CN108530467A - A kind of process for purification of Cefprozil and products thereof - Google Patents

A kind of process for purification of Cefprozil and products thereof Download PDF

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Publication number
CN108530467A
CN108530467A CN201810410979.8A CN201810410979A CN108530467A CN 108530467 A CN108530467 A CN 108530467A CN 201810410979 A CN201810410979 A CN 201810410979A CN 108530467 A CN108530467 A CN 108530467A
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cefprozil
solution
fecl
sncl
purification
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杨明
王俊臣
钱丹
樊振
张垒
吉令
杨秋燕
赵臻
陈金春
年蓓蕾
任真
周香莹
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TIANFANG PHARMACEUTICAL CO Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D501/00Heterocyclic 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
    • C07D501/14Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/207-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/227-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D501/00Heterocyclic 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
    • C07D501/02Preparation
    • C07D501/12Separation; Purification

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

The invention discloses a kind of process for purification of Cefprozil and products thereof, which includes:Cefprozil DMF compounds are added in purified water, adds hydrochloric acid to be adjusted to solution clarification, obtains clarified solution;FeCl is added into above-mentioned clarified solution3Solution, filtering, obtains filtrate;Into above-mentioned filtrate plus then SnCl is added in ammonium hydroxide, adjusting pH=4.5~5.52·2H2The methanol solution of O filters, and cold water is washed, and acetone washing, vacuum drying obtains Cefprozil.This method can effectively remove the impurity such as impurity A (D-pHPG), 7 ACA, but the yield of Cefprozil is 76%, trans-isomer content is only 8.0%~9.0% in the Cefprozil product of preparation, obtained Cefprozil product purity is up to 99.8%, color is shallower, and quality meets new edition standards of pharmacopoeia.

Description

A kind of process for purification of Cefprozil and products thereof
Technical field
The invention belongs to the process for purification technical fields of cephalosporin analog antibiotic drug, and in particular to a kind of essence of Cefprozil Method processed.
Background technology
Cefprozil (Cefprozil), chemical name are:(6R, 7R) -7 [[(2R) -2- amino -2- (to hydroxy-pheny) Acetyl] amino] -8- oxos -3- [(E) -propyl- 1- alkenyls] -5- thia -1- azabicyclos-[4,2,0] oct-2-ene -2- formic acid, It is the second generation that U.S.'s Bristol Myers Squibb (Bristol-Myer Squibb) company develops, and listed in the U.S. in 1992 New-type wide-spectrum oral cephalosporin, structural formula are as follows:
Cefprozil is second generation cephalosporin class antibiotic, has broad-spectrum antibacterial action, to apostematosa pneumonia and agalasisa Streptococcus acts on by force the S. aureus L-forms of methicillin-sensitivity, also has inhibiting effect to Hemophilus influenzae, is usually used on treatment adult Lower respiratory tract infection, urethral infection and enteric infection, the upper lower respiratory tract infection such as otitis media in children, tonsillitis, pneumonia are secreted The infection of urine system and enteric infection.
Cefprozil DMF compounds are that Cefprozil and salt, structural formula formed by DMF are as follows:
Cefprozil DMF compounds obtain cefprozil monohydrate after sloughing DMF, the Cefprozil DMF before not refining Compound color is faint yellow or off-white color, and major impurity has:Impurity A (D-pHPG), 7-ACA, impurity B (cephalo Amoxycillin), impurity D, impurity F, impurity H, the open loop of impurity J, Z- Cefprozil, E- Cefprozil open loops etc., concrete structure formula is shown in As follows, free refine of Cefprozil DMF compounds has significant impact to Cefprozil quality,
Currently, the Cefprozil of industrialized production is usually present that color is partially yellow, purity is low, transisomer is higher etc. and asks Topic.The process for purification of existing Cefprozil is mainly:The water of Cefprozil DMF compounds addition certain temperature or methanol is direct Heating stirring, filters to obtain Cefprozil, these methods can only remove DMF and a small amount of D-pHPG (impurity A), to other Impurity cannot be removed effectively, and temperature causes product colour partially yellow compared with Gao Shihui.In addition, United States Pharmacopeia is clearly stipulate that clinical use Cefprozil:Cis-content 89%~94%, trans content 6%~11%.
Therefore, it is badly in need of a kind of method for capableing of the refined Cefprozil of deeper time, more Cefprozil DMF can be removed Impurity present in compound, to improve the purity of Cefprozil drug.
Invention content
The purpose of the present invention is to provide a kind of process for purification of Cefprozil, to overcome existing Cefprozil color inclined The problem yellow, purity is low, transisomer is higher.
To realize said one or multiple purposes, in one embodiment of the invention, the present invention provides a kind of heads The process for purification of spore propylene, this includes the following steps:
(1) Cefprozil DMF compounds are added in purified water, add hydrochloric acid to be adjusted to solution clarification, obtains clarified solution;
(2) FeCl is added into above-mentioned clarified solution3Solution stirs, and filtering obtains filtrate;
(3) add ammonium hydroxide into above-mentioned filtrate, adjust pH=4.5~5.5;
(4) SnCl is added into step (3) acquired solution2·2H2The methanol solution of O stirs, and filters, and cold water is washed, acetone Washing, vacuum drying, obtains Cefprozil.
Wherein, readily soluble in an acidic solution due to Cefprozil and Cefprozil DMF compounds slightly soluble in water, therefore select Select acid solution adjust the compounds of DMF containing Cefprozil solution to clarify;
In step (3), when adjusting pH value to 4.5~5.5, Cefprozil crystallization yield can be made higher.
In a preferred embodiment of the invention, described the present invention provides a kind of process for purification of Cefprozil FeCl3The concentration of solution is 0.01~0.05mol/L, preferably 0.02~0.03mol/L;
The FeCl3The preparation process of solution includes:By the FeCl of 2.7g~13.5g3·6H2O solids are dissolved in purified water In, it is then transferred to the volumetric flask of 1L, adds water constant volume to get the FeCl that concentration is 0.01~0.05mol/L3Solution.
In a preferred embodiment of the invention, described the present invention provides a kind of process for purification of Cefprozil SnCl2·2H2The concentration of the methanol solution of O is 0.002~0.05mol/L, preferably 0.005~0.03mol/L;
The SnCl2·2H2The preparation process of the methanol solution of O includes:By the SnCl of 0.45g~11.29g2·2H2O is solid Body dissolves in methyl alcohol, is then transferred to the volumetric flask of 1L, and methanol constant volume is added to get concentration to be 0.002~0.05mol/L SnCl2·2H2The methanol solution of O.
In a preferred embodiment of the invention, the present invention provides a kind of process for purification of Cefprozil, steps (1) initial purity of the compound of Cefprozil DMF described in is 98.0~99.0 weight %;
And/or the Cefprozil DMF compounds and the mass ratio of purified water are 0.2: 1 to 1: 1, preferably 0.4: 1.
In a preferred embodiment of the invention, the present invention provides a kind of process for purification of Cefprozil, steps (1) acid solution described in is preferably hydrochloric acid.
In a preferred embodiment of the invention, the present invention provides a kind of process for purification of Cefprozil, steps (2) clarified solution described in and FeCl3The mass ratio of solution is 35: 1 to 45: 1, preferably 36: 1.
In a preferred embodiment of the invention, the present invention provides a kind of process for purification of Cefprozil, steps (3) filtrate described in and SnCl2·2H2The mass ratio of the methanol solution of O is 57: 1 to 23: 1, preferably 30: 1;
And/or the vacuum drying temperature is 38~45 DEG C, preferably 40 DEG C, vacuum drying time is 1~5h, excellent It is selected as 3h.
Wherein, when vacuum drying, temperature is relatively low to cannot be removed effectively solvent, and temperature is higher to cause Cefprozil trans- different Structure body content increases, controlled at 38~45 DEG C when experiment;Drying time long increase energy consumption, the time is too short to lead to solvent Remain higher, control drying time is 1~5h when experiment.
In a preferred embodiment of the invention, the present invention provides a kind of process for purification of Cefprozil, steps (3) pH value described in is 5.
In a preferred embodiment of the invention, the present invention provides a kind of process for purification of Cefprozil, the party Method includes:Cefprozil DMF compounds are slowly added into purified water, adds hydrochloric acid to be adjusted to solution clarification, adds FeCl3Solution, 0.5~1h is stirred, filtering adds ammonium hydroxide tune pH=5.0, adds SnCl2·2H2The methanol solution of O stirs 0.5~1h, filters, cold water It washes, acetone washing, 40 DEG C of vacuum drying 3h obtain Cefprozil.
In one embodiment of the invention, the present invention provides a kind of Cefprozils, and the Cefprozil is by above-mentioned Process for purification is made.
In one embodiment of the invention, the present invention provides a kind of pharmaceutical composition, which includes Cefprozil and pharmaceutical acceptable carrier, diluent and/or excipient is made by above-mentioned process for purification at least one.
Compared with prior art, the present invention has the advantages that:
(1) process for purification of Cefprozil provided by the invention, the FeCl of use3Solution can be compound with Cefprozil DMF Impurity A (D-pHPG), 7-ACA and other impurities in object are coordinated, and are formed precipitation, are removed the impurity, can Effectively remove impurity A (D-pHPG), 7-ACA, other known impurities D, impurity F, impurity H, impurity J, Z- cephalo third Alkene open loop, E- Cefprozil open loops do not detect, yield 72%.
(2) SnCl is used in the present invention2·2H2The methanol solution of O can remove FeCl extra in reaction solution3So that gained Without containing newly-increased impurity in Cefprozil product.
(3) FeCl is being added in the present invention3After solution, SnCl is added2·2H2Adjust before the methanol solution of O pH=4.5~ 5.5, impurity A, impurity B, impurity D can be removed, while reducing Cefprozil reaction content of isomer;The Cefprozil of preparation produces Trans-isomer content is only 8.0%~9.0% in product, and obtained Cefprozil product purity is up to 99.8%, and color is shallower, Quality meets new edition standards of pharmacopoeia 6%~11%, enhances the market competitiveness of enterprise.
(4) process for purification that the present invention uses does not use toxic reagent, ensure that gained Cefprozil product safety, nothing Evil, easy to operate, repeatability is strong.
Description of the drawings
Attached drawing described herein is used to provide further understanding of the present invention, and is constituted part of this application.Attached In figure:
Fig. 1 be according to an embodiment of the invention in use Cefprozil DMF compounds HPLC figure.
Fig. 2 is the HPLC figures of 1 obtained Cefprozil according to an embodiment of the invention.
Fig. 3 is the HPLC figures of 2 obtained Cefprozils according to an embodiment of the invention.
Fig. 4 is the HPLC figures of 3 obtained Cefprozils according to an embodiment of the invention.
Specific implementation mode
Technical scheme of the present invention is further described in detail below, it is to be understood that protection scope of the present invention It is not restricted by specific implementation.
Experimental method used in following embodiments is conventional method unless otherwise specified.
Material used in above-described embodiment, reagent etc., are commercially available unless otherwise specified.
Experiment condition:
Method:High performance liquid chromatography (HPLC)
Chromatographic column:SB-Phenyl(5μm 4.6*250mm)
Mobile phase:Mobile phase A is 0.23% ammonium dihydrogen phosphate, and Mobile phase B is methanol
According to the form below carries out linear gradient elution
Column temperature:30℃
Detection wavelength:225nm;
Sample size:20μl;
The source of Cefprozil DMF compounds:
HPLC detections, gained Cefprozil DMF compounds are carried out under these experimental conditions to Cefprozil DMF compounds Measurement result is as shown in table 1 below, and the retention time of impurity A (D-pHPG) is 2.327 minutes, the guarantor of impurity 7-ACA It is 18.717 minutes to stay the time, the retention time of impurity B (cefadroxil) is 10.464 minutes;Cefprozil DMF compounds Purity be 98.8% (referring to Fig. 1).
Table 1
Peak # Retention time Area Highly Area %
1 2.327 92610 17208 0.329
2 3.994 16065 1413 0.057
3 4.970 15258 1442 0.054
4 10.464 96507 5434 0.342
5 18.717 11673 7256 0.412
6 27.624 25682367 936677 91.144
7 37.162 2158944 91966 7.662
It amounts to 28177923 1061396 100.000
Embodiment 1:
A kind of process for purification of Cefprozil, step include:
It takes 57mL purified waters in there-necked flask, is cooled to 5-10 DEG C, be slowly added to the Cefprozil DMF compounds of 57g, drip Enriching hydrochloric acid to solution is clarified;
Add the FeCl of a concentration of 0.02mol/L of 3mL3Solution, 5-10 DEG C of stirring 0.5-1h of temperature control, filtering;
The SnCl of a concentration of 0.03mol/L of 0-5 DEG C of dropwise addition 3.3mL of temperature control2·2H2The methanol solution of O adds ammonium hydroxide tune pH =5.0,1h is stirred, is filtered, 20mL cold water is washed, the washing of 30mL acetone, and 40 DEG C of vacuum drying 3h obtain Cefprozil product 43.4g。
The measurement result of gained Cefprozil HPLC is as shown in table 2 below, and the Cefprozil purity that the present embodiment obtains is 99.8%, trans-isomer content 8.2% (referring to Fig. 2), yield is 71.9%.
Table 2
Peak # Retention time Area Highly Area %
1 11.078 22527 1056 0.129
2 27.882 15980672 460129 91.674
3 37.304 1428946 49253 8.197
It amounts to 17432146 510439 100.000
Embodiment 2:
A kind of process for purification of Cefprozil, step include:
It takes 57mL purified waters in there-necked flask, is cooled to 5-10 DEG C, be slowly added to 57g Cefprozil DMF compounds, be added dropwise Concentrated hydrochloric acid to solution is clarified;
Add the FeCl of a concentration of 0.02mol/L of 3mL3Solution, 5-10 DEG C of stirring 0.5-1h of temperature control, filtering;
The SnCl of a concentration of 0.03mol/L of 0-5 DEG C of dropwise addition 2mL of temperature control2·2H2The methanol solution of O adds ammonium hydroxide tune pH= 5.0,0.5-1h is stirred, is filtered, 20mL cold water is washed, the washing of 30mL acetone, and 40 DEG C of vacuum drying 3h obtain Cefprozil product 43.2g。
The measurement result of gained Cefprozil HPLC is as shown in table 3 below, and the Cefprozil purity that the present embodiment obtains is 99.7%, trans-isomer content 8.7% (referring to Fig. 3), yield is 71.5%.
Table 3
Peak # Retention time Area Highly Area %
1 4.783 14247 1590 0.077
2 11.044 22356 1038 0.121
3 27.810 16811826 487844 91.094
4 37.215 1606997 55171 8.707
It amounts to 18455425 545642 100.000
Embodiment 3:
A kind of process for purification of Cefprozil, step include:
It takes 57mL purified waters in there-necked flask, is cooled to 5-10 DEG C, be slowly added to the Cefprozil DMF compounds of 57g, drip Enriching hydrochloric acid to solution is clarified;
Add the FeCl of a concentration of 0.02mol/L of 4mL3Solution, 5-10 DEG C of stirring 0.5-1h of temperature control, filtering;
The SnCl of a concentration of 0.025mol/L of 0~5 DEG C of dropwise addition 5mL of temperature control2·2H2The methanol solution of O adds ammonium hydroxide tune pH =5.0,0.5h is stirred, is filtered, 20mL cold water is washed, the washing of 30mL acetone, and 40 DEG C of vacuum drying 3h obtain Cefprozil product 43.6g。
The measurement result of gained Cefprozil HPLC is as shown in table 4 below, and the Cefprozil purity that the present embodiment obtains is 99.6%, trans-isomer content 8.9% (referring to Fig. 4), yield is 72.1%.
Table 4
The description of the aforementioned specific exemplary embodiment to the present invention is in order to illustrate and illustration purpose.These descriptions It is not wishing to limit the invention to disclosed precise forms, and it will be apparent that according to the above instruction, can much be changed And variation.The purpose of selecting and describing the exemplary embodiment is that explaining the specific principle of the present invention and its actually answering With so that those skilled in the art can realize and utilize the present invention a variety of different exemplary implementation schemes and Various chooses and changes.The scope of the present invention is intended to be limited by claims and its equivalents.

Claims (10)

1. a kind of process for purification of Cefprozil, which is characterized in that described method includes following steps:
(1) Cefprozil DMF compounds are added in purified water, add hydrochloric acid to be adjusted to solution clarification, obtains clarified solution;
(2) FeCl is added into above-mentioned clarified solution3Solution stirs, and filtering obtains filtrate;
(3) add ammonium hydroxide into above-mentioned filtrate, adjust pH=4.5~5.5;
(4) SnCl is added into step (3) acquired solution2·2H2The methanol solution of O stirs, and filters, and cold water is washed, acetone washing, Vacuum drying, obtains Cefprozil.
2. process for purification according to claim 1, which is characterized in that the FeCl3The concentration of solution is 0.01~ 0.05mol/L, preferably 0.02~0.03mol/L;
The FeCl3The preparation process of solution includes:By the FeCl of 2.7g~13.5g3·6H2O solids are dissolved in purified water, It is then transferred to the volumetric flask of 1L, adds water constant volume to get the FeCl that concentration is 0.01~0.05mol/L3Solution.
3. process for purification according to claim 1, which is characterized in that the SnCl2·2H2The concentration of the methanol solution of O is 0.002~0.05mol/L, preferably 0.005~0.03mol/L;
The SnCl2·2H2The preparation process of the methanol solution of O includes:By the SnCl of 0.45g~11.29g2·2H2O solids are molten Solution in methyl alcohol, is then transferred to the volumetric flask of 1L, and methanol constant volume is added to get concentration to be 0.002~0.05mol/L SnCl2·2H2The methanol solution of O.
4. process for purification according to claim 1, which is characterized in that Cefprozil DMF compounds described in step (1) Initial purity is 98.0~99.0 weight %;
And/or the Cefprozil DMF compounds and the mass ratio of purified water are 0.2: 1 to 1: 1, preferably 0.4: 1.
5. process for purification according to claim 1, which is characterized in that acid solution is preferably hydrochloric acid described in step (1).
6. process for purification according to claim 1, which is characterized in that clarified solution and FeCl described in step (2)3Solution Mass ratio is 35: 1 to 45: 1, preferably 36: 1.
7. process for purification according to claim 1, which is characterized in that filtrate and SnCl described in step (3)2·2H2O's The mass ratio of methanol solution is 57: 1 to 23: 1, preferably 30: 1;
And/or the vacuum drying temperature is 38~45 DEG C, preferably 40 DEG C, vacuum drying time is 1~5h, preferably 3h。
8. process for purification according to claim 1, which is characterized in that pH value is 5 described in step (3).
9. a kind of Cefprozil, which is characterized in that the Cefprozil is by the refined side described in any one of claim 1-8 Method is made.
10. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes at least one by appointing in claim 1-8 Cefprozil and pharmaceutical acceptable carrier, diluent and/or excipient is made in process for purification described in meaning one.
CN201810410979.8A 2018-05-02 2018-05-02 A kind of process for purification of Cefprozil and products thereof Pending CN108530467A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101780085A (en) * 2010-02-26 2010-07-21 汕头金石制药总厂 Cefprozil medicinal composition
CN102030762A (en) * 2010-12-02 2011-04-27 苏州致君万庆药业有限公司 Preparation method of cefprozil
CN102408438A (en) * 2010-09-26 2012-04-11 石药集团中奇制药技术(石家庄)有限公司 Preparation method of cefprozil monohydrate
CN105061469A (en) * 2015-07-28 2015-11-18 天津医药集团津康制药有限公司 Free refining method of cefprozil DMF compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101780085A (en) * 2010-02-26 2010-07-21 汕头金石制药总厂 Cefprozil medicinal composition
CN102408438A (en) * 2010-09-26 2012-04-11 石药集团中奇制药技术(石家庄)有限公司 Preparation method of cefprozil monohydrate
CN102030762A (en) * 2010-12-02 2011-04-27 苏州致君万庆药业有限公司 Preparation method of cefprozil
CN105061469A (en) * 2015-07-28 2015-11-18 天津医药集团津康制药有限公司 Free refining method of cefprozil DMF compound

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Application publication date: 20180914