CN100484526C - Compounding method of cefpirome sulfate raw material and uses thereof - Google Patents
Compounding method of cefpirome sulfate raw material and uses thereof Download PDFInfo
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- CN100484526C CN100484526C CNB2008100011903A CN200810001190A CN100484526C CN 100484526 C CN100484526 C CN 100484526C CN B2008100011903 A CNB2008100011903 A CN B2008100011903A CN 200810001190 A CN200810001190 A CN 200810001190A CN 100484526 C CN100484526 C CN 100484526C
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Abstract
The invention provides a cefpirome sulfate aseptic powder injection, which is composed of cefpirome sulfate and anhydrous sodium carbonate. The invention is characterized in that: the weight ratio of the cefpirome sulfate to the soda ash is 4-6: 1; selected auxiliary materials by the aseptic powder injection have low cost and the product has good clarity and stability. Meanwhile, the invention also provides a preparation method of cefpirome sulfate which is used as raw medicine by the aseptic powder injection. Cefotaxime acid is used as raw material and reacted with trimethylsilyl iodide and 2, 3-cyclopenopyridine, and then reacted with hydrochloric acid solution of potassium iodide to obtain cefpirome hydriodate. The cefpirome hydriodate is dissolved in sodium carbonate solution to react, and then pH value is adjusted to 1-2 by sulfuric acid. After processing, the white solid cefpirome sulfate is obtained. The raw materials used have low cost and reaction conditions are mild. Furthermore, the raw medicine prepared by the method has high purity and yield.
Description
Technical field
The present invention relates to a kind of cefpirome sulfate sterile powder pin, also relate to a kind of synthetic method of Cefpirome Sulfate.
Background technology
Cefpirome Sulfate (Cefpirome Sulfate) is succeeded in developing the earliest by German Hoechst, and at first goes on the market in Mexico, Sweden in 1992, and trade name Cefrom sells in states such as Britain, France, Germany, Japan, Korea S later in succession.Cefpirome as the 4th generation cephalosporin, be to the strongest antibiotic of gram-positive bacteria antibacterial activity in the known third generation and the 4th generation cephalosporin.The klebsiella of multidrug resistant Enterobacter, citric acid bacteria and ceftazidime hydrolytic enzyme and escherichia coli etc. all there is effect.In addition, compare with third generation cephalosporin in the past, cefpirome has strengthened anti-gram positive bacteria activity, especially streptococcus, streptococcus pneumoniae etc. is had very strong activity, especially the insensitive golden Portugal of general third generation cephalosporin bacterium, form staph and enterococcus is also had antibacterial action.
The Cefpirome Sulfate chemical name is: (6R, 7R)-7-[(Z)-2-(thiazolamine-4-yl)-2-methoxyimino acetylamino]-3-(6,7-dihydro-5H-cyclopenta [b] pyridine-1-ylmethyl)-and 8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxyl monosulfate, chemical structural formula is:
The synthetic method of Cefpirome Sulfate has multiple, and patent CN1587267 discloses a kind of synthetic route, and concrete steps are as follows:
(1) preparation of cefpirome hydriodate
Iodotrimethylsilane is dissolved in the dry acetonitrile, is cooled to 5 ℃, add 2,3-cyclopenta pyridine, maintain the temperature at below 20 ℃, add cefotaxime, the gained mixture heated refluxed 2 hours; Solution is cooled to 5 ℃, under cooling and stirring, adds potassium iodide in 5 minutes and be dissolved in 2M HCl solution, put the refrigerator overnight after-filtration and collect the precipitation that forms, precipitation is washed with frozen water, and sucking filtration is done, reuse washing with acetone, drying obtain yellow crystal cefpirome two iodate hydrogen salts, yield 79.0%; Mp:178-180 ℃;
(2) preparation of Cefpirome Sulfate
In reaction bulb, drop into cefpirome two iodate hydrogen salts, pretreated 711 type strong-base anion-exchange resins, toluene and water in stirring at room, dissolve up to two iodate hydrogen salts, separate biphasely, organic facies washing merges water and washes with toluene, with charcoal treatment 15 minutes, filter macroporous resin HZ861 type post on the aqueous solution, earlier use deionized water rinsing, reuse 10% alcohol flushing is collected positive component, be evaporated to volume approximately, be cooled to 5 ℃, use the 6M sulfuric acid acidation to PH1.3, be added dropwise to cold ethanol approximately, separate out crystalline deposit, stirred 2 hours, filter at 5 ℃, washing with alcohol, vacuum drying gets the off-white color crystallization, yield 64%-65%;
(3) Cefpirome Sulfate process for purification
Under 100 grades of cleaning conditions, with thick product with deionized water dissolving, activated carbon treatment 15 minutes, filter,, be evaporated to volume approximately with 0.45 and 0.22 micron microporous filter membrane aseptic filtration, be cooled to 5 ℃, stir down, add 1M sulphuric acid, ethanol is separated out post precipitation, continues to stir 3 hours, filter,, drain with cold sterilized water washing, vacuum drying gets Cefpirome Sulfate, refining yield 85%-88%.
Patent CN1587267 is to be raw material with the cefotaxime, make the Cefpirome Sulfate product, that single step reaction at the synthetic Cefpirome Sulfate of cefpirome hydriodate, use 711 type strong basic anion-exchange resins to remove iodide ion, because exchanger resin has bigger absorption to product, make ultimate yield lower, and the exchanger resin cost that uses is than higher.
The structural instability of Cefpirome Sulfate is met the water capacity and is easily degraded, and therefore is made into aseptic powder injection and is used for clinical.The solution ph of Cefpirome Sulfate is 1.6-2.6, and the PH tolerance range of human body is at 4.0-9.0, and the pH of blood is 7.4, needs to add alkaline matter and regulate its PH, makes the scope of its PH satisfy the Human Physiology adaptability at 5.0-7.5.Patent CN2004100658900 discloses the aseptic powder injection of Cefpirome Sulfate, and adjuvant uses aminoacid, even use a large amount of aminoacid, its PH shows still acid more intense after the aseptic powder injection solution water of gained, is not suitable for the human injection and uses.Therefore, use aminoacid to do adjuvant and make the cefpirome sulfate sterile powder pin, cost is higher, and drug administration by injection human body bad adaptability.
Summary of the invention
Advantages such as the object of the present invention is to provide a kind ofly with the cefpirome sulfate sterile powder pin, the composition of this powder pin is simple, and the cost of raw material is low, technology simple, stability is strong, clarity is good.
For realizing that purpose of the present invention provides a kind of cefpirome sulfate sterile powder pin, this powder pin is made up of Cefpirome Sulfate and natrium carbonicum calcinatum, it is characterized in that, the weight ratio of Cefpirome Sulfate and natrium carbonicum calcinatum is 4～6: 1.
The weight ratio of above-mentioned Cefpirome Sulfate and natrium carbonicum calcinatum preferred 4.5～5.5: 1, more preferably 5: 1.
In the disclosed Cefpirome Sulfate prescription of patent CN2004100658900, when the ratio of Cefpirome Sulfate and the amount of substance of L-lysine reaches 1:3.5, be that mass ratio is: 1.2:1, its PH reaches 6.74, Cefpirome Sulfate and L-arginine quality amount of substance are 1:2, be that mass ratio is 1.8:1, its PH reaches 5.47, and the used adjuvant natrium carbonicum calcinatum of the present invention, when the mass ratio of Cefpirome Sulfate and natrium carbonicum calcinatum is 5:1, its Ph can reach 6.0, so the present invention greatly reduces cost of material.
As well known to those skilled in the art, the solution that all injection powder pins are made in use, its PH should be at human body tolerance range 4.0-9.0, the solution ph of Cefpirome Sulfate is 1.6-2.6, the inventor is that the PH of two kinds of Cefpirome Sulfate powder pins of L-arginine and natrium carbonicum calcinatum tests to adjuvant respectively, two kinds of samples are respectively after placing 6 months, detect the PH situation of change of its aqueous solution, experimental result is seen experimental example 1, finds that the cefpirome sulfate sterile powder pin of making cosolvent with natrium carbonicum calcinatum is more suitable for human injection's usefulness.
The preparation method at cefpirome sulfate sterile powder of the present invention end is: under aseptic condition Cefpirome Sulfate and natrium carbonicum calcinatum solid powder essence are become 80-100 order fine powder, precision takes by weighing cefpirome sulfate sterile powder, the natrium carbonicum calcinatum aseptic powder of recipe quantity, with above-mentioned two kinds of fine powders by the dilution method mix homogeneously that progressively increases step by step, the gained raw material changes the sterile preparation workshop over to, by every certain effective ingredient delicate metering packing, gland promptly gets Cefpirome Sulfate powder pin.
Cefpirome sulfate sterile powder pin of the present invention is by the natrium carbonicum calcinatum hydrotropy and regulate its PH, just good, the stability of the clarity with above-mentioned preparation method gained cefpirome sulfate sterile powder pin has improved under aseptic condition, the inventor has done accelerated test to this injectable powder, sees experimental example 2.
Cefpirome Sulfate of the present invention, its preparation method is:
(1) preparation of hydroiodic acid cefpirome
With cefotaxime acid, Iodotrimethylsilane, 2,3-cyclopenta pyridine heating reflux reaction in organic solvent, the hydrochloric acid solution with potassium iodide reacts afterwards, obtains the hydroiodic acid cefpirome;
(2) Cefpirome Sulfate preparation
The hydroiodic acid cefpirome is dissolved in the sodium carbonate liquor, add activated carbon decolorizing, aseptic filtration, with sulphuric acid the PH of filtrate filtered is adjusted to 1-2, adding ethanol has solid to occur, and stirring and being cooled to temperature is 0 ℃, sucking filtration, gained filter cake washing with alcohol obtains the white solid Cefpirome Sulfate after the drying.
Be the synthetic route chart of Cefpirome Sulfate below:
In the above-mentioned preparation method step (1), organic solvent is selected dichloromethane for use.
The toxicity of dichloromethane is low, and boiling point is low, and reactant can be good at being dissolved in the dichloromethane solvent, so reactant is lower in the temperature of back flow reaction, the structure of reactant or product is difficult for destroyed.
The mp:179-181 of the hydroiodic acid cefpirome that above-mentioned preparation method step (1) obtains ℃.
The yield 78.7-81.4% of hydroiodic acid cefpirome described in the above-mentioned preparation method step (1).
In the above-mentioned preparation method step (2), the concentration of the amount of substance of described sodium carbonate liquor is 0.1mol/L.
In the above-mentioned preparation method step (2), the amount of substance of solute is than being 1:1-2, its preferred 1:1.4 in described hydroiodic acid cefpirome and the sodium carbonate liquor.
The employing sodium carbonate liquor is removed the iodide ion in the cefpirome hydriodate, and sodium iodide, sodium sulfate that the reaction back generates are dissolved in ethanol, sodium iodide can be separated with the product Cefpirome Sulfate with sodium sulfate so add ethanol.The gained Cefpirome Sulfate can be directly by the various pharmaceutical dosage forms of prescription preparation.
In the sodium carbonate liquor content of solute excessive slightly be good, make the hydroiodic acid cefpirome be converted into free cefpirome fully, if sodium carbonate amount is too much, it is many to make that product contains impurity, otherwise sodium carbonate amount very little, the conversion ratio of hydroiodic acid cefpirome is low, and the purity of final products is lower.
Hydroiodic acid cefpirome described in the above-mentioned preparation method step (2) is dissolved in sodium carbonate liquor at room temperature to carry out.
In the above-mentioned preparation method step (2), described vitriolic mass fraction is 15%-25%, and it is preferred 20% years old.
In the above-mentioned preparation method step (2), the mp:198 of described Cefpirome Sulfate-200 ℃.
In the above-mentioned preparation method step (2), the most preferably value of described regulator solution PH is 1.5.
The yield 63.1-65.2% of Cefpirome Sulfate described in the above-mentioned preparation method step (2).
The purity of the resulting Cefpirome Sulfate of above-mentioned preparation method is 99.8% (HLPC normalization).
CN1587267 compares with the documents patent, in the disclosed Cefpirome Sulfate synthetic method of patent CN1587267, utilize 711 type strong basic anion-exchange resins to remove iodide ion, and then POV cefpirome, wanting of 711 type strong basic anion-exchange resin prices and sodium carbonate is high, even ion exchange resin can utilize once more, but the eluting of resin, the reduction need equally the power consumption, sodium carbonate is more suitable for suitability for industrialized production by contrast.
In the disclosed Cefpirome Sulfate synthetic method of patent CN1587267, prepared Cefpirome Sulfate also needs further refining, total recovery can not reach medicinal standard for being up to 45% and the Cefpirome Sulfate that the present invention makes is further refining, and total recovery reaches 49.6%.So the synthetic method of Cefpirome Sulfate of the present invention is economy but also simple not only.
This method is a kind of economy, the synthetic method that is fit to suitability for industrialized production, high yield, utilizes the prepared Cefpirome Sulfate of this synthetic method can prepare the medicine of different dosage form according to the requirement of writing out a prescription.
Description of drawings
Accompanying drawing 1 is preparation technology's flow chart of cefpirome sulfate sterile powder pin.
The specific embodiment
Below in conjunction with example the present invention is described in further detail.
Embodiment 1
The preparation of cefpirome sulfate sterile powder pin, every bottle of Cefpirome Sulfate active component is 1.0g, prepares 1000 bottles altogether.
Preparation method: precision takes by weighing 1000g cefpirome sulfate sterile powder, 200g natrium carbonicum calcinatum aseptic powder under aseptic condition, place pressed powder mixer uniform mixing, the gained raw material changes the sterile preparation workshop over to, by the packing of every bottle of 1g effective ingredient delicate metering, gland promptly gets Cefpirome Sulfate powder pin.
Embodiment 2-6 changes the weight ratio of Cefpirome Sulfate and natrium carbonicum calcinatum, and preparation method is identical with implementing 2.
| Component | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 6 |
| Cefpirome Sulfate (aseptic powder)/g | 1000 | 1000 | 500 | 500 | 2000 | 2000 |
| Natrium carbonicum calcinatum (aseptic powder)/g | 250 | 125 | 100 | 160 | 400 | 200 |
| Every bottle of effective ingredient weight/g | 1 | 1 | 0.5 | 0.5 | 2 | 2 |
Embodiment 7
(1) preparation of hydroiodic acid cefpirome
Will (45.5g, 0.1mol) cefotaxime acid adds in the 900ml dichloromethane, and (100ml, 0.7mol) Iodotrimethylsilane is with (the gained mixture heated refluxed 2 hours, was cooled to and stabilized to 5 ℃ for 100ml, 0.85mol) 2,3-cyclopenta pyridine in adding again.Stir the 250mL2mol/L hydrochloric acid solution that adds the 60g potassium iodide down, have solid to occur, ice bath was placed 2 hours down, changed the refrigerator overnight crystallization over to, filter, frozen water is washed, and acetone is washed, the dry 60.6g yellow crystals that gets, be the hydroiodic acid cefpirome, mp:179-181 ℃, yield 78.7%.
(2) Cefpirome Sulfate preparation
Will (52g, 0.068mol) the hydroiodic acid cefpirome is dissolved in the 920ml0.1mol/L sodium carbonate liquor, adds activated carbon decolorizing 20 minutes, aseptic filtration, filtrate is transferred pH value to 1.5 with 20% sulphuric acid, and adding ethanol has solid to occur, continue to stir 1 hour, turbid solution is cooled to 0 ℃, sucking filtration, the filter cake washing with alcohol, filter, filtration cakes torrefaction gets white solid 27.0g, i.e. Cefpirome Sulfate, purity is 99.8% (HLPC normalization method), yield 64.87%.
Embodiment 8
The preparation method of present embodiment cefpirome two hydriodates is identical with embodiment 7 steps (1).
The Cefpirome Sulfate preparation
Will (52g, 0.068mol) the hydroiodic acid cefpirome is dissolved in the 700ml0.1mol/L sodium carbonate liquor, adds activated carbon decolorizing 20 minutes, aseptic filtration, filtrate is transferred pH value to 1.8 with 20% sulphuric acid, and adding ethanol has solid to occur, continue to stir 1 hour, turbid solution is cooled to 0 ℃, sucking filtration, the filter cake washing with alcohol, filter, filtration cakes torrefaction gets white solid 26.3g, i.e. Cefpirome Sulfate, purity is 99.7% (HLPC normalization method), yield 63.1%.
Embodiment 9
The preparation method of present embodiment cefpirome two hydriodates is identical with embodiment 7 steps (1).
The Cefpirome Sulfate preparation
Will (52g, 0.068mol) the hydroiodic acid cefpirome is dissolved in the 1200ml0.1mol/L sodium carbonate liquor, adds activated carbon decolorizing 20 minutes, aseptic filtration, filtrate is transferred pH value to 1.2 with 20% sulphuric acid, and adding ethanol has solid to occur, continue to stir 1 hour, turbid solution is cooled to 0 ℃, sucking filtration, filter cake washing with alcohol, filtration cakes torrefaction after the filtration gets white solid 26.7g, be Cefpirome Sulfate, purity is 99.76% (HLPC normalization method), yield 64.2%.
Experimental example 1
The PH of this experimental example Cefpirome Sulfate powder of the present invention pin and the disclosed Cefpirome Sulfate powder of patent CN2004100658900 pin tests contrast, Cefpirome Sulfate minute hand of the present invention adopts embodiment 2 technologies, and patent CN2004100658900 adopts embodiment 1 disclosed preparation method.
The comparison of PH after the placement of table 1 this patent and contrast patented product
| The Cefpirome Sulfate sample | PH after January | PH after February | PH after March | PH after June |
| The present invention | 6.0 | 6.0 | 5.8 | 5.7 |
| Patent CN2004100658900 | 3.94 | 3.94 | 3.90 | 3.89 |
Experimental example 2
This experimental example is that the cefpirome sulfate sterile powder pin is carried out stability test, adopts two stable inspection methods of Chinese Pharmacopoeia version in 2000, and the product of embodiment 1-3 is carried out accelerated test.
The cefpirome sulfate sterile powder pin was placed 6 months through 40 ± 2 ℃ of temperature, relative humidity 75 ± 5%, carried out accelerated test.See the following form (drug content is 100% before not placing).
The stable accelerated test of table 2 product of the present invention
| Sample | Principal agent amount (%) after January | Principal agent amount (%) after February | Principal agent amount (%) after March | Principal agent amount (%) after June |
| Embodiment 1 | 99.9 | 99.9 | 99.8 | 99.7 |
| Embodiment 2 | 99.9 | 99.8 | 99.8 | 99.6 |
| Embodiment 3 | 99.9 | 99.8 | 99.7 | 99.6 |
Show that from last table obvious change does not take place its drug content, observed its outward appearance and other test items simultaneously and all do not taken place obviously to change.
This cefpirome sulfate sterile powder pin is placed test in 9 months through room temperature and is investigated, and the result shows that its appearance character, content and identification check and other inspection items all do not take place obviously to change, and illustrates that the injection Cefpirome Sulfate is basicly stable.
Claims (8)
1, a kind of Cefpirome Sulfate powder pin is made up of Cefpirome Sulfate and natrium carbonicum calcinatum, it is characterized in that, the weight ratio of Cefpirome Sulfate and natrium carbonicum calcinatum is 4～6: 1.
2, Cefpirome Sulfate powder pin according to claim 1 is characterized in that, the weight ratio of Cefpirome Sulfate and natrium carbonicum calcinatum is 4.5～5.5: 1.
3, Cefpirome Sulfate powder pin according to claim 1 and 2 is characterized in that, the weight ratio of Cefpirome Sulfate and natrium carbonicum calcinatum is 5: 1.
4, Cefpirome Sulfate powder pin according to claim 1 is characterized in that the preparation method of described Cefpirome Sulfate is:
(1) preparation of hydroiodic acid cefpirome
With cefotaxime acid, Iodotrimethylsilane, 2,3-cyclopenta pyridine heating reflux reaction in organic solvent, with the hydrochloric acid solution solution reaction of potassium iodide, obtain the hydroiodic acid cefpirome afterwards;
(2) Cefpirome Sulfate preparation
The hydroiodic acid cefpirome is dissolved in the sodium carbonate liquor, adds activated carbon decolorizing, aseptic filtration, with sulphuric acid the PH of filtrate filtered is adjusted to 1-2, adding ethanol has solid to occur, and stirs 0 ℃ of cooling, sucking filtration, gained filter cake washing with alcohol obtains the white solid Cefpirome Sulfate after the drying.
5, Cefpirome Sulfate powder pin according to claim 4 is characterized in that, is 0.1mol/L in the concentration of the amount of substance of the sodium carbonate liquor described in the step (2).
6, Cefpirome Sulfate powder pin according to claim 4 is characterized in that, in step (2), the amount of substance of solute is than being 1:1-2 in described hydroiodic acid cefpirome and the sodium carbonate liquor.
7, Cefpirome Sulfate powder pin according to claim 4 is characterized in that, in step (2), the amount of substance of solute is than being 1:1.4 in described hydroiodic acid cefpirome and the sodium carbonate liquor.
8, Cefpirome Sulfate powder pin according to claim 4 is characterized in that, in step (2), described regulator solution pH value is 1.5.
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| CN102584856A (en) * | 2011-12-27 | 2012-07-18 | 开封豫港制药有限公司 | Method for preparing cefpirome sulfate |
| CN103127128A (en) * | 2013-03-08 | 2013-06-05 | 海南卫康制药(潜山)有限公司 | Cefpirome sulfate pharmaceutical composition powder injection |
| CN103224505B (en) * | 2013-05-27 | 2015-10-14 | 华北制药河北华民药业有限责任公司 | A kind of preparation method of Cefpirome Sulfate |
| CN103601738A (en) * | 2013-12-04 | 2014-02-26 | 哈药集团制药总厂 | Preparation method of cefpirome hydriodate |
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| 头孢匹罗的合成. 程冬萍等人.应用化工，第35卷第3期. 2006 |
| 头孢匹罗的合成. 程冬萍等人.应用化工，第35卷第3期. 2006 * |
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