CN102617611B - Preparation method of biapenem aseptic powder - Google Patents
Preparation method of biapenem aseptic powder Download PDFInfo
- Publication number
- CN102617611B CN102617611B CN 201110030674 CN201110030674A CN102617611B CN 102617611 B CN102617611 B CN 102617611B CN 201110030674 CN201110030674 CN 201110030674 CN 201110030674 A CN201110030674 A CN 201110030674A CN 102617611 B CN102617611 B CN 102617611B
- Authority
- CN
- China
- Prior art keywords
- biapenem
- water
- preparation
- reaction
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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, 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 anerobe are all had fungicidal activity preferably; Stable to people DHP-I, need not to unite use with the DHP-I inhibitor, and stable to β-Nei Xiananmei; Pharmacokinetic property is good, and toxicity is low, plays an important role in treatment infectious diseases field.
At present, it is raw material that the preparation method of biapenem mainly is to use the compound of formula V, removes protecting group 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; remove protecting group in pH is 5.6 phosphate buffered saline buffer, aftertreatment needs obtain product after purification on adsorbent resins, and wherein a large amount of elutriants need concentrated freeze-dried; and the easily degraded in solution of hydrocarbon mould vinyl compound 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, remove protecting group in phosphate buffered saline buffer, 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 2,4-dimethoxy-benzyl; X is selected from chlorion, trifluoroacetic acid radical ion or methanesulfonate ion.
The biapenem of list marketing is the sterile powder injection that injectable is used, and could be used for clinically so biapenem will 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; The rising temperature can increase the solubleness of biapenem in water slightly, but has also accelerated the degradation speed of biapenem simultaneously; In the process of preparation A Peinan aseptic powder, need make water dissolve the biapenem crude product, use filtering with microporous membrane then, use the organic solvent recrystallization again, poorly soluble causing needs very a large amount of water in the large-scale industrialization production, and this has just prolonged the operating 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 providing a kind of preparation method stable, maneuverable biapenem aseptic powder.
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-[(4R of formula II, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-the nitro carbobenzoxy-(Cbz) of 4-methyl-2--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, add alkaline matter, be catalyzer with palladium carbon, with hydrogen reaction, reaction adds ethanol after finishing in reaction solution, filter the biapenem crude product of collection type I.
Formula II formula I.
Wherein, described organic solvent is selected from tetrahydrofuran (THF); Alkaline matter is selected from 2,6-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-[(4R of formula II, 5S, 6S)-6-[(1R)-and the nitro carbobenzoxy-(Cbz) of 1-hydroxyethyl-4-methyl-2--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, add alkaline matter, be catalyzer with palladium carbon, with hydrogen reaction, reaction adds ethanol after finishing in reaction solution, filter the biapenem crude product of collection type I;
B) be the water for injection of 3-6 with the molten pH of biapenem crude product among the step a, to wherein adding gac, elimination gac rear filtrate filtering with microporous membrane adds ethanol in the filtrate, and stirring and crystallizing is filtered and obtained the biapenem aseptic powder.
Wherein, the organic solvent described in the step a is selected from tetrahydrofuran (THF); Basic solvent is selected from 2,6-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 acetic acid 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; Described 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-[(4R of formula II, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-the nitro carbobenzoxy-(Cbz) of 4-methyl-2--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 tetrahydrofuran (THF), adds 2, the 6-lutidine, be catalyzer with palladium carbon, under 10-20 ℃ temperature with hydrogen reaction, after reaction finishes, in reaction solution, add ethanol, filter the biapenem crude product of collection type I;
B) the biapenem crude product among the step a being dissolved in acetic acid, 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 filtrate, 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-[(4R of formula II, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-the nitro carbobenzoxy-(Cbz) of 4-methyl-2--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, be catalyzer with palladium carbon in the mixed solution of damping fluid and organic solvent, with hydrogen reaction, reaction finishes the biapenem crude product of back collection type I;
B) the biapenem crude product among the step a is dissolved in the water for injection that pH is 3-6, to wherein adding gac, elimination gac rear filtrate filtering with microporous membrane adds ethanol in the filtrate, 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 tetrahydrofuran (THF).
PH among the step b is that the water for injection of 3-6 uses acetic acid 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; Described 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-[(4R of formula II, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-the nitro carbobenzoxy-(Cbz) of 4-methyl-2--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, be catalyzer with palladium carbon in the mixed solution of magnesium acetate damping fluid and tetrahydrofuran (THF), with hydrogen reaction, reaction finishes the biapenem crude product of back collection type I;
B) the biapenem crude product among the step a being dissolved in acetic acid, 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 filtrate, 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 crude product is dissolved in the water for injection that pH is 3-6, and to wherein adding gac, elimination gac rear filtrate filtering with microporous membrane adds ethanol in the filtrate, and stirring and crystallizing is filtered and obtained the biapenem aseptic powder.
Wherein, described pH is that the water for injection of 3-6 uses acetic acid 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; Described 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 crude product is dissolved in acetic acid, 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 filtrate, 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 by formula III and formula IV forms, and wherein the compound of formula III and formula IV can have been bought from the market.As all disclosing the synthetic method of formula II compound among Chinese patent application CN101121716, the CN101747352.
Formula II formula III
Formula IV
The preparation method of biapenem provided by the invention, in reduction step, by using alkaline matter, preferably use 2, the 6-lutidine, make that the reduction step reaction is more thorough, reaction does not need the resin column chromatography purification after finishing, and directly adds ethanol, biapenem will be separated out from reaction solution, just can obtain the higher biapenem crude product of purity by simple filtering step, and reaction yield is very high, suitable industrialization prepares biapenem in a large number; In treating process, by using acetic acid that water for injection is adjusted to suitable pH value, and with the water for injection temperature that raises, increased the solvability of biapenem in water, and the beat all stability that increases the biapenem aqueous solution, effectively control the degraded of biapenem in treating process, made that treating process is easier carries out quality control, improved the yield of purification step simultaneously.
Embodiment
The specific embodiment of the present invention is not mean that content of the present invention to limit the invention in order better to illustrate.The 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)-the 1-hydroxyethyl]-the nitro carbobenzoxy-(Cbz) of 4-methyl-2--7-oxo-1-azabicyclic [3.2.0] hept-2-ene"-3-yl] sulfenyl-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4]-triazole-4-muriate (II) synthetic
In reactor, 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 crude product is synthetic
75Kg water for injection is heated to 30-35 ℃, adds formula II compound 5Kg, stir adding 25L tetrahydrofuran (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.Filtrate 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 crude product, yield 74%.
1.3 the biapenem crude product is synthetic
50Kg water for injection is heated to 30-35 ℃, adds formula II compound 5Kg, stir adding 25L tetrahydrofuran (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.Filtrate 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 crude product, yield 72.5%.
1.4 the biapenem crude product is synthetic
In autoclave, 14Kg formula II compound is added in the mixed solution of 84Kg magnesium acetate damping fluid (pH5.6) and 25Kg tetrahydrofuran (THF), stirring and dissolving adds 7Kg 7.5%Pd/C, feeds hydrogen, reacts 1-1.5h under 1.5-2.5MPa pressure.Reaction finishes after-filtration, and palladium carbon washes with less water.Be 5.5 with filtrate with 0.1N hydrochloric acid adjust pH as needs, then with 68Kg ethyl 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 crude product, yields 66.1% of getting.
1.5 the preparation of biapenem aseptic powder
In sterile workshop, to be heated to 60 ℃ with the 125Kg water for injection that acetic acid is regulated pH=4.0 earlier, add biapenem crude product 6.25Kg again, stirring and dissolving, if do not clarify, add water for injection to clarification, add activated carbon insulation 15 minutes, the elimination activated carbon, filtrate is with 0.22 μ m filtering with microporous membrane, filtrate checks clarity, and qualified back adds through 0.22 μ m filtering with microporous membrane 2 times of volume of ethanol of water for injection that clarity is qualified in filtrate, be 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, to be heated to 60 ℃ with the 125Kg water for injection that acetic acid is regulated pH=4.5 earlier, add biapenem crude product 6.25Kg again, stirring and dissolving, if do not clarify, add water for injection to clarification, add activated carbon insulation 15 minutes, the elimination activated carbon, filtrate is with 0.22 μ m filtering with microporous membrane, filtrate checks clarity, and qualified back adds through 0.22 μ m filtering with microporous membrane 2 times of volume of ethanol of water for injection that clarity is qualified in filtrate, be 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, to be heated to 40 ℃ with the 125Kg water for injection that acetic acid is regulated pH=4 earlier, add biapenem crude product 6.25Kg again, stirring and dissolving, if do not clarify, add water for injection to clarification, add activated carbon insulation 15 minutes, the elimination activated carbon, filtrate is with 0.22 μ m filtering with microporous membrane, filtrate checks clarity, and qualified back adds through 0.22 μ m filtering with microporous membrane 2 times of volume of ethanol of water for injection that clarity is qualified in filtrate, be 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, to be heated to 40 ℃ with the 125Kg water for injection that acetic acid is regulated pH=4.5 earlier, add biapenem crude product 6.25Kg again, stirring and dissolving, if do not clarify, add water for injection to clarification, add activated carbon insulation 15 minutes, the elimination activated carbon, filtrate is with 0.22 μ m filtering with microporous membrane, filtrate checks clarity, and qualified back adds through 0.22 μ m filtering with microporous membrane 2 times of volume of ethanol of water for injection that clarity is qualified in filtrate, be 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 crude product 3Kg; add water for injection 270Kg; be heated to 40 ℃; stirring and dissolving, if do not clarify, add water for injection to clarification; add activated carbon insulation 15 minutes; the elimination activated carbon, filtrate checks clarity with 0.22 μ m filtering with microporous membrane, filtrate; qualified back adds through 0.22 μ m filtering with microporous membrane; 2 times of volume of ethanol of water for injection that clarity is qualified in filtrate, be cooled to-10-5 ℃ stirring and crystallizing 2-3 hour filtration; 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 crude product 3Kg; add water for injection 270Kg; be heated to 60 ℃; stirring and dissolving, if do not clarify, add water for injection to clarification; add activated carbon insulation 15 minutes; the elimination activated carbon, filtrate checks clarity with 0.22 μ m filtering with microporous membrane, filtrate; qualified back adds through 0.22 μ m filtering with microporous membrane; 2 times of volume of ethanol of water for injection that clarity is qualified in filtrate, be cooled to-10-5 ℃ stirring and crystallizing 2-3 hour filtration; 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 high performance liquid chromatography (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: be weighting agent with the octadecylsilane chemically bonded silica, 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 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 solution in contrast; 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 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%) measurement result sees 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 the pH value of acetic acid adjusting water for injection behind 4-4.5, the water-soluble raising of biapenem, the stability in the solution also improves, and purity and the yield of the aseptic powder for preparing all are improved, and constant product quality is controlled.
Claims (6)
1. the preparation method of a biapenem, it comprises the steps:
With the 6-[(4R of formula II, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-the nitro carbobenzoxy-(Cbz) of 4-methyl-2--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, adds alkaline matter, be catalyzer with palladium carbon, with hydrogen reaction, reaction adds ethanol after finishing in reaction solution, filter the biapenem crude product of collection type I
Wherein, described organic solvent is selected from tetrahydrofuran (THF), and described alkaline matter is selected from 2,6-lutidine.
2. the preparation method of the described biapenem of claim 1, wherein, temperature of reaction is 5-30 ℃.
3. the preparation method of each described biapenem among the claim 1-2, wherein, described water and volume of organic solvent are than being 1:1-3:1.
4. the preparation method of a biapenem sterilized powder comprises the steps:
A) with the 6-[(4R of formula II, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-the nitro carbobenzoxy-(Cbz) of 4-methyl-2--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, add alkaline matter, be catalyzer with palladium carbon, with hydrogen reaction, reaction adds ethanol after finishing in reaction solution, filter the biapenem crude product of collection type I;
B) the biapenem crude product 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 filtering with microporous membrane, add ethanol in the filtrate, stirring and crystallizing is filtered and is obtained the biapenem aseptic powder, and the organic solvent described in the step a is selected from tetrahydrofuran (THF), alkaline matter described in the step a is selected from 2,6-lutidine.
5. the preparation method of the described biapenem sterilized powder of claim 4, wherein, the temperature of reaction among the step a is 5-30 ℃.
6. the preparation method of each described biapenem sterilized powder among the claim 4-5, wherein, the water described in the step a and volume of organic solvent are than being 1:1-3:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110030674 CN102617611B (en) | 2011-01-28 | 2011-01-28 | Preparation method of biapenem aseptic powder |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110030674 CN102617611B (en) | 2011-01-28 | 2011-01-28 | Preparation method of biapenem aseptic powder |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102617611A CN102617611A (en) | 2012-08-01 |
| CN102617611B true CN102617611B (en) | 2013-07-10 |
Family
ID=46557865
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110030674 Active CN102617611B (en) | 2011-01-28 | 2011-01-28 | Preparation method of biapenem aseptic powder |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102617611B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927867A (en) * | 2005-09-08 | 2007-03-14 | 上海医药工业研究院 | Synthesis method of biapenem |
| CN1995040A (en) * | 2006-01-05 | 2007-07-11 | 上海医药工业研究院 | 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method |
| CN101121716A (en) * | 2007-09-28 | 2008-02-13 | 严洁 | Synthesis method for biapenem |
| CN101805359A (en) * | 2010-04-10 | 2010-08-18 | 浙江华海药业股份有限公司 | Method for preparing biapenem with high purity |
-
2011
- 2011-01-28 CN CN 201110030674 patent/CN102617611B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927867A (en) * | 2005-09-08 | 2007-03-14 | 上海医药工业研究院 | Synthesis method of biapenem |
| CN1995040A (en) * | 2006-01-05 | 2007-07-11 | 上海医药工业研究院 | 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method |
| CN101121716A (en) * | 2007-09-28 | 2008-02-13 | 严洁 | Synthesis method for biapenem |
| CN101805359A (en) * | 2010-04-10 | 2010-08-18 | 浙江华海药业股份有限公司 | Method for preparing biapenem with high purity |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102617611A (en) | 2012-08-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102617611B (en) | Preparation method of biapenem aseptic powder | |
| CN100497338C (en) | 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method | |
| CN111548383B (en) | Process for preparing beta-nicotinamide mononucleotide | |
| CN101935321A (en) | Method for synthesizing 1 beta methyl carbapenem antibiotic | |
| WO2011091968A1 (en) | Method for producing nebivolol | |
| EP2407468A2 (en) | Improved method for preparing meropenem using zinc powder | |
| CN115028670B (en) | Preparation method of N-acetyl-D-galactosamine trimer precursor | |
| CN101914098B (en) | Preparation method of Meropenem trihydrate crystals | |
| CN101768174B (en) | Method for preparing biapenem | |
| CN101891742A (en) | Preparation method of meropenem trihydrate crystal | |
| CN107325082A (en) | A kind of preparation method of high-purity Afatinib | |
| CN101805359B (en) | Method for preparing biapenem with high purity | |
| CN110684024A (en) | Synthetic method of moxifloxacin degradation impurities | |
| CN101279925B (en) | Tetrabenzyl voglibose, preparation and application thereof | |
| CN102675383B (en) | Preparation method of full benzyl protection beta-aromatic oxygen glucoside | |
| SE439630B (en) | SET TO MAKE MORANOLINE AND N-METHYLMORANOLINE | |
| CN109988127A (en) | It is poor to the method for -10- deacetylate pacilitaxel taxol from 7 | |
| CN102234240B (en) | Method for synthesizing L-BMAA (Beta-Methylamino L-Alanine) hydrochloride | |
| CN106478636B (en) | Ticagrelor crystal form and preparation method | |
| WO2013152609A1 (en) | Method for synthesizing sapropterin dihydrochloride | |
| CN111944855B (en) | Method for synthesizing (R) -1- (4- (benzyloxy) -3-nitrophenyl) -2-bromoethanol | |
| CN113817005A (en) | Azithromycin related substance and synthesis method thereof | |
| CN105567778B (en) | A kind of preparation method of 6-amino-penicillanic acid | |
| CN110872305B (en) | Fluorocamptothecin medicament derivative and preparation and application thereof | |
| CN104628720A (en) | Refining method of moxifloxacin hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD. Free format text: FORMER NAME: JIANGSU ZHENGDA TIANQING PHARMACEUTICAL CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Patentee after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Patentee before: Jiangsu Chiatai Tianqing Pharmaceutical Co., Ltd. |