CN103450225A - Preparation method of cefoxitin sodium - Google Patents
Preparation method of cefoxitin sodium Download PDFInfo
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- CN103450225A CN103450225A CN2013103699511A CN201310369951A CN103450225A CN 103450225 A CN103450225 A CN 103450225A CN 2013103699511 A CN2013103699511 A CN 2013103699511A CN 201310369951 A CN201310369951 A CN 201310369951A CN 103450225 A CN103450225 A CN 103450225A
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Abstract
The invention discloses a preparation method of cefoxitin sodium. The preparation method comprises the following steps: (1) bromizing, for example, the site 7 of a main nucleus of cefalotin by using an NBS (N-bromosuccinimide) reagent to form a bromination compound; performing nucleophilic substitution at the site 5 by using a methoxyl group to generate an intermediate IV; (2) performing acyl group hydrolysis on the site 3 of the intermediate IV to obtain an intermediate V; (3) substituting hydrogen atoms on the hydroxyl group by using chloriosulfonyl isocyanate, and then hydrolyzing to obtain the cefoxitin sodium. The method has the advantages of simple process, high product yield, high purity and high reaction selectivity; no special equipment is used in the production; the preparation method is suitable for industrial production.
Description
Technical field
The present invention relates to the material medicine preparation field, be specifically related to a kind of preparation method of cefoxitin sodium.
Background technology
Cefoxitin sodium, chemical name is: (6R, 7S)-3-carbamyl yloxymethyl-7-methoxyl group-8-oxo-7-[2 (2-thiophene, acetamido)]-the assorted nitrogen dicyclo of 5-thia-1--[4,2,0]-oct-2-ene-formic acid sodium salt, molecular formula: C
16h
16n
3naO
7s
2, molecular weight: 449.43, chemical structural formula is as follows:
Cefoxitin sodium, by U.S. Merk company development, listing in 1994, be that the cephamycin C that produced by streptomycete is through the semi-synthetic class new antibiotic made.Cefoxitin sodium is due to can the anti-bacteria Cell wall synthesis and kill bacteria, and due to structural singularity, stable to bacteriogenic β-lactamase, there is huge market potential.
At present, the synthetic method of cefoxitin sodium, have a lot of documents and patent report.Its synthetic route mainly contains 3: (1) take cephamycin as raw material, first the amino on its carboxylic acid side chain is modified, then its tetra-atomic ring is modified, this route exist technique loaded down with trivial details, need the shortcomings such as noble metal catalyst, therefore never meet the demand of industrialized production; (2) take cephalothin acid or sodium salt as raw material, first modify the C of 7-amino-cephalosporanic acid (7-ACA)
3side chain on position, then modify C
7bit amino side chain or take cephalothin acid or sodium salt is raw material, first modify the C of 7-ACA
7the bit amino side chain, then modify C
3side chain on position, although this route raw material is cheap and easy to get, need to use molecular sieve and reactions steps generally all longer in reaction process, therefore also never can suitability for industrialized production; (3) take methoxyl group cephamycin (7-MAC) is raw material, first modifies the C of 7-MAC
7the bit amino side chain, then modify the side chain on the C3 position, although this route synthesis step is simplified, 7-MAC is expensive and be difficult to obtain, therefore also be not applied to industrialized production always.
Publication number is the preparation method that the CN101007812A Chinese patent application discloses antibacterial drugs cefoxitin; 7a-methoxyl group-7 beta-aminos-the Cephalosporanic acid (7-MAC) of take is raw material; through the reaction of 2-thiophene acetyl, hydrolysis reaction and carbamyl reaction; obtain cefoxitin (I); the method has improved the productive rate of cefoxitin and sodium salt thereof effectively; avoid harsh reaction conditions, saved production cost.
Disclose a kind of preparation method of cefoxitin sodium in the Chinese patent application that publication number is CN101235045A, take cefoxitin as raw material, carried out carbamyl, 3 Imported Ammonia methanoyl methyl, generate intermediate product; Intermediate product and methyl alcohol-lithium methoxide solution reaction, introduce the oxygen methyl for 7, generates cefoxitin acid; Cefoxitin acid is dissolved in organic solvent, adds ethyl acetate (or methyl alcohol) solution of sodium salt, suction filtration, drying under reduced pressure, obtain cefoxitin sodium.
Summary of the invention
The invention provides a kind of preparation method of cefoxitin sodium, the simple and raw material of this preparation method's step be easy to get and the selectivity of reacting good, yield and the purity of product are high.
A kind of preparation method of cefoxitin sodium, comprise the steps:
(1) in organic solvent, under the condition that methylsulfonic acid exists, cefoxitin (II) and NBS(N-bromo-succinimide) and sodium methylate carry out successively the intermediate product that substitution reaction obtains methoxy substitution, carry out salify with hexahydroaniline after this intermediate product acidifying and obtain 7-α-methoxyl group-7-[(2-thienyl) kharophen]-4-Cephalosporanic acid cyclohexylamine salt (IV);
(2) 7-α-methoxyl group step (1) obtained-7-[(2-thienyl) kharophen]-4-Cephalosporanic acid cyclohexylamine salt (IV) reaction that is hydrolyzed under alkaline condition obtains hydrolysate, after this hydrolysate is acidified and acetic acid benzyl star salify obtain 3-hydroxyl first-7-α-[(2-thienyl) kharophen]-4-Cephalosporanic acid acetic acid benzyl star salt (V);
(3) 3-hydroxyl first step (2) obtained-7-α-[(2-thienyl) kharophen]-4-Cephalosporanic acid acetic acid benzyl star salt (V) carries out acylation reaction with Sulfuryl chloride isocyanate, react completely by processing and obtain cefoxitin acid later, obtain described cefoxitin sodium (I) after cefoxitin acid and Sodium.alpha.-hydroxypropionate salify;
Reaction process is shown below:
Starting raw material cefoxitin of the present invention easily obtains, and through three steps, obtains described cefoxitin sodium, simple to operate.Wherein, the existence of the methylsulfonic acid in step (1), improved the selectivity of reaction greatly, and yield and the purity of the product finally obtained are high.
In step (1), described organic solvent is halogenated hydrocarbon solvent or/and alcoholic solvent, is preferably the mixed solvent of methylene dichloride and methyl alcohol, and the volume ratio of described methylene dichloride and methyl alcohol is 9:1～13:1, and now, the yield of product is high, and selectivity is good.Wherein, total consumption of described organic solvent, without strict especially requirement, can fully dissolve raw material to get final product.
In step (1), as preferably, the temperature of substitution reaction is-75～-55 ℃; As further preferred, the temperature of reaction is-70～-60 ℃; Because cephalosporin compound all has the lactan tetra-atomic ring, can only be when temperature be lower stable existence, in the reaction system that has water to exist, the attack of water molecules is easy to make the tetra-atomic ring hydrolysis of lactan, and when particularly temperature of reaction is too high, the cephalosporin compound open loop is decomposed rapidly.Under the above-mentioned condition of the inventor, byproduct of reaction reduces, and product purity is high, and product yield is high.
In step (1), as preferably, in step (1), described cefoxitin is 1:1.5～1:2 with the ratio of the amount of substance of NBS; Described cefoxitin is 1:20～1:30 with the ratio of the amount of substance of sodium methylate.
In step (1), the time of substitution reaction is 3～6h, and as preferably, the time of substitution reaction is 3～5h.
In step (1), after substitution reaction completes the intermediate product that obtains methoxy substitution, conscientious following processing: in reaction system, add S-WAT, acetic acid and saturated nacl aqueous solution stir, be warming up to 0 ℃ after 3 hours, regulating pH value with the hydrochloric acid of 2mol/L is 2, separatory, the organic layer washing, drip hexahydroaniline solution to PH6.5, add isopropyl ether, under 0 ℃, stir 2h, separate out white crystal, standing over night, filter, and filter cake is washed with acetone, drying, obtain 7-α-methoxyl group-7-[(2-thienyl) kharophen]-4-Cephalosporanic acid cyclohexylamine salt.
In step (2), as preferably, hydrolysis reaction carries out in the mixed solvent of water and methyl alcohol, and the volume ratio of water and methyl alcohol is 1:1～2, now, and hydrolysis reaction most effective.
Owing in step (2), having ester and acid amides, can be in the situation that there be water to be hydrolyzed, hydrolysis reaction can carry out under strong acid or highly basic catalytic condition, the environment of reaction system is crucial, reaction system is under weak base or alkaline condition, speed of response is suitable, and product yield is also considerable, therefore adopt the requirement that meets with this understanding large production.In step (2), as preferably, the pH value of described alkaline condition is 8～10, and this alkaline condition is regulated by sodium hydroxide, and alkalescence is excessively strong, can cause the tetra-atomic ring open loop, and side reaction increases.As preferably, the temperature of described hydrolysis reaction is 20～30 ℃.
In step (2), the time of hydrolysis reaction is 7～9h.
In step (2), after described hydrolysis reaction completes, the hydrolysate obtained is handled as follows: regulate PH with acetic acid, be warming up to 25 ℃, add ethyl acetate and acetic acid benzyl star, keep 25 ℃ of stirring reaction 2h, filter, filter cake is water successively.Ethyl acetate drip washing, drying obtains 3-hydroxyl first-7-α-[(2-thienyl) kharophen]-4-Cephalosporanic acid acetic acid benzyl star salt (V).
As preferably, in step (3), acylation reaction is at the THF(tetrahydrofuran (THF)) in carry out, now, reaction yield and selectivity are the highest.
As preferably, in step (3), ratio=the 1:1.5 of described 3-hydroxyl first-7-α-[(2-thienyl) kharophen]-4-Cephalosporanic acid acetic acid benzyl star salt and the amount of substance of chloro sulfonyl isocyanate, due to the unstable of chloro sulfonyl isocyanate, when two kinds of quantitative responses such as reactant position, understand some decomposition, the amount of participating in reaction is less than calculated amount, and when excessive, unnecessary meeting is reacted with intermediate compound IV, the by product increase causes the productive rate of target product to reduce.
As preferably, in step (3), the speed that drips described chloro sulfonyl isocyanate is that 8～12d(drips)/min(minute), temperature of reaction is-65～-55 ℃, the reaction times is 12～14 hours.Chloro sulfonyl isocyanate solid is extremely unstable, give out the gas with irritating smell in the water in air solution, drip too fast meeting make temperature of reaction too high easily and other positions of reaction substrate react, cause byproduct of reaction to increase, therefore its rate of addition is controlled to 8～12d/min; The impact of temperature on speed of response and productive rate, intensification is accelerated speed of response, but productive rate is not along with the rising of temperature is increased always, more likely lactam nucleus is destroyed, and by product increases, therefore control temperature of reaction at-65～-55 ℃, product yield and purity is fine control all.The inventor screens above-described condition by experiment, and, on the basis of its condition, target product productive rate and purity are all improved largely.
In step (3), described dropping chloro sulfonyl isocyanate solution, be in advance it to be dissolved in to precooling in tetrahydrofuran (THF), dripped, and avoided direct dropping to produce irritating smog, the accuracy that impact feeds intake.
In step (3), after acylation reaction completes, be handled as follows: reaction solution is poured in the distilled water of precooling, stirred 2h, add ethyl acetate, by not tolerant filtration, add 10% sodium chloride solution in filtrate.Stir 10min.Separatory, organic layer is washed with 10% sodium chloride solution, and adjusting pH value with the hydrochloric acid of 2mol/L is 2.0, separates out white crystal, and standing over night is filtered, and filter cake washs by ethyl acetate, vacuum-drying.Obtain cefoxitin acid.Add acetone soln, under 30 ℃, add Sodium.alpha.-hydroxypropionate, stir 10min, then add acetone, the vacuum-drying of gained solid filtering, obtain cefoxitin sodium.
Compared with prior art, the present invention has following advantage:
Preparation method of the present invention, step (1) adopts NBS reagent by 7 brominations of cefoxitin master core, forms brominated compound; The recycling methoxyl group is to the bromine atoms nucleophilic substitution of 5, production intermediate compound IV; In step (2), 3 acyl groups that are hydrolyzed of intermediate compound IV obtain intermediate V; In step (3), utilize the hydrogen atom on the Sulfuryl chloride isocyanate substituted hydroxy, and then hydrolysis, the finished product both obtained.
Organic solvent content residual in gained cefoxitin sodium product of the present invention is low, all significantly lower than " two ones of Chinese pharmacopoeia versions in 2010 are to the limited amount in the regulation of residual solvent.
Preparation method's operating procedure of the present invention is simple, and cost is low, and production need not any specific installation, and yield and the purity of product are high, and the selectivity of reaction high (can reach 92.4%) is applicable to suitability for industrialized production.
Embodiment
Embodiment 1
7-α-methoxyl group-7-[(2-thienyl) kharophen]-4-Cephalosporanic acid cyclohexylamine salt (IV) synthetic
(1) methylene dichloride 324ml, methyl alcohol 36ml, cefoxitin 360g are added in three neck reaction flasks, be cooled to-20 ℃.Stir.Add methylsulfonic acid 10.12g, cooling, add in batches the NBS(N-bromo-succinimide) and (256g), add sodium methylate (1163g), fully stirring reaction 2h, add S-WAT 8.24g, acetic acid 60ml, saturated nacl aqueous solution after reacting completely.React and be warming up to 0 ℃ after 3 hours, regulating pH value with the hydrochloric acid of 2mol/L is 2, separatory, the organic layer washing, drip hexahydroaniline solution to PH6.5, adds isopropyl ether, stir 2h under 0 ℃, separate out white crystal, standing over night, filter, filter cake is washed with acetone, drying, obtaining compound IV 443.5g(yield is 97.9%, purity is 97.6%);
Above-claimed cpd is carried out to ultimate analysis, result is as follows: C:52.53%, H:5.95%, N:21.32%, O:7.98%, S:12.20%(is mass percent), with 7-α-methoxyl group-7-[(2-thienyl) kharophen]-theoretical value of 4-Cephalosporanic acid cyclohexylamine salt: C:52.55%, H:5.94%, N:21.31%, O:7.99.6%, S:12.2%(is mass percent) conform to.
Show that above-claimed cpd is 7-α-methoxyl group-7-[(2-thienyl) kharophen]-4-Cephalosporanic acid cyclohexylamine salt.
Embodiment 2
Synthesizing of 3-hydroxyl first-7-α-[(2-thienyl) kharophen]-4-Cephalosporanic acid acetic acid benzyl star salt (IV)
(2), by water 130.4ml, methyl alcohol 146.4ml joins in three neck reaction flasks, cooling, adds compound IV 410g, cooling.Slowly adding the sodium hydroxide solution tune pH value of the 4mol/L of precooling is 10, is stirred well to complete reaction.Regulate PH with acetic acid, heat up and adjust PH, be warming up to 25 ℃, add ethyl acetate, acetic acid benzyl star 16g, keep 25 ℃ of stirring reaction 2h.Filter, filter cake is water successively.Ethyl acetate drip washing, it is 96% that drying obtains compound V287.11g(yield, purity is 97.63%).
Embodiment 3
Synthesizing of cefoxitin sodium (I)
(3) by compound IV 287.11g, THF joins three neck reaction flasks, cooling, adds the Sulfuryl chloride isocyanate 158.97g of precooling in batches, is stirred well to complete reaction.Reaction solution is poured in the distilled water of precooling, stirred 2h, add ethyl acetate, by not tolerant filtration, add 10% sodium chloride solution in filtrate.Stir 10min.Separatory, organic layer is washed with 10% sodium chloride solution, and adjusting pH value with the hydrochloric acid of 2mol/L is 2.0, separates out white crystal, and standing over night is filtered, and filter cake washs by ethyl acetate, vacuum-drying.Obtain cefoxitin acid.Add acetone soln, under 30 ℃, add Sodium.alpha.-hydroxypropionate 2.0g, stir 10min, then add acetone, the vacuum-drying of gained solid filtering, obtaining cefoxitin sodium 319.59g(yield is 95%, purity is 99.5%).
Above-claimed cpd is carried out to ultimate analysis, and result is as follows: C:42.74%, H:3.59%, N:9.36%, S:14.29%(is mass percent), with the theoretical value of cefoxitin sodium: C:42.76%, H:3.59%, N:9.35%, S:14.27%(is mass percent) conform to.Show that above-claimed cpd is cefoxitin sodium.
Comparative Examples 1
The first step: get 2.00 kilograms of cefoxitins, add 704 milliliters of triethylamines, 20 liters of ether; Add 1.07 kilograms of chloro sulfonyl isocyanates, stirring reaction 6 hours.Reaction solution is cooling, then add 0.5 liter of 95% ethanol, stir about 30 minutes.By the reaction solution concentrating under reduced pressure, add cold water, stir 20 minutes.Suction filtration, washing, vacuum-drying, obtain 1.7 kilograms of faint yellow solids (being intermediate product), yield 85.8%.
Second step: in dry reactor, add 5 liters of anhydrous methanols, be cooled to-70 ℃; Add lithium 32.7 grams under whipped state, stir about 1 hour, obtain lithium methoxide solution.In another dry reactor, add 1.70 kilograms of intermediate products, 15 liters of dehydrated alcohols, stirring and dissolving, be cooled to-70 ℃; Add prefabricated lithium methoxide solution, insulation reaction 40 minutes, add acetic acid, and regulating pH value is 4.0 left and right.Be warming up to room temperature, decompression and solvent recovery, residuum adds cold water, has a large amount of solids to separate out.Suction filtration, wash twice, and 75% recrystallizing methanol for filter cake, obtain 1.46 kilograms of white solids (being cefoxitin acid), yield: 85.95%.
The 3rd step: by 1.45 kilograms of cefoxitin acids, ethyl acetate 15L, drop in reactor, and stirring at room is dissolved, and adds activated carbon decolorizing 30min, filters, then sterile filtration, bacteria-free filtrate is pressed in sterilisable chamber; By Sodium isooctanoate 564 grams, after ethyl acetate 5L stirring and dissolving, sterile filtration, be pressed into sterilisable chamber, is placed in high-order dropwise adding tank.The Sodium isooctanoate bacteria-free filtrate is slowly dropped in the cefoxitin acid sterile liquid, and under room temperature, agitation and dropping is approximately 1.5 hours.Dropwise slow stirring 2 hours.Filter, filter cake washs by ethyl acetate, drains, and vacuum-drying, obtain 1.37 kilograms of off-white color crystalline powders (being cefoxitin sodium), yield: 94.5%.
Differentiate
HPLC differentiates
Method: sample and the cefoxitin sodium reference substance of getting embodiment 3 preparations, (get potassium primary phosphate 1.0g and Sodium phosphate dibasic 1.8g with phosphate buffered saline buffer, adding water 900ml dissolves, regulating pH value with phosphoric acid or 10mol/L sodium hydroxide solution is 7.1 ± 0.1, be diluted with water to 1000ml) make every 1ml containing the solution of 0.3mg, according to the test of the high performance liquid chromatography under the assay item, trial-product should be consistent with the retention time of reference substance main peak.
Result: in the color atlas of assay item record, the retention time of the sample main peak of embodiment 3 preparations is all consistent with the retention time of the main peak of cefoxitin reference substance, meets the requirements.
The flame reaction of sodium salt
Method: get the sample of embodiment 3 preparations, according to two appendix III of Chinese Pharmacopoeia version in 2010, the flame reaction differential method of sodium salt is tested, and should show the flame reaction of sodium salt, and result is aobvious sodium salt flame reaction all, meets the requirements.
Structural Identification
Embodiment 3 products obtained therefroms are carried out to Structural Identification, and method and result are as follows:
Ultimate analysis
Embodiment 3 analytical resultss show, percentage composition and the theoretical value of CHO are basically identical.
Nuclear magnetic resonance spectrum
In mass spectroscopy cefoxitin sodium ESI-MS (m/z), quasi-molecular ion peak [M-1]
+(not comprising crystal water) is 425.5, with C in its molecular formula
16h
16n
3naO
7s
2conform to.
The above analysis result, the chemical structure of the sample of embodiment 3 can be proved conclusively as cefoxitin sodium.
Related substance
Related substance according to " high effective liquid chromatography for measuring in two attached V D of Chinese pharmacopoeia version in 2010:
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica, be weighting agent; Water-acetonitrile-glacial acetic acid (840:160:10) is moving phase, and the detection wavelength is 254nm, flow velocity 1.0ml/min, and the detection wavelength is 254nm.The resolution at cefoxitin sodium peak and other assorted peaks should be up to specification, and theoretical plate number, should be lower than 2800 by the cefoxitin sodium peak.
Detection method: the cefoxitin sodium sample of getting embodiment 3 and Comparative Examples 1 preparation, add respectively phosphate buffered saline buffer and (get potassium primary phosphate 1.0g and Sodium phosphate dibasic 1.8g, adding water 900ml dissolves, regulating pH value with phosphoric acid or 10mol/L caustic lye of soda is 7.1 ± 0.1, be diluted with water to 1000ml, mix, filter and get final product) make every 1ml approximately containing the solution of cefoxitin 0.3mg, as need testing solution; Get need testing solution 20 μ l injection liquid chromatographies, record to principal constituent peak retention time 2 times of color atlas.By normalization method calculate each impurity peak area and, must not be greater than 2% of total peak area, and the maximum contaminant peak must not be greater than 1% of total peak area.
Result is as follows: in the cefoxitin sodium sample of embodiment 3 and Comparative Examples 1 preparation, related substance is respectively 0.12%, 0.18%, 0.14%, and the single impurity peak area of 3.2%(is with respect to the per-cent of the main peak area of contrast solution); Measurement result shows: in the color atlas of cefoxitin sodium highly finished product solution, single impurity peak area is less than the main peak area (1.0%) of contrast solution, meets the requirements.
Claims (10)
1. the preparation method of a cefoxitin sodium, is characterized in that, comprises the steps:
(1) in organic solvent, under the condition that methylsulfonic acid exists, cefoxitin and NBS and sodium methylate carry out the intermediate product that substitution reaction obtains methoxy substitution successively, after this intermediate product acidifying, with the hexahydroaniline salify, obtain 7-α-methoxyl group-7-[(2-thienyl) kharophen]-4-Cephalosporanic acid cyclohexylamine salt;
(2) 7-α-methoxyl group step (1) obtained-7-[(2-thienyl) kharophen]-reaction that is hydrolyzed under alkaline condition of 4-Cephalosporanic acid cyclohexylamine salt obtains hydrolysate, after this hydrolysate is acidified and acetic acid benzyl star salify obtain 3-hydroxyl first-7-α-[(2-thienyl) kharophen]-4-Cephalosporanic acid acetic acid benzyl star salt;
(3) 3-hydroxyl first step (2) obtained-7-α-[(2-thienyl) kharophen]-4-Cephalosporanic acid acetic acid benzyl star salt and Sulfuryl chloride isocyanate carry out acylation reaction; react completely by processing and obtain cefoxitin acid later, after cefoxitin acid and Sodium.alpha.-hydroxypropionate salify, obtain described cefoxitin sodium.
2. the preparation method of cefoxitin sodium according to claim 1, is characterized in that, the mixed solvent that described organic solvent is methylene dichloride and methyl alcohol, and the volume ratio of described methylene dichloride and methyl alcohol is 9:1～13:1.
3. the preparation method of cefoxitin sodium according to claim 1 and 2, is characterized in that, in step (1), the temperature of substitution reaction is-75～-55 ℃.
4. the preparation method of cefoxitin sodium according to claim 1 and 2, is characterized in that, in step (1), described cefoxitin is 1:1.5～1:2 with the ratio of the amount of substance of NBS; Described cefoxitin is 1:20～1:30 with the ratio of the amount of substance of sodium methylate.
5. the preparation method of cefoxitin sodium according to claim 1, is characterized in that, in step (2), hydrolysis reaction carries out in the mixed solvent of water and methyl alcohol, and the volume ratio of water and methyl alcohol is 1:1～1:2.
6. the preparation method of cefoxitin sodium according to claim 1, is characterized in that, in step (2), the pH value of described alkaline condition is 8～10.
7. the preparation method of cefoxitin sodium according to claim 1, is characterized in that, in step (2), the temperature of described hydrolysis reaction is 20～30 ℃.
8. the preparation method of cefoxitin sodium according to claim 1, is characterized in that, in step (3), acylation reaction is carried out in THF.
9. the preparation method of cefoxitin sodium according to claim 1, is characterized in that, in step (3), described chloro sulfonyl isocyanate adopts the mode dripped to be fed intake, the speed of dropping be 8～12d drip/minute.
10. the preparation method of cefoxitin sodium according to claim 1, is characterized in that, in step (3), the temperature of acylation reaction is-65～-55 ℃.
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| CN104072521A (en) * | 2014-06-27 | 2014-10-01 | 广东省石油化工研究院 | Preparation method for cefoxitin acid |
| CN104402908A (en) * | 2014-10-23 | 2015-03-11 | 胡梨芳 | Cefoxitin sodium compound entity and composition and uses thereof |
| CN104402909A (en) * | 2014-11-12 | 2015-03-11 | 盐城开元医药化工有限公司 | Synthetic method of cefoxitin acid |
| CN104447800A (en) * | 2014-11-21 | 2015-03-25 | 辽宁天华化工有限责任公司 | Synthesis technology of cefoxitin acid |
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| CN106995453A (en) * | 2017-04-01 | 2017-08-01 | 齐鲁安替制药有限公司 | Crystallization of the alpha methoxy cefoxitin of cephalosporin intermediate 7 and preparation method thereof |
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| CN104402908A (en) * | 2014-10-23 | 2015-03-11 | 胡梨芳 | Cefoxitin sodium compound entity and composition and uses thereof |
| CN104402909A (en) * | 2014-11-12 | 2015-03-11 | 盐城开元医药化工有限公司 | Synthetic method of cefoxitin acid |
| CN104402909B (en) * | 2014-11-12 | 2017-03-15 | 盐城开元医药化工有限公司 | A kind of synthetic method of cefoxitin acid |
| CN104447800A (en) * | 2014-11-21 | 2015-03-25 | 辽宁天华化工有限责任公司 | Synthesis technology of cefoxitin acid |
| CN104890950A (en) * | 2015-04-27 | 2015-09-09 | 四川制药制剂有限公司 | Injection cefoxitin sodium preparation technology for automatically examining products |
| CN106995453A (en) * | 2017-04-01 | 2017-08-01 | 齐鲁安替制药有限公司 | Crystallization of the alpha methoxy cefoxitin of cephalosporin intermediate 7 and preparation method thereof |
| CN106995453B (en) * | 2017-04-01 | 2019-05-03 | 齐鲁安替制药有限公司 | The crystallization and preparation method thereof of 7 α of cephalosporin intermediate-methoxyl group cefoxitin |
| CN110396105A (en) * | 2018-09-10 | 2019-11-01 | 广东金城金素制药有限公司 | Mei Fu elder generation cefoxitin sodium pharmaceutical preparation prevents infection application in gastrointestinal surgery |
| CN109651403A (en) * | 2018-12-29 | 2019-04-19 | 上海上药新亚药业有限公司 | A kind of synthetic method of cefoxitin sodium |
| CN109651403B (en) * | 2018-12-29 | 2022-01-07 | 上海上药新亚药业有限公司 | Synthesis method of cefoxitin sodium |
| CN110396102A (en) * | 2019-01-15 | 2019-11-01 | 广东金城金素制药有限公司 | Cefoxitin sodium pharmaceutical preparation is in vaginal hysterectomy, abdominal cavity uterectomy, the preoperative prevention infection application of (palace) production of cutting open the belly |
| CN110396102B (en) * | 2019-01-15 | 2021-05-04 | 广东金城金素制药有限公司 | Cefoxitin sodium compound pharmaceutical preparation and application thereof in prevention of infection before vaginal hysterectomy, abdominal hysterectomy and cesarean section (uterine) |
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