CN102311431A - Method for preparing anhydrous beta-aztreonam - Google Patents
Method for preparing anhydrous beta-aztreonam Download PDFInfo
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- CN102311431A CN102311431A CN201110253213A CN201110253213A CN102311431A CN 102311431 A CN102311431 A CN 102311431A CN 201110253213 A CN201110253213 A CN 201110253213A CN 201110253213 A CN201110253213 A CN 201110253213A CN 102311431 A CN102311431 A CN 102311431A
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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 prepare the method for high-purity beta-aztreonam, belong to field of medicine and chemical technology by α-aztreonam.
Background technology
Aztreonam is the monobactam microbiotic of first synthetic clinically, is developed by the Bristol-Myers Squibb company of the U.S., and 1986 in Pakistan, goes on the market with trade(brand)name Azactam in Indonesia in 1988.1987 in Japan's listing, simultaneously in listings such as Germany, Spain, France.Material inlet China in 2002, preparation was within the border produced listing in 1997 in China by Shi Guibao company.Aztreonam has the anti-microbial activity of height to most of aerobic gram-negative bacterias; The enterobacteriaceae lactobacteriaceae such as pneumobacillus and OKCY holder bacterium, gas bacillus, bacillus cloacae, proteus, Serratia, citric acid bacterium genus, Shigella that comprises intestinal bacteria, Klebsiella, and hemophilus influenza, gonococcus, meningococcus etc.Be applicable to the various infection of treatment due to the responsive aerobic gram-negative bacteria in clinical, as: skin soft-tissue infections such as urinary tract infections, lower respiratory infection, septicemia, IAI, 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 following:
Aztreonam has polycrystallinity, and the aztreonam of report has 4 kinds of crystalline forms, i.e. α, β, γ, δ at present; Wherein the aztreonam through conventional condensation hydrolysis prepared in reaction all is α-aztreonam, and its water cut is amorphous powder in the 7.5-15% scope; Crystallinity is poor, and poor stability very easily reddens; Be difficult for long-term the placement, be not suitable for medicinally, therefore should change into stable crystalline form through changeing brilliant form.And β-aztreonam is anhydrous aztreonam, and is nonhygroscopic, good crystalline, and good fluidity is easy to packing, and stability is high, and is suitable medicinal, so α-aztreonam is converted into the approach that β-aztreonam is the at present general medicinal aztreonam of preparation.
There is several different methods to prepare β-aztreonam at present.U.S. Patent application US946,838 have reported its preparation method: promptly join α-aztreonam in 55-60 ℃ the absolute ethyl alcohol and dissolve, crystal is separated out in cooling then, is title product.Other has report to utilize aztreonam under alkaline condition, to be dissolved in ethanol adds the anhydrous hydrogen chloride solution gas again after sterile filtration the free aztreonam of mode, promptly gets title product.In addition, one Chinese patent application CN1545514 also can make title product with the mode of 60 times of absolute ethyl alcohols through the heating for dissolving crystallisation by cooling, and it is that mixed dissolution also can obtain target compound to increase its solvability that CN200610161071 changes single solvent.
Yet above method all exists bigger technological deficiency or hidden danger of quality.The method of putting down in writing among the U.S. Patent application US946838 adopts the heat dissolving, and destroy product structure for a moment and be prone to cause its decomposition, the 2nd, even temporary transient dissolving, but the time is shorter, can't be impracticable in the production through sterile filtration.Present general amine-HCl-ethanol preparation method; Because the severe corrosive of hydrogen chloride gas; Particularly the aggressiveness of cl ions has proposed higher requirement to sterile equipment; The secular erosion of cl ions simultaneously all has injury in various degree to clean area is anticorrosion with equipment material, has bigger hidden trouble of equipment and quality risk.Method with extensive dissolution with solvents is the same with high-temperature digestion, is unfavorable for suitability for industrialized production, and the mixed solvent dissolving equally needs extensive solvent, and mixed solvent is difficult for reclaiming and applying mechanically.
Summary of the invention
To the defective of above method, the purpose of this invention is to provide a kind of method for preparing the sterile bulk drug of high-purity anhydrous β-aztreonam.
The objective of the invention is to realize through following technical scheme:
The present invention provides a kind of method for preparing anhydrous beta-aztreonam, wherein, said method comprising the steps of:
1) under the normal temperature, α-aztreonam is added in the organic solvent, add the organic bases neutralization, dissolve clearly, the decolouring degerming gets into the aseptic crystallization jar;
2) add the organic acid neutralization, regulate the pH value, cooling is stirred, crystallization, and growing the grain 30min makes anhydrous beta-aztreonam.
Further, according to preceding method, in step 1), said organic solvent comprises: ethanol, acetone or Virahol, preferred alcohol; The used quality of said organic solvent is 5-20 a times of α-aztreonam quality, and preferred 10-12 doubly is best crystallization content.Organic solvent is except that ethanol; The same solvent for preparing aztreonam that also can be used as of single acetone; From the practicality and the consideration of controlling cost, do not consider with the mixed solvent preparation, but do not represent that the alcohol ketone mixed solvent is infeasible; In fact, the same title product for preparing of mixed solvent of rudimentary alcohol ketone (below five carbon).
Further, according to preceding method, in step 1), said organic bases comprises: triethylamine, Trimethylamine 99, N, dinethylformamide (DMF), N, N-diethylammonium propylamine, n-Butyl Amine 99, preferred triethylamine, N, N-diethylammonium propylamine, n-Butyl Amine 99, more preferably triethylamine.The dissolving of α-aztreonam is except that triethylamine commonly used, and organic amines such as diethylammonium propylamine, DMF, Trimethylamine 99 all can be used as solvating agent.
Further, according to preceding method, in step 2) in, said organic acid comprises: monoprotic acid such as formic acid, acetate, phenylformic acid, polyprotonic acids such as oxalic acid, Hydrocerol A, or organic sulfonic acids such as methylsulfonic acid, tosic acid, preferable formic acid and oxalic acid.
Further, according to preceding method, in step 2) in, the regulation range of said pH value is 1-3, preferred pH value is 2.
Further, according to preceding method, in step 1) and 2) in, said neutral temperature is-5-35 ℃, and preferred 15-25 ℃; In step 2) in, said crystalline temperature is-5-35 ℃, and preferred-5-25 ℃.Solvent temperature and Tc all are in the scope of the conventional permission of microbiotic, that is-5-35 ℃, but from production practicality and cost control, 15-25 ℃ be in and optimum temps ,-5-25 ℃ is the crystallization optimum temps.
According to prior art processes; Quality is had the potential hidden danger except that having the erosion of direct etching apparatus of hydrogen chloride gas and potential cl ions with amine-HCl-ethanol preparation technology, others such as production practicality, scale, solvent recuperation utilization etc. all have greater advantage than additive method.For remedying the potential impact of HCl gas and cl ions, the present invention adopts organic acid to replace inorganic acid, through actual proof; Formic acid, acetate, monoprotic acid such as phenylformic acid; And oxalic acid, polyprotonic acids such as Hydrocerol A can replace hydrochloric acid, but halogenated acid (like trichoroacetic acid(TCA), trifluoroacetic acid or halogenated aromatic acid) is owing to have except the cl ions influence equally; Organic sulfonic acid also can replace hydrochloric acid as methylsulfonic acid, tosic acid simultaneously, simultaneously stainless steel is not produced corrosion.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
Content of the present invention is further explained and explained to following method through testing.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.
Reference examples 1: amine-HCl-ethanol preparation method
1) in 500 enamel dissolving vessels, adds the 500L absolute ethyl alcohol; Adding 40kg water cut is α-aztreonam of 11%; Stir, 25 ℃ add triethylamine 10L down, treat to dissolve fully the back and add gac 4kg decolouring 30min; Be pressed in the pipeline that full pipe lining gathers the tetrafluoro corrosionproof protection, in sterile filtration is pressed into the crystallizer that liner gathers tetrafluoro;
2) in another 300L liner gathers the stainless cylinder of steel of tetrafluoro, be pressed into 10% anhydrous hydrochloric acid ethanol, add activated carbon 0.5kg, be pressed into after decolouring that (the full liner of all pipelines gathers tetrafluoro in the crystallizer that is pressed into step 1) after whole process is gathered the pipeline degerming of tetrafluoro corrosion-proof lining; Hermetically sealed), regulating the pH value is 2-3, crystallization 2h; Centrifugal through antiseptic whizzer; 100L anhydrous propanone washing back oven dry gets β-aztreonam finished product, altogether 32.5kg.Because above equipment still possibly contact with hydrogen chloride gas, stainless steel equipment carries out rotproofing without exception, and every batch made regular check on the crystallizer inwall, prevents to corrode hidden danger.
Reference examples 2: amine-HCl-ethanol preparation method
1) in three-necked bottle, add the 500ml absolute ethyl alcohol, adding 40g water cut is α-aztreonam of 11%, stirs, and 25 ℃ add triethylamine 10ml down, treats to dissolve fully back adding gac 4g, and room temperature decolouring 30min filters, and filtrating adds in the 1000ml crystallizer;
2) get the 100ml round-bottomed flask in addition, add 30% anhydrous hydrochloric acid ethanol 50ml, add gac 0.5g, room temperature decolouring 30min; Filter with the stainless steel sterilizing filter, mother liquor is added dropwise in the crystallizer of step 1), and regulating the pH value is 2.1, stirs and separates out crystallization; Growing the grain 2h filters 100ml washing with acetone, drying; Get β-aztreonam elaboration 31.9g, yield 79.97%, water cut 0.9%, content 98.61%.
Embodiment 1:
1) in three-necked bottle, add the 500ml absolute ethyl alcohol, adding 40g water cut is α-aztreonam of 11%, stirs, and 25 ℃ add triethylamine 10ml down, treats to dissolve fully back adding gac 4g, and room temperature decolouring 30min filters, and filtrating adds in the 1000ml crystallizer;
2) get the 100ml round-bottomed flask in addition, add 30% anhydrous formic acid ethanol 50ml, add gac 0.5g, room temperature decolouring 30min; Filter with the stainless steel sterilizing filter, mother liquor is added dropwise in the crystallizer of step 1), and regulating the pH value is 2.5, stirs and separates out crystallization; Growing the grain 2h filters 100ml washing with acetone, drying; Get β-aztreonam elaboration 31.5g, yield 78.75%, water cut 1.2%, content 98.8%.
Embodiment 2:
1) in three-necked bottle, add the 500ml absolute ethyl alcohol, adding 40g water cut is α-aztreonam of 11%, stirs, and 25 ℃ add triethylamine 10ml down, treats to dissolve fully back adding gac 4g, and room temperature decolouring 30min filters, and filtrating adds in the 1000ml crystallizer;
2) get the 100ml round-bottomed flask in addition, add 30% anhydrous oxalic acid ethanol 50ml, add gac 0.5g, room temperature decolouring 30min; Filter with the stainless steel sterilizing filter, mother liquor is added dropwise in the crystallizer of step 1), and regulating the pH value is 2, stirs and separates out crystallization; Growing the grain 2h filters 100ml washing with acetone, drying; Get β-aztreonam elaboration 33.5g, yield 83.75%, water cut 1.2%, content 98.71%.
Embodiment 3:
1) in three-necked bottle, add the 500ml absolute ethyl alcohol, adding 40g water cut is α-aztreonam of 11%, stirs, and 25 ℃ add triethylamine 10ml down, treats to dissolve fully back adding gac 4g, and room temperature decolouring 30min filters, and filtrating adds in the 1000ml crystallizer;
2) get the 100ml round-bottomed flask in addition, add 30% dry-out benzene formic acid ethanol 50ml, add gac 0.5g, room temperature decolouring 30min; Filter with the stainless steel sterilizing filter, mother liquor is added dropwise in the crystallizer of step 1), and regulating the pH value is 2, stirs and separates out crystallization; Growing the grain 2h filters 100ml washing with acetone, drying; Get β-aztreonam elaboration 33.8g, yield 84.5%, water cut 1.12%, content 98.5%.
Embodiment 4:
1) in three-necked bottle, add the 500ml absolute ethyl alcohol, adding 40g water cut is α-aztreonam of 11%, stirs, and 25 ℃ add triethylamine 10ml down, treats to dissolve fully back adding gac 4g, and room temperature decolouring 30min filters, and filtrating adds in the 1000ml crystallizer;
2) get the 100ml round-bottomed flask in addition, add 30% anhydrous methylsulfonic acid ethanol 50ml, add gac 0.5g, room temperature decolouring 30min; Filter with the stainless steel sterilizing filter, mother liquor is added dropwise in the crystallizer of step 1), and regulating the pH value is 2, stirs and separates out crystallization; Growing the grain 2h filters 100ml washing with acetone, drying; Get β-aztreonam elaboration 32.9g, yield 82.25%, water cut 1.08%, content 98.43%.
Used acid is organic acid among the above embodiment, and Sterile Filtration is Stainless Steel Filter, filters the back without washing, directly places after one day corrosion phenomena all not occur, and acidic alcohol then has stronger corrosion iron rust vestige to Stainless Steel Filter in the reference examples.
Claims (10)
1. a method for preparing anhydrous beta-aztreonam is characterized in that, said method comprising the steps of:
1) under the normal temperature, α-aztreonam is added in the organic solvent, add the organic bases neutralization, dissolve clearly, the decolouring degerming gets into the aseptic crystallization jar;
2) add the organic acid neutralization, regulate the pH value, cooling is stirred, crystallization, and growing the grain 30min makes anhydrous beta-aztreonam.
2. method according to claim 1, in step 1), said organic solvent comprises: ethanol, acetone or Virahol, preferred alcohol.
3. method according to claim 1 and 2, the used quality of said organic solvent are 5-20 times of α-aztreonam quality, and preferred 10-12 doubly.
4. method according to claim 1, in step 1), said organic bases comprises: triethylamine, Trimethylamine 99, N; Dinethylformamide (DMF), N, N-diethylammonium propylamine, n-Butyl Amine 99, preferred triethylamine, N; N-diethylammonium propylamine, n-Butyl Amine 99, more preferably triethylamine.
5. method according to claim 1 is in step 2) in, said organic acid comprises: monoprotic acid, polyprotonic acid or organic sulfonic acid.
6. method according to claim 5, said monoprotic acid comprises: formic acid, acetate or phenylformic acid, said polyprotonic acid comprises: oxalic acid or Hydrocerol A, said organic sulfonic acid comprises: methylsulfonic acid or tosic acid.
7. according to claim 1 or 5 described methods, said organic acid is formic acid or oxalic acid.
8. method according to claim 1 is in step 2) in, the regulation range of said pH value is 1-3, preferred pH value is 2.
9. according to each described method of claim 1, in step 1) and 2) in, said neutral temperature is-5-35 ℃, and preferred 15-25 ℃.
10. according to each described method among the claim 1-9, in step 2) in, said crystalline temperature is-5-35 ℃, and preferred-5-25 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232449A (en) * | 2013-05-08 | 2013-08-07 | 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 |
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| 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 |
-
2011
- 2011-08-30 CN CN201110253213.1A patent/CN102311431B/en active Active
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 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232449A (en) * | 2013-05-08 | 2013-08-07 | 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 |
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