CN102311431B - Method for preparing anhydrous beta-aztreonam - Google Patents
Method for preparing anhydrous beta-aztreonam Download PDFInfo
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- CN102311431B CN102311431B CN201110253213.1A CN201110253213A CN102311431B CN 102311431 B CN102311431 B CN 102311431B CN 201110253213 A CN201110253213 A CN 201110253213A CN 102311431 B CN102311431 B CN 102311431B
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Abstract
The invention provides a method for preparing anhydrous beta-aztreonam. Based on preparation methods of amine-HCl-ethanol in the prior art, the method provided by the invention comprises steps of replacing inorganic acid with organic acid, carrying out neutralization, cooling and crystallizing, thus avoiding the corrosion of inorganic acid to equipment in clean areas and latent quality risk, guaranteeing the quality stability of the product and making the production to keep running normally.
Description
Technical field
The present invention relates to a kind of process for purification of β-aztreonam, be specifically related to be prepared by α-aztreonam the method for high-purity beta-aztreonam, belong to field of medicine and chemical technology.
Background technology
Aztreonam is first artificial synthetic monobactam microbiotic clinically, by the Bristol-Myers Squibb company of the U.S., is developed, and within 1986, in Pakistan, 1988 Nian Indonesia go on the market with trade(brand)name Azactam.1987 in Japan's listing, simultaneously in listings such as Germany, Spain, France.Material inlet China in 2002, preparation You Shiguibao company produces listing within the border in 1997 Nian China.Aztreonam has the anti-microbial activity of height to most of aerobic gram-negative bacterias, comprise the enterobacteriaceae lactobacteriaceaes such as the pneumobacillus of intestinal bacteria, Klebsiella and OKCY holder bacterium, gas bacillus, bacillus cloacae, proteus, Serratia, citric acid bacterium genus, Shigella, and hemophilus influenza, gonococcus, meningococcus etc.In clinical, be applicable to treat the various infection due to responsive aerobic gram-negative bacteria, as: the skin soft-tissue infections such as urinary tract infections, lower respiratory infection, septicemia, intra-abdominal infection, gynecological infection, postoperative wound and burn, ulcer etc.Its chemical name is: [2S-[2 α, 3 β (Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo group-3-azetidinyl) amino]-2-oxo ethylidene] amino] oxo]-2 Methylpropionic acid, molecular formula is: C
13h
17n
5o
8s
2, chemical structure is as follows:
Aztreonam has polycrystallinity, at present the aztreonam of report has 4 kinds of crystalline forms, i.e. α, β, γ, δ, and the aztreonam of wherein preparing by conventional condensation hydrolysis reaction is all α-aztreonam, its water content is within the scope of 7.5-15%, for amorphous powder, crystallinity is poor, poor stability, very easily redden, be difficult for long-term placement, be not suitable for medicinally, therefore should change into stable crystalline form by turning brilliant form.And β-aztreonam is anhydrous ammonia leaven, nonhygroscopic, good crystalline, good fluidity, is easy to packing, and stability is high, suitable medicinal, so α-aztreonam is converted into the approach that β-aztreonam is the current general medicinal aztreonam of preparation.
There is at present several different methods to prepare β-aztreonam.U.S. Patent application US946,838 have reported its preparation method: α-aztreonam is joined in the dehydrated alcohol of 55-60 ℃ and dissolved, then cooling crystallize out, is target product.Separately there is report to utilize aztreonam under alkaline condition, to be dissolved in the free aztreonam of mode that ethanol adds anhydrous hydrogen chloride solution gas after sterile filtration again, obtain target product.In addition, with 60 times of dehydrated alcohols, the mode by heating for dissolving crystallisation by cooling also can make target product to Chinese patent application CN1545514, and it is that mixed dissolution also can obtain target compound to increase its solvability that CN200610161071 changes single solvent.
Yet all there is larger technological deficiency or hidden danger of quality in above method.The method of recording in U.S. Patent application US946838 adopts heat to dissolve, and destroy product structure for a moment and easily cause it to decompose, the 2nd, even if temporarily dissolve, but the time is shorter, cannot, by sterile filtration, be impracticable in production.Current general amine-HCl-ethanol preparation method, severe corrosive due to hydrogen chloride gas, particularly the aggressiveness of chlorion has proposed higher requirement to sterile equipment, the long-term erosion of chlorion simultaneously has injury in various degree to clean area is anticorrosion with equipment material, has larger hidden trouble of equipment and quality risk.The same with high-temperature digestion by the method for extensive dissolution with solvents, be unfavorable for suitability for industrialized production, mixed solvent dissolves equally needs extensive solvent, and mixed solvent is difficult for reclaiming and applying mechanically.
Summary of the invention
For the defect of above method, the object of this invention is to provide a kind of method of preparing the sterile bulk drug of high-purity anhydrous β-aztreonam.
The object of the invention is to be achieved through the following technical solutions:
The invention provides a kind of method of preparing anhydrous beta-aztreonam, wherein, said method comprising the steps of:
1) under normal temperature, α-aztreonam is added in organic solvent, add organic bases neutralization, molten clear, decolouring degerming, enters aseptic crystallization tank;
2) add organic acid neutralization, regulate pH value, cooling, stir, crystallization, growing the grain 30min, makes anhydrous beta-aztreonam.
Further, according to preceding method, in step 1) in, described organic solvent comprises: ethanol, acetone or Virahol, preferred alcohol; Described organic solvent quality used is 5-20 times of α-aztreonam quality, and preferably 10-12 is doubly best crystallization content.Organic solvent is except ethanol, the same solvent that also can be used as preparing aztreonam of single acetone, for practicality and the consideration of controlling cost, do not consider to prepare with mixed solvent, but do not represent that alcohol ketone mixed solvent is infeasible, in fact, the same target product of preparing of mixed solvent of rudimentary alcohol ketone (five carbon are following).
Further, according to preceding method, in step 1) in, described organic bases comprises: triethylamine, Trimethylamine 99, DMF (DMF), N, N-diethyl propylamine, n-Butyl Amine 99, preferred triethylamine, N, N-diethyl propylamine, n-Butyl Amine 99, more preferably triethylamine.The dissolving of α-aztreonam is except conventional triethylamine, and the organic amines such as diethyl propylamine, DMF, Trimethylamine 99 all can be used as solvating agent.
Further, according to preceding method, in step 2) in, described organic acid comprises: the monoprotic acid such as formic acid, acetic acid, phenylformic acid, the polyprotonic acids such as oxalic acid, citric acid, or organic sulfonic acid, preferable formic acid and the oxalic acid such as methylsulfonic acid, tosic acid.
Further, according to preceding method, in step 2) in, the regulation range of described pH value is 1-3, preferably pH value is 2.
Further, according to preceding method, in step 1) and 2) in, the temperature of described neutralization is-5-35 ℃, preferably 15-25 ℃; In step 2) in, the temperature of described crystallization is-5-35 ℃, preferably-5-25 ℃.Solvent temperature and Tc are all in the scope of the conventional license of microbiotic, that is-5-35 ℃, but for production practicality and cost control, 15-25 ℃ be in and optimum temps ,-5-25 ℃ is crystallization optimum temps.
According to prior art processes, by amine-HCl-ethanol preparation technology, except having hydrogen chloride gas directly etching equipment and potential Chloride Attack has potential hidden danger quality, such as production practicality, scale, recycled solvent etc. of other side all has greater advantage than additive method.For making up the potential impact of HCl gas and chlorion, the present invention adopts organic acid to replace inorganic acid, through actual proof, formic acid, acetic acid, the monoprotic acid such as phenylformic acid, and oxalic acid, the polyprotonic acids such as citric acid can replace hydrochloric acid, but halogenated acid (as trichoroacetic acid(TCA), trifluoroacetic acid or halogenated aromatic acid) is owing to having equally except chlorion impact, organic sulfonic acid also can replace hydrochloric acid as methylsulfonic acid, tosic acid simultaneously, stainless steel is not produced to corrosion simultaneously.Like this, hydrogen chloride gas can obtain basic solution to the etching problem of sterile equipment, also needn't promote temperature simultaneously or change solvent systems, and aseptic and quality stability is guaranteed, and maintenance of the equipment and cost reduce greatly, and quality risk is controlled preferably.
Embodiment
Following methods carrys out further to explain and illustrate content of the present invention by experiment.But the embodiment providing should not be understood to protection domain of the present invention to be construed as limiting.
reference examples 1: amine-HCl-ethanol preparation method
1) in 500 enamel dissolving vessels, add 500L dehydrated alcohol, adding 40kg water content is α-aztreonam of 11%, stir, at 25 ℃, add triethylamine 10L, add until completely dissolved gac 4kg decolouring 30min, be pressed in the pipeline of full pipe lining polytetrafluoro corrosionproof protection, in sterile filtration is pressed into the crystallizer of liner polytetrafluoro;
2) in the stainless cylinder of steel of another 300L liner polytetrafluoro, be pressed into 10% anhydrous hydrochloric acid ethanol, add activated carbon 0.5kg, be pressed into the pipeline degerming of omnidistance polytetrafluoro corrosion-proof lining after decolouring after, be pressed into step 1) crystallizer in (the full liner polytetrafluoro of all pipelines, hermetically sealed), regulating pH value is 2-3, crystallization 2h, centrifugal through antiseptic whizzer, 100L anhydrous propanone washing post-drying, obtains β-aztreonam finished product, altogether 32.5kg.Because above equipment still may contact with hydrogen chloride gas, stainless steel equipment carries out rotproofing without exception, and every batch made regular check on crystallizer inwall, prevents Corrosion Potential.
reference examples 2: amine-HCl-ethanol preparation method
1) in three-necked bottle, add 500ml dehydrated alcohol, adding 40g water content is α-aztreonam of 11%, stirs, and adds triethylamine 10ml at 25 ℃, adds until completely dissolved gac 4g, and room temperature decolouring 30min, filters, and filtrate adds in 1000ml crystallizer;
2) separately get 100ml round-bottomed flask, add 30% anhydrous hydrochloric acid ethanol 50ml, add gac 0.5g, room temperature decolouring 30min, filters with stainless steel sterilizing filter, and mother liquor is added dropwise to step 1) crystallizer in, regulating pH value is 2.1, stirs crystallization, growing the grain 2h, filter, 100ml washing with acetone, dry, obtain β-aztreonam fine work 31.9g, yield 79.97%, water content 0.9%, content 98.61%.
embodiment 1:
1) in three-necked bottle, add 500ml dehydrated alcohol, adding 40g water content is α-aztreonam of 11%, stirs, and adds triethylamine 10ml at 25 ℃, adds until completely dissolved gac 4g, and room temperature decolouring 30min, filters, and filtrate adds in 1000ml crystallizer;
2) separately get 100ml round-bottomed flask, add 30% anhydrous formic acid ethanol 50ml, add gac 0.5g, room temperature decolouring 30min, filters with stainless steel sterilizing filter, and mother liquor is added dropwise to step 1) crystallizer in, regulating pH value is 2.5, stirs crystallization, growing the grain 2h, filter, 100ml washing with acetone, dry, obtain β-aztreonam fine work 31.5g, yield 78.75%, water content 1.2%, content 98.8%.
embodiment 2:
1) in three-necked bottle, add 500ml dehydrated alcohol, adding 40g water content is α-aztreonam of 11%, stirs, and adds triethylamine 10ml at 25 ℃, adds until completely dissolved gac 4g, and room temperature decolouring 30min, filters, and filtrate adds in 1000ml crystallizer;
2) separately get 100ml round-bottomed flask, add 30% anhydrous oxalic acid ethanol 50ml, add gac 0.5g, room temperature decolouring 30min, filters with stainless steel sterilizing filter, and mother liquor is added dropwise to step 1) crystallizer in, regulating pH value is 2, stirs crystallization, growing the grain 2h, filter, 100ml washing with acetone, dry, obtain β-aztreonam fine work 33.5g, yield 83.75%, water content 1.2%, content 98.71%.
embodiment 3:
1) in three-necked bottle, add 500ml dehydrated alcohol, adding 40g water content is α-aztreonam of 11%, stirs, and adds triethylamine 10ml at 25 ℃, adds until completely dissolved gac 4g, and room temperature decolouring 30min, filters, and filtrate adds in 1000ml crystallizer;
2) separately get 100ml round-bottomed flask, add 30% dry-out benzene formic acid ethanol 50ml, add gac 0.5g, room temperature decolouring 30min, filters with stainless steel sterilizing filter, and mother liquor is added dropwise to step 1) crystallizer in, regulating pH value is 2, stirs crystallization, growing the grain 2h, filter, 100ml washing with acetone, dry, obtain β-aztreonam fine work 33.8g, yield 84.5%, water content 1.12%, content 98.5%.
embodiment 4:
1) in three-necked bottle, add 500ml dehydrated alcohol, adding 40g water content is α-aztreonam of 11%, stirs, and adds triethylamine 10ml at 25 ℃, adds until completely dissolved gac 4g, and room temperature decolouring 30min, filters, and filtrate adds in 1000ml crystallizer;
2) separately get 100ml round-bottomed flask, add 30% anhydrous methylsulfonic acid ethanol 50ml, add gac 0.5g, room temperature decolouring 30min, filters with stainless steel sterilizing filter, and mother liquor is added dropwise to step 1) crystallizer in, regulating pH value is 2, stirs crystallization, growing the grain 2h, filter, 100ml washing with acetone, dry, obtain β-aztreonam fine work 32.9g, yield 82.25%, water content 1.08%, content 98.43%.
In above embodiment, acid used is organic acid, and Sterile Filtration is Stainless Steel Filter, after filtration, without washing, directly places after one day and does not all occur corrosion phenomena, and in reference examples, acidic alcohol has stronger corrosion iron rust vestige to Stainless Steel Filter.
Claims (11)
1. a method of preparing anhydrous beta-aztreonam, is characterized in that, said method comprising the steps of:
1) under normal temperature, α-aztreonam is added in organic solvent, add organic bases neutralization, molten clear, decolouring degerming, enters aseptic crystallization tank; Described organic bases is triethylamine, Trimethylamine 99, DMF, N, N-diethyl propylamine or n-Butyl Amine 99;
2) add organic acid neutralization, regulate pH value, cooling, stir, crystallization, growing the grain 30min, makes anhydrous beta-aztreonam;
Wherein, in step 1) and 2) in, the temperature of described neutralization is 15-25 ℃.
2. method according to claim 1, in step 1) in, described organic solvent is ethanol, acetone or Virahol.
3. method according to claim 1 and 2, described organic solvent quality used be α-aztreonam quality 5-20 doubly.
4. method according to claim 3, described organic solvent quality used be α-aztreonam quality 10-12 doubly.
5. method according to claim 1, in step 2) in, described organic acid is monoprotic acid, polyprotonic acid or organic sulfonic acid.
6. method according to claim 5, described monoprotic acid is formic acid, acetic acid or phenylformic acid, and described polyprotonic acid is oxalic acid or citric acid, and described organic sulfonic acid is methylsulfonic acid or tosic acid.
7. method according to claim 1 or 5, described organic acid is formic acid or oxalic acid.
8. method according to claim 1, in step 2) in, the regulation range of described pH value is 1-3.
9. method according to claim 8, in step 2) in, described pH value is 2.
10. according to the method described in any one in claim 1-9, in step 2) in, the temperature of described crystallization is-5-35 ℃.
11. methods according to claim 10, in step 2) in, the temperature of described crystallization is-5～25 ℃.
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| CN103232449B (en) * | 2013-05-08 | 2014-04-09 | 四川省惠达药业有限公司 | Aztreonam compound, as well as preparation method and pharmaceutical composition thereof |
| CN105055407A (en) * | 2015-09-15 | 2015-11-18 | 青岛华之草医药科技有限公司 | Medicine aztreonam composition for curing infectious diseases |
| CN105646475A (en) * | 2016-03-04 | 2016-06-08 | 中山福运生物科技有限公司 | Method for producing beta-aztreonam sterile powder |
| CN112645942A (en) * | 2020-12-17 | 2021-04-13 | 山东罗欣药业集团恒欣药业有限公司 | Novel crystal form of compound for treating bacterial infection and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0070024B1 (en) * | 1981-07-13 | 1985-06-26 | E.R. Squibb & Sons, Inc. | The crystalline anhydrous form of (3s-(3 alpha(z),4 beta))-3-(((2-amino-4-thiazolyl)(1-carboxy-1-methylethoxy)-imino)-acetyl)-amino)-4-methyl-2-oxo-1-azetidinesulfonic acid, method for its preparation, mixture and pharmaceutical composition containing it |
| CN1681812A (en) * | 2002-08-05 | 2005-10-12 | 特瓦药厂有限公司 | Preparation of aztreonam |
| CN102086196A (en) * | 2011-01-28 | 2011-06-08 | 海南灵康制药有限公司 | Novel method for refining aztreonam |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0070024B1 (en) * | 1981-07-13 | 1985-06-26 | E.R. Squibb & Sons, Inc. | The crystalline anhydrous form of (3s-(3 alpha(z),4 beta))-3-(((2-amino-4-thiazolyl)(1-carboxy-1-methylethoxy)-imino)-acetyl)-amino)-4-methyl-2-oxo-1-azetidinesulfonic acid, method for its preparation, mixture and pharmaceutical composition containing it |
| CN1681812A (en) * | 2002-08-05 | 2005-10-12 | 特瓦药厂有限公司 | Preparation of aztreonam |
| CN102086196A (en) * | 2011-01-28 | 2011-06-08 | 海南灵康制药有限公司 | Novel method for refining aztreonam |
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