CN104892636B - A kind of method for preparing CTX sodium crystal - Google Patents
A kind of method for preparing CTX sodium crystal Download PDFInfo
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- CN104892636B CN104892636B CN201510264083.XA CN201510264083A CN104892636B CN 104892636 B CN104892636 B CN 104892636B CN 201510264083 A CN201510264083 A CN 201510264083A CN 104892636 B CN104892636 B CN 104892636B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- 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 discloses a kind of novel method for preparing CTX sodium crystal.At 10~30 DEG C, CTX sodium solution is added in 5~15 times of organic solvents of its volume, is cooled to 0~9 DEG C, through filtering, washing, being dried to obtain the unformed powder of Cefotaxime Sodium.During unformed powder is placed in into 2~40 DEG C, the atmosphere of organic solvent atmosphere or water that relative humidity is 32~100%, stands and turn brilliant 24~48 hours, by washing, filter, be dried to obtain Cefotaxime Sodium crystal product.Methods described efficiently avoid the gelation problem during dissolved, simple to operate, and process total moles yield is more than 80%.The main granularity of gained crystal product up to 100 μm, content is high, crystallinity is high, good stability.
Description
Technical field
The invention belongs to Chemical Engineering medicine crystallization technique field, and in particular to a kind of preparation side of CTX sodium crystal
Method.
Background technology
Cefotaxime Sodium (cefotaxime sodium) is the semi-synthetic cynnematin of the third generation, with has a broad antifungal spectrum, antibacterial
The advantages of acting on strong, toxic and side effect is small, the treatment that clinical practice is infected in various sensitive bacterias.Cefotaxime Sodium molecular formula
C16H16N5O7S2Na, molecular weight 477.44, chemical name is (6R, 7R-3- [(acetoxyl group) methyl] -7- [(2- amino -4- thiophenes
Oxazolyl)-(methoxyimino) second phthalein amido] -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- sodium formates
Salt, its structural formula is as follows.
The preparation process of the CTX sodium crystal of report is general in two steps at present：First pass through salt-forming reaction and obtain cephalo thiophene
Oxime sodium solution, the method for then being crystallized using solution prepares CTX sodium crystal.It is first in method disclosed in CN101486719A
First carrying out salt-forming reaction in acetone-water mixed solvent obtains CTX sodium solution, is then added thereto to acetone and crystallizes out
Cefotaxime Sodium.Acetone volume fraction is 80.5% in its initial acetone-water mixed solvent, and content is very high, then a large amount of additions third
Ketone, due to Cefotaxime Sodium indissoluble in acetone, so degree of supersaturation is larger in solution, primary nucleation is difficult to avoid that, easily into
Glue, has a strong impact on stirring and mixing effect, crystal product quality.It is anti-that CN102584854A propositions carry out into salt in anhydrous system
Should, it is subsequently adding crystallization solvent crystalline cephem thiophene oxime sodium.Cefotaxime Sodium is in anhydrous solvent formamide, acetamide, two used
It is readily soluble in first sulfoxide, easily increased sharply because of degree of supersaturation during follow-up addition crystallization solvent and cause that outburst nucleation causes into
Glue.CN103275101A discloses a kind of by controlling solvent composition, crystal seed size and consumption, prepares CTX sodium crystal
Method.This method avoid gelling, but control condition is more harsh, and increased the preparation of crystal seed, adding procedure, operating procedure
It is more, easily the dust in air is incorporated into crystallizer, easily make crystallizing system microbiological contamination.Method is same disclosed in CN103319504A
Sample needs to add crystal seed, and dissolved agent addition is excessive before adding crystal seed, and plastic is still difficult to avoid that.WO2004063203A1 first
The mixed solvent of alcohol, ethanol, acetone and methyl acetate, ethyl acetate etc. carries out salt-forming reaction as reaction dissolvent, then adds again
Enter esters solvent crystalline cephem thiophene oxime sodium.The poor performance of Cefotaxime Sodium is dissolved due to reaction dissolvent used, therefore amine need to be added
Class solvent is as cosolvent.But cosolvent has strong and stimulating, it is awkward, and harm health.
The above-mentioned method for preparing CTX sodium crystal is all that poor solvent is added in CTX sodium solution, this
Process is particularly easy to gelling phenomenon occur：As poor solvent is added, degree of supersaturation constantly increases, and CTX sodium molecule can lead to
Cross self assembly to be woven into network structure and wrap up solvent, in sticky deadlock is partly flowed, Cefotaxime Sodium is sticky for outward appearance
In colloid enrichment and with bulk solution split-phase.Plastic has a strong impact on product quality, and jelly sticks to agitating paddle
Or wall, reduce heat transfer, mass-transfer efficiency, or even influence whole operation process.This is also that current solution crystal process prepares cephalo
The subject matter that thiophene oxime sodium crystal is present.Therefore, it is necessary to develop a kind of be avoided that gelling, high income, preparation simple to operate
The method of CTX sodium crystal, and good stability, purity Cefotaxime Sodium crystal product high can be obtained.
The content of the invention
In order to overcome the defect of prior art, the invention provides a kind of method for crystallising for preparing Cefotaxime Sodium, effectively
The plastic during dissolved Cefotaxime Sodium is avoided, obtained crystal stability is good, simple to operate, it is easy to realization of industrialization.
The invention discloses a kind of method for crystallising for preparing Cefotaxime Sodium, technical scheme includes：
(1) at 10~30 DEG C, the CTX sodium solution that concentration is 0.14~0.7g/mL is added to organic solvent
In, 0~9 DEG C is then cooled to, filter, wash, dry, obtain the unformed powder of Cefotaxime Sodium；
(2) the unformed powder that will be obtained be placed in 2~40 DEG C, organic solvent atmosphere or relative humidity be 32~100%
In the atmosphere of water, stand and turn 24~48h of crystalline substance, be washed out, filter, drying, obtain Cefotaxime Sodium crystal product.
The above method, the preparation method of CTX sodium solution is in step (1), prepares sodium acetate solution, and stirring is lower to be added
Entering cefotaxime acid carries out salt-forming reaction, to solution clarification；Activated carbon decolorizing filtering is added, CTX sodium solution is obtained, with
This is raw material, carries out the operation of step (1).The solvent for preparing sodium acetate is selected from water, formamide, N-N dimethylformamides, isopropyl
One or more in alcohol, ethyl acetate, ethanol, acetone of mixture；The mol ratio of sodium acetate and cefotaxime acid for 1~
1.2:1。
The above method, in step (1) organic solvent be selected from methyl alcohol, n-butanol, methyl acetate, ethyl acetate, butyl acetate,
One or more in acetone or butanone of mixture；Organic solvent volume is 5~15 times of Cefotaxime Sodium liquor capacity.
The above method, the 10~240min of addition time of CTX sodium solution in step (1).
The above method, the rate of temperature fall described in step (1) is 0.2~1 DEG C/min.
The above method, drying condition is in step (1), temperature -70~0 DEG C, 7~100Pa of absolute pressure, dries 12~36h.
The above method, the organic solvent atmosphere described in step (2) is methyl alcohol, ethanol, isopropanol, n-butanol, acetone, first
In acid amides, N-N dimethylformamides, N-N dimethylacetylamides, 1-METHYLPYRROLIDONE, dimethyl sulfoxide, toluene or dichloromethane
It is a kind of at 2~40 DEG C formed saturated vapor.
The crystallization process of Cefotaxime Sodium, usually poor solvent is added in CTX sodium solution carries out dissolved,
And it is particularly easy to gelling phenomenon occur in this process, plastic has a strong impact on product quality, and jelly is adhered to
In agitating paddle or wall, heat transfer, mass-transfer efficiency, or even influence whole operation process are reduced.The inventive method and previous methods
It is completely different, it is characterized in, within shorter 10~240min times, CTX sodium solution is added in poor solvent.
A small amount of CTX sodium solution quickly mixes with substantial amounts of poor solvent, causes solution to be in superelevation hypersaturated state, quickly
The Cefotaxime Sodium of precipitation is unformed aggregation, without any adhesion characteristics, efficiently avoid gelling phenomenon.At -70~0 DEG C
Under carry out low-temperature reduced-pressure drying, can effectively reduce the energy and movement velocity of solvent molecule, it is to avoid in drying process be gelled, obtain
To amorphous powder.It is a kind of solid state of thermodynamic instability that this is unformed, and its easy deliquescence, heat decomposition temperature is low, guarantee the quality
Phase is short.Therefore, the method invention further provides amorphous pellets to be converted into high quality crystal product, by unformed
Grain is placed in 2~40 DEG C, in the air of constant humidity or organic solvent atmosphere, solvent molecule is adsorbed to enter unformed CTX
Inside sodium so that spore thiophene oxime sodium molecule is reset, the periodic structure of formation rule turns crystalline substance and obtains CTX sodium crystal.Product grain
Degree is big, content is high, and crystallinity is high, good stability, overcomes unformed defect.
A kind of new method of CTX sodium crystal for preparing disclosed by the invention has compared with existing preparation method
Following beneficial effect：The method first prepares amorphous pellets, and can be effectively prevented from the gelling phenomenon during dissolved；So
Under amorphous pellets are placed in into stationary temperature, atmosphere afterwards, it is converted into that crystallinity is high, good stability crystal product, overcomes
The problem of unformed easy deliquescence, stability difference.More than 96%, step (2) molar yield is 83.5% for step (1) molar yield
More than, total moles yield is more than 80%；Crystal product Content of Cefotaxime Sodium is higher than 95.0%, and product is brilliant as shown in Figure 1
Body diffraction peak intensity, shows that its crystallinity is high；206 ± 2 DEG C of crystal decomposition temperature shown in accompanying drawing 2, show its good stability；Accompanying drawing 3
It is the microphotograph of crystal, accompanying drawing 4 is Lens capsule figure, it is seen that 100 μm or so of the main granularity of crystal, distribution is concentrated, grain
Degree convergence is consistent, so the big rate of filtration of crystal size is fast, solves conventional method easily gelling and small grain size product filtration difficulty
Problem.The inventive method is simple to operate, it is easy to realized in laboratory and industrial production.
Brief description of the drawings
Fig. 1：The powder x-ray diffraction collection of illustrative plates of gained Cefotaxime Sodium crystal product of the invention；
Fig. 2：The thermal gravimetric analysis curve of gained Cefotaxime Sodium crystal product of the invention；
Fig. 3：The microphotograph of gained Cefotaxime Sodium crystal product of the invention；
Fig. 4：The particle size distribution figure of gained Cefotaxime Sodium crystal product of the invention；
Fig. 5：The microphotograph of the gained Cefotaxime Sodium crystal product of the embodiment of the present invention 3；
Fig. 6：The particle size distribution figure of the gained Cefotaxime Sodium crystal product of the embodiment of the present invention 4.
Specific embodiment
Embodiment 1：
The formamide solution of 0.029g/mL sodium acetates is prepared, adds cefotaxime acid, sodium acetate to be rubbed with cefotaxime acid
You are than being 1.2:1, activated carbon decolorizing is added after stirring reaction, the CTX sodium solution of clarification is filtrated to get, concentration is
0.14g/mL.Take 30mL CTXs sodium solution in the 100min it is interior drop to 20 DEG C in 300mL methyl alcohol.After completion of dropping with
The rate of temperature fall of 1 DEG C/min is cooled to 5 DEG C, and through filtering, methyl alcohol washing at -70 DEG C, 24h is dried under absolute pressure 36Pa, obtains cephalo
The unformed powder of thiophene oxime sodium, molar yield 97%.The unformed powder that will be obtained is statically placed in the water that 30 DEG C of relative humidity is 32%
24h in atmosphere, washing, filtering after at 40 DEG C drying under reduced pressure 36h, obtain crystal product, molar yield 84%.The process is always received
Rate is 81.5%, and crystal product content is 95.5%.
The X-ray diffracting spectrum of gained crystal product such as accompanying drawing 1, diffraction peak intensity shows that its crystallinity is high；Opened at 207 DEG C
Begin to decompose, illustrate that heat endurance is good；As shown in Figure 3, as shown in Figure 4, the main granularity of crystal is 100 to size distribution to crystallogram
μm, granularity is big and distribution is concentrated.
Embodiment 2：
The sodium acetate N-N dimethyl formamide solutions of 0.13g/mL are prepared, cefotaxime acid, sodium acetate and cephalo thiophene is added
The mol ratio of oxime acid is 1.1:1, activated carbon decolorizing is added after stirring reaction, the CTX sodium solution of clarification is filtrated to get, it is dense
It is 0.70g/mL to spend.Take 30mL CTXs sodium solution in the 10min it is interior drop to 20 DEG C at 300mL ethanol and ethyl acetate it is mixed
In bonding solvent.5 DEG C, filtering, ethyl acetate washing are cooled to the rate of temperature fall of 1 DEG C/min after completion of dropping.At -60 DEG C, absolutely
12h is dried under pressure 100pa, the unformed powder of Cefotaxime Sodium is obtained, molar yield is 96%.The unformed powder that will be obtained is quiet
Be placed in 48h in 2 DEG C of saturated steams, after washing, filtering at 40 DEG C drying under reduced pressure 28h, obtain crystal product, molar yield is
83.6%.Process total moles yield is 80.3%, and crystal product content is 95.0%.
Resulting crystal product X-ray diffracting spectrum such as accompanying drawing 1, diffraction peak intensity shows that crystallinity is high；Decomposition temperature
It is 207 DEG C, illustrates that heat endurance is good；The main granularity of crystal is 110 μm, and granularity is big and distribution is concentrated.
Embodiment 3：
Prepare the aqueous solution of the sodium acetate of 0.048g/mL, add cefotaxime acid, sodium acetate and cefotaxime acid mole
Than being 1:1, activated carbon decolorizing is added after stirring reaction, the CTX sodium solution of clarification is filtrated to get, concentration is 0.28g/mL.
Take at 30mL CTXs sodium solution drops to 10 DEG C in 20min in 150mL ethyl acetate.After completion of dropping with 0.2 DEG C/
The rate of temperature fall of min is cooled to 0 DEG C, and through filtering, ethyl acetate washing at -60 DEG C, 36h is dried under absolute pressure 100pa, obtained to the end
The spore thiophene unformed powder of oxime sodium, molar yield is 98%.The unformed powder that will be obtained is statically placed in 20 DEG C of saturated steams
24h, washing, filtering after at 40 DEG C drying under reduced pressure 24h, obtain crystal product, molar yield is 85.5%.Process total moles are received
Rate is 83.8%, and crystal product content is 95.8%.
Resulting crystal product X-ray diffracting spectrum such as accompanying drawing 1, diffraction peak intensity shows that its crystallinity is high；Thermal decomposition
Occur at 206 DEG C, heat endurance is good；As shown in Figure 5, the main granularity of crystal is 80 μm to crystallogram.
Embodiment 4：
The sodium acetate formamide of 0.058g/mL and the solution of isopropanol miscible agent are prepared, cefotaxime acid, sodium acetate is added
It is 1.2 with the mol ratio of cefotaxime acid:1.Activated carbon decolorizing is added after stirring reaction, the Cefotaxime Sodium of clarification is filtrated to get
Solution, concentration is 0.28g/mL.Take 450mL acetone and ethanol at 30mL CTXs sodium solution drops to 10 DEG C in 100min
Mixed solvent in.0 DEG C is cooled to the rate of temperature fall of 0.2 DEG C/min after completion of dropping, through filtering, acetone washing, -40
DEG C, 24h is dried under absolute pressure 36Pa, the unformed powder of Cefotaxime Sodium is obtained, molar yield is 96%.The unformed powder that will be obtained
End is statically placed in 24h in 40 DEG C of atmosphere of N-N dimethylformamides, after washing, filtering at 40 DEG C drying under reduced pressure 24h, obtain crystalline substance
Body product, molar yield is 83.5%.Process total moles yield is 80.2%, and crystal product content is 95.1%.
Resulting crystal product X-ray diffracting spectrum such as accompanying drawing 1, diffraction peak intensity shows that its crystallinity is high；Thermal decomposition
Occur at 207 DEG C, illustrate that heat endurance is good；As shown in Figure 6, the main granularity of crystal is 150 μm to Lens capsule, granularity it is big and
Distribution is concentrated.
Embodiment 5：
The sodium acetate N-N dimethylformamides of 0.079g/mL and the miscible agent solution of acetone are prepared, CTX is added
Acid, sodium acetate is 1.1 with the mol ratio of cefotaxime acid:1.Activated carbon decolorizing is added after stirring reaction, clarification is filtrated to get
CTX sodium solution, concentration is 0.42g/mL.Take 450mL at 30mL CTXs sodium solution drops to 30 DEG C in 240min
In n-butanol.9 DEG C are cooled to the rate of temperature fall of 0.5 DEG C/min after completion of dropping, through filtering, n-butanol is washed, at -20 DEG C,
24h is dried under absolute pressure 7Pa, the unformed powder of Cefotaxime Sodium is obtained, molar yield is 96.5%.The unformed powder that will be obtained
Be statically placed in 30h in 20 DEG C of isopropanol atmosphere, after washing, filtering at 40 DEG C drying under reduced pressure 24h, obtain crystal product, mole receive
Rate is 83.5%.Process total moles yield is 80.6%, and crystal product content is 95.4%.
The X-ray diffracting spectrum of resulting crystal product such as accompanying drawing 1, diffraction peak intensity shows that its crystallinity is high；Heat point
Solution temperature is 207 DEG C, and heat endurance is good；The main granularity of crystal is 120 μm, and granularity is big and homogeneous.
Embodiment 6：
The sodium acetate water of 0.096g/mL and the miscible agent solution of ethanol are prepared, cefotaxime acid, sodium acetate and cephalo is added
The mol ratio of thiophene oxime acid is 1:1.Activated carbon decolorizing is added after stirring reaction, the CTX sodium solution of clarification is filtrated to get, it is dense
It is 0.56g/mL to spend.Take at 30mL CTXs sodium solution drops to 30 DEG C in 240min in 150mL butyl acetates.Drip
9 DEG C are cooled to the rate of temperature fall of 0.5 DEG C/min after finishing, are filtered afterwards, washed with 60mL butyl acetates, at 0 DEG C, dried under 7pa
12h, obtains the unformed powder of Cefotaxime Sodium, and molar yield is 96.5%.The unformed powder that will be obtained is statically placed in 40 DEG C of second
36h in alcohol atmosphere, washing, filtering after at 40 DEG C drying under reduced pressure 24h, obtain crystal product, molar yield is 84%.The process
Total moles yield is 81.1%, and crystal product content is 95.7%.
The X-ray diffracting spectrum of resulting crystal product such as accompanying drawing 1, diffraction peak intensity shows that its crystallinity is high；Heat point
Solution temperature is 206 DEG C, illustrates that heat endurance is good；The main granularity of crystal is 100 μm, and granularity is big and distribution is concentrated.
The preparation method of the CTX sodium crystal for disclosing and proposing of the invention, those skilled in the art can be by using for reference this
The links such as literary content, appropriate feed change, technological parameter are realized.The method of the present invention is entered by preferred embodiment with product
Gone description, person skilled substantially can not departing from present invention, spirit and scope to method described herein and
Product is modified or suitably change realizes the technology of the present invention with combining.In particular, it is all similar to replace
Change and change apparent to those skilled in the art, they be considered as being included in spirit of the invention, scope and
In content.
Claims (8)
1. a kind of preparation method of CTX sodium crystal；It is characterized in that step is as follows：
(1) at 10~30 DEG C, the CTX sodium solution that concentration is 0.14~0.7g/mL is added in organic solvent, so
After be cooled to 0~9 DEG C, filtering, washing, dry, obtain the unformed powder of Cefotaxime Sodium；
(2) the unformed powder that will be obtained is placed in 2~40 DEG C, organic solvent atmosphere or water that relative humidity is 32~100%
In atmosphere, stand and turn 24~48h of crystalline substance, be washed out, filter, drying, obtain Cefotaxime Sodium crystal product；
Organic solvent is selected from methyl alcohol, n-butanol, methyl acetate, ethyl acetate, butyl acetate, acetone, fourth in described step (1)
One or more in ketone of mixture；Organic solvent atmosphere described in described step (2) is methyl alcohol, ethanol, isopropanol,
A kind of saturation formed at 2~40 DEG C in n-butanol, formamide, N, N-dimethylformamide or 1-METHYLPYRROLIDONE
Steam.
2. the method for claim 1, it is characterized in that in described step (1) CTX sodium solution preparation method：
Sodium acetate solution is prepared, the lower addition cefotaxime acid of stirring carries out salt-forming reaction, to solution clarification；Add activated carbon decolorizing mistake
Filter, obtains CTX sodium solution.
3. method as claimed in claim 2, it is characterized in that the solvent of described preparation sodium acetate is selected from water, formamide, N, N
One or more in dimethylformamide, isopropanol, ethyl acetate, ethanol or acetone of mixture.
4. method as claimed in claim 2, it is characterized in that described sodium acetate is 1~1.2 with the mol ratio of cefotaxime acid:
1。
5. the method for claim 1, it is characterized in that organic solvent volume is molten Cefotaxime Sodium in described step (1)
5~15 times of liquid product.
6. the method for claim 1, it is characterized in that in described step (1) the addition time of CTX sodium solution be
10~240min.
7. the method for claim 1, it is characterized in that the rate of temperature fall described in described step (1) be 0.2~1 DEG C/
min。
8. the method for claim 1, it is characterized in that drying condition is in described step (1), temperature -70~0 DEG C, absolutely
7~100Pa of pressure, dries 12~36h.
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| CN106279208A (en) * | 2016-08-15 | 2017-01-04 | 陕西顿斯制药有限公司 | A kind of cefotaxime sodium compound utilizing fluid mechanics principle to prepare and preparation thereof |
| CN109081847A (en) * | 2017-06-14 | 2018-12-25 | 郝志艳 | A kind of 1/2 water cefotaxime sodium compound |
| CN109096305A (en) * | 2017-06-20 | 2018-12-28 | 刘兆娟 | A kind of 1/4 water cefotaxime sodium compound |
| CN113876723A (en) * | 2021-11-11 | 2022-01-04 | 海南海灵化学制药有限公司 | Preparation process of cefotaxime sodium for injection |
| CN114989194B (en) * | 2022-06-07 | 2023-09-26 | 艾美科健（中国）生物医药有限公司 | Method for reducing polymer in cefotaxime sodium |
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| WO2004063203A1 (en) * | 2003-01-10 | 2004-07-29 | Orchid Chemicals & Pharmaceuticals Ltd | Process for the preparation of cefotaxime sodium |
| US20050119244A1 (en) * | 2003-12-02 | 2005-06-02 | Acs Dobfar S.P.A. | Process for preparing cephalosporins with salified intermediate |
| CN103275101B (en) * | 2013-05-17 | 2015-08-05 | 天津大学 | Prepare the method for cefotaxime sodium crystal |
| CN103319504A (en) * | 2013-06-28 | 2013-09-25 | 华北制药河北华民药业有限责任公司 | Crystallization method for cefotaxime sodium |
| CN104086569B (en) * | 2014-07-29 | 2016-10-26 | 石药集团中诺药业（石家庄）有限公司 | A kind of preparation method of cefotaxime sodium |
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