CN103450225B - The preparation method of cefoxitin sodium - Google Patents
The preparation method of cefoxitin sodium Download PDFInfo
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Abstract
The preparation method who the invention discloses a kind of cefoxitin sodium, comprising: (1) adopts NBS reagent by as 7 of the main core of cefoxitin brominations, forms brominated compound; Recycling methoxyl group is to the bromine atoms nucleophilic displacement of fluorine of 5, production intermediate compound IV; 3 acyl groups that are hydrolyzed of step (2) intermediate compound IV obtain intermediate V; Step (3) is utilized the hydrogen atom on chlorosulphonyl isocyanate substituted hydroxy, and then hydrolysis, has both obtained cefoxitin sodium. The method technique is simple, and product yield is high, and purity is high, and reaction selectivity is high, and production need not any special installation, is applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to material medicine preparation field, be specifically related to a kind of preparation side of cefoxitin sodiumMethod.
Background technology
Cefoxitin sodium, chemical name is: (6R, 7S)-3-carbamyl yloxymethyl-7-methoxyl group-8-oxo-7-[2 (2-thiophene, acetamido)] assorted nitrogen dicyclo-[4,2, the 0]-Xin of-5-thia-1--2-alkene-formic acid sodium salt, molecular formula: C16H16N3NaO7S2, molecular weight: 449.43, chemical structural formulaAs follows:
Cefoxitin sodium, is developed by Merk company of the U.S., and listing in 1994, is to be produced by streptomyceteCephamycin C through the semi-synthetic class new antibiotic making. Cefoxitin sodium is due to canAnti-bacteria Cell wall synthesis and kill bacteria, and due to structural particularity, bacterium is producedBeta-lactamase stable, there is huge market potential.
At present, the synthetic method of cefoxitin sodium, has a lot of documents and patent report. Its synthetic routeMainly contain 3: (1), taking cephamycin as raw material, is first modified the amino on its carboxylic acid side chain,Then its four-membered ring is modified, this route exist technique loaded down with trivial details, need noble metal catalyst etc.Shortcoming, therefore never meet the demand of industrialized production; (2) with cephalothin acid or sodium saltFor raw material, first modify the C of 7-amino-cephalosporanic acid (7-ACA)3Side chain on position, then modifiesC7Bit amino side chain or taking cephalothin acid or sodium salt as raw material, first modifies the C of 7-ACA7Position ammoniaBase side chain, then modifies C3Side chain on position, although this route raw material is cheap and easy to get, reactionIn process, need to use molecular sieve and reactions steps generally all longer, therefore also never can industrializationProduce; (3) taking methoxyl group cephalosporin (7-MAC) as raw material, first modify the C of 7-MAC7Bit amino side chain, then modifies the side chain on C3 position, although this route synthesis step simplify,That 7-MAC is expensive and be difficult to obtain, therefore be not also applied to industrialized production always.
Publication number is that CN101007812A Chinese patent application discloses antibacterial drugs cefoxitinPreparation method, taking 7a-methoxyl group-7 beta-amino-cephalosporanic acid (7-MAC) as raw material, through 2-thiopheneFen acetyl glycosylation reaction, hydrolysis and carbamylization reaction, obtain Cefoxitin (I), the partyMethod has improved the productive rate of Cefoxitin and sodium salt thereof effectively, has avoided harsh reaction condition, savesProduction cost.
Publication number is to disclose a kind of cefoxitin sodium in the Chinese patent application of CN101235045APreparation method, taking cefoxitin as raw material, carry out carbamyl, 3 Imported Ammonia methanoyl firstBase, generates intermediate product; Intermediate product and methyl alcohol-lithium methoxide solution reaction, introduce oxygen methyl for 7,Generate cefoxitin acid; Cefoxitin acid is dissolved in organic solvent, add sodium salt ethyl acetate (orMethyl alcohol) solution, suction filtration, drying under reduced pressure, obtains cefoxitin sodium.
Summary of the invention
The invention provides a kind of preparation method of cefoxitin sodium, this preparation method's step is simple and formerMaterial be easy to get and react selectively good, yield and the purity of product are high.
A preparation method for cefoxitin sodium, comprises the steps:
(1) in organic solvent, under the condition that methanesulfonic acid exists, cefoxitin (II) and NBS(N-bromo-succinimide) and sodium methoxide carry out substitution reaction and obtain the centre of methoxy substitution successivelyProduct, carries out salify with cyclohexylamine after this intermediate product acidifying and obtains 7-α-methoxyl group-7-[(2-thienyl)Acetylamino]-4-cephalosporanic acid cyclohexylamine salt (IV);
(2) 7-α-methoxyl group-7-[(2-thienyl step (1) being obtained) acetylamino]-4-cephaloAlkanoic acid cyclohexylamine salt (IV) is hydrolyzed to react and obtains hydrolysate under alkali condition, and this hydrolysis is producedThing acidified after and acetic acid benzyl star salify obtain 3-hydroxyl first-7-α-[(2-thienyl) acetylamino]-4-Cephalosporanic acid acetic acid benzyl star salt (V);
(3) 3-hydroxyl first-7-α-[(2-thienyl) acetylamino]-4-cephalo step (2) being obtainedAlkanoic acid acetic acid benzyl star salt (V) and chlorosulphonyl isocyanate carry out acylation reaction, after reacting completely throughPost processing obtains cefoxitin acid, obtains described Cefoxitin after cefoxitin acid and sodium lactate salifySodium (I);
Course of reaction is shown below:
Initiation material cefoxitin of the present invention easily obtains, and obtains described cephalo through three stepsWestern fourth sodium, simple to operate. Wherein, the existence of the methanesulfonic acid in step (1), has improved anti-greatlyThat answers is selective, and yield and the purity of the product finally obtaining are high.
In step (1), described organic solvent is that halogenated hydrocarbon solvent is or/and alcohols solvent is preferredFor the mixed solvent of carrene and methyl alcohol, described carrene and the volume ratio of methyl alcohol are9:1～13:1, now, the yield of product is high, selectively good. Wherein, total use of described organic solventAmount, without strict especially requirement, can fully be dissolved raw material.
In step (1), as preferably, the temperature of substitution reaction is-75～-55 DEG C; As furtherPreferably, the temperature of reaction is-70～-60 DEG C; Because cephalosporin compound all has lactams four-membered ring,Can only be when temperature be lower stable existence, in the reaction system that has water to exist, the entering of hydroneAttack the four-membered ring hydrolysis that is easy to make lactams, when particularly reaction temperature is too high, cephalosporin compound is openedRing decomposes rapidly. Under the above-mentioned condition of the inventor, byproduct of reaction reduces, and product purity is high, producesThing yield is high.
In step (1), as preferably, in step (1), described cefoxitin and NBS'sThe ratio of amount of substance is 1:1.5～1:2; Described cefoxitin with the ratio of the amount of substance of sodium methoxide is1:20～1:30。
In step (1), the time of substitution reaction is 3～6h, as preferably, and the time of substitution reactionBe 3～5h.
In step (1), substitution reaction completes after the intermediate product that obtains methoxy substitution, conscientious asLower processing: add sodium sulfite in reaction system, acetic acid and saturated nacl aqueous solution stir, and 3 is littleTime after be warming up to 0 DEG C, regulating pH value with the hydrochloric acid of 2mol/L is 2, separatory, organic layer washing,Drip cyclohexylamine solution to PH6.5, add isopropyl ether, at 0 DEG C, stir 2h, separate out white crystal,Hold over night, filters, and filter cake is washed with acetone, dry, obtains 7-α-methoxyl group-7-[(2-thienyl) acetylAmino]-4-cephalosporanic acid cyclohexylamine salt.
In step (2), as preferably, hydrolysis carries out in the mixed solvent of water and methyl alcohol,The volume ratio of water and methyl alcohol is 1:1～2, now, and hydrolysis most effective.
Owing to having ester and acid amides in step (2), can in the situation that having water, be hydrolyzed hydrolysisReaction can be carried out under strong acid or highly basic catalytic condition, and the environment of reaction system is crucial, reactionSystem is under weak base or alkali condition, and reaction speed is suitable, and product yield is also considerable, therefore adoptMeet with this understanding the requirement of large production. In step (2), as preferably, described alkaline barThe pH value of part is 8～10, and this alkali condition regulates by NaOH, and alkalescence is excessively strong, can leadCause four-membered ring open loop, side reaction increases. As preferably, the temperature of described hydrolysis is 20～30 DEG C.
In step (2), the time of hydrolysis is 7～9h.
In step (2), after described hydrolysis completes, the hydrolysate obtaining carries out as followsProcess: regulate PH with acetic acid, be warming up to 25 DEG C, add ethyl acetate and acetic acid benzyl star, keep 25 DEG CStirring reaction 2h, filters, and filter cake is water successively. Ethyl acetate drip washing, the dry 3-hydroxyl first that obtains-7-α-[(2-thienyl) acetylamino]-4-cephalosporanic acid acetic acid benzyl star salt (V).
As preferably, in step (3), acylation reaction is at THF(oxolane) in carry out, thisTime, reaction yield and selectively the highest.
As preferably, in step (3), described 3-hydroxyl first-7-α-[(2-thienyl) acetylamino]-4-Ratio=the 1:1.5 of cephalosporanic acid acetic acid benzyl star salt and the amount of substance of chloro sulfonyl isocyanate, due to chlorineFor the unstability of sulfonyl isocyanate, in the time of the quantitative responses such as two kinds of reactant positions, understand some pointSeparate, the amount of participating in reaction is less than amount of calculation, and when excessive, unnecessary meeting is reacted with intermediate compound IV,Accessory substance increase causes the productive rate of target product to reduce.
As preferably, in step (3), the speed that drips described chloro sulfonyl isocyanate is 8～12d(dripping)/min(minute), reaction temperature is-65～-55 DEG C, the reaction time is 12～14 hours. ChlorineExtremely unstable for sulfonyl isocyanate solid, give out and there is penetrating odor in water in air solutionGas, drips too fast meeting too high other positions easy and reaction substrate of reaction temperature is reacted,Cause byproduct of reaction to increase, therefore its rate of addition is controlled to 8～12d/min; Temperature is to reactionThe impact of speed and productive rate, heats up reaction speed is accelerated, but productive rate is not along with the rising one of temperatureDirectly increase that more likely lactam nucleus is destroyed, accessory substance increases, and exists therefore control reaction temperature-65～-55 DEG C, product yield and purity is fine control all. The inventor screens the above by experimentCondition, and on the basis of its condition, target product productive rate and purity all obtain largelyImprove.
In step (3), described dropping chloro sulfonyl isocyanate solution, is dissolved in advancePrecooling in oxolane, is dripping, and has avoided direct dropping to produce irritating smog, and impact is thrownThe accuracy of material.
In step (3), after acylation reaction completes, be handled as follows: reactant liquor is poured in advanceIn cold distilled water, stir 2h, add ethyl acetate, by not tolerant filtration, in filtrate, add10% sodium chloride solution. Stir 10min. Separatory, organic layer is washed with 10% sodium chloride solution,Adjusting pH value with the hydrochloric acid of 2mol/L is 2.0, separates out white crystal, and hold over night is filtered filter cakeWith ethyl acetate washing, vacuum drying. Obtain cefoxitin acid. Add acetone soln, at 30 DEG C,Add sodium lactate, stir 10min, then add acetone, the vacuum drying of gained solid filtering, obtains to the endThe western fourth sodium of spore.
Compared with prior art, tool of the present invention has the following advantages:
Preparation method of the present invention, step (1) adopts NBS reagent by 7 bromines of the main core of cefoxitinChange, form brominated compound; Recycling methoxyl group is to the bromine atoms nucleophilic displacement of fluorine of 5, in the middle of producingBody IV; In step (2), 3 acyl groups that are hydrolyzed of intermediate compound IV obtain intermediate V; StepSuddenly in (3), utilize the hydrogen atom on chlorosulphonyl isocyanate substituted hydroxy, and then hydrolysis, bothObtain final products.
Organic solvent content residual in gained cefoxitin sodium product of the present invention is low, all significantlyLower than two of " Chinese pharmacopoeia " versions in 2010 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 special installation, producesYield and the purity of product are high, and the selective height (can reach 92.4%) of reaction is applicable to suitability for industrialized production.
Detailed description of the invention
Embodiment 1
7-α-methoxyl group-7-[(2-thienyl) acetylamino]-4-cephalosporanic acid cyclohexylamine salt (IV) synthetic
(1) carrene 324ml, methyl alcohol 36ml, cefoxitin 360g are added to three neck reaction bulbsIn, be cooled to-20 DEG C. Stir. Add methanesulfonic acid 10.12g, cooling, add in batches NBS(N-bromo-succinimide) (256g), adds sodium methoxide (1163g), fully stirring reaction 2h,After reacting completely, add sodium sulfite 8.24g, acetic acid 60ml, saturated nacl aqueous solution. Reaction 3After hour, be warming up to 0 DEG C, regulating pH value with the hydrochloric acid of 2mol/L is 2, separatory, and organic layer washing,Drip cyclohexylamine solution to PH6.5, add isopropyl ether, at 0 DEG C, stir 2h, separate out white crystal,Hold over night, filters, and filter cake is washed with acetone, and dry, obtaining compound IV 443.5g(yield is 97.9%,Purity is 97.6%);
Above-claimed cpd is carried out to elementary analysis, and result is as follows: C:52.53%, and H:5.95%, N:21.32%,O:7.98%, S:12.20%(is mass percent), with 7-α-methoxyl group-7-[(2-thienyl) acetylAmino] 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) acetylamino]-4-cephalosporanic acid ringHexylamine salt.
Embodiment 2
3-hydroxyl first-7-α-[(2-thienyl) acetylamino]-4-cephalosporanic acid acetic acid benzyl star salt (IV) closesBecome
(2), by water 130.4ml, methyl alcohol 146.4ml joins in three neck reaction bulbs, cooling, addsCompound IV 410g, cooling. Slowly add the sodium hydroxide solution of the 4mol/L of precooling to adjust pH valueBe 10, be stirred well to complete reaction. Regulate PH with acetic acid, heat up and adjust PH, be warming up to 25 DEG C,Add ethyl acetate, acetic acid benzyl star 16g, keeps 25 DEG C of stirring reaction 2h. Filter, filter cake is used successivelyWater. Ethyl acetate drip washing, being dried and obtaining compound V287.11g(yield is 96%, purity is97.63%）。
Embodiment 3
Synthesizing of cefoxitin sodium (I)
(3), by compound IV 287.11g, THF joins three neck reaction bulbs, cooling, adds in batchesThe chlorosulphonyl isocyanate 158.97g of precooling, is stirred well to complete reaction. Reactant liquor is poured in advanceIn cold distilled water, stir 2h, add ethyl acetate, by not tolerant filtration, in filtrate, add10% sodium chloride solution. Stir 10min. Separatory, organic layer is washed with 10% sodium chloride solution,Adjusting pH value with the hydrochloric acid of 2mol/L is 2.0, separates out white crystal, and hold over night is filtered filter cakeWith ethyl acetate washing, vacuum drying. Obtain cefoxitin acid. Add acetone soln, at 30 DEG C,Add sodium lactate 2.0g, stir 10min, then add acetone, the vacuum drying of gained solid filtering,Be 95% to cefoxitin sodium 319.59g(yield, purity is 99.5%).
Above-claimed cpd is carried out to elementary analysis, and result is as follows: C:42.74%, and 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 CefoxitinSodium.
Comparative example 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. Reactant liquor is cooling, then addEnter 0.5 liter of 95% ethanol, stir about 30 minutes. By reactant liquor reduced pressure concentration, add cold water, stirMix 20 minutes. Suction filtration, washing, vacuum drying, obtains faint yellow solid (being intermediate product) 1.7Kilogram, yield 85.8%.
Second step: in dry reactor, add 5 liters of absolute methanols, be cooled to-70 DEG C; Stir shapeUnder state, add 32.7 grams of lithiums, stir about 1 hour, obtain lithium methoxide solution. At another dry reactionIn device, add 1.70 kilograms of intermediate products, 15 liters of absolute ethyl alcohols, stirring and dissolving, is cooled to-70 DEG C;Add prefabricated lithium methoxide solution, insulation reaction 40 minutes, adds acetic acid, and regulating pH value is 4.0Left and right. Be warming up to room temperature, decompression and solvent recovery, residue adds cold water, has a large amount of solids to separate out.Suction filtration, washing twice, 75% recrystallizing methanol for filter cake, obtains white solid and (is CefoxitinAcid) 1.46 kilograms, yield: 85.95%.
The 3rd step: by 1.45 kilograms of cefoxitin acids, ethyl acetate 15L, drops in reactor chamberTemperature stirring and dissolving, adds activated carbon decolorizing 30min, filters, then aseptic filtration, bacteria-free filtrate is pressedEnter in desinfection chamber; By 564 grams of sodium iso-octoates, after ethyl acetate 5L stirring and dissolving, aseptic filtration,Be pressed into desinfection chamber, be placed in high-order dropwise adding tank. Sodium iso-octoate bacteria-free filtrate is slowly dropped to CefoxitinIn acid sterile liquid, agitation and dropping approximately 1.5 hours under room temperature. Dropwise slow stirring 2 hours. CrossFilter, filter cake washs with ethyl acetate, drains, and vacuum drying, obtains off-white color crystalline powder and (isCefoxitin sodium) 1.37 kilograms, yield: 94.5%.
Differentiate
HPLC differentiates
Method: get sample and cefoxitin sodium reference substance prepared by embodiment 3, use phosphate buffer(get potassium dihydrogen phosphate 1.0g and sodium hydrogen phosphate 1.8g, the 900ml that adds water dissolves, with phosphoric acid or 10mol/It is 7.1 ± 0.1 that L sodium hydroxide solution regulates pH value, is diluted with water to 1000ml) make every 1mlContaining the solution of 0.3mg, according to the high performance liquid chromatography test under assay item, test sample with contrastThe retention time of product main peak should be consistent.
Result: in the chromatogram of assay item record, the guarantor of sample main peak prepared by embodiment 3Stay the time all consistent with the retention time of the main peak of Cefoxitin reference substance, meet the requirements.
The flame reaction of sodium salt
Method: get sample prepared by embodiment 3, according to two annex 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 all aobvious sodium salt flame is anti-Should, meet the requirements.
Structural Identification
Embodiment 3 products obtained therefroms are carried out to Structural Identification, and method and result are as follows:
Elementary analysis
Embodiment 3 analysis results show, percentage composition and the theoretical value of CHO are basically identical.
Nuclear magnetic resoance spectrum
In mass spectral analysis cefoxitin sodium ESI-MS (m/z), quasi-molecular ion peak [M-1]+(do not comprise knotBrilliant water) be 425.5, with C in its molecular formula16H16N3NaO7S2Conform to.
The above analysis result, the chemical constitution of the sample of embodiment 3 can be confirmed as CefoxitinSodium.
Related substance
Related substance is according to the high performance liquid chromatography in two attached VD of " Chinese pharmacopoeia " version in 2010Measure:
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica be filler; Water-Acetonitrile-glacial acetic acid (840:160:10) is mobile phase, and detection wavelength is 254nm, flow velocity 1.0ml/min,Detection wavelength is 254nm. The separating degree at cefoxitin sodium peak and other assorted peaks should conform with the regulations, theoryThe number of plates, should be lower than 2800 by cefoxitin sodium peak.
Detection method: get Cefoxitin sodium sample prepared by embodiment 3 and comparative example 1, add respectively phosphate(get potassium dihydrogen phosphate 1.0g and sodium hydrogen phosphate 1.8g, the 900ml that adds water dissolves buffer solution, uses phosphorusIt is 7.1 ± 0.1 that acid or 10mol/L caustic lye of soda regulate pH value, is diluted with water to 1000ml, mixedEven, filter and get final product) make the solution that every 1ml approximately contains Cefoxitin 0.3mg, as need testing solution;Get need testing solution 20 μ l injection liquid chromatographies, record chromatogram to 2 of principal component peak retention timeDoubly. By normalization method calculate each impurity peak area and, must not be greater than 2% of total peak area, andLarge impurity peaks must not be greater than 1% of total peak area.
Result is as follows: in Cefoxitin sodium sample prepared by embodiment 3 and comparative example 1, related substance dividesBe not 0.12%, 0.18%, 0.14%, the single impurity peak area of 3.2%(is with respect to the master of contrast solutionThe percentage of peak area); Measurement result shows: single in the chromatogram of cefoxitin sodium highly finished product solutionIndividual impurity peak area is less than the main peak area (1.0%) of contrast solution, meets the requirements.
Claims (1)
1. a preparation method for cefoxitin sodium, is characterized in that, step is as follows:
(1) by carrene 324ml, methyl alcohol 36ml, cefoxitin 360g adds in three neck reaction bulbs, be cooled to-20 DEG C, stir, add methanesulfonic acid 10.12g, cooling, add in batches NBS256g, add sodium methoxide 1163g, fully stirring reaction 2h, after reacting completely, add sodium sulfite 8.24g, acetic acid 60ml, saturated nacl aqueous solution, react and be warming up to 0 DEG C after 3 hours, with the salt acid for adjusting pH value of 2mol/L be 2, separatory, organic layer washing, drip cyclohexylamine solution to pH6.5, add isopropyl ether, at 0 DEG C, stir 2h, separate out white crystal, hold over night, filter, filter cake is washed with acetone, dry, obtain 7-α-methoxyl group-7-[(2-thienyl) acetylamino]-4-cephalosporanic acid cyclohexylamine salt 443.5g, yield is 97.9%, purity is 97.6%,
(2) by water 130.4ml, methyl alcohol 146.4ml joins in three neck reaction bulbs, cooling, add 7-α-methoxyl group-7-[(2-thienyl) acetylamino]-4-cephalosporanic acid cyclohexylamine salt 410g, cooling, the sodium hydroxide solution adjust pH that slowly adds the 4mol/L of precooling is 10, be stirred well to complete reaction, use second acid for adjusting pH, heat up and adjust pH, be warming up to 25 DEG C, add ethyl acetate, acetic acid benzyl star 16g, keep 25 DEG C of stirring reaction 2h, filter, filter cake is water successively, ethyl acetate drip washing, dry 3-hydroxyl first-7-α-[(2-thienyl) acetylamino]-4-cephalosporanic acid acetic acid benzyl star salt 287.11g that obtains, yield is 96%, purity is 97.63%,
(3) by 3-hydroxyl first-7-α-[(2-thienyl) acetylamino]-4-cephalosporanic acid acetic acid benzyl star salt 287.11g, THF joins three neck reaction bulbs, cooling, add the chlorosulphonyl isocyanate 158.97g of precooling in batches, be stirred well to complete reaction, reactant liquor is poured in the distilled water of precooling, stir 2h, add ethyl acetate, by not tolerant filtration, in filtrate, add 10% sodium chloride solution, stir 10min, separatory, organic layer is washed with 10% sodium chloride solution, with the hydrochloric acid adjust pH of 2mol/L be 2.0, separate out white crystal, hold over night, filter, filter cake washs with ethyl acetate, vacuum drying, obtain cefoxitin acid, add acetone soln, at 30 DEG C, add sodium lactate 2.0g, stir 10min, add again acetone, the vacuum drying of gained solid filtering, obtain cefoxitin sodium 319.59g, yield is 95%, purity is 99.5%.
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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 |
| CN104402908B (en) * | 2014-10-23 | 2017-10-27 | 胡梨芳 | Cefoxitin sodium compound entity and combinations thereof and purposes |
| 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 |
| CN104447800B (en) * | 2014-11-21 | 2016-11-16 | 辽宁天华生物药业有限公司 | A kind of synthetic 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 |
| 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 |
| CN110396105B (en) * | 2018-09-10 | 2021-03-19 | 广东金城金素制药有限公司 | Application of cefixime sodium mefrefirstly pharmaceutical preparation in gastrointestinal tract operation infection prevention |
| 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 |
| 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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| CN101235045A (en) * | 2008-02-26 | 2008-08-06 | 芦红代 | Method for preparing cefoxitin sodium |
| CN102153567A (en) * | 2010-05-28 | 2011-08-17 | 重庆天地药业有限责任公司 | Method for preparing cefoxitin acid |
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| WO2004083217A1 (en) * | 2003-03-20 | 2004-09-30 | Orchid Chemicals & Pharmaceuticals Ltd | An improved process for the preparation of cefoxitin |
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| CN101007812A (en) * | 2007-01-26 | 2007-08-01 | 深圳信立泰药业有限公司 | Antibacterial drugs cefoxitin preparation process |
| CN101235045A (en) * | 2008-02-26 | 2008-08-06 | 芦红代 | Method for preparing cefoxitin sodium |
| CN102153567A (en) * | 2010-05-28 | 2011-08-17 | 重庆天地药业有限责任公司 | Method for preparing cefoxitin acid |
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