CN109081837A - The method for separating and preparing of mezlocillin sodium impurity A - Google Patents
The method for separating and preparing of mezlocillin sodium impurity A Download PDFInfo
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- CN109081837A CN109081837A CN201811248179.7A CN201811248179A CN109081837A CN 109081837 A CN109081837 A CN 109081837A CN 201811248179 A CN201811248179 A CN 201811248179A CN 109081837 A CN109081837 A CN 109081837A
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Abstract
The invention belongs to pharmaceutical technology fields, it is related to a kind of refining methd of antibiotic medicinal compound impurity, more particularly to the method for separating and preparing of mezlocillin sodium impurity A, the method for separating and preparing of mezlocillin sodium impurity A disclosed by the invention, the following steps are included: being reacted with base reagent and mezlocillin sodium impurity A being made using mezlocillin sodium as raw material.Technical solution of the present invention passes through mezlocillin sodium and aqueous slkali, acid solution and inorganic salts at room temperature, and filtration washing is dry to obtain mezlocillin sodium impurity A.The present invention also provides the refining methds for isolating and purifying mezlocillin sodium impurity A, and impurity A purity is made and is greater than 95%, can be applied to research of the chemical standard product, belong to field of medicaments.
Description
Technical field
The present invention relates to a kind of refining methds of antibiotic medicinal compound impurity, and in particular to mezlocillin sodium impurity
The method for separating and preparing of A, belongs to pharmaceutical technology field.
Background technique
The chemical name of mezlocillin sodium are as follows: (2R, 5R, 6R) -3,3- dimethyl -6- [(R) -2 [3- (methyl yellow acyl) -2- oxygen
Generation -1- imidazolidine formamido group] -2- phenylacetylamino] -7- oxo -4- thia -1- azabicyclo [3.2.0]-heptane -2- first
Acid sodium-salt has a structure in which
Mezlocillin sodium is a kind of semi-synthetic penicillins antibiotic, for white or off-white powder or crystallization；It is odorless or
Slightly special smelly, the bitter of band.Clinically green monad false to copper, escherichia coli, pneumobacillus, proteus, Enterobacter,
Citrobacter, Serratia, acinetobacter and there is inhibiting effect to the gram-positive cocci of penicillin-susceptible.
Mezlocillin sodium belongs to beta-lactam penicillin antibiotics, due to the unstability of beta-lactam, causes closing
Plurality of impurities is inevitably generated during at mezlocillin sodium.Impurity of the drug and drug quality, safety and efficiency
Closely related, therefore, importance of the Control of Impurities in pharmaceutical synthesis, exploitation, detection is more and more paid attention to.Mei Luoxi
The chemical structural formula of woods sodium impurity A is as follows, records there is presently no document and openly reports its synthetic method:
During producing mezlocillin sodium, need to carry out the control test of impurity A using reference substance.The current country is still
Wei You research institution is capable of providing the reference substance and preparation method of efficient mezlocillin sodium impurity A, and the external commercially available production of import
Product there are expenses it is high, formality is cumbersome, the arrival period is long the problems such as.And impurity A synthesis is difficult, unstable easy drop after synthesis
Solution, and a large amount of by-products are easily generated in the synthesis process, yield is low, causes commercial product purity not high.
Summary of the invention
It is an object of the invention to overcome drawbacks described above of the existing technology, the mezlocillin sodium impurity of optimization is provided
The preparation method of A provides high-purity reference standards for the quality control and inspection of mezlocillin sodium.
The present invention, which is that the following technical solution is employed, to be realized:
The method for separating and preparing of present invention offer mezlocillin sodium impurity A, comprising the following steps:
Using mezlocillin sodium as raw material, is reacted with base reagent and mezlocillin sodium impurity A is made；
The structure of the mezlocillin sodium is as shown in formula I:
The structure of the mezlocillin sodium impurity A is as shown in formula II:
Further, after reaction, acid solution is added into reaction system, adjusts the pH value of reaction system to acidity,
Inorganic salts are added, filtration drying obtains solid.
Above-mentioned base reagent is one or more of potassium hydroxide, sodium hydroxide and ammonia.
Above-mentioned potassium hydroxide, sodium hydroxide concentration of aqueous solution be 0.1-0.5mol/mL, the aqueous solution quality hundred of the ammonia
Dividing concentration is 25-28%.
Above-mentioned acid solution is one of formic acid, phosphoric acid, acetic acid, hydrochloric acid and trifluoroacetic acid solution or combinations thereof；It adjusts anti-
The pH value for answering system is 2-5.
To promote reaction product dehydration, salt is added as dehydrating agent.Common inorganic salts, preferably hydrogen can be used in above-mentioned salt
One or more of calcium oxide, sodium hydroxide, calcium chloride, sodium chloride, potassium chloride.
After dehydration, laundry treatment products, cleaning solution is one or more of water, ethyl alcohol, ether, acetone, washing
1-2 times, obtain mezlocillin sodium impurity A.Washing times are excessive, will cause impurity A loss, influence impurity A yield.
Specifically, being added in the aqueous solution of base reagent using compound shown in formula I as raw material, after being stirred at room temperature, add
Enter acid solution, adjusting solution ph is 2-5, adds inorganic salts, and it is miscellaneous to obtain mezlocillin sodium after dry for filtration washing 1-2 times
Matter A.In the present invention, " room temperature " refers to environment temperature, usually 18 DEG C to 35 DEG C, preferably 22 DEG C to 30 DEG C.
It is including following the present invention also provides the refining methd using the above-mentioned mezlocillin sodium impurity A of liquid chromatography purification
Step:
(1) preparation of test solution: by 50% acetonitrile of the mezlocillin sodium impurity A being prepared through the above steps
Sufficiently dissolution, is obtained by filtration test solution；
(2) liquid chromatography purification: carrying out preparation purifying by semi-preparative liquid chromatogram for above-mentioned test solution, wherein
Chromatographic condition are as follows:
Chromatographic column: Shim-pack GIST C18；
Mobile phase: A is 0.01%-0.5% percent by volume aqueous solutions of organic acids, and B is acetonitrile；Mobile phase A: Mobile phase B
=65:35-80:20；
Flow velocity: 15-20mL/min；
Type of elution: isocratic elution, mobile phase A keep volumetric concentration constant, at the uniform velocity elute with Mobile phase B；
Detection wavelength: 210nm and 254nm；
The corresponding compound fraction of chromatographic peak is collected, it is dry to get smart to mezlocillin sodium impurity A that gained is prepared solution
Product.
Preferred chromatographic condition, isocratic elution mobile phase volume ratio is mobile phase A: Mobile phase B=75 in step (2):
25。
Further, mobile phase A is aqueous formic acid, acetic acid aqueous solution, trifluoroacetic acid aqueous solution in step (2).
Compared with prior art, the beneficial effect that the present invention obtains is:
(1) the technical scheme is that a kind of refining methd for preparing mezlocillin sodium impurity A easy to operate, the skill
The preparation route of art scheme is short, easy post-processing, reagent are easy to get and pollution-free.
(2) present invention uses semi-preparative liquid chromatogram, the mezlocillin sodium impurity A that preparative separation goes out, and purity is more than
95%, much higher than the purity of commercial standard reference substance.Single preparation time is less than 15min simultaneously, effectively shortens disengaging time,
And separating degree is good, simple process effectively avoids conventional method that impurity A is caused to be degraded, stable product quality, related solvent pair
Clean environment is friendly.
(3) impurity that the high-purity mezlocillin sodium impurity A obtained through the invention can be used in mezlocillin sodium production
Qualitative and quantitative analysis provides important directive significance for safe medication to improve the quality standard of mezlocillin sodium.
Detailed description of the invention
Fig. 1 is that the mezlocillin sodium impurity A that embodiment 1 is prepared is produced using semi-preparative liquid chromatograph preparation gained
The HPLC of object schemes.
Fig. 2 is that the mezlocillin sodium impurity A that embodiment 1 is prepared is produced using semi-preparative liquid chromatograph preparation gained
The HPLC of object schemes.
Fig. 3 is that the mezlocillin sodium impurity A that embodiment 2 is prepared is produced using semi-preparative liquid chromatograph preparation gained
The HPLC of object schemes.
Fig. 4 is that the mezlocillin sodium impurity A that embodiment 2 is prepared is produced using semi-preparative liquid chromatograph preparation gained
The HPLC of object schemes.
Fig. 5 is that the mezlocillin sodium impurity A that embodiment 3 is prepared is produced using semi-preparative liquid chromatograph preparation gained
The HPLC of object schemes.
Fig. 6 is that the mezlocillin sodium impurity A that embodiment 4 is prepared is produced using semi-preparative liquid chromatograph preparation gained
The HPLC of object schemes.
Fig. 7 is that the mezlocillin sodium impurity A that embodiment 9 is prepared is produced using semi-preparative liquid chromatograph preparation gained
The HPLC of object schemes.
Specific embodiment
Method of the invention is illustrated below by specific embodiment, but the present invention is not limited thereto.
Experimental method described in following embodiments is unless otherwise specified conventional method；The reagent and material,
Using analytical reagents, unless otherwise specified, commercially obtain.Ammonium hydroxide is that mass percentage concentration is 25%-28%,
Purchased from along Cheng Huagong.The processing that is further purified that gained slightly mentions product is carried out by half preparative high-performance liquid chromatographic instrument of Shimadzu LC-20A.
One, the separation preparation of mezlocillin sodium impurity A
Embodiment 1
At room temperature, into 2.0g mezlocillin sodium, the potassium hydroxide solution 60mL of 0.1mol/mL is added, stirs 30min
Afterwards, the hydrochloric acid solution of 0.5mol/mL is added dropwise dropwise, adjusts the pH value of solution to 3, after 20g calcium chloride solid stirring 5min is added,
Filtering is eluted once with 5mL water, then primary with 5mL ethanol rinse, and 1.1g solid is obtained after drying at room temperature.According to version in 2015
Chinese Pharmacopoeia measurement, is filler with octadecylsilane chemically bonded silica；Mobile phase be buffer (take potassium dihydrogen phosphate 4.9g and
Dipotassium hydrogen phosphate 0.45g is diluted to 1000mL with water dissolution): acetonitrile, by volume 80:20 isocratic elution, flow velocity 1.0mL/
min；30 DEG C of column temperature, Detection wavelength 210nm；Retention time 11.1min.Calculate to obtain yield 70%.
Embodiment 2
At room temperature, into 2.0g mezlocillin sodium, the sodium hydroxide solution 60mL of 0.1mol/mL is added, stirs 30min
Afterwards, phosphoric acid solution is added dropwise dropwise, adjusts the pH value of solution to 4, after 20g calcium chloride solid stirring 5min is added, 5mL is used in filtering
Water elution is primary then primary with 5mL ethanol rinse, and 1.1g solid is obtained after drying at room temperature.Calculate to obtain yield 67%.
Embodiment 3
At room temperature, into 2.0g mezlocillin sodium, ammonium hydroxide 60mL is added, after stirring 30min, it is molten that acetic acid is added dropwise dropwise
Liquid adjusts the pH value of solution to 5, and after adding 15g solid potassium chloride stirring 10min, filtering is eluted twice, room with 5mL acetone
1.2g solid, yield 52% are obtained after temperature is dry.
Embodiment 4
At room temperature, into 2.0g mezlocillin sodium, the potassium hydroxide solution 60mL of 0.1mol/mL is added, stirs 40min
Afterwards, formic acid solution is added dropwise dropwise, adjusts the pH value of solution to 5, after adding 20g solid sodium chloride stirring 10min, filters, use
The elution of 5mL water obtains 1.0g solid, yield 55% twice, after drying at room temperature.
Embodiment 5
At room temperature, into 2.0g mezlocillin sodium, potassium hydroxide (0.1mol/mL) and sodium hydroxide (0.2mol/ is added
ML phosphoric acid solution is added dropwise dropwise, adjusts the pH value of solution to 4, adds 10g hydrogen-oxygen after stirring 40min by) mixed solution 60mL
After changing sodium solid stirring 10min, filtering obtains 1.1g solid, yield 62% with the elution of 5mL ether twice, after drying at room temperature.
Embodiment 6
At room temperature, into 1.5g mezlocillin sodium, the potassium hydroxide solution 40mL of 0.2mol/mL is added, stirs 30min
Afterwards, the hydrochloric acid solution of 0.5mol/mL is added dropwise dropwise, adjusts the pH value of solution to 3, adds 10g solid sodium chloride stirring 10min
Afterwards, it filters, is eluted once with 5mL water, then primary with 5mL ethanol rinse, 0.8g solid, yield 65% are obtained after drying at room temperature.
Embodiment 7
At room temperature, into 1.5g mezlocillin sodium, the potassium hydroxide solution 60mL of 0.1mol/mL is added, stirs 40min
Afterwards, the hydrochloric acid solution of 0.5mol/mL is added dropwise dropwise, adjusts the pH value of solution to 2, adds 10g calcium chloride solid stirring 10min
Afterwards, it filters, obtains 0.7g solid, yield 51% twice, after drying at room temperature with the elution of 5mL ether.
Embodiment 8
At room temperature, into 1.2g mezlocillin sodium, the sodium hydroxide solution 30mL of 0.1mol/mL is added, stirs 20min
Afterwards, formic acid solution is added dropwise dropwise, adjusts the pH value of solution to 5, after adding 15g calcium chloride solid stirring 10min, filters, use
The elution of 5mL water obtains 0.7g solid, yield 58% twice, after drying at room temperature.
Embodiment 9
At room temperature, into 1.0g mezlocillin sodium, the sodium hydroxide solution 30mL of 0.5mol/mL is added, stirs 20min
Afterwards, trifluoroacetic acid solution is added dropwise dropwise, adjusts the pH value of solution to 4, after adding 10g calcium hydroxide solid stirring 10min, mistake
Filter obtains 0.5g solid, yield 66% with the elution of 5mL water twice, after drying at room temperature.
Embodiment 10
At room temperature, into 1.0g mezlocillin sodium, the potassium hydroxide solution 60mL of 0.1mol/mL is added, stirs 20min
Afterwards, formic acid and acetic acid mixed solution are added dropwise dropwise, adjusts the pH value of solution to 5, after 20g calcium chloride solid stirring 10min is added,
Filtering is eluted once with 5mL water, then primary with 5mL ethanol rinse, and 0.5g solid, yield 54% are obtained after drying at room temperature.
Two, the purification of mezlocillin sodium impurity A
By chromatographic isolation and the component of selective enumeration method mixture such mixture can be carried out it is comprehensive qualitative or
Quantitative analysis.Currently, technical staff use half preparative HPLC primarily to from mixture enrichment or purification of target chemical combination
Object.But semi-preparative chromatographic condition separates condition used with typical analytic type and produces difference, causes for complicated sample
The enriching and recovering of target compound is difficult to the chromatographic condition using analytic type in product.Embodiment 9-15 utilizes half preparative liquid phase color
Spectra system and purification condition are refined to mezlocillin sodium impurity A is made in above-described embodiment.
The mezlocillin sodium impurity A that above-described embodiment 1-4,9 are obtained is accurately weighed, is dissolved with 50% acetonitrile, and quantitative
It is diluted to the solution of 100mg/mL, as test solution.
Embodiment 9
The test solution of embodiment 1 is subjected to preparation purifying by semi-preparative liquid chromatogram, wherein chromatographic condition are as follows:
Chromatographic column: Shim-pack GIST C18 (20mm × 250mm, 5 μm)；
Mobile phase: A is 0.01% aqueous formic acid, and B is acetonitrile；Mobile phase A: Mobile phase B=75:25；
Flow velocity: 15mL/min；
Type of elution: isocratic elution, mobile phase A keep volumetric concentration constant, at the uniform velocity elute with Mobile phase B；
Detection wavelength: 210nm and 254nm；
The corresponding compound fraction of chromatographic peak main peak is collected, it is dry to get miscellaneous to mezlocillin sodium that gained is prepared solution
Matter A highly finished product, as shown in Figure 1, mezlocillin sodium impurity A purity is 99.56% in Fig. 1.
Embodiment 10
The test solution of embodiment 1 is subjected to preparation purifying by semi-preparative liquid chromatogram, wherein chromatographic condition are as follows:
Chromatographic column: Shim-pack GIST C18 (20mm × 250mm, 5 μm)；
Mobile phase: A is 0.01% acetic acid aqueous solution, and B is acetonitrile；Mobile phase A: Mobile phase B=65:35；
Flow velocity: 15mL/min；
Type of elution: isocratic elution, mobile phase A keep volumetric concentration constant, at the uniform velocity elute with Mobile phase B；
Detection wavelength: 210nm and 254nm；
The corresponding compound fraction of chromatographic peak main peak is collected, it is dry to get miscellaneous to mezlocillin sodium that gained is prepared solution
For matter A highly finished product as shown in Fig. 2, in Fig. 2, mezlocillin sodium impurity A purity is 88.41%.
Embodiment 11
The test solution of embodiment 2 is subjected to preparation purifying by semi-preparative liquid chromatogram, wherein chromatographic condition are as follows:
Chromatographic column: Shim-pack GIST C18 (20mm × 250mm, 5 μm)；
Mobile phase: A is 0.01% aqueous formic acid, and B is acetonitrile；Mobile phase A: Mobile phase B=75:25；
Flow velocity: 15mL/min；
Type of elution: isocratic elution, mobile phase A keep volumetric concentration constant, at the uniform velocity elute with Mobile phase B；
Detection wavelength: 210nm and 254nm；
The corresponding compound fraction of chromatographic peak main peak is collected, it is dry to get miscellaneous to mezlocillin sodium that gained is prepared solution
Matter A highly finished product.As shown in figure 3, mezlocillin sodium impurity A purity is 85.39% in Fig. 3.
Embodiment 12
The test solution of embodiment 2 is subjected to preparation purifying by semi-preparative liquid chromatogram, wherein chromatographic condition are as follows:
Chromatographic column: Shim-pack GIST C18 (20mm × 250mm, 5 μm)；
Mobile phase: A is 0.1% aqueous formic acid, and B is acetonitrile；Mobile phase A: Mobile phase B=75:25；
Flow velocity: 15mL/min；
Type of elution: isocratic elution, mobile phase A keep volumetric concentration constant, at the uniform velocity elute with Mobile phase B；
Detection wavelength: 210nm and 254nm；
The corresponding compound fraction of chromatographic peak main peak is collected, it is dry to get miscellaneous to mezlocillin sodium that gained is prepared solution
Matter A highly finished product.As shown in figure 4, mezlocillin sodium impurity A purity is 87.27% in Fig. 4.
Embodiment 13
The test solution of embodiment 3 is subjected to preparation purifying by semi-preparative liquid chromatogram, wherein chromatographic condition are as follows:
Chromatographic column: Shim-pack GIST C18 (20mm × 250mm, 5 μm)；
Mobile phase: A is 0.5% trifluoroacetic acid aqueous solution, and B is acetonitrile；Mobile phase A: Mobile phase B=80:20；
Flow velocity: 18mL/min；
Type of elution: isocratic elution, mobile phase A keep volumetric concentration constant, at the uniform velocity elute with Mobile phase B；
Detection wavelength: 210nm and 254nm；
The corresponding compound fraction of chromatographic peak main peak is collected, it is dry to get miscellaneous to mezlocillin sodium that gained is prepared solution
Matter A highly finished product.As shown in figure 5, mezlocillin sodium impurity A purity is 63.08% in Fig. 5.
Embodiment 14
The test solution of embodiment 4 is subjected to preparation purifying by semi-preparative liquid chromatogram, wherein chromatographic condition are as follows:
Chromatographic column: Shim-pack GIST C18 (20mm × 250mm, 5 μm)；
Mobile phase: A is 0.01% trifluoroacetic acid aqueous solution, and B is acetonitrile；Mobile phase A: Mobile phase B=75:25；
Flow velocity: 18mL/min；
Type of elution: isocratic elution, mobile phase A keep volumetric concentration constant, at the uniform velocity elute with Mobile phase B；
Detection wavelength: 210nm and 254nm；
The corresponding compound fraction of chromatographic peak main peak is collected, it is dry to get miscellaneous to mezlocillin sodium that gained is prepared solution
Matter A highly finished product.As shown in fig. 6, mezlocillin sodium impurity A purity is 74.41% in Fig. 6.
Embodiment 15
The test solution of embodiment 9 is subjected to preparation purifying by semi-preparative liquid chromatogram, wherein chromatographic condition are as follows:
Chromatographic column: Shim-pack GIST C18 (20mm × 250mm, 5 μm)；
Mobile phase: A is 0.01% aqueous formic acid, and B is acetonitrile；Mobile phase A: Mobile phase B=75:25；
Flow velocity: 20mL/min；
Type of elution: isocratic elution, mobile phase A keep volumetric concentration constant, at the uniform velocity elute with Mobile phase B；
Detection wavelength: 210nm and 254nm；
The corresponding compound fraction of chromatographic peak main peak is collected, it is dry to get miscellaneous to mezlocillin sodium that gained is prepared solution
Matter A highly finished product.As shown in fig. 7, mezlocillin sodium impurity A purity is 97.88% in Fig. 7.
Certainly, above content is only presently preferred embodiments of the present invention, be should not be construed as limiting to implementation of the invention
Example range.The present invention is also not limited to the example above, and those skilled in the art are in essential scope of the invention
Interior made all the changes and improvements etc., should all belong in patent covering scope of the invention.
Claims (10)
1. a kind of method for separating and preparing of mezlocillin sodium impurity A, it is characterised in that: the following steps are included:
Using mezlocillin sodium as raw material, is reacted with base reagent and mezlocillin sodium impurity A is made；
The structure of the mezlocillin sodium is as shown in formula I:
The structure of the mezlocillin sodium impurity A is as shown in formula II:
2. the method for separating and preparing of mezlocillin sodium impurity A according to claim 1, it is characterised in that: reaction is in water
It carries out, after, acid solution is added into reaction system, adjusts the pH value of reaction system to acidity, adds inorganic salts, filter
It is dry to obtain solid.
3. the method for separating and preparing of mezlocillin sodium impurity A according to claim 2, it is characterised in that: the base reagent
For one or more of potassium hydroxide, sodium hydroxide and ammonia.
4. the method for separating and preparing of mezlocillin sodium impurity A according to claim 3, it is characterised in that: the hydroxide
Potassium, sodium hydroxide concentration of aqueous solution be 0.1-0.5mol/mL, the aqueous solution mass percentage concentration of the ammonia is 25%-28%.
5. the method for separating and preparing of mezlocillin sodium impurity A according to claim 2, it is characterised in that: the acid solution
For one of formic acid, phosphoric acid, acetic acid, hydrochloric acid and trifluoroacetic acid solution or combinations thereof；The pH value for adjusting reaction system is 2-5.
6. the method for separating and preparing of mezlocillin sodium impurity A according to claim 2, it is characterised in that: the inorganic salts
For one or more of calcium hydroxide, sodium hydroxide, calcium chloride, sodium chloride, potassium chloride.
7. the method for separating and preparing of mezlocillin sodium impurity A according to claim 2, it is characterised in that: inorganic salts are added
Afterwards, laundry treatment products being carried out to solid, cleaning solution is one or more of water, ethyl alcohol, ether, acetone, it washs 1-2 times,
It is dry to obtain mezlocillin sodium impurity A.
8. the refining methd for the mezlocillin sodium impurity A that method for separating and preparing according to claim 1-7 obtains,
Characterized by comprising the following steps:
(1) preparation of test solution: mezlocillin sodium impurity A is sufficiently dissolved with 50% acetonitrile, it is molten that test sample is obtained by filtration
Liquid；
(2) liquid chromatography purification: above-mentioned test solution is subjected to preparation purifying by semi-preparative liquid chromatogram, wherein chromatography
Condition are as follows:
Chromatographic column: Shim-pack GIST C18；
Mobile phase: A is 0.01%-0.5% aqueous solutions of organic acids, and B is acetonitrile；Mobile phase A: Mobile phase B=65:35-80:20；
Flow velocity: 15-20mL/min；
Type of elution: isocratic elution, mobile phase A keep volumetric concentration constant, at the uniform velocity elute with Mobile phase B；
Detection wavelength: 210nm and 254nm；
The corresponding compound fraction of chromatographic peak is collected, gained is prepared into solution drying and is refined to get to mezlocillin sodium impurity A
Product.
9. refining methd according to claim 8, it is characterised in that: isocratic elution mobile phase volume ratio in step (2)
For mobile phase A: Mobile phase B=75:25.
10. refining methd according to claim 8, it is characterised in that: mobile phase A is aqueous formic acid, second in step (2)
Aqueous acid, trifluoroacetic acid aqueous solution.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112745313A (en) * | 2020-12-31 | 2021-05-04 | 济南朗科医药技术有限公司 | Preparation method of mezlocillin sodium specific impurity ring-opening mezlocinolate |
| CN114112612A (en) * | 2021-10-28 | 2022-03-01 | 丽珠集团福州福兴医药有限公司 | Separation and purification method of teicoplanin I5 impurity and application thereof |
-
2018
- 2018-10-25 CN CN201811248179.7A patent/CN109081837A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112745313A (en) * | 2020-12-31 | 2021-05-04 | 济南朗科医药技术有限公司 | Preparation method of mezlocillin sodium specific impurity ring-opening mezlocinolate |
| CN114112612A (en) * | 2021-10-28 | 2022-03-01 | 丽珠集团福州福兴医药有限公司 | Separation and purification method of teicoplanin I5 impurity and application thereof |
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Application publication date: 20181225 |