CN105001239A - Cefmenoxime hydrochloride compound entity used for children and preparation thereof - Google Patents
Cefmenoxime hydrochloride compound entity used for children and preparation thereof Download PDFInfo
- Publication number
- CN105001239A CN105001239A CN201510281878.1A CN201510281878A CN105001239A CN 105001239 A CN105001239 A CN 105001239A CN 201510281878 A CN201510281878 A CN 201510281878A CN 105001239 A CN105001239 A CN 105001239A
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- CN
- China
- Prior art keywords
- cefmenoxime
- hydrochloride compound
- children
- cefmenoxime hydrochloride
- compound entity
- 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.)
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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
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
Abstract
The invention provides a cefmenoxime hydrochloride compound entity used for children. The structural formula is as shown in specifications. The cefmenoxime hydrochloride compound entity is prepared through the steps that step1, water is added into a cefmenoxime hydrochloride crude product, sodium carbonate is added, stirring is performed for dissolving, an extracting agent is added, and then the cefmenoxime hydrochloride crude product is transferred into a pressure-resistant container in a filling mode, vibrated in a sealed mode after being defoamed and taken out after being frozen in a temperature control mode; step2, an organic phase is removed, after a solid is melted, active carbon is added, stirring is performed for discoloring, and filtering is performed; step3, pH of filtrate is adjusted to 1.5-2.3 through hydrochloride acid, and then crystal growing, filtering, washing with water and vacuum drying at 40 DEG C are performed to obtain the cefmenoxime hydrochloride compound entity. The cefmenoxime hydrochloride prepared through the method has the advantages of having few impurities, being high in purity and the like compared with a traditional technology.
Description
Technical field
The present invention relates to a kind of children's with cefmenoxime hydrochloride compound entity and preparation thereof, belong to medicinal chemistry art.
Background technology
Cefmenoxime Hemihydrochloride chemical name is (6R, 7R)-7-[2-(2-amino-4-thiazolyl) (methoxyimino) acetamido]-3-[[(1-methyl isophthalic acid H-tetrazolium-5-base)-sulphur]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid hydrochloride, also known as Cefmenoxime, Bestcall, be third generation cephalo, all have anti-microbial effect to Gram-negative and positive aerophil and anerobe.In Gram-negative bacteria, slightly stronger than cefotiam to the anti-microbial effect of intestinal bacteria, pneumobacillus, obviously be better than the Kefzol of the first-generation, to influenza bite blood bacillus, Bacillus proteus, serratia marcesens, Citrobacter, enterobacter anti-microbial effect also stronger, also have very strong anti-microbial effect to Bacteroides.In gram-positive microorganism, also stronger to micrococcus scarlatinae, pneumococcal anti-microbial effect.Also powerful anti-microbial effect is had to Peptococcus, Peptostreptococcus.Beta lactamase is stablized.This product is applicable to responsive microbial septicemia, meningitis, respiratory tract infection, pyothorax, liver and courage infection, peritonitis, urinary tract infection, genital system infection and burn and surgical wound infection etc.
The preparation of prior art Cefmenoxime Hemihydrochloride is generally taked: in cefmenoxime acid, add water formulated suspension, add sodium carbonate stirring and dissolving, sterile filtration after activated carbon decolorizing, filtrate added drop-wise hydrochloric acid, and stirred crystallization, filters after washing.This preparation method is simple to operate, and the Cefmenoxime Hemihydrochloride prepared also can meet Chinese Pharmacopoeia standard.But, because Cefmenoxime Hemihydrochloride dissolves difficulty, and cephalosporin product poor stability in the solution, in dissolving, overlong time can cause cefmenoxime to be degraded, and impurity increases.Children's torso each side is still in growth phase, and the side effect that Drug-related causes can show particularly evident, controls Drug-related content in pediatric pharmaceuticals, seems particularly important.The purity how improving children's's Cefmenoxime Hemihydrochloride is current problem demanding prompt solution, has great Social benefit and economic benefit.
Summary of the invention
The object of the invention is to provide a kind of preparation method of new cefmenoxime hydrochloride compound, adds novel purification technique, and the cefmenoxime hydrochloride compound impurity obtained obviously is reduced, and purity and stability obtain larger raising.
For achieving the above object, the present invention is by the following technical solutions:
A kind of children's uses cefmenoxime hydrochloride compound entity, the structure of this cefmenoxime hydrochloride compound entity as shown in formula I,
Children's as claimed in claim 1 uses cefmenoxime hydrochloride compound entity, it is characterized in that, described cefmenoxime hydrochloride compound is prepared by following steps:
(1) Cefmenoxime Hemihydrochloride crude product adds water, and stirs and slowly drips sodium hydrogen carbonate solution until clarification, add extraction agent, be transferred to and be full of in pressure vessel, sealing vibration after removal bubble, the freezing rear taking-up of temperature control;
(2) remove organic phase, solid adds gac after melting, and stirs decolouring, filters;
(3) filtrate is with salt acid for adjusting pH to 1.2-2.0, and growing the grain, filters, wash with water, 40 DEG C of vacuum-dryings and get final product.
Preferably, in described step (1), Cefmenoxime Hemihydrochloride strength of solution is no more than 0.3g/ml.
Preferably, described extraction agent is several mixing of ethyl acetate, chloroform, ether or more.
Preferably, in described step (1), the volume ratio of described extraction agent and described water is 1:100 ~ 200.
Preferably, described temperature control freezing temp is greater than the fusing point of extraction agent.
Preferably, in described step (1), be refrigerated to aqueous portion and freeze rear taking-up.
Preferably, in described step (1), regulate pH to 1.5.
The present invention also provides a kind of children's with the preparation of cefmenoxime hydrochloride compound entity, and said preparation is powder injection, comprises Cefmenoxime Hemihydrochloride and anhydrous sodium carbonate; By weight, Cefmenoxime Hemihydrochloride is 100 parts, and anhydrous sodium carbonate is 24.2 parts.
Technique scheme has following beneficial effect: in refrigerating process, aqueous solvent is frozen into ice, volumetric expansion increases, internal pressure in airtight pressure vessel is increased, thus the solubleness of the organic impurity that improve in Cefmenoxime Hemihydrochloride in extraction agent, reduce the foreign matter content in finished product; In the process of simultaneously water condensation Cheng Bing, because organic impurity is extruded in ice, further increase extraction efficiency, reduce foreign matter content; Compared with the Cefmenoxime Hemihydrochloride that traditional technology is obtained, the Cefmenoxime Hemihydrochloride impurity that the present invention obtains obviously is reduced, thus has good stability, purity advantages of higher.
Embodiment
Set forth the specific embodiment of the present invention further below:
Embodiment 1
(1) take cefmenoxime crude product 100g, add water 1000ml, stirs and slowly drip 4% sodium hydrogen carbonate solution until clarification, add 10ml ethyl acetate under stirring, be transferred in 1000ml pressure vessel, guarantee to be full of and bubble removal, sealed vessel, vibration, takes out after the freezing 3h of temperature control-18 DEG C;
(2) remove organic phase, after ice-out, add 10g gac, stir decolouring, filter;
(3) filtrate is transferred to crystallizer, temperature control 10 ~ 15 DEG C, regulates pH to 1.5 with dilute hydrochloric acid, and continue growing the grain 1h, suction filtration, washes with water, 40 DEG C of vacuum-dryings and get final product.Maximum list assorted 0.13%, always mixes 0.23%.
Embodiment 2
(1) take cefmenoxime crude product 100g, add water 1000ml, stirs and slowly drip 4% sodium hydrogen carbonate solution until clarification, add 10ml chloroform under stirring, be transferred in 1000ml pressure vessel, guarantee to be full of and bubble removal, sealed vessel, vibration, takes out after the freezing 3h of temperature control-18 DEG C;
(2) remove organic phase, after ice-out, add 10g gac, stir decolouring, filter;
(3) filtrate is transferred to crystallizer, temperature control 10 ~ 15 DEG C, regulates pH to 1.7 with dilute hydrochloric acid, and continue growing the grain 1h, suction filtration, washes with water, 40 DEG C of vacuum-dryings and get final product.Maximum list assorted 0.19%, always mixes 0.29%.
Embodiment 3
(1) take cefmenoxime crude product 100g, add water 1000ml, stirs and slowly drip 4% sodium hydrogen carbonate solution until clarification, add 7ml ethyl acetate under stirring, be transferred in 1000ml pressure vessel, guarantee to be full of and bubble removal, sealed vessel, vibration, takes out after the freezing 3h of temperature control-18 DEG C;
(2) remove organic phase, after ice-out, add 10g gac, stir decolouring, filter;
(3) filtrate is transferred to crystallizer, temperature control 10 ~ 15 DEG C, regulates pH to 1.5 with dilute hydrochloric acid, and continue growing the grain 1h, suction filtration, washes with water, 40 DEG C of vacuum-dryings and get final product.Maximum list assorted 0.17%, always mixes 0.24%.
Embodiment 4 (comparative example)
Take cefmenoxime crude product 100g, add water 1000ml, stirs and slowly drip 4% sodium hydrogen carbonate solution until clarification, add 10g gac, stirs decolouring, filters; Filtrate is transferred to crystallizer, temperature control 10 ~ 15 DEG C, regulates pH to 1.5 with dilute hydrochloric acid, and continue growing the grain 1h, suction filtration, washes with water, 40 DEG C of vacuum-dryings and get final product.Maximum list assorted 0.25%, always mixes 0.53%.
Embodiment 5
The Cefmenoxime Hemihydrochloride prepared by above-described embodiment, by weight, mixes packing with anhydrous sodium carbonate in the ratio of 100:24.2 is aseptic, obtains cefmenoxime hydrochloride in powder injection.
More than describe preferred embodiment of the present invention in detail.Should be appreciated that those of ordinary skill in the art just design according to the present invention can make many modifications and variations without the need to creative work.Therefore, all technician in the art, all should by the determined protection domain of claims under this invention's idea on the basis of existing technology by the available technical scheme of logical analysis, reasoning, or a limited experiment.
Claims (9)
1. children's uses a cefmenoxime hydrochloride compound entity, it is characterized in that, the structure of this cefmenoxime hydrochloride compound entity as shown in formula I,
2. children's as claimed in claim 1 uses cefmenoxime hydrochloride compound entity, and it is characterized in that, described cefmenoxime hydrochloride compound is prepared by following steps:
(1) Cefmenoxime Hemihydrochloride crude product adds water, and stirs and slowly drips sodium hydrogen carbonate solution until clarification, add extraction agent, be transferred to and be full of in pressure vessel, sealing vibration after removal bubble, the freezing rear taking-up of temperature control;
(2) remove organic phase, solid adds gac after melting, and stirs decolouring, filters;
(3) filtrate is with salt acid for adjusting pH to 1.2-2.0, and growing the grain, filters, wash with water, 40 DEG C of vacuum-dryings and get final product.
3. children's as claimed in claim 2 uses cefmenoxime hydrochloride compound entity, and it is characterized in that, in described step (1), Cefmenoxime Hemihydrochloride strength of solution is no more than 0.3g/ml.
4. children's as claimed in claim 2 uses cefmenoxime hydrochloride compound entity, and it is characterized in that, described extraction agent is several mixing of ethyl acetate, chloroform, ether or more.
5. children's as claimed in claim 2 uses cefmenoxime hydrochloride compound entity, and it is characterized in that, in described step (1), the volume ratio of described extraction agent and described water is 1:100 ~ 200.
6. children's as claimed in claim 2 uses cefmenoxime hydrochloride compound entity, and it is characterized in that, described temperature control freezing temp is greater than the fusing point of extraction agent.
7. children's as claimed in claim 2 uses cefmenoxime hydrochloride compound entity, it is characterized in that, in described step (1), is refrigerated to aqueous portion and freezes rear taking-up.
8. children's as claimed in claim 2 uses cefmenoxime hydrochloride compound entity, it is characterized in that, in described step (1), regulates pH to 1.5.
9. comprise children's described in any one of claim 1-8 with a preparation for cefmenoxime hydrochloride compound entity, it is characterized in that, described preparation is powder injection, comprises described Cefmenoxime Hemihydrochloride and anhydrous sodium carbonate; By weight, described Cefmenoxime Hemihydrochloride is 100 parts, and described anhydrous sodium carbonate is 24.2 parts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510281878.1A CN105001239A (en) | 2015-05-28 | 2015-05-28 | Cefmenoxime hydrochloride compound entity used for children and preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510281878.1A CN105001239A (en) | 2015-05-28 | 2015-05-28 | Cefmenoxime hydrochloride compound entity used for children and preparation thereof |
Publications (1)
| Publication Number | Publication Date |
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| CN105001239A true CN105001239A (en) | 2015-10-28 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN201510281878.1A Pending CN105001239A (en) | 2015-05-28 | 2015-05-28 | Cefmenoxime hydrochloride compound entity used for children and preparation thereof |
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| CN (1) | CN105001239A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566352A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102179063A (en) * | 2011-03-23 | 2011-09-14 | 苏州汇通色谱分离纯化有限公司 | High pressure liquid-liquid extraction method |
| CN102603772A (en) * | 2012-03-08 | 2012-07-25 | 哈药集团制药总厂 | Method for preparing sterile cefmenoxime hydrochloride compound |
| CN102816174A (en) * | 2012-09-10 | 2012-12-12 | 天津市嵩锐医药科技有限公司 | Amorphous cefmenoxime hydrochloride compound |
| CN103159786A (en) * | 2011-12-13 | 2013-06-19 | 辽宁海思科制药有限公司 | Preparation method for high-purity sterilized cefmenoxime hydrochloride and pharmaceutical composition containing cefmenoxime hydrochloride |
-
2015
- 2015-05-28 CN CN201510281878.1A patent/CN105001239A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102179063A (en) * | 2011-03-23 | 2011-09-14 | 苏州汇通色谱分离纯化有限公司 | High pressure liquid-liquid extraction method |
| CN103159786A (en) * | 2011-12-13 | 2013-06-19 | 辽宁海思科制药有限公司 | Preparation method for high-purity sterilized cefmenoxime hydrochloride and pharmaceutical composition containing cefmenoxime hydrochloride |
| CN102603772A (en) * | 2012-03-08 | 2012-07-25 | 哈药集团制药总厂 | Method for preparing sterile cefmenoxime hydrochloride compound |
| CN102816174A (en) * | 2012-09-10 | 2012-12-12 | 天津市嵩锐医药科技有限公司 | Amorphous cefmenoxime hydrochloride compound |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566352A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefmenoxine hydrochloride compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
| WO2017140074A1 (en) * | 2016-02-18 | 2017-08-24 | 海南灵康制药有限公司 | Cefmenoxime hydrochloride new crystalline form and formulation |
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Application publication date: 20151028 |
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| RJ01 | Rejection of invention patent application after publication |