdinir acid double salt and its preparation | |
| CN109651402B (en) | Preparation process of cefazedone sodium | |
| CN103232475B (en) | A kind of preparation method of Aspoxicillin trihydrate | |
| CN108033972B (en) | Synthesis method of cefprozil | |
| CN109553630B (en) | Synthesis method of cefazedone sodium | |
| US11124526B2 (en) | Crystalline beta-lactamase inhibitor | |
| US7482486B2 (en) | Methods for the preparation and formulation of magnesium valproate hydrate | |
| EP2520578A1 (en) | Process for purification of cephalosporins | |
| CN102898443B (en) | The process for purification of high yield super-clean high-purity Cefodizime Sodium | |
| CN111004255A (en) | Preparation method of cefcapene lactone compound or hydrochloride thereof | |
| US4634556A (en) | Crystalline sodium (5R, 6S, 8R)-6-(1-hydroxyethyl)-2-(2-carbamoyloxyethylthio)-penem-3-carboxylate and process for making same | |
| CN111100144B (en) | Synthesis process of cefathiamidine | |
| KR100378731B1 (en) | Method for producing crystalline cefuroxime axetil ester | |
| CN108299468B (en) | Refining method of cefprozil | |
| CN113185538B (en) | Preparation method of cefpodoxime acid | |
| CN1295234C (en) | Cefuroxime axetil diastereoisomer separating method | |
| KR100327708B1 (en) | Method for producing crystalline cefuroxime axetil | |
| EP1073625B1 (en) | Tilidine mesylate, processes for its preparation and pharmaceutical composition thereof | |
| KR101670857B1 (en) | Method for preparing cefroxadine | |
| CN113461709A (en) | Synthesis method of penethamate hydroiodide | |
| CN117069739A (en) | Preparation method of high-purity sodium cefuroxime axetil | |
| KR100202279B1 (en) | Process for preparing cefuroxime ester derivatives |
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 | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200629 Address after: 322118, 519, Zhenjiang South Road, Dongyang, Zhejiang, Jinhua, Hengdian Applicant after: ZHEJIANG APELOA TOSPO PHARMACEUTICAL Co.,Ltd. Applicant after: APELOA PHARMACEUTICAL Co.,Ltd. Address before: 322118, 519, Zhenjiang South Road, Dongyang, Zhejiang, Jinhua, Hengdian Applicant before: ZHEJIANG APELOA TOSPO PHARMACEUTICAL Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |