CN104086569B - A kind of preparation method of cefotaxime sodium - Google Patents
A kind of preparation method of cefotaxime sodium Download PDFInfo
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- CN104086569B CN104086569B CN201410365593.1A CN201410365593A CN104086569B CN 104086569 B CN104086569 B CN 104086569B CN 201410365593 A CN201410365593 A CN 201410365593A CN 104086569 B CN104086569 B CN 104086569B
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- cefotaxime
- acetone
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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
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses the preparation method of a kind of cefotaxime sodium, with cefotaxime acid as initiation material, generation cefotaxime acid is reacted with anhydrous sodium acetate, in the process, selecting purified water, butanol and acetone is recrystallisation solvent, controls mixing speed when crystallizing, crystallization temperature, the cefotaxime sodium good fluidity finally given, the requirement of subpackage in production can be met, and every quality index of gained cefotaxime sodium all meets the requirement of medicinal standard, it is possible to meet the needs of clinical application.
Description
Technical field
The invention belongs to technical field prepared by crude drug in medical science, be specifically related to a kind of antibiotic cefotaxime sodium
Preparation method.
Background technology
Cefotaxime sodium is clinical conventional antibiotic, and injectable powder, intramuscular injection or intravenous, for the multiple sense caused by sensitive organism
Dye.
Cefotaxime sodium for injection is obtained through aseptic subpackaged by cefotaxime sodium crude drug, and the process of subpackage is all
Mechanically actuated, loading amount can be adjusted according to actual needs.Owing to loading amount automatically controls, therefore machinery subpackage is to cephalo thiophene
The mobility of oxime sodium raw materials medicine requires higher, and in the case of poor fluidity, the loading amount deviation of cefotaxime sodium is relatively big, causes subpackage
Defective work quantity too much, not only the cost of manufacturer increases, and causes waste greatly, the most also gives patient's
Medication brings potential safety hazard.Poor fluidity also results in the blocking of subpackage line, cancel closedown, it is impossible to realize high-volume, serialization
Aseptic subpackaged, it addition, the maintenance of machine needs aseptically to carry out, the cost of overhaul is the highest.
The problem of cefotaxime sodium crude drug poor fluidity seems simple, but drawback is a lot, annoyings this area skill always
Art personnel, it is impossible to effectively solved.
Summary of the invention
To be solved by this invention is the problem of cefotaxime sodium crude drug poor fluidity, thus overcomes due to poor fluidity
The series of problems caused.
In order to realize purpose of the present invention, inventor provide techniques below scheme.
A kind of preparation method of cefotaxime sodium, with cefotaxime acid as initiation material, including following operating procedure:
A. temperature control 26-30 DEG C, is sequentially added into purified water and anhydrous sodium acetate, stirring, after solid all dissolves, adds head
The acid of spore thiophene oxime, stirs to solution clarification；
B. adding activated carbon, stirring decolouring in step a gained settled solution, use sterile film to filter, gained is filtered
Liquid is standby；
C. in step c gained filtrate, add butanol, stir, temperature control 12-18 DEG C, control speed of agitator 150-180
Rev/min, stream adds acetone, when there being solid to separate out in solution, stops adding acetone and stopping stirring, stands growing the grain 30-40 minute；
D. open stirring, control speed of agitator 150-180 rev/min, temperature control 12-18 DEG C, continue stream and add acetone；
E., after stopping to add acetone, continue stirring, be cooled to 0-5 DEG C, growing the grain 50-60 minute；
F. the feed liquid sucking filtration after step e growing the grain being terminated, filter cake washing with acetone, it is then dried to cefotaxime sodium moisture
≤ 3%.
The preparation method of above-mentioned cefotaxime sodium, in step a, purified water is 10:7 with the weight ratio of anhydrous sodium acetate.
The preparation method of above-mentioned cefotaxime sodium, in step a, anhydrous sodium acetate is 6.5-with the weight ratio of cefotaxime acid
7:20。
The preparation method of above-mentioned cefotaxime sodium, in step c, described butanol is 1 with the volume ratio of purified water in step a:
1。
The preparation method of above-mentioned cefotaxime sodium, in step c, it is 1-1.5 hour that stream adds the time of acetone.
The preparation method of above-mentioned cefotaxime sodium, in step d, it is purification water body in step a that continuation stream adds the volume of acetone
Long-pending 6-7 times.In this step, the addition of acetone is according to cefotaxime sodium dissolubility in mixed solvent and to need control
The amount that the impurity of system separates out requires and determines.
The preparation method of above-mentioned cefotaxime sodium, in step d, continue stream adding the time used by acetone is 2-3 hour.
Inventor, in research process, gropes and repeatedly failure through constantly, recognizes after summarizing all experimental results
For, prepare cefotaxime sodium with cefotaxime acid for initiation material, the mixing speed when solvent of crystallization, crystallization is to affect cephalo
The key factor of thiophene oxime sodium mobility, technical scheme the most provided by the present invention have selected suitable recrystallisation solvent and stirring
Under conditions of rotating speed, it is possible to obtain mobility preferable cefotaxime sodium crude drug, meet the requirement of subpackage.
In the preparation method of cefotaxime sodium of the present invention, using purified water, butanol, acetone mixed solution as crystallization
Solvent, controls stir speed (S.S.) simultaneously during adding acetone and is 150-180 rev/min, the cefotaxime sodium prepared
The angle of repose measured is 28-32 °, and mobility is preferable.
The method of the invention, defines the weight ratio of anhydrous sodium acetate and cefotaxime acid, it can be ensured that cefotaxime
Acid reaction is complete, and anhydrous sodium acetate also will not be excessive too many, will not make the most miscellaneous while improving cefotaxime sodium yield
The amount of matter substantially increases.
The method of the invention, defines that the time adding acetone in step c, step d is all defined, and add is too fast
Or excessively fine crystals all can be caused to increase slowly, ultimately result in cefotaxime sodium mobility and be deteriorated.Control the addition used time of acetone, and
At the uniform velocity adding, the cefotaxime sodium granular size of precipitation is more uniform, and mobility is more preferable.
In the preparation process of cefotaxime sodium, the reactant liquor of anhydrous sodium acetate and cefotaxime acid can add activated carbon and enter
Row decolouring, in order to obtain the cefotaxime sodium that color level is relatively low.The 0.18%-of the consumption preferred cefotaxime acid weight of activated carbon
0.2%, both can ensure that decolorizing effect, reaction mass will not have been lost again, it is ensured that yield.
The preparation method of cefotaxime sodium of the present invention, by limiting the kind of recrystallisation solvent, the ratio of recrystallisation solvent
And the rotating speed of stirring during crystallization, finally give good fluidity and be suitable to the cefotaxime sodium of subpackage, and the cefotaxime obtained
The quality of sodium meets the requirement of medicinal standard.
The present invention uses butanol and acetone to crystallize, and butanol can effectively dissolve pigment, reduces the color level of cefotaxime sodium；
After using acetone, compared with the butyl ester that tradition uses, when being dried, the moisture of cefotaxime sodium can reach to close in relatively short period of time
Lattice；The average weight yield of the method also improves 1.5% simultaneously.By adjusting many correlative factors in preparation process, embody
The angle of repose of cefotaxime sodium mobility is reduced to about 30 ° from 45 °, and mobility significantly promotes, and is fully able to meet visitor
The requirement of family serialization subpackage.
Detailed description of the invention
Below in conjunction with specific embodiment, content of the present invention is further described in detail.
Embodiment 1
Temperature control 26 DEG C, adds anhydrous sodium acetate 350g in 500mL purified water, stir molten clear after, add cefotaxime acid
1000g, stirs and clarifies to solution, adds 2g activated carbon decolorizing 10min, then uses sterile film to filter, adds in filtrate
Entering butanol 500mL, stir 5min, control stirring 150 revs/min, temperature control 12 DEG C, stream adds acetone, observes the change of solution, when sending out
When having solid to separate out in existing solution, stopping adding acetone, stop stirring, stream adds 1h when acetone shares, and stands growing the grain 30min, with
After, to open stirring, control speed of agitator 150 revs/min, temperature control 12 DEG C, in 2 hours, continue stream add acetone 3L, acetone adds
After, feed liquid is cooled to 0 DEG C, growing the grain 50 minutes, feed liquid is carried out sucking filtration, filter cake washing with acetone three times, put into baking box, temperature control
63-65 DEG C, being dried to moisture≤3%, obtain cefotaxime sodium 1010g, weight yield is 101%.
Embodiment 2
Temperature control 30 DEG C, adds anhydrous sodium acetate 3.25kg in 4.64L purified water, stir molten clear after, add cefotaxime
Acid 10kg, stirs and clarifies to solution, adds 18g activated carbon decolorizing 10min, then uses sterile film to filter, in filtrate
Adding butanol 4.64L, stir 5min, control stirring 180 revs/min, temperature control 18 DEG C, stream adds acetone, observes the change of solution, when
When finding have solid to separate out in solution, stopping adding acetone, stop stirring, stream adds 1.5h when acetone shares, and stands growing the grain
40min, subsequently, opens stirring, controls speed of agitator 180 revs/min, temperature control 18 DEG C, continues stream and add acetone in 3 hours
32.48L, after acetone adds, is cooled to 5 DEG C by feed liquid, and feed liquid is carried out sucking filtration, filter cake washing with acetone three by growing the grain 60 minutes
Secondary, to put into baking box, temperature control 63-65 DEG C, be dried to moisture≤3%, obtain cefotaxime sodium 10.2kg, weight yield is 102%.
The product prepared according to method described in embodiment 1 and embodiment 2 is detected by inventor, result such as table
Shown in 1.
Table 1
| Detection sample | Content | Color level | Acidity | Cefotaxime polymer | Residual solvent |
| Embodiment 1 | 95.6% | 2# | 5.6 | 0.04% | Acetone 0.028%；Butanol does not detects |
| Embodiment 2 | 94.8% | 2# | 5.5 | 0.04% | Acetone 0.029%；Butanol does not detects |
Inventor has also carried out accelerated test to the product prepared according to method described in embodiment 1 and embodiment 2, knot
Fruit is as shown in table 2.
Accelerated test condition: temperature 40 ± 2 DEG C-, relative humidity 75 ± 5%, under conditions of place 6 months, exist respectively
0,1,2,3, sampling last day in June detects.
Table 2 cefotaxime sodium accelerated test data
Inventor is with the FT-104B Repose angle gauge product to preparing according to method described in embodiment 1 and embodiment 2
Product are detected, and result is as shown in table 3.
Table 3
| Detection sample | Angle of repose |
| Embodiment 1 | 28° |
| Embodiment 2 | 32° |
Claims (5)
1. a preparation method for cefotaxime sodium, with cefotaxime acid as initiation material, it is characterised in that include following operation
Step:
A. temperature control 26-30 DEG C, is sequentially added into purified water and anhydrous sodium acetate, stirring, after solid all dissolves, adds cephalo thiophene
Oxime acid, stirs to solution clarification；
B. adding activated carbon, stirring decolouring in step a gained settled solution, use sterile film to filter, gained filtrate is standby
With；
C. in step c gained filtrate, add butanol, stir, temperature control 12-18 DEG C, control speed of agitator 150-180 rev/min
Clock, stream adds acetone, when there being solid to separate out in solution, stops adding acetone and stopping stirring, stands growing the grain 30-40 minute；
D. open stirring, control speed of agitator 150-180 rev/min, temperature control 12-18 DEG C, continue stream and add acetone；
E., after stopping to add acetone, continue stirring, be cooled to 0-5 DEG C, growing the grain 50-60 minute；
F. the feed liquid sucking filtration after step e growing the grain being terminated, filter cake washing with acetone, be then dried to cefotaxime sodium moisture≤
3%；
Wherein, in step d, continue stream adding the volume of acetone is in step a 6-7 times of purified water volume；Continue stream and add acetone institute
It it is 2-3 hour with the time.
The preparation method of a kind of cefotaxime sodium the most according to claim 1, it is characterised in that in step a purified water with
The weight ratio of anhydrous sodium acetate is 10:7.
The preparation method of a kind of cefotaxime sodium the most according to claim 1, it is characterised in that Glacial acetic acid in step a
Sodium is 6.5-7:20 with the weight ratio of cefotaxime acid.
The preparation method of a kind of cefotaxime sodium the most according to claim 1, it is characterised in that in step c, described butanol
It is 1:1 with the volume ratio of purified water in step a.
The preparation method of a kind of cefotaxime sodium the most according to claim 1, it is characterised in that in step c, stream adds acetone
Time be 1-1.5 hour.
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| CN201410365593.1A CN104086569B (en) | 2014-07-29 | 2014-07-29 | A kind of preparation method of cefotaxime sodium |
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| CN201410365593.1A CN104086569B (en) | 2014-07-29 | 2014-07-29 | A kind of preparation method of cefotaxime sodium |
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| CN104086569B true CN104086569B (en) | 2016-10-26 |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892636B (en) * | 2015-05-21 | 2017-06-16 | 天津大学 | A kind of method for preparing CTX sodium crystal |
| CN105884800A (en) * | 2015-10-28 | 2016-08-24 | 石药集团中诺药业（石家庄）有限公司 | Novel cefotaxime sodium compound |
| CN107049958A (en) * | 2017-04-26 | 2017-08-18 | 四川制药制剂有限公司 | The preparation technology of cefotaxime sodium for injection powder-injection |
| 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 |
| CN113666947A (en) * | 2021-07-23 | 2021-11-19 | 无锡海伦生物科技有限公司 | Preparation method of cefotaxime sodium |
| CN114028336B (en) * | 2021-10-20 | 2023-04-04 | 华北制药河北华民药业有限责任公司 | Preparation method of cefotaxime sodium for injection |
| CN114874237B (en) * | 2022-04-21 | 2024-01-19 | 华北制药河北华民药业有限责任公司 | Refining method of 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 |
| WO2005040175A2 (en) * | 2003-10-22 | 2005-05-06 | Ranbaxy Laboratories Limited | Process for the preparation of cephem carboxylic acids |
| CN101486719A (en) * | 2009-02-17 | 2009-07-22 | 福建省福抗药业股份有限公司 | Method for converting cefotaxime acid into sodium salt crystal |
| CN102584854A (en) * | 2012-02-02 | 2012-07-18 | 瑞阳制药有限公司 | Preparation technology of anhydrous crystal of cefotaxime sodium |
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