CN102127068A - Method for synthesizing aztreonam compound - Google Patents
Method for synthesizing aztreonam compound Download PDFInfo
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- CN102127068A CN102127068A CN 201010624073 CN201010624073A CN102127068A CN 102127068 A CN102127068 A CN 102127068A CN 201010624073 CN201010624073 CN 201010624073 CN 201010624073 A CN201010624073 A CN 201010624073A CN 102127068 A CN102127068 A CN 102127068A
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- aztreonam
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Abstract
The invention relates to a method for synthesizing an aztreonam compound. The method comprises the following steps of: (1) adding water and a water-soluble non-aqueous solvent into a reaction container, adding trans-3(S)-amino-4-methyl-2-keto-1-azetidine sulfonic acid, triethylamine and (Z)-2-[(2-aminothiazole-4-radical)-(benzothiazole-2-sulfenyl carbonyl) methylamine oxygroup]-2-methylpropanoic acid tert-butyl ester for reacting, and adjusting the pH with acid and separating crystals out to obtain tertiary butyl aztreonam; and (2) subjecting the tertiary butyl aztreonam and acid-water mixed liquor to reaction and performing post-treatment to obtain aztreonam. By adopting the method, the reaction time can be shortened, the reaction speed can be increased, the production cost can be lowered, and environmental pollution can be reduced.
Description
Technical field
The invention belongs to medical technical field, particularly, relate to a kind of method of synthetic aztreonam compound.
Background technology
Aztreonam is that first is used for clinical monocycle-beta-lactam antibiotics.By Bristol-Myers Squibb Co.'s exploitation, at first went on the market in 1984 in Italy.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-oxidation ethylidene] amino] oxo]-2 Methylpropionic acid.Molecular formula: C
13H
17N
5O
8S.Molecular weight: 435.44.Structural formula:
Aztreonam is strong to the effect of Gram-negative bacteria, and is stable to multiple β-Nei Xiananmei plasmid-mediated and the karyomit(e) mediation.The drug-fast bacterial strain of some cephalo or Penicillin antibiotics is still responsive to aztreonam.And this product is safe and effective in clinical use, is widely used in multiple infection, and clinical effective rate is all more than 85%.Aztreonam has following characteristics: 1) do not induce bacterium to produce the beta-lactam acyl, and highly stable to bacteriogenic most of β-Nei Xiananmeis simultaneously.2) tissue penetration is strong, reaches very high Plasma Concentration after the injection rapidly, and bioavailability can be distributed widely in interior each tissue of body and the body fluid subsequently up to 90%.3) mainly drain by glomerular filtration and tubular secretion, can in urine, keep long-time height bacteriocidal concentration with original shape.4) behind injection 0.5g～2g, can reach very high bacteriocidal concentration, and after 6～8 hours, still be several times～hundreds of times of bacteriocidal concentrations of common pathogen MIC90.5) aztreonam is better than third generation cephalosporin and aminoglycoside antibiotics to the antimicrbial power of most gram negative aerobic bacterias.
The synthetic method of aztreonam has lot of documents; U.S. Pat 4775670A's a kind of preparation method of aztreonam has reported for work; pointed out to carry out dehydration reaction with dicyclohexylcarbodiimide with 2-(2-amino-4-thiazolyl)-2-(1-phenylbenzene methoxy carbonyl-1-methyl ethoxy) acetimidic acid hydrochloride and (2S-is trans)-3-amino-2-methyl-4-oxo-1-azetidinyl sulfonic acid; take off diphenyl-methyl protection with trifluoroacetic acid and phenylmethylether then and make the method for aztreonam, the reagent that uses in this method is poisonous and cost an arm and a leg.Be not suitable for large-scale industrialization production.
Chinese patent CN101171251A provides a kind of one pot of method for preparing aztreonam, and this method uses azetidine and TAEM as starting raw material, does not need to isolate the intermediate t-bu aztreonam and directly carries out next step reaction.Though this method has reduced operation steps, quality product is wayward, and does not obtain simplifying in the industrial production operation.
Chinese patent CN101514200A provides a kind of synthetic method of aztreonam; with (thiazolamine-4-yl)-2-(special butoxy carbonyl)-isopropyl oxygen imino acetate-2-mercaptobenzothiazole ester and (3S-is trans)-3-amino-4-methyl-2-oxo-1-azetidin alkyl sulfonic acid is starting raw material; with 1; 4-dioxane and N-methylmorpholine are reaction solvent; adopt the mixed aqueous solution deprotection base of acetate and hydrochloric acid, the preparation aztreonam.This method has been selected the big solvent of toxicity for use, is unfavorable for environmental protection, is not suitable for industrial mass production.
Summary of the invention
In order to overcome the many disadvantages of prior art, as the infeasibility of producing, poor efficiency, unstable product quality etc., the object of the present invention is to provide a kind of novel method of producing aztreonam, this method flow process that can simplify the operation, reduce production costs, improve the quality of products, will bring great convenience for suitability for industrialized production.
The method of synthetic aztreonam compound provided by the invention comprises the steps:
1) non-aqueous solvent that in reaction vessel, adds entry and dissolve each other with water, add trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid, triethylamine and (Z)-2-[(2-aminothiazole-4-yl again)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester reacts, with separating out crystal behind the acid accent pH, obtain t-bu aztreonam;
2) mixed solution of t-bu aztreonam and acetate and water is reacted, aftertreatment obtains aztreonam.
Preferably, in the step 1, add trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid, stir and be cooled to-40～5 ℃; Begin to drip triethylamine then, to the pH value be 5.0～9.0; Add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester, add up to raw material, continued insulation reaction 1～3 hour, and added gac and stir, filter, be cooled to-40～5 ℃, with the concentrated hydrochloric acid adjust pH is 1.0～1.5, and the adularescent crystal is separated out, insulation crystallization 2 hours, filter, get t-bu aztreonam;
Preferably, in the step 2, t-bu aztreonam is added in acetate, the water mixed solution, be heated to 50～55 ℃ and stirred 0.5～3 hour, filter; Be cooled to-40～5 ℃, stop to stir, leaving standstill crystallization 2～6 hours; Filter, obtain white solid, stir with freezing non-aqueous solvent and wash 0.5～3 hour, filter, same eluent solvent gets aztreonam.
Preferably, in the step 1, the described non-aqueous solvent that dissolves each other with water is selected from one or more in methyl alcohol, ethanol and the acetone.
Preferably, in the step 1, the charging capacity of purified water and the non-aqueous solvent that dissolves each other with water (" charging capacity " measured in mass among the present invention, down with) is 12～18 times of trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid charging capacity, and water is preferably purified water; Preferably, the non-aqueous solvent that dissolves each other with water account for water and the charging capacity of the non-aqueous solvent that dissolves each other with water 40%～60%; Preferably, (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-2 Methylpropionic acid tert-butyl ester charging capacity is 3 times of trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid charging capacity.
Preferably, in the step 1, add (Z)-2-[(2-aminothiazole-4-yl in the process of dropping triethylamine simultaneously)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester, preferably, (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester is successional a small amount of adding.
Preferably, in the step 1, add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-time of the 2 Methylpropionic acid tert-butyl ester was controlled at 1～10 hour;
Preferably, add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-process of the 2 Methylpropionic acid tert-butyl ester in, control pH value is 5.0～9.0; Preferably, add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-temperature during the 2 Methylpropionic acid tert-butyl ester is controlled at-40～5 ℃.
Preferably, the mass ratio of described acetate and water is 1～3: 1～3, preferred 1: 1; Preferably, the quality that adds acetate, water mixed solvent is 1～5 times of t-bu aztreonam, preferred 3 times.
Preferably, in the step 2, described freezing non-aqueous solvent temperature is-40～0 ℃; Preferably, described freezing non-aqueous solvent is selected from one or more in methyl alcohol, ethanol and the acetone.
Method of the present invention specifically describes as follows:
1) adds purified water and the non-aqueous solvent that dissolves each other with water, adding trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid in the reaction vessel, stir and be cooled to-40～5 ℃.Begin to drip triethylamine, to the pH value be 5.0～9.0.Add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester, in reinforced process, need control pH, control reaction temperature, add up to raw material, continue thermal reacting for two hours, add gac and stirred 0.5 hour.Filtering, be cooled to-40～5 ℃, is 1.0～1.5 with the concentrated hydrochloric acid adjust pH, and the adularescent crystal is separated out, and insulation crystallization 2 hours filters, and gets t-bu aztreonam.
T-bu aztreonam is added in acetate, the water mixed solution, be heated to 50～55 ℃ and stirred 1 hour, filter.Be cooled to-40～5 ℃, stop to stir, leaving standstill crystallization 2～6 hours.Filter, obtain white solid, stir with freezing non-aqueous solvent and wash 1 hour, filter, same eluent solvent gets aztreonam.
The described non-aqueous solvent that can dissolve each other with water is one of methyl alcohol, ethanol, acetone and any mixture thereof, the non-aqueous solvent that dissolves each other with water account for purified water and the charging capacity of the non-aqueous solvent that dissolves each other with water 40%～60%.The charging capacity of purified water and the non-aqueous solvent that dissolves each other with water is 12～18 times of trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid charging capacity.
(Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-2 Methylpropionic acid tert-butyl ester charging capacity is 3 times of trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid charging capacity.Add (Z)-2-[(2-aminothiazole-4-yl in the process of dropping triethylamine simultaneously)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester.
The beneficial effect of the inventive method is as follows:
Use the non-aqueous solvent that purified water reaches and water dissolves each other to substitute acetonitrile of the prior art, tetrahydrofuran (THF), trifluoroacetic acid equal solvent, reduced production cost, reduce environmental pollution as mixed solvent.Simultaneously, adopt triethylamine with (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester adds control pH value, temperature simultaneously.Reduce the reaction times like this, accelerate speed of reaction.Cut down the consumption of energy, save production cost.
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
Add purified water 175g, methyl alcohol 140g in the reaction vessel, add trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid 20g, stir and be cooled to-20 ℃.Keep temperature, begin to drip triethylamine, to the pH value of solution value be 6.0.Begin to add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-2 Methylpropionic acid tert-butyl ester 60g, in reinforced process, drip triethylamine, all the time control the pH value and be between 5.0～9.0, temperature is-20～-10, the time is controlled in 2 hours and adds.Continue reaction 2 hours.Filter, be cooled to-10 ℃, with concentrated hydrochloric acid adjust pH to 1.5, the adularescent crystal is separated out, and insulation crystallization 2 hours filters, and obtains t-bu aztreonam.
T-bu aztreonam is added in the acetate, water mixed solvent of 3 times of amounts (acetate: water=5: 5, volume ratio), be heated to 50 ℃ and stirred 1 hour, filter.Be cooled to-20 ℃, left standstill crystallization 4 hours.Filter, obtain white solid.White solid stirs with-10 ℃ of dehydrated alcohols and washes 1 hour, filters, and-10 ℃ of dehydrated alcohol drip washing get aztreonam 35.8g, and yield is 74.1%, and HPLC purity is 99.2%.
Embodiment 2
Add purified water 200g, ethanol 100g, acetone 100g in the reaction vessel, add trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid 28g, stir and be cooled to-30 ℃.Keep temperature, begin to drip triethylamine, to the pH value of solution value be 8.0.Add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-2 Methylpropionic acid tert-butyl ester 84g, in reinforced process, control the pH value all the time and be between 5.0～9.0, temperature is at-20～0 ℃.Be controlled in two hours and add.Continue reaction 2 hours, add gac and stirred 0.5 hour.Filter, be cooled to-10 ℃, with concentrated hydrochloric acid adjust pH to 1.0～1.5, the adularescent crystal is separated out, and insulation crystallization 2 hours filters, and obtains t-bu aztreonam.
The acetate, the water (acetate: water=5: 5) in the mixed solvent, be heated to 50 ℃ and stirred 1 hour, filter that t-bu aztreonam are added 3 times of amounts.Be cooled to-10 ℃, left standstill crystallization 4 hours.Filter, obtain white solid.White solid stirs with-10 ℃ of methyl alcohol and washes 1 hour, filters, and-10 ℃ of methyl alcohol drip washing get aztreonam 51.2g, and yield is 75.6%, and purity is 99.2%.
Embodiment 3
Add purified water 350kg, acetone 280kg in the reaction vessel, add trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid 40kg, stir and be cooled to-20 ℃.Keep temperature, begin to drip triethylamine, to the pH value of solution value be 5.0.Add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-2 Methylpropionic acid tert-butyl ester 120kg, in reinforced process, control the pH value all the time and be between 5.0～9.0, temperature is at-30～-20 ℃.Be controlled in 6 hours and add.Continue reaction 2 hours, add gac and stirred 0.5 hour.Filter, be cooled to-20 ℃, with concentrated hydrochloric acid adjust pH to 1.0～1.5, the adularescent crystal is separated out, and insulation crystallization 2 hours filters, and obtains t-bu aztreonam.
T-bu aztreonam is added (acetate: water=5: 5), be heated to 50 ℃ and stirred 1 hour, filter in the acetate, water mixed solvent of 3 times of amounts.Be cooled to-20 ℃, left standstill crystallization 4 hours.Filter, obtain white solid.White solid stirs with-10 ℃ of acetone and washes 1 hour, filters, and-10 ℃ of acetone drip washing get aztreonam 74.6, and yield is 77.0%, and purity is 99.1%.
Embodiment 4
Add purified water 350kg, methyl alcohol 280kg in the reaction vessel, add trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid 40kg, stir and be cooled to-20 ℃.Keep temperature, begin to drip triethylamine, to the pH value of solution value be 8.5.Add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-2 Methylpropionic acid tert-butyl ester 120kg, in reinforced process, control the pH value all the time and be between 5.0～9.0, temperature is at-20～5 ℃.Be controlled in 6 hours and add.Continue reaction 2 hours, add gac and stirred 0.5 hour.Filter, be cooled to-10 ℃, with concentrated hydrochloric acid adjust pH to 1.0～1.5, the adularescent crystal is separated out, and insulation crystallization 2 hours filters, and obtains t-bu aztreonam.
T-bu aztreonam is added (acetate: water=5: 5), be heated to 50 ℃ and stirred 1 hour, filter in the acetate, water mixed solvent of 3 times of amounts.Be cooled to-20～5 ℃, left standstill crystallization 4 hours.Filter, obtain white solid.White solid stirs with-10 ℃ of acetone and washes 1 hour, filters, and-10 ℃ of acetone drip washing get aztreonam 73.2kg, and yield is 75.6%, and purity is 99.0%.
Compared with prior art, the beneficial effect of synthetic method of the present invention is as follows:
That embodiment of the invention 1-4 has used is more cheap, pollute lower methyl alcohol, ethanol, acetone and water mixture as reaction soln.Simultaneously, in the process of charging reaction, temperature, the pH value of control reaction all the time, augmenting response speed shortens the reaction times, has saved energy consumption.Simple acetate, the water mixture of using can make the recovery of solvent convenient as the hydrolysis reaction solvent, reduced blowdown.
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, this modification of this that made or improvement without departing from theon the basis of the spirit of the present invention all belongs to the scope of protection of present invention.
Claims (10)
1. the method for a synthetic aztreonam compound comprises the steps:
1) non-aqueous solvent that in reaction vessel, adds entry and dissolve each other with water, add trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid, triethylamine and (Z)-2-[(2-aminothiazole-4-yl again)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester reacts, with separating out crystal behind the acid accent pH, obtain t-bu aztreonam;
2) make the reaction of t-bu aztreonam and sour water mixed solution, aftertreatment obtains aztreonam.
2. synthetic method as claimed in claim 1 is characterized in that, in the step 1, adds trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid, stirs and is cooled to-40～5 ℃; Begin to drip triethylamine then, to the pH value be 5.0～9.0; Add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester, add up to raw material, continued insulation reaction 1～3 hour,, filter, be cooled to-40～5 ℃, with the concentrated hydrochloric acid adjust pH is 1.0～1.5, and the adularescent crystal is separated out, insulation crystallization 2 hours, filter, get t-bu aztreonam;
3. synthetic method as claimed in claim 1 is characterized in that, in the step 2, t-bu aztreonam is added in acetate, the water mixed solution, is heated to 50～55 ℃ and stirs 0.5～3 hour, filters; Be cooled to-40～5 ℃, stop to stir, leaving standstill crystallization 2～6 hours; Filter, obtain white solid, stir with freezing non-aqueous solvent and wash 0.5～3 hour, filter, same eluent solvent gets aztreonam.
4. as claim 1 or 3 described synthetic methods, it is characterized in that in the step 1, the described non-aqueous solvent that dissolves each other with water is selected from one or more in methyl alcohol, ethanol and the acetone.
5. synthetic method as claimed in claim 1 is characterized in that, in the step 1, the charging capacity of purified water and the non-aqueous solvent that dissolves each other with water is 12～18 times of trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid charging capacity; Preferably, the mass percent concentration of non-aqueous solvent is 40%～60%, preferably, (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-2 Methylpropionic acid tert-butyl ester charging capacity is 3 times of trans-3 (S)-amino-4-methyl-2-oxo-1-azetidinyl sulfonic acid charging capacity.
6. synthetic method as claimed in claim 1, it is characterized in that, in the step 1, add (Z)-2-[(2-aminothiazole-4-yl in the process of dropping triethylamine simultaneously)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester, preferably, (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-the 2 Methylpropionic acid tert-butyl ester is successional a small amount of adding.
7. synthetic method as claimed in claim 1 is characterized in that, in the step 1, adds (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-time of the 2 Methylpropionic acid tert-butyl ester was controlled at 1～10 hour;
8. synthetic method as claimed in claim 1 is characterized in that, adds (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-process of the 2 Methylpropionic acid tert-butyl ester in, control pH value is 5.0～9.0; Preferably, add (Z)-2-[(2-aminothiazole-4-yl)-(benzothiazole-2-base sulfenyl carbonyl) methylene amido oxygen base]-temperature during the 2 Methylpropionic acid tert-butyl ester is controlled at-40～5 ℃.
9. synthetic method as claimed in claim 1 is characterized in that, the mass ratio of described acetate and water is 1: 1; Preferably, adding acetate, water mixed solvent is 3 times of t-bu aztreonam.
10. synthetic method as claimed in claim 1 is characterized in that, in the step 2, described freezing non-aqueous solvent temperature is-40～0 ℃; Preferably, described freezing non-aqueous solvent is selected from one or more in methyl alcohol, ethanol and the acetone.
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| CN103570707A (en) * | 2012-07-21 | 2014-02-12 | 重庆圣华曦药业股份有限公司 | Improved synthetic method of aztreonam |
| CN105001215A (en) * | 2015-08-03 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Aztreonam compound serving as sterilization medicine and preparation method thereof |
| CN105085511A (en) * | 2015-05-29 | 2015-11-25 | 石药集团中诺药业（石家庄）有限公司 | Novel aztreonam compound |
| CN106520857A (en) * | 2016-08-25 | 2017-03-22 | 艾美科健（中国）生物医药有限公司 | Method for synthesizing aztreonam through enzyme method |
| CN111448182A (en) * | 2017-10-02 | 2020-07-24 | 阿里萨制药有限公司 | Aztreonam derivative and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103570707A (en) * | 2012-07-21 | 2014-02-12 | 重庆圣华曦药业股份有限公司 | Improved synthetic method of aztreonam |
| CN103570707B (en) * | 2012-07-21 | 2016-03-09 | 重庆圣华曦药业股份有限公司 | A kind of synthetic method of aztreonam of improvement |
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| CN105085511B (en) * | 2015-05-29 | 2018-04-06 | 石药集团中诺药业（石家庄）有限公司 | A kind of new aztreonam compound |
| CN105001215A (en) * | 2015-08-03 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Aztreonam compound serving as sterilization medicine and preparation method thereof |
| CN106520857A (en) * | 2016-08-25 | 2017-03-22 | 艾美科健（中国）生物医药有限公司 | Method for synthesizing aztreonam through enzyme method |
| CN106520857B (en) * | 2016-08-25 | 2020-01-07 | 艾美科健（中国）生物医药有限公司 | Method for synthesizing aztreonam by enzyme method |
| CN111448182A (en) * | 2017-10-02 | 2020-07-24 | 阿里萨制药有限公司 | Aztreonam derivative and application thereof |
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