CN102617611A - Preparation method of biapenem aseptic powder - Google Patents
Preparation method of biapenem aseptic powder Download PDFInfo
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Abstract
The invention relates to a preparation method of biapenem aseptic powder. Specifically, in a preparation process of a biapenem crude product, an alkaline substance of 2,6-lutidine is used so that post-reaction treatment is simple and a yield is high. In a preparation process of biapenem aseptic powder, acetic acid is utilized for adjustment of a pH value of water so that dissolvability and stability of biapenem in water are improved. Biapenem aseptic powder prepared through the preparation method has a high yield and controllable quality.
Description
Technical field
The present invention relates to the preparation method of a kind of biapenem and aseptic powder thereof.
Background technology
Biapenem is the hydrocarbon mould carbapenem antibiotic of a new generation, and its chemical name is: 6-[(4R, 5S; 6S)-6-[(1R)-the 1-hydroxyethyl]-4-methyl-2-carboxyl-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl-6; 7-dihydro-5H-pyrazolo [1,2-α] [1,2; 4] triazole-4-inner salt, structure is suc as formula shown in the I.It has antimicrobial spectrum widely, and Gram-negative, Gram-positive, aerophil and anerobes are all had fungicidal activity preferably; Stable to people DHP-I, need not to unite use with the DHP-I suppressor factor, and stable to β-Nei Xiananmei; Pharmacokinetic property is good, and toxicity is low, plays an important role in treatment infection field.
At present, it is raw material that the preparation method of biapenem mainly is to use the compound of formula V, removes protection base and obtains, and mainly contains following several method:
1. patent CN101121716 and document Toshio Kumagai, J.O.C., 1998; 63:8145-8149 has reported with the zinc powder to be catalyzer; In pH is 5.6 phosphate buffered saline buffer, remove the protection base, aftertreatment needs after purification on adsorbent resins, obtain product, and wherein a large amount of elutriants needs concentrated freeze-dried; And hydrocarbon mould vinyl compound is prone to degraded in solution, is difficult to produce in enormous quantities.
2. document Kenneth J.Wildonger, Journal of antibiotics, 1993,46 (12): 1866-1882 has reported with Pd (OH)
2Be catalyzer, in phosphate buffered saline buffer, remove protection base, through ion exchange resin Dowex 50-X4 purifying, concentrate, obtain product after the freeze-drying, yield is lower than 30%.
Method in above-mentioned patent and the document all needs the resin purification mode to handle, and complex steps and yield are lower, is unfavorable for very much industrialized production.Provide a kind of simple to operate, the higher biapenem preparation method of yield is in demand.
Formula V formula I
Wherein: R is benzyl, 4-nitrobenzyl, 3-nitrobenzyl, methoxy-benzyl or 2, the 4-dimethoxy-benzyl; X is selected from cl ions, trifluoroacetic acid radical ion or methanesulfonate ion.
The biapenem of list marketing is the sterile powder injection that injectable is used, and just can be used for clinically so will biapenem be prepared into aseptic powder, does not see at present the preparation method who has bibliographical information to cross the biapenem aseptic powder.Because the biapenem solvability is relatively poor, slightly soluble in water, a spot of biapenem just need a large amount of water to dissolve fully; Simultaneously, the biapenem aqueous solution stable bad places behind the several hrs that the content of related substance will obviously increase in the solution, and the prompting biapenem has been placed of a specified duration in water and can have been degraded; Elevated temperature can increase the solubleness of biapenem in water slightly, but has also quickened the degradation speed of biapenem simultaneously; In the process of preparation A Peinan aseptic powder, need make water dissolve the biapenem bullion, use filtering with microporous membrane then; Use the organic solvent recrystallization again, poorly soluble cause large-scale industrialization produce in the very a large amount of water of needs, this has just prolonged the running time; Increased the degradation speed of biapenem in water; Cause related substance to increase, the difficult control of the quality of product is very disadvantageous to producing the biapenem aseptic powder.Therefore, it is in demand a kind of preparation method stable, maneuverable biapenem aseptic powder being provided.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of stable, maneuverable biapenem, specifically comprise the steps:
With the 6-of formula II [(4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-is to nitro carbobenzoxy-(Cbz)-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1; 2-α] [1,2,4] triazole-4-muriate is raw material, in the mixed solution of water and organic solvent; Adding alkaline matter, is catalyzer with palladium carbon, with hydrogen reaction; Reaction adds ethanol after finishing in reaction solution, filter the biapenem bullion of collection type I.
Formula II formula I.
Wherein, described organic solvent is selected from THF; Alkaline matter is selected from 2, the 6-lutidine; Temperature of reaction is 5-30 ℃, preferred 10-20 ℃; Water and volume of organic solvent ratio are 1: 1～3: 1, preferred 2: 1-3: 1, and most preferably 3: 1.
Further aspect of the present invention provides a kind of to be stablized, the preparation method of maneuverable biapenem aseptic powder, specifically comprises the steps:
A) with the 6-of formula II [(4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl-4-methyl-2-to nitro carbobenzoxy-(Cbz)-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1; 2-α] [1,2,4] triazole-4-muriate is raw material, in the mixed solution of water and organic solvent; Adding alkaline matter, is catalyzer with palladium carbon, with hydrogen reaction; Reaction adds ethanol after finishing in reaction solution, filter the biapenem bullion of collection type I;
B) the biapenem bullion among the step a being dissolved pH is the water for injection of 3-6, and to wherein adding gac, elimination gac rear filtrate is used filtering with microporous membrane, adds ethanol in the filtrating, and stirring and crystallizing is filtered and obtained the biapenem aseptic powder.
Wherein, the organic solvent described in the step a is selected from THF; Basic solvent is selected from 2, the 6-lutidine; Temperature of reaction is 5-30 ℃, preferred 10-20 ℃; Water and volume of organic solvent ratio are 1: 1～3: 1, preferred 2: 1-3: 1, and most preferably 3: 1.
PH among the step b is that the water for injection of 3-6 uses acetate to regulate its pH value; The preferred 4-4.5 of described pH value; Described millipore filtration is selected from the millipore filtration of 0.22 μ m; Said water for injection is heated to the 40-80 degree in advance, preferred 40-60 degree, more preferably 60 degree; Used water for injection and ethanol volume ratio are 1: 2.
The concrete preparation method of biapenem aseptic powder provided by the invention is:
A) with the 6-of formula II [(4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-is to nitro carbobenzoxy-(Cbz)-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl-6; 7-dihydro-5H-pyrazolo [1,2-α] [1,2; 4] triazole-4-muriate is a raw material, in the mixed solution of water and THF, adds 2; The 6-lutidine is a catalyzer with palladium carbon, under 10-20 ℃ temperature and hydrogen reaction; Reaction adds ethanol after finishing in reaction solution, filter the biapenem bullion of collection type I;
B) the biapenem bullion among the step a being dissolved in acetate, to regulate pH be that the temperature of 4-4.5 is in the water for injection of 40-60 degree; To wherein adding gac, elimination gac rear filtrate adds ethanol with 0.22 μ m filtering with microporous membrane in the filtrating; Stirring and crystallizing is filtered and is obtained the biapenem aseptic powder.Described water and volume of organic solvent ratio are 1: 1～3: 1, preferred 2: 1-3: 1, and most preferably 3: 1.
Further aspect of the present invention provides a kind of to be stablized, the preparation method of maneuverable biapenem aseptic powder, specifically comprises the steps:
A) with the 6-of formula II [(4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-is to nitro carbobenzoxy-(Cbz)-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl-6; 7-dihydro-5H-pyrazolo [1,2-α] [1,2; 4] triazole-4-muriate is a raw material; In the mixed solution of damping fluid and organic solvent, be catalyzer with palladium carbon, with hydrogen reaction, reaction finishes the biapenem bullion of back collection type I;
B) the biapenem bullion among the step a is dissolved in the water for injection that pH is 3-6, to wherein adding gac, elimination gac rear filtrate is used filtering with microporous membrane, adds ethanol in the filtrating, and stirring and crystallizing is filtered and obtained the biapenem aseptic powder.
Wherein, the damping fluid among the step a is selected from magnesium acetate damping fluid, sodium-acetate buffer, zinc acetate damping fluid, Potassium ethanoate damping fluid, ammonium acetate buffer; Preferred magnesium acetate damping fluid; Organic solvent is selected from THF.
PH among the step b is that the water for injection of 3-6 uses acetate to regulate its pH value; The preferred 4-4.5 of described pH value; Described millipore filtration is selected from the millipore filtration of 0.22 μ m; Said water for injection is heated to the 40-80 degree in advance, preferred 40-60 degree, more preferably 60 degree; Used water for injection and ethanol volume ratio are 1: 2.
The preparation method of biapenem aseptic powder provided by the invention specifically comprises the steps:
A) with the 6-of formula II [(4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-is to nitro carbobenzoxy-(Cbz)-7-oxo-1-azabicyclic [3,2,0] hept-2-ene"-3-yl] sulfenyl-6; 7-dihydro-5H-pyrazolo [1,2-α] [1,2; 4] triazole-4-muriate is a raw material; In the mixed solution of magnesium acetate damping fluid and THF, be catalyzer with palladium carbon, with hydrogen reaction, reaction finishes the biapenem bullion of back collection type I;
B) the biapenem bullion among the step a being dissolved in acetate, to regulate pH be that the temperature of 4-4.5 is in the water for injection of 40-60 degree; To wherein adding gac, elimination gac rear filtrate adds ethanol with 0.22 μ m filtering with microporous membrane in the filtrating; Stirring and crystallizing is filtered and is obtained the biapenem aseptic powder.
Further aspect of the present invention provides a kind of process for purification of biapenem, comprising:
The biapenem bullion is dissolved in the water for injection that pH is 3-6, and to wherein adding gac, elimination gac rear filtrate is used filtering with microporous membrane, adds ethanol in the filtrating, and stirring and crystallizing is filtered and obtained the biapenem aseptic powder.
Wherein, described pH is its pH value of water for injection use acetate adjusting of 3-6; The preferred 4-4.5 of described pH value; Described millipore filtration is selected from the millipore filtration of 0.22 μ m; Said water for injection is heated to the 40-80 degree in advance, preferred 40-60 degree, more preferably 60 degree; Water for injection and ethanol volume ratio are 1: 2.
The process for purification of biapenem provided by the invention comprises:
The biapenem bullion is dissolved in acetate, and to regulate pH be that the temperature of 4-4.5 is in the water for injection of 40-60 degree; To wherein adding gac, elimination gac rear filtrate adds ethanol with 0.22 μ m filtering with microporous membrane in the filtrating; Stirring and crystallizing is filtered and is obtained the biapenem aseptic powder.
The preparation of the raw material formula II compound that the present invention uses can be with reference to prior art, and the side chain condensation through formula III and formula IV forms, and wherein the compound of formula III and formula IV can have been bought from market.As all disclosing the compound method of formula II compound among one Chinese patent application CN101121716, the CN101747352.
Formula II formula III
Formula IV
The preparation method of biapenem provided by the invention is in reduction step, through using alkaline matter; Preferred use 2, the 6-lutidine makes that the reduction step reaction is more thorough; Reaction does not need the resin column chromatography purification after finishing, and directly adds ethanol, and biapenem will be separated out from reaction solution; Just can obtain the higher biapenem bullion of purity through simple filtering step, and reaction yield is very high, suitable industriallization prepares biapenem in a large number; In treating process; Through use acetate water for injection is adjusted to suitable pH value, and, has increased the solvability of biapenem in water the water for injection elevated temperature; And the beat all stability that increases the biapenem aqueous solution; Effectively control the degraded of biapenem in treating process, made treating process carry out quality control more easily, improved the yield of purification step simultaneously.
Embodiment
Embodiment of the present invention is not mean that content of the present invention to limit the invention in order better to explain.Formula III compound that uses in the embodiment of the invention and formula IV compound are provided by the Shenzhen Henderson Technology Co., Ltd.
The preparation of embodiment 1 biapenem aseptic powder
1.16-[(4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-is to nitro carbobenzoxy-(Cbz)-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] and sulfenyl-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4]-triazole-4-muriate (II) synthetic
In reaction kettle, add acetonitrile 104Kg, formula III compound (MAP) 16.5Kg and formula IV compound 5.9Kg, stir; Mixture is cooled to 0-5 ℃, to wherein dripping diisopropylethylamine 5.3Kg, drips and finishes; Maintain the temperature at 0-5 ℃ and continue about 3.5 hours of reaction down; The solid of separating out in the reaction solution is leached the dry formula II compound 14Kg that gets the light yellow solid shape, productive rate: 94%.
M.p.=162.0-163.6 ℃ (decomposition).
1.2 the biapenem bullion is synthetic
75Kg water for injection is heated to 30-35 ℃, adds formula II compound 5Kg, stir adding 25L THF down, stirring and dissolving.Mixture is cooled to 5-10 ℃, stirs slowly to add 2.1Kg 2, the tetrahydrofuran solution of 6-lutidine down.In solution, add palladium carbon, add in the autoclave hydrogenation.Under 2.5MPa pressure, 10-20 ℃ was reacted 2 hours.Extract reaction solution after reacting completely out, filter, palladium carbon washes with less water.Filtrating is stirred the ethanol that adds 235Kg 95% down, and ice-water bath was to 0-5 ℃ of stirring 3 hours.Filter, use the washing with alcohol filter cake, 40 ℃ of decompression oven dry obtain 2.5Kg biapenem bullion, yield 74%.
1.3 the biapenem bullion is synthetic
50Kg water for injection is heated to 30-35 ℃, adds formula II compound 5Kg, stir adding 25L THF down, stirring and dissolving.Mixture is cooled to 5-10 ℃, stirs slowly to add 2.1Kg 2, the tetrahydrofuran solution of 6-lutidine down.In solution, add palladium carbon, add in the autoclave hydrogenation.Under 2.5MPa pressure, 10-20 ℃ was reacted 2 hours.Extract reaction solution after reacting completely out, filter, palladium carbon washes with less water.Filtrating is stirred the ethanol that adds 150Kg 95% down, and ice-water bath was to 0-5 ℃ of stirring 3 hours.Filter, use the washing with alcohol filter cake, 40 ℃ of decompression oven dry obtain 2.48Kg biapenem bullion, yield 72.5%.
1.4 the biapenem bullion is synthetic
In autoclave, 14Kg formula II compound is added in the mixed solution of 84Kg magnesium acetate damping fluid (pH5.6) and 25Kg THF, stirring and dissolving adds 7Kg 7.5%Pd/C, feeds hydrogen, reaction 1-1.5h under 1.5-2.5MPa pressure.Reaction finishes after-filtration, and palladium carbon washes with less water.To filtrate like needs, to use 0.1N hydrochloric acid adjust pH be 5.5, and then with 68Kg ETHYLE ACETATE washing 2 times, water layer stirs and adds ethanol 200Kg down, and mixture is cooled to 0-5 ℃, stirs filtration 2-3 hour.40 ℃ of dry 6.25Kg solid biapenem bullion, yields 66.1% of getting.
1.5 the preparation of biapenem aseptic powder
In sterile workshop, will be heated to 60 ℃ with the 125Kg water for injection that acetate is regulated pH=4.0 earlier, add biapenem bullion 6.25Kg again, stirring and dissolving; If do not clarify, add water for injection to clarification, add activated carbon insulation 15 minutes; Elimination activated carbon, filtrating are with 0.22 μ m filtering with microporous membrane, and filtrating is checked clarity; Qualified back adds in filtrating through 0.22 μ m filtering with microporous membrane, and 2 times of volume of ethanol of water for injection that clarity is qualified are cooled to-10-5 ℃ stirring and crystallizing 2-3 hour; Filter, 40 ℃ of drying under reduced pressure get biapenem sterilized powder 5.1Kg, yield 81.6%.
The preparation of embodiment 2 biapenem aseptic powder
In sterile workshop, will be heated to 60 ℃ with the 125Kg water for injection that acetate is regulated pH=4.5 earlier, add biapenem bullion 6.25Kg again, stirring and dissolving; If do not clarify, add water for injection to clarification, add activated carbon insulation 15 minutes; Elimination activated carbon, filtrating are with 0.22 μ m filtering with microporous membrane, and filtrating is checked clarity; Qualified back adds in filtrating through 0.22 μ m filtering with microporous membrane, and 2 times of volume of ethanol of water for injection that clarity is qualified are cooled to-10-5 ℃ stirring and crystallizing 2-3 hour; Filter, 40 ℃ of drying under reduced pressure get biapenem sterilized powder 5.3Kg, yield 84.8%.
The preparation of embodiment 3 biapenem aseptic powder
In sterile workshop, will be heated to 40 ℃ with the 125Kg water for injection that acetate is regulated pH=4 earlier, add biapenem bullion 6.25Kg again, stirring and dissolving; If do not clarify, add water for injection to clarification, add activated carbon insulation 15 minutes; Elimination activated carbon, filtrating are with 0.22 μ m filtering with microporous membrane, and filtrating is checked clarity; Qualified back adds in filtrating through 0.22 μ m filtering with microporous membrane, and 2 times of volume of ethanol of water for injection that clarity is qualified are cooled to-10-5 ℃ stirring and crystallizing 2-3 hour; Filter, 40 ℃ of drying under reduced pressure get biapenem sterilized powder 5.09Kg, yield 81.5%.
The preparation of embodiment 4 biapenem aseptic powder
In sterile workshop, will be heated to 40 ℃ with the 125Kg water for injection that acetate is regulated pH=4.5 earlier, add biapenem bullion 6.25Kg again, stirring and dissolving; If do not clarify, add water for injection to clarification, add activated carbon insulation 15 minutes; Elimination activated carbon, filtrating are with 0.22 μ m filtering with microporous membrane, and filtrating is checked clarity; Qualified back adds in filtrating through 0.22 μ m filtering with microporous membrane, and 2 times of volume of ethanol of water for injection that clarity is qualified are cooled to-10-5 ℃ stirring and crystallizing 2-3 hour; Filter, 40 ℃ of drying under reduced pressure get biapenem sterilized powder 5.2Kg, yield 83.2%.
The preparation of embodiment 5 biapenem aseptic powder
In sterile workshop, get biapenem bullion 3Kg, add water for injection 270Kg, be heated to 40 ℃; Stirring and dissolving if do not clarify, is added water for injection to clarification, adds activated carbon insulation 15 minutes; Elimination activated carbon, filtrating are with 0.22 μ m filtering with microporous membrane, and filtrating is checked clarity; Qualified back adds in filtrating through 0.22 μ m filtering with microporous membrane, and 2 times of volume of ethanol of water for injection that clarity is qualified are cooled to-10-5 ℃ stirring and crystallizing 2-3 hour; Filter, 40 ℃ of drying under reduced pressure get biapenem sterilized powder 2.25Kg, yield 75%.
The preparation of embodiment 6 biapenem aseptic powder
In sterile workshop, get biapenem bullion 3Kg, add water for injection 270Kg, be heated to 60 ℃; Stirring and dissolving if do not clarify, is added water for injection to clarification, adds activated carbon insulation 15 minutes; Elimination activated carbon, filtrating are with 0.22 μ m filtering with microporous membrane, and filtrating is checked clarity; Qualified back adds in filtrating through 0.22 μ m filtering with microporous membrane, and 2 times of volume of ethanol of water for injection that clarity is qualified are cooled to-10-5 ℃ stirring and crystallizing 2-3 hour; Filter, 40 ℃ of drying under reduced pressure get biapenem sterilized powder 2.10Kg, yield 70%.
Embodiment 7 determination of related substances
Stipulate down with reference to HPLC (two appendix V of Chinese Pharmacopoeia version in 2000 D) item.
Specimen: get the biapenem aseptic powder that makes among the embodiment 1-6.
Chromatographic condition: with the octadecylsilane chemically bonded silica is weighting agent, 40 ℃ of column temperatures; Mobile phase A is acetonitrile-10mM potassium phosphate buffer (regulating pH to 3.0 with phosphoric acid) [3:97]; Mobile phase B is an acetonitrile.Gradient elution: 0-10 minute, 100%A; 10 to 25 minutes, A100% to 75%, B0% to 25%; 25 to 35 minutes, 25%B, 75%A kept 10 minutes; Turn back to 100%A at last.Flow velocity is 1.0mg/min; The detection wavelength is 210nm.Theoretical plate number is calculated by biapenem should be not less than 2000.
Assay method: get the about 40mg of specimen, add 10ml water, ultrasonic dissolution shakes up, as need testing solution.Precision is measured in right amount, and thin up becomes solution that every ml contains biapenem 40ug as contrast solution; Measure contrast solution 10ul, inject liquid chromatograph, regulate the sensitivity of instrument, making the main peak peak height is the 15%-25% of full range.Measure each 10u l of contrast solution and specimen solution again, inject liquid chromatograph respectively.Except that the blank solvent peak, measure all impurity peaks peak area sums, must not be greater than 1.5 times of the main peak area of contrast solution.(1.5%) measures the result and see table 1.
The related substance of table 1 biapenem aseptic powder
| Specimen | Related substance |
| The biapenem aseptic powder of embodiment 1 | 0.33％ |
| The biapenem aseptic powder of embodiment 2 | 0.33％ |
| The biapenem aseptic powder of embodiment 3 | 0.35％ |
| The biapenem aseptic powder of embodiment 4 | 0.28％ |
| The biapenem aseptic powder of embodiment 5 | 1.86％ |
| The biapenem aseptic powder of embodiment 6 | 1.82％ |
The data declaration of table 1, the related substance of the biapenem aseptic powder that embodiment 1-4 prepares is few, and the purity of aseptic powder is fine; The related substance of the biapenem aseptic powder that embodiment 5,6 prepares is many slightly, and the purity of aseptic powder is low slightly.This shows, use pH value that acetic acid regulates water for injection behind 4-4.5, the water-soluble raising of biapenem, the stability in the solution also improves, and the purity and the yield of the aseptic powder for preparing all are improved, and constant product quality is controlled.
Claims (10)
1. the preparation method of a biapenem, it comprises the steps:
With the 6-of formula II [(4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl-4-methyl-2-to nitro carbobenzoxy-(Cbz)-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1; 2-α] [1,2,4] triazole-4-muriate is raw material, in the mixed solution of water and organic solvent; Adding alkaline matter, is catalyzer with palladium carbon, with hydrogen reaction, after reaction finishes; In reaction solution, add ethanol, filter the biapenem bullion of collection type I
Formula II formula I.
2. the preparation method of the described biapenem of claim 1, wherein, described organic solvent is selected from THF.
3. the preparation method of claim 1 or 2 described biapenems, wherein, described alkaline matter is selected from 2, the 6-lutidine.
4. the preparation method of each described biapenem among the claim 1-3, wherein, temperature of reaction is 5-30 ℃, preferred 10-20 ℃.
5. the preparation method of a biapenem sterilized powder comprises the steps:
A) with the 6-of formula II [(4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl-4-methyl-2-to nitro carbobenzoxy-(Cbz)-7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1; 2-α] [1,2,4] triazole-4-muriate is raw material, in the mixed solution of water and organic solvent; Adding alkaline matter, is catalyzer with palladium carbon, with hydrogen reaction; Reaction adds ethanol after finishing in reaction solution, filter the biapenem bullion of collection type I;
B) the biapenem bullion that obtains among the step a is dissolved in the water for injection that pH is 3-6, to wherein adding gac, elimination gac rear filtrate is used filtering with microporous membrane, adds ethanol in the filtrating, and stirring and crystallizing is filtered and obtained the biapenem aseptic powder.
6. the preparation method of the described biapenem sterilized powder of claim 5, wherein, the organic solvent described in the step a is selected from THF.
7. the preparation method of claim 5 or 6 described biapenem sterilized powdeies, wherein, the alkaline matter described in the step a is selected from 2, the 6-lutidine.
8. the preparation method of each described biapenem sterilized powder among the claim 5-7, wherein, pH is that the water for injection of 3-6 uses acetate to regulate its pH value among the step b; The preferred 4-4.5 of described pH value.
9. the preparation method of each described biapenem sterilized powder among the claim 5-8, wherein, water for injection is heated to the 40-80 degree in advance among the step b, preferred 40-60 degree, more preferably 60 degree.
10. the preparation method of a described biapenem sterilized powder of people among the claim 5-9, wherein, water for injection and alcoholic acid volume ratio are 1: 2 among the step b.
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| CN102617612A (en) * | 2011-01-29 | 2012-08-01 | 江苏正大天晴药业股份有限公司 | Biapenem B-type crystallinity |
| CN103497207A (en) * | 2011-01-29 | 2014-01-08 | 正大天晴药业集团股份有限公司 | Biapenem B-type crystals |
| CN103570750A (en) * | 2013-11-15 | 2014-02-12 | 安徽悦康凯悦制药有限公司 | Preparation process of biapenem |
| CN109946396A (en) * | 2019-03-26 | 2019-06-28 | 深圳市海滨制药有限公司 | A method of using high effective liquid chromatography for measuring Biapenem and/or related substance |
| CN113912629A (en) * | 2021-11-01 | 2022-01-11 | 石药集团中诺药业（石家庄）有限公司 | Crystallization method of biapenem |
| CN115368385A (en) * | 2022-08-24 | 2022-11-22 | 山东希尔康泰药业有限公司 | Biapenem production process and system |
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| CN102617612A (en) * | 2011-01-29 | 2012-08-01 | 江苏正大天晴药业股份有限公司 | Biapenem B-type crystallinity |
| CN102617612B (en) * | 2011-01-29 | 2013-07-17 | 江苏正大天晴药业股份有限公司 | Biapenem B-type crystallinity |
| CN103497207A (en) * | 2011-01-29 | 2014-01-08 | 正大天晴药业集团股份有限公司 | Biapenem B-type crystals |
| CN103497207B (en) * | 2011-01-29 | 2015-09-30 | 正大天晴药业集团股份有限公司 | Biapenem B-type crystallinity |
| CN103570750A (en) * | 2013-11-15 | 2014-02-12 | 安徽悦康凯悦制药有限公司 | Preparation process of biapenem |
| CN109946396A (en) * | 2019-03-26 | 2019-06-28 | 深圳市海滨制药有限公司 | A method of using high effective liquid chromatography for measuring Biapenem and/or related substance |
| CN109946396B (en) * | 2019-03-26 | 2022-02-08 | 深圳市海滨制药有限公司 | Method for determining biapenem and/or related substances by adopting high performance liquid chromatography |
| CN113912629A (en) * | 2021-11-01 | 2022-01-11 | 石药集团中诺药业（石家庄）有限公司 | Crystallization method of biapenem |
| CN115368385A (en) * | 2022-08-24 | 2022-11-22 | 山东希尔康泰药业有限公司 | Biapenem production process and system |
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