CN106478670A - A kind of new crystallization of cefotetan acid and preparation method thereof - Google Patents

A kind of new crystallization of cefotetan acid and preparation method thereof Download PDF

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CN106478670A
CN106478670A CN201610790298.XA CN201610790298A CN106478670A CN 106478670 A CN106478670 A CN 106478670A CN 201610790298 A CN201610790298 A CN 201610790298A CN 106478670 A CN106478670 A CN 106478670A
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preparation
cefotetan
acid
cefotetan acid
butanone
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CN106478670B (en
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曹龙祥
董自波
牛犇
丁小华
邵建国
朱佳
李萍
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JUMPCAN PHARMACEUTICAL GROUP Co Ltd
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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
    • C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/12—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

A kind of new crystallization of cefotetan acid and preparation method thereof.The present invention provides a kind of [6R (6a, 7 α)] 7 [[[4 (2 amino, 1 carboxyl 2 oxo ethylidene) 1, 3 dithietane 2 base] carbonyl] amino] 7 methoxyl group 3 [[(1 methyl 1H tetrazolium 5 base) is thio] methyl] 8 oxo, 5 thia 1 azabicyclos [4, 2, 0] novel crystal forms of pungent 2 alkene 2 formic acid, angle of reflection 2 θ of the X ray powder diffraction pattern of this crystal formation is at 11.66 ± 0.1 °, 17.53 ± 0.1 °, 17.72 ± 0.1 °, 18.91 ± 0.1 °, 20.01 ± 0.1 °, 21.02 ± 0.1 °, 22.24 ± 0.1 °, at 23.33 ± 0.1 °, there is characteristic peak.This compound crystal form has preferable stability, and its preparation process is simple, preparation cost lower, can industrialized production.

Description

A kind of new crystallization of cefotetan acid and preparation method thereof
Technical field
The invention belongs to drug invention field is and in particular to a kind of new crystallization of cefotetan acid compound and preparation method thereof.
Background technology
Cefotetan acid (Cefotetan), chemical name [6R- (6 α, 7 α)] -7- [[[4- (2- amino -1- carboxyl -2- oxo Asia second Base) -1,3- dithietane -2- base] carbonyl] amino] -7- methoxyl group -3- [[(1- methyl isophthalic acid H- tetrazolium -5- base) is thio] Methyl] -8- oxo -5- thia -1- azabicyclo [4,2,0] oct-2-ene -2- formic acid is the of Japanese Yamanouchi pharmacy exploitation Secondary cephalosporins, in March, 1984 in Japan's listing, and are loaded into day anti-base.Structural formula is as follows：
This product is cephamycin-type, and effect is approximate with third generation cephalosporin.It is extremely stable to various bacteriogenic lactamases, There is good antibacterial action to gram-negative bacteria and anaerobe.Particularly to escherichia coli, Serratia, Proteus, rub Root fungus genus, Providencia, false unicellular Pseudomonas and influenza bacterium antibacterial action stronger than cefmetazole and cefoxitin.But To gram positive bacteria effect not as good as a generation and secondary cephalosporin.Clinic be mainly used in respiratory tract, pulmonary infection, abdominal infection, Urinary tract infection, gynecological infection and otitis media etc..
Cefotetan acid is a kind of conventional pharmaceutical intermediate, and its polarity is less, poorly water-soluble, clinically for convenience of use, with Its sodium salt makes dosage form.But because Cefotetan Disodium is very unstable, meet the water capacity during producing, store and using easy Degraded, relevant material can increase sharply, and causes product unqualified, can not use, and this makes to the safety of production, storage and medicine With all bringing great difficulty.
The cefotetan acid obtaining is synthesized such as in prior art：A kind of amorphous head is protected in patent application CN103724359A Spore replaces the preparation method of smooth acid.Chinese patent CN101050219A discloses a kind of preparation method of Cefotetan Disodium, wherein Cefotetan acid is to separate out to obtain in sodium bicarbonate and hydrochloric acid, and CN101050219A reports a kind of preparation side of cefotetan Method, wherein cefotetan acid are to separate out to obtain in aqueous phase.Above-described prior art synthesis has obtained different crystal structure Cefotetan acid.
The present inventor, during preparing cefotetan, has obtained a kind of new crystalline substance different from prior art by solvent crystallize The cefotetan acid compound of type, and by checking, the cefotetan acid of this crystal formation has preferable stability, and its system Standby process is simple, preparation cost be lower, can industrialized production.
Content of the invention
It is an object of the invention to provide a kind of novel crystallization of cefotetan acid of excellent in stability, the X-ray powder of this crystal formation Angle of reflection 2 θ of last diffraction pattern 11.66 ± 0.1 °, 17.53 ± 0.1 °, 17.72 ± 0.1 °, 18.91 ± 0.1 °, 20.01 ± 0.1 °, 21.02 ± 0.1 °, 22.24 ± 0.1 °, there is characteristic peak at 23.33 ± 0.1 °.
Another object of the present invention is to providing a kind of preparation method of described crystal formation cefotetan acid.
For realizing the purpose of the present invention, the present invention adopts the following technical scheme that：
Crystal formation cefotetan acid of the present invention obtains X-ray powder diffraction figure using the test of Cu-K alpha ray, such as description Shown in accompanying drawing Fig. 1.
The crystal formation of cefotetan acid of the present invention, it contains the water of crystallization no less than 1.5 molecules, and fusing point is 130 ± 2 DEG C, Means of differential scanning calorimetry absworption peak is at 120～165 DEG C.
The cefotetan acid of crystal formation has more excellent stability as mentioned above.
A kind of preparation method of cefotetan acid novel crystal forms of the present invention, the method comprises the following steps：
(1) cefotetan acid crude products are dissolved in 2-butanone and the mixed solution of water, obtain the 2-butanone/water of cefotetan acid Solution；
(2) add sodium chloride, stirring, standing, layering in the 2-butanone/aqueous solution of the cefotetan acid of step (1) gained, take Organic faciess；
(3) after the organic faciess of step (2) gained being concentrated, Deca dehydrated alcohol, crystallize, washing, filtration, vacuum drying, obtain head Spore replaces smooth acid crystal.
In above-mentioned preparation method, in the mixed solution of 2-butanone and water described in step (1) mass fraction of 2-butanone and water it Than for 1:1, control 10～20 DEG C of temperature.
Stirring described in step (2) and time of repose are respectively 15 minutes.
0～5 DEG C of stirring and crystallizing temperature described in step (3), mixing time 2 hours, stand -10 DEG C of growing the grain temperature, rearing crystal time 10 hours, vacuum drying temperature was 20～30 DEG C.
Medicine, in crystallization, if adopting different solvents and technique, can form different crystal structures, and that is, the polycrystalline of medicine is existing As.The change of polymorph in pharmaceuticals can change property, quality and the drug effect of medicine.The present invention is tied to cefotetan acid crude products again Crystalline substance, has obtained a kind of cefotetan acid of novel crystal forms.Show that the cefotetan acid that the present invention provides has preferably by checking Stability.
Obtain it is not necessary to from other because cefotetan acid crude products can directly be reacted by the cefotetan acid novel crystal forms of the present invention Crystal conversion, also has the advantages that simple to operate, reaction time is short, safe and efficient, preparation cost is relatively low and is particularly suitable for work Industry metaplasia is produced.
Brief description
The diffraction pattern of the X-ray powder of Fig. 1 embodiment 2 gained cefotetan acid compound；
The TGA analysis chart of Fig. 2 embodiment 2 gained cefotetan acid compound；
The DSC figure of Fig. 3 embodiment 2 gained cefotetan acid compound；
The infrared spectrogram of Fig. 4 embodiment 2 gained cefotetan acid compound；
The liquid phase figure of 0 day placed by Fig. 5 embodiment 3 gained cefotetan acid sample；
Fig. 6 embodiment 3 gained cefotetan acid sample is placed in 40 DEG C of placements liquid phase figure of 5 days；
Fig. 7 embodiment 3 gained cefotetan acid is placed in 60 DEG C of placements liquid phase figure of 5 days；
Fig. 8 embodiment 3 gained cefotetan acid is placed in the liquid phase figure placed under the illumination of (4500 ± 500) LX 5 days.
Specific embodiment
Unless otherwise defined, all technology that the present invention uses and the implication of scientific terminology are common with the technical field of the invention The implication that technical staff is generally understood that is identical.Generally, the name that the present invention uses and Examination on experimental operation are all known in this field Or conventional, if not specializing, in the embodiment of the present invention, test reagent used and material are all commercially available.In order that Technical problem solved by the invention, technical scheme and beneficial effect become more apparent, below in conjunction with specific embodiment, to this Invention is further described, rather than limits the present invention.
Prepared by embodiment 1 cefotetan acid crude products
(1) amidation process
By the dichloromethane dissolving of 7-MAC pre-cooling, add in reactor, stirring is cooled to less than -10 DEG C, add N, N- diformazan Base aniline, stirring 10 hours, Deca chloracetyl chloride and dichloromethane mixed solution, not higher than -5 DEG C of temperature control.Reactant liquor 6% sulfur Acid solution wash twice, stirs 10 minutes, and layering obtains organic layer.Washed with frozen water again, stand split-phase, collect intermediate compound I dichloro Dichloromethane.
(2) take off diphenyl ester reaction
The dichloromethane solution of intermediate compound I is added in reactor, is cooled to less than 5 DEG C, add n-butyl alcohol, after stirring 15 minutes Add cooled trifluoroacetic acid/methyl phenyl ethers anisole solution, 0～5 DEG C of stirring reaction, until reaction terminates, obtain reactant liquor, stand-by.
After reactant liquor is processed, in 30～35 DEG C of concentrating under reduced pressure.Dehydrated alcohol and isopropanol dissolving, temperature is added in concentrated solution Control at 0～10 DEG C, Deca contains the aqueous isopropanol of Sodium isooctanoate., regulation system pH value to 6.0 ± 0.2, stirs 15 minutes.Filter Cake is washed with the mixed solution of dehydrated alcohol and isopropanol, continues centrifugation to dry, 30～35 DEG C of vacuum drying of filter cake, obtains intermediate II.
(3) cefotetan acid synthesis
Sequentially add cooled purified water, intermediate II in reactor, open stirring.Deca 5% sodium bicarbonate solution, adjusts Section pH value 5.7～6.0, stirring makes solid be completely dissolved.Then EDETATE SODIUM, sodium bicarbonate are sequentially added by rate of charge.Reaction Liquid is passed through CO2Gas, and Deca trisodium saline solution, control pH value of reaction system 7.5～8.5,0～5 DEG C of temperature.Completion of dropping Afterwards, control system pH value 7.9～8.1, reacts 8 hours.
Then pass to CO2Gas, adjusts reacting liquid pH value 7.5～7.8, and HPLC monitors isomerization, until isomer≤ 5.0%.Filtrate, with 9% aqueous hydrochloric acid solution regulation system pH to 0.7～1.0, separates out solid, centrifugal filtration, obtains cefotetan acid Wet product.
The preparation of embodiment 2 cefotetan acid novel crystal forms
The cefotetan acid crude products obtaining in embodiment 1 are added to (W in 2-butanone and the mixed solution of waterButanone：WWater=1:1), control 10～20 DEG C of temperature processed, stirs and is completely dissolved to solid.Add sodium chloride in feed liquid, stir 15 minutes, stand 15 minutes, point Layer, takes organic faciess.Organic faciess are concentrated into about half volume at 20～30 DEG C.Concentration finishes, and concentrated solution keeps 20～30 DEG C of interior temperature, Deca dehydrated alcohol while stirring.Completion of dropping, is cooled to 0～5 DEG C, and stirring makes crystal separate out for 2 hours, continues to be cooled to -10 DEG C, partial crystallization ripening 10 hours, filter.Filter cake washing with alcohol, 20～30 DEG C are vacuum dried 12 hours, obtain cefotetan acid, HPLC method assay：98.82%.The X-ray diffraction of gained cefotetan acid crystalline product, TGA, DSC and infared spectrum are such as Shown in Figure of description 1, Fig. 2, Fig. 3, Fig. 4.
Powder X-ray diffraction condition determination：CuK α line,(monochromatic tube), tube voltage 40KV, tube current 40mA.Gained crystallizes Powder X-ray diffraction measurement result shown in Figure 1.For the crystallization of gained, angle of reflection 2 θ of X-ray powder diffraction figure 11.66 ± 0.1 °, 17.53 ± 0.1 °, 17.72 ± 0.1 °, 18.91 ± 0.1 °, 20.01 ± 0.1 °, 21.02 ± 0.1 °, 22.24 ± 0.1 °, there is characteristic peak at 23.33 ± 0.1 °.Additionally, angle of reflection 2 θ of X-ray powder diffraction figure 9.89 ± 0.1°、10.47±0.1°、11.42±0.1°、11.97±0.1°、13.31±0.1°、13.78±0.1°、14.25±0.1°、 14.48 ± 0.1 °, 16.36 ± 0.1 °, 24.34 ± 0.1 °, 25.88 ± 0.1 °, have at 29.14 ± 0.1 ° compared with ebb.
Table 1 is cefotetan acid new crystal form X ray powder diffraction data of the present invention.
Table 1：
Moisture content：Theoretical value (containing 1.5 water)：4.48%
Thermogravimetic analysis (TGA) (TGA) measured value：4.682%
Differential scanning calorimetry (DSC) records fusing point：130.1℃
By the infrared spectrogram of the new crystallization of the present invention as shown in Figure of description 4 and following table.
Table 2 is cefotetan acid novel crystal forms ir data of the present invention.
Table 2：
The study on the stability test of embodiment 3 cefotetan acid novel crystal forms
In order to investigate the heat stability of this product, material sample is placed in 40 DEG C, 60 DEG C, shadow under the illumination of (4500 ± 500) LX Ring 30 days, sampled respectively at the 5th, 10,30 days, investigate appearance character, relevant material, changes of contents, the results are shown in Table 3.Sample is 0 My god, at 40 DEG C, 60 DEG C, place HPLC-UV detection such as Figure of description 5, the figure of 5 days under the illumination of (4500 ± 500) LX respectively 6th, shown in Fig. 7, Fig. 8.
Wherein in the cefotetan acid sample placement Liquid Detection collection of illustrative plates (i.e. Figure of description 5) of 0 day, peak table is as follows：
Peak table
Detector A Ch1 254nm
Peak # Retention time Area Highly Area % Separating degree Theoretical tray # Tailing factor
1 4.134 3924 667 0.026 0.000 10181 1.156
2 5.116 6172 888 0.041 5.598 11972 1.021
3 5.817 3527 412 0.023 3.346 10052 1.035
4 7.710 1188 70 0.008 6.218 6708 0.785
5 8.675 2467 119 0.016 2.201 4810 0.731
6 9.372 2055 114 0.014 1.498 7551 1.090
7 17.413 8273 323 0.054 14.726 11118 1.086
8 20.437 15089843 263463 99.371 2.845 3111 1.054
9 24.940 14235 330 0.094 3.517 8305 1.167
10 27.490 1197 47 0.008 3.030 34877 0.699
11 44.218 52468 497 0.346 12.987 7921 1.435
Amount to 15185349 266930 100.000
It is as follows that cefotetan acid sample is placed in peak table in 40 DEG C of placements Liquid Detection collection of illustrative plates (i.e. Figure of description 6) of 5 days：
Peak table
Detector A Ch1 254nm
Peak # Retention time Area Highly Area % Separating degree Theoretical tray # Tailing factor
1 6.430 11181 1488 0.040 0.000 15490 1.059
2 7.144 1089 142 0.004 3.420 18315 0.954
3 7.426 9158 1089 0.033 1.270 16337 1.122
4 9.339 1677 113 0.006 6.593 11524 0.885
5 10.374 4945 274 0.018 2.539 7893 1.035
6 11.286 5496 253 0.020 1.867 7834 1.118
7 12.654 2077 73 0.007 2.542 7982 1.655
8 20.087 4616 205 0.017 13.026 19555 0.926
9 20.915 15528 582 0.056 1.247 12337 1.034
10 23.997 27684568 442732 99.189 2.657 3751 1.037
11 29.138 29603 634 0.106 3.754 9892 0.978
12 31.762 10550 216 0.038 2.578 21619 1.180
13 37.254 20272 229 0.073 3.978 6168 0.793
14 50.764 110291 961 0.395 7.075 11161 1.414
Amount to 27911051 448990 100.000
It is as follows that cefotetan acid sample is placed in peak table in 60 DEG C of placements Liquid Detection collection of illustrative plates (i.e. Figure of description 7) of 5 days：
Peak table
Detector A Ch1 254nm
Peak # Retention time Area Highly Area % Separating degree Theoretical tray # Tailing factor
1 2.589 27549 2910 0.083 0.000 2098 1.406
2 3.257 5737 508 0.017 2.463 1696 0.977
3 3.589 96000 12189 0.290 1.245 4415 1.071
4 3.912 3645 420 0.011 1.426 4366 1.080
5 4.186 3664 417 0.011 1.141 4714 1.211
6 5.661 2682 173 0.008 4.743 3590 1.147
7 6.544 128496 5214 0.388 1.733 1662 0.932
8 8.598 3115 129 0.009 3.211 2916 1.016
9 10.225 10061 335 0.030 2.318 2844 1.047
10 12.833 1600 51 0.005 3.932 8410 1.597
11 14.133 1421 54 0.004 2.245 8934 0.000
12 16.334 32565232 570241 98.272 2.045 1766 0.923
13 20.704 72611 1179 0.219 2.682 2366 0.988
14 23.083 40546 601 0.122 1.339 2488 1.184
15 26.462 33106 452 0.100 1.873 3631 1.078
16 38.338 142237 1151 0.429 5.317 3201 1.073
Amount to 33137703 596022 100.000
Cefotetan acid sample is placed in Liquid Detection collection of illustrative plates (the i.e. Figure of description placed under the illumination of (4500 ± 500) LX 5 days 8) in, peak table is as follows：
Peak table
Detector A Ch1 254nm
Peak # Retention time Area Highly Area % Separating degree Theoretical tray # Tailing factor
1 6.380 1423 79 0.018 0.000 5052 0.700
2 7.026 1554 150 0.019 2.057 10899 0.837
3 7.650 2956 205 0.037 1.823 5445 1.182
4 8.370 3021 205 0.037 1.805 7599 0.976
5 9.786 1083 51 0.013 3.173 5926 0.704
6 12.281 1700 104 0.021 5.399 13971 1.333
7 14.823 8007207 241732 99.138 4.003 4819 1.001
8 17.742 16856 533 0.209 3.436 7050 0.947
9 19.394 4992 201 0.062 2.218 14503 1.084
10 22.575 2844 91 0.035 4.122 10078 1.186
11 25.340 1618 64 0.020 3.555 23870 1.921
12 30.459 31556 434 0.391 2.730 1551 1.279
Amount to 8076809 243848 100.000
Table 3 is the new crystal of cefotetan acid of the present invention accelerated test result under high temperature, high humidity, illumination condition respectively
Table 3：
Measurement result finds, the cefotetan acid compound of the present invention place 30 days at 60 DEG C after content and the change about material Relatively more apparent, but cefotetan acid compounds content is basically unchanged under other circumstances, relevant material no substantially increases, and In the range of bound requirements.Experimental result illustrates that the cefotetan acid compound of the present invention has preferable storage stability.
The dissolubility of embodiment 4 cefotetan acid novel crystal forms investigates test
The solvent that may be used according to the solvent used in cefotetan acid synthesis technique and quality testing, we have selected water, Dichloromethane, methanol, ethanol, n-butyl alcohol, butanone, ethyl acetate, as solvent, are ground to the dissolubility of cefotetan acid Study carefully.
According to《Chinese Pharmacopoeia》Two note on the use solubility test methods of version in 2010, weigh the test sample being ground into fine powder, are placed in 25 ± 2 In the solvent of DEG C certain capacity, every strength shaking in 5 minutes 30 seconds, observe the dissolving situation in 30 minutes, such as no visually may be used The particles of solute seen, that is, be considered as being completely dissolved, result see table.
Table 4 is the new crystal of cefotetan acid of the present invention dissolving situation in different solvents respectively
Table 4：
As can be seen from the table, cefotetan acid compound in water, dichloromethane, methanol, n-butyl alcohol, ethyl acetate hardly Molten, slightly soluble in 100mL ethanol, dissolves in 100mL butanone.Result shows the crystalchecked of the cefotetan acid of the present invention, It is not susceptible to go bad.
It should be noted that although the present invention is disclosed above with preferred embodiment, so it is not limited to the present invention, any ripe Practise this those skilled in the art, without departing from the spirit and scope of the present invention, any modification, equivalent and improvement of being made etc., all Should be included within protection scope of the present invention.

Claims (7)

1. [[[(2- amino -1- carboxyl -2- oxo is sub- for 4- for cefotetan acid [6R- (6 α, 7 α)] -7- as shown in formula (1) for the one kind Ethyl) -1,3- dithietane -2- base] carbonyl] amino] -7- methoxyl group -3- [[(1- methyl isophthalic acid H- tetrazolium -5- base) sulfur Generation] methyl] -8- oxo -5- thia -1- azabicyclo [4,2,0] oct-2-ene -2- carboxylic acid compounds,
It is characterized in that, described cefotetan acid compound is crystal formation, the angle of reflection 2 of the X-ray powder diffraction figure of this crystal formation θ 11.66 ± 0.1 °, 17.53 ± 0.1 °, 17.72 ± 0.1 °, 18.91 ± 0.1 °, 20.01 ± 0.1 °, 21.02 ± 0.1 °, 22.24 ± 0.1 °, there is characteristic peak at 23.33 ± 0.1 °.
2. the crystal formation of cefotetan acid compound as claimed in claim 1, its fusion point is 130 ± 2 DEG C.
3. the crystal formation of cefotetan acid compound as claimed in claim 1 or 2, means of differential scanning calorimetry endothermic peak 120～ 165℃.
4. a kind of preparation method of crystal formation as described in claim 1,2 or 3 it is characterised in that described preparation method include as Lower step：
(1) cefotetan acid crude products are dissolved in 2-butanone and the mixed solution of water, obtain the 2-butanone/water of cefotetan acid Solution；
(2) add sodium chloride, stirring, standing, layering in the 2-butanone/aqueous solution of the cefotetan acid of step (1) gained, take Organic faciess；
(3) after the organic faciess of step (2) gained being concentrated, Deca dehydrated alcohol, crystallize, washing, filtration, vacuum drying, obtain head Spore replaces smooth acid crystal.
5. the preparation method of preparation as claimed in claim 4 is it is characterised in that the mixing of 2-butanone and water described in step (1) In solution, the ratio of the mass fraction of 2-butanone and water is 1:1, control 10～20 DEG C of temperature.
6. the preparation method of preparation as claimed in claim 4 is it is characterised in that stirring and time of repose described in step (2) divide It is not 15 minutes.
7. the preparation method of preparation as claimed in claim 4 is it is characterised in that stirring and crystallizing temperature 0～5 described in step (3) DEG C, mixing time 2 hours, stand -10 DEG C of growing the grain temperature, rearing crystal time 10 hours, vacuum drying temperature is 20～30 DEG C.
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CN101050219A (en) * 2006-04-07 2007-10-10 上海医药科技发展有限公司 Method for preparing cefotetan bisodium
CN103073563A (en) * 2013-01-23 2013-05-01 海南通用三洋药业有限公司 Preparation method for cefotetan disodium
CN104086572A (en) * 2013-04-01 2014-10-08 北京澳林森科技有限公司 Novel technology for preparing cefotetan by one-pot synthesis method
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