CN110483554A - A kind of method of purification of brizolina - Google Patents
A kind of method of purification of brizolina Download PDFInfo
- Publication number
- CN110483554A CN110483554A CN201910851736.2A CN201910851736A CN110483554A CN 110483554 A CN110483554 A CN 110483554A CN 201910851736 A CN201910851736 A CN 201910851736A CN 110483554 A CN110483554 A CN 110483554A
- Authority
- CN
- China
- Prior art keywords
- brizolina
- phase
- purification
- cephazoline
- methylene chloride
- 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
- 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
- C07D501/12—Separation; Purification
-
- 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
- C07D501/36—Methylene radicals, substituted by sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a kind of methods of purification of brizolina, are related to the purification technique field of brizolina.After the completion of including the following steps: the synthesis of (1) cephazoline, after adding water to hydrolyze, methylene chloride is added into hydrolyzate, adds hydrochloric acid, controls pH=1.3~1.6, stands, split-phase, water phase discards, and collects methylene chloride phase；(2) water is added into methylene chloride phase, adjusts pH=6.4~6.7 with sodium hydroxide solution, stand, split-phase discards methylene chloride phase, the cephazoline sodium solution after being purified.This method of the present invention is easy to operate, and the period is short, and discharge of wastewater is few, has environment-friendly advantage, the content of product brizolina is high, and dopant species are few, and impurity content is low, drug safety.
Description
Technical field
The present invention relates to the purification technique fields of brizolina.
Background technique
Cephazoline is first generation cephalosporin, has a broad antifungal spectrum.In addition to enterococcus spp, methicillin-resistant Staphylococcus belong to,
This product has good antibacterial activity, streptococcus pneumonia and hemolytic streptococcus quick to this product height other gram-positive coccis
Sense.Corynebacterium diphtheriae, bacillus anthracis, Listeria and clostruidium are also very sensitive to this product.This product is uncommon to part large intestine angstrom
Bacterium, proteus mirabilis and Klebsiella Pneumoniae have good antibacterial activity, but poor to the antibacterial action of S. aureus L-forms.Typhoid fever bar
Bacterium, Shigella and neisseria are sensitive to this product, other enterobacteriaceae lactobacteriaceaes, acinetobacter calcoaceticus and antibiotic resitance of P. aeruginosa.
Producing enzyme gonococcus is to this product drug resistance；Haemophilus influenzae only medium sensitivity.Grain-positive anaerobic bacteria and certain Grain-negative anaerobism
How sensitive bacterium is to this product.Bacteroides fragilis drug resistance.
Brizolina alias cephazolin, Aneet, cephazoline, Cefazolin, ancef, elder generation
Cutting edge of a knife or a sword quinoline, Cefazolin, cefazolin.Chemical name: (6R, 7R) -3- [[(5- methyl-1,3,4- thiadiazoles -2- base) sulphur] methyl] -7-
[(1H-TETRAZOLE -1- base) acetylamino] -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- formic acid sodium salt.English
Literary fame claims: cefazolin sodium sal.Molecular formula: C14H13N8NaO4S3.Molecular weight: 476.48.CAS NO.27164-
46-1, EINECS 248-278-4.Structural formula:
Character: white or pale white crystals powder, almost odorless, bitter.Product 1.05g is approximately equivalent to cephazoline alkali
Base 1g.Product 1g includes sodium ion about 2.1mmol (2.1mEq).The product are soluble easily in water, 10% pH value of water solution 4.5~6.It is water-soluble
Liquid is unstable, and room temperature preservation uses in 24 hours；Refrigerator saves 5 days, and potency reduces by 10%.If refrigeration has crystallization to be precipitated, can use
It is used after warm water warm dissolution.
The method of purification of existing brizolina are as follows: after the completion of cephazoline synthesis, the hydrolyzate containing cephazoline is used
Alumina column absorption is trapped, and impurity enters mother liquor outflow, then, then is eluted with sodium acetate solution, after being purified
Cephazoline solution, later period finally obtain brizolina in crystallization.Cumbersome, intermediate link, which goes wrong, is easy to cause matter
Deviation is measured, a large amount of waste water is generated and causes environmental protection treatment burden big, operation cycle length is easy to cause degradation and new impurity to generate.And its
He is similar with means such as resin column purifications, with alumina column same problem and defect.
How separating-purifying, control product impurity, control product quality, make that dopant species are few, the low drug of limit, directly
It connects and influences drug safety, therefore, the purification of brizolina product is studied, and is had a very important significance.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of methods of purification of brizolina, and this method is easy to operate,
Period is short, and discharge of wastewater is few, has environment-friendly advantage, and the content of product brizolina is high, and dopant species are few, and impurity content is low,
Drug safety.
In order to solve the above technical problems, the technical solution used in the present invention is: a kind of method of purification of brizolina,
Include the following steps:
(1) after the completion of cephazoline synthesis, after adding water to hydrolyze, methylene chloride is added into hydrolyzate, adds hydrochloric acid, control
PH=1.3~1.6 processed are stood, and split-phase, water phase discards, and collect methylene chloride phase；
(2) water is added into methylene chloride phase, adjusts pH=6.4~6.7 with sodium hydroxide solution, stand, split-phase discards
Methylene chloride phase, the cephazoline sodium solution after being purified.
Preferably, in step (1), the concentration of cephazoline is 200~400g/L in hydrolyzate.
Preferably, in step (1), the volumetric usage of methylene chloride is 0.5~2 times of hydrolyzate volume.
Preferably, in step (1), the mass fraction concentration of hydrochloric acid is 5~15%.
Preferably, in step (2), water is added into methylene chloride phase, the volumetric usage of water is methylene chloride body used
Long-pending 1~3 times.
Preferably, in step (2), the mass fraction concentration of sodium hydroxide solution is 5~15%.
Preferably, it in step (2), to the cephazoline sodium solution after purification, is crystallized, it is pure to obtain brizolina
Product；Recrystallisation solvent is acetone；The volumetric usage of recrystallisation solvent is 3~5 times of brizolina liquor capacity；Crystallization temperature is 10
~15 DEG C.
The beneficial effects of adopting the technical scheme are that
(1) the method for the present invention is easy to operate, and the period is short, and discharge of wastewater is few, has environment-friendly advantage, product brizolina
Content is high, and dopant species are few, and impurity content is low, drug safety.
(2) the method for the present invention discharge of wastewater is few, generates a large amount of waste water in alumina column elution and regenerative process, the present invention subtracts
Few waste water dosage 60%, has environment-friendly advantage.
(3) due to also using methylene chloride in cephazoline synthesis, the methylene chloride generated after extraction can merge recycling
It recycles, does not generate new solvent type.
(4) the method for the present invention is easy to operate, and unlike alumina column, early period, mid-term, later period require to control, this hair
PH value is only controlled in bright operating process, split-phase is fairly simple, and the time cycle shortens 40%.
(5) the method for the present invention dissolves sex differernce using brizolina, after the completion of cephazoline synthesis, contains cephazoline
Hydrolyzate, methylene chloride is added and is extracted, into methylene chloride, adds water, after adjusting pH, brizolina enters water
Phase, obtains separating-purifying, and unknown impuritie is reduced.
Specific embodiment
The present invention will be further described in detail with reference to the specific embodiments.
The synthesis of cephazoline
In 100ml methylene chloride, 10g 7-ACT is added dropwise triethylamine until being completely dissolved, adds equimolar tetrazole
The acid anhydrides that acetic acid and pivaloyl chloride are mixed to form carries out condensation reaction, is condensed 2 hours beginning sample detections at -5~-10 DEG C, directly
Stop reaction after being lower than 1% to 7-ACT condensation product content, then, 200ml water is added, reaction is hydrolyzed, stirring 15 minutes quiet
After setting 15 minutes, split-phase separates lower layer's methylene chloride phase, collects water phase, obtains the hydrolyzate of cephazoline.Or referring to other existing
There is the synthetic method of cephazoline.
Embodiment 1
After the completion of cephazoline synthesis, after adding water to hydrolyze, 50ml bis- is added in the hydrolyzate 100ml of the 2g containing cefazolin
Chloromethanes is added dropwise to 10% hydrochloric acid of mass fraction while stirring, controls pH=1.3~1.6, is then allowed to stand 10 minutes.Split-phase, water
It mutually discards, collects methylene chloride phase, 100ml water is added, stirs on one side, use 10% sodium hydroxide solution tune pH of mass fraction on one side
=6.4~6.7, stand 10 minutes.Split-phase discards methylene chloride phase, the cephazoline sodium solution after being purified, yield
92.4%, content 98.1, single miscellaneous 0.21%.To the cephazoline sodium solution after purification, is crystallized, it is pure to obtain brizolina
Product；Recrystallisation solvent is acetone；The volumetric usage of recrystallisation solvent is 3 times of brizolina liquor capacity；Crystallization temperature be 10~
15℃。
Embodiment 2
After the completion of cephazoline synthesis, after adding water to hydrolyze, 80ml is added in the hydrolyzate 100ml of the 2.5g containing cefazolin
Methylene chloride is added dropwise to 12% hydrochloric acid of mass fraction while stirring, controls pH=1.3~1.6, is then allowed to stand 10 minutes.Split-phase,
Water phase discards, and collects methylene chloride phase, and 150ml water is added, stirs on one side, uses 10% sodium hydroxide solution tune of mass fraction on one side
PH=6.4~6.7 stand 10 minutes.Split-phase discards methylene chloride phase, the cephazoline sodium solution after being purified, yield
93.0%, content 98.2, single miscellaneous 0.23%.To the cephazoline sodium solution after purification, is crystallized, it is pure to obtain brizolina
Product；Recrystallisation solvent is acetone；The volumetric usage of recrystallisation solvent is 4 times of brizolina liquor capacity；Crystallization temperature be 10~
15℃。
Embodiment 3
After the completion of cephazoline synthesis, after adding water to hydrolyze, 100ml is added in the hydrolyzate 100ml of the 1.5g containing cefazolin
Methylene chloride is added dropwise to 8% hydrochloric acid of mass fraction while stirring, controls pH=1.3~1.6, is then allowed to stand 10 minutes.Split-phase,
Water phase discards, and collects methylene chloride phase, and 120ml water is added, stirs on one side, uses 8% sodium hydroxide solution tune of mass fraction on one side
PH=6.4~6.7 stand 10 minutes.Split-phase discards methylene chloride phase, the cephazoline sodium solution after being purified, yield
88%, content 98.6, single miscellaneous 0.15%.To the cephazoline sodium solution after purification, is crystallized, it is pure to obtain brizolina
Product；Recrystallisation solvent is acetone；The volumetric usage of recrystallisation solvent is 5 times of brizolina liquor capacity；Crystallization temperature be 10~
15℃。
The method of purification of existing brizolina: after the completion of cephazoline synthesis, the hydrolyzate containing cephazoline uses oxygen
Change the absorption of aluminium column to be trapped, impurity enters mother liquor outflow, then, then is eluted with sodium acetate solution, the head after being purified
Spore oxazoline solution, later period recrystallization finally obtain brizolina.Cumbersome, intermediate link, which goes wrong, is easy to cause quality
Deviation generates a large amount of waste water and causes environmental protection treatment burden big, and operation cycle length is easy to cause degradation and new impurity to generate.Existing oxygen
The yield for changing the brizolina product that aluminium column adsorption method obtains is 90.2%, content 89.0%, single miscellaneous 0.25%.The present invention
The method of purification of brizolina, easy to operate, the period is short, and discharge of wastewater is few, has environment-friendly advantage, product brizolina
Content is high, and dopant species are few, and impurity content is low, drug safety.
The above is only the preferred embodiment of the present invention, are not intended to limit the invention, and those skilled in the art are come
It says, without departing from the principle of the present invention, several improvement, the retouching, equivalent replacement that can also be made should be included in this
Within the protection scope of invention.
Claims (7)
1. a kind of method of purification of brizolina, which comprises the steps of:
(1) after the completion of cephazoline synthesis, after adding water to hydrolyze, methylene chloride is added into hydrolyzate, adds hydrochloric acid, controls pH
=1.3~1.6, it stands, split-phase, water phase discards, and collects methylene chloride phase；
(2) water is added into methylene chloride phase, adjusts pH=6.4~6.7 with sodium hydroxide solution, stand, split-phase discards dichloro
Methane phase, the cephazoline sodium solution after being purified.
2. a kind of method of purification of brizolina according to claim 1, it is characterised in that: in step (1), hydrolyzate
The concentration of middle cephazoline is 200~400g/L.
3. a kind of method of purification of brizolina according to claim 1, it is characterised in that: in step (1), dichloromethane
The volumetric usage of alkane is 0.5~2 times of hydrolyzate volume.
4. a kind of method of purification of brizolina according to claim 1, it is characterised in that: in step (1), hydrochloric acid
Mass fraction concentration is 5~15%.
5. a kind of method of purification of brizolina according to claim 1, it is characterised in that: in step (2), to dichloro
Water is added in methane phase, the volumetric usage of water is 1~3 times of methylene chloride volume used.
6. a kind of method of purification of brizolina according to claim 1, it is characterised in that: in step (2), hydroxide
The mass fraction concentration of sodium solution is 5~15%.
7. a kind of method of purification of brizolina according to claim 1, it is characterised in that: in step (2), to purification
Cephazoline sodium solution afterwards, is crystallized, and cephazoline sodium pure product is obtained；Recrystallisation solvent is acetone；The volume of recrystallisation solvent
Dosage is 3~5 times of brizolina liquor capacity；Crystallization temperature is 10~15 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910851736.2A CN110483554A (en) | 2019-09-10 | 2019-09-10 | A kind of method of purification of brizolina |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910851736.2A CN110483554A (en) | 2019-09-10 | 2019-09-10 | A kind of method of purification of brizolina |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110483554A true CN110483554A (en) | 2019-11-22 |
Family
ID=68557125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910851736.2A Pending CN110483554A (en) | 2019-09-10 | 2019-09-10 | A kind of method of purification of brizolina |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110483554A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111548357A (en) * | 2020-04-16 | 2020-08-18 | 华北制药河北华民药业有限责任公司 | High-purity cefazolin sodium and preparation method of pharmaceutical preparation thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4327211A (en) * | 1980-11-26 | 1982-04-27 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for preparation of cephalosporin compounds |
| CN102321101A (en) * | 2011-07-28 | 2012-01-18 | 哈药集团制药总厂 | Preparation method of cefazolin sodium |
| CN104327100A (en) * | 2014-09-30 | 2015-02-04 | 华北制药河北华民药业有限责任公司 | Preparation technology of high-purity flomoxef sodium |
| CN105541870A (en) * | 2016-02-01 | 2016-05-04 | 中山市金城道勃法制药有限公司 | Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium |
-
2019
- 2019-09-10 CN CN201910851736.2A patent/CN110483554A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4327211A (en) * | 1980-11-26 | 1982-04-27 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for preparation of cephalosporin compounds |
| CN102321101A (en) * | 2011-07-28 | 2012-01-18 | 哈药集团制药总厂 | Preparation method of cefazolin sodium |
| CN104327100A (en) * | 2014-09-30 | 2015-02-04 | 华北制药河北华民药业有限责任公司 | Preparation technology of high-purity flomoxef sodium |
| CN105541870A (en) * | 2016-02-01 | 2016-05-04 | 中山市金城道勃法制药有限公司 | Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium |
Non-Patent Citations (1)
| Title |
|---|
| 曹卫凯: "头孢唑啉钠的合成研究", 《医药工艺与工程》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111548357A (en) * | 2020-04-16 | 2020-08-18 | 华北制药河北华民药业有限责任公司 | High-purity cefazolin sodium and preparation method of pharmaceutical preparation thereof |
| CN111548357B (en) * | 2020-04-16 | 2021-07-13 | 华北制药河北华民药业有限责任公司 | High-purity cefazolin sodium and preparation method of pharmaceutical preparation thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102010426B (en) | Method for preparing ceftizoxime sodium | |
| CN102321101B (en) | Preparation method of cefazolin sodium | |
| CN101584665B (en) | Cefotiam hydrochloride medicament composition sterile powder injection and preparation method thereof | |
| FI65432C (en) | EXAMINATION OF ANTIBACTERIA 7BETA-ARYLMALONAMIDO-7ALFA-METHOXY-3-THIADIAZOLYLTHIOMETHYL-1-DETIA-1-OXA-3-CEFEM-4-CARBONSYROR ELER DERIVAT | |
| CN101613359B (en) | Method for synthesizing cefuroxime sodium | |
| CN101812076B (en) | Cefuroxime sodium and preparation method thereof | |
| CN100506210C (en) | Ceftezole sodium powder injection and synthesizing method thereof | |
| JPH021148B2 (en) | ||
| CN110483554A (en) | A kind of method of purification of brizolina | |
| CN104644630A (en) | Amoxicillin sodium and sulbactam sodium preparation for injection and preparation method thereof | |
| CN110372727A (en) | Cefoperon acid δ3Isomers and Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers | |
| CN109553626B (en) | Refining method of ceftizoxime sodium | |
| CN103319503A (en) | Preparation method of cefdinir | |
| CN105622634A (en) | Method for producing ceftizoxime acid | |
| CN102911186B (en) | Ceftizoxime sodium preparation and refining method | |
| CN108912145B (en) | Preparation method of alpha-pivaloyl cefditoren pivoxil | |
| CN109517001B (en) | Preparation method of cefotiam hydrochloride | |
| CN106317080A (en) | Ceftazidime compound prepared by adopting coupling crystallization technology and preparation thereof | |
| JPH04500819A (en) | Improvements in or related to organic compounds | |
| CN106565749B (en) | The method for promoting Cefamandole Nafate quality using three-dimensional column plate purification solvent | |
| CN104230956B (en) | A kind of preparation method of cefoxitin | |
| CN104230955B (en) | A kind of preparation method to the acid of hydroxyl penicillin V and salt thereof | |
| CN103374019B (en) | A kind of preparation method of Cefuroxime Sodium | |
| WO2013010297A1 (en) | Method for purifying ceftizoxime sodium | |
| CN110143973A (en) | A kind of preparation process of Flomoxef Sodium |
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: 20191122 |
|
| RJ01 | Rejection of invention patent application after publication |