78110-38-0

Basic information

• Product Name: Aztreonam
• Synonyms: Aztreonam L-Arginine;(E)-2-(((1-(2-aminothiazol-4-yl)-2-((2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid;Aztreonam/arginine;Aztreonam(β-form);Aztreonam94-103% (HPLC);Aztreonam and Sodium Carbonate;(2s-(2-alpha,3-beta(z)))-dinyl)amino)-2-oxoethylidene)amino)oxy)-2-methyl;antibioticsquibb26,776
• CAS NO: 78110-38-0
• Molecular Formula: C₁₃H₁₇N₅O₈S₂
• Molecular Weight: 435.43
• EINECS: 278-839-9
• Product Categories: API;TISERTON;Active Pharmaceutical Ingredients;Antibacterial;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Heterocycles;Sulfur & Selenium Compounds;Aztreonam ada@tuskwei.com whatsapp;8618031153937
• Mol File: 78110-38-0.mol
• Article Data: 15

Chemical Properties

• Melting Point: 227°C
• Appearance: /solid
• Density: 1.83
• Refractive Index: 1.6460 (estimate)
• Storage Temp.: Store at 0-5°C
• Solubility: DMSO (Slightly), Water (Slightly, Heated, Sonicated)
• PKA: pKa -0.7(H2O t=RT Iunde?ned) (Uncertain);2.75(H3O t=RT Iunde?ned) (Uncertain);3.91(H4O t=RT Iunde?ned) (Uncertain)
• Water Solubility: Soluble in DMF/water (1:1) at 50 mg/ml
• Merck: 14,925
• CAS DataBase Reference: Aztreonam(CAS DataBase Reference)
• NIST Chemistry Reference: Aztreonam(78110-38-0)
• EPA Substance Registry System: Aztreonam(78110-38-0)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22-36/37/38
• Safety Statements: 22-24/25-36-26
• WGK Germany: 2
• RTECS: UA2451400
• Hazardous Substances Data: 78110-38-0(Hazardous Substances Data)

Usage

Outline

Aztreonam is a novel kind ofβ-lactam antibiotics belonging to monobactams. In 1978 it was first discovered from the culture brot of New Jersey soil purple bacterium Chromobacterium violaceum, it has been obtained with synthesis method. Mechanism Aztreonam belongs to bacteria fungicides. It can quickly go through the outer membrane of Gram-negative aerobic bacteria wall, while it has a high affinity with the penicillin-binding protein 3 (PBP-3) . By acting on the PBP-3 and inhibiting synthesis of bacterial cell wall , it leads to cell lysis and death. Aztreonam has a narrow antimicrobial spectrum, it only has antibacterial effect on aerobic gram-negative bacilli , such as E. coli, Klebsiella, Serratia spp, Proteus mirabilis, indole-positive Proteus, Citrobacter, influenza addicted blood coli, Pseudomonas aeruginosa and other Pseudomonas, some Enterobacter, Neisseria gonorrhoeae. The product is highly stable to β-lactamase produced by many bacteria .it is inactive in Gram-positive bacteria and anaerobic bacteria . Aztreonam compared with ceftazidime, gentamicin, it effect on aerogenes, and Enterobacter cloacae is higher than ceftazidime, but lower than gentamicin; the effect on Pseudomonas aeruginosa is lower than ceftazidime , and similar to gentamicin .

indications

It is mainly used for the treatment of infections caused by susceptible strains which include the respiratory system, urinary, reproductive system infections (including acute gonorrhea), intra-abdominal infections, skin and soft tissue infections, before surgery preventing infections, other serious infections, such as sepsis.

Precautions

1.contraindication: patients allergic to the products or having a history of allergy on lidocaine and other local anesthetics or having anaphylactic shock on other β-lactam drugs are banned. 2. caution following: It does not exist cross-allergic reactions between aztreonam and penicillins, but people having allergy body and allergic to penicillins, cephalosporins should take caution. renal dysfunction patients should take caution. aztreonam does not have toxicity for liver , but the patients having impaired liver function should observe the dynamic changes. It has been reported that in patients with alcoholic cirrhosis , the total clearance of the products can be reduced by 20-25%. pregnant and lactating women, infants and young children should use with caution. 3. The impact of drugs on clinical outcomes: direct anti-human globulin test (Coombs test) can be positive. there may be a temporary increase of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and serum creatinine values after medication among a few patients, part thromboplastin time (PTT) and prothrombin time (PT) may be extended. adverse reactions are skin symptoms such as skin rashes, purpura, pruritus (approximately 2%); gastrointestinal symptoms such as diarrhea, nausea, vomiting, taste changes, jaundice, and drug-induced hepatitis (approximately 2%); local irritation such as thrombophlebitis. Injection site swelling (approximately 2.4%); there are other neurological symptoms, vaginitis, oral lesions, fatigue, dizziness, and bleeding. 4. Long-term medication should pay attention to monitoring of liver, kidney and hematopoietic system. The above information is edited by the lookchem of Tian Ye.

Chemical properties

white or colorless powder crystals, melting at 227 ℃ (decomposition). It is dissolved in dimethyl formamide, slightly soluble in methanol, very slightly soluble in ethanol, insoluble in toluene, chloroform or ethyl acetate. Aztreonam disodium: C13 H15N5Na2O8 . Acute toxicity LD50 (mg/kg): 3300 intravenous injection in mice, 6600 in rats intraperitoneally.

Uses

Different sources of media describe the Uses of 78110-38-0 differently. You can refer to the following data:
1. It is Mainly used for the infections caused by sensitive gram-negative bacteria , including pneumonia, pleurisy, abdominal infections, biliary tract infections, bone and joint infections, skin and soft tissue inflammation, especially for urinary tract infections, but also for sepsis. Because this product has good resistance to enzyme performance, therefore, when a microorganism is not sensitive to penicillins, cephalosporins, aminoglycosides and other drugs ,the product should often be effective.
2. The first totally synthetic monocyclic β-lactam antibiotic.
3. antiserotonin
4. Aztreonam is a synthetic β-lactam antibiotic of the monobactam class. It is effective against Gram-negative bacteria but inactive against Gram-positive bacteria. Its mechanism of action involves the inhibition of mucopeptide synthesis in the bacterial cell wall, thereby blocking peptidoglycan crosslinking. Aztreonam is resistant to hydrolysis by some β-lactamases, but is inactivated by extended-spectrum β-lactamases.
5. The first totally synthetic monocyclic ?lactam antibiotic

production method

Threonine for raw materials,chloride resulting from the chlorination forms an amide through ammonolysis, protect α-amino with benzyl chloroformate,esterifyβ-hydroxy with methanesulfonyl chloride , the amide group is sulfonated with sulfuric acid tetrabutylammonium , then it is cyclized to generate azetidine derivative in the potassium bicarbonate, then after hydrogen and Deprotection, produce 3-amino-2-methyl-4-oxo-1-sulfo-N oxetane. Afetr dehydration amidation of side chains Azetidine derivative and thiazole derivatives obtained in the above, hydrolyse to deprotect and to obtain aztreonam.

Acute toxicity

Intraperitoneal-rat LD50: 2549 mg/kg; intraperitoneal-Mouse LD50: 2897 mg/kg.

Flammability and hazard characteristics

Combustible; combustion produces toxic fumes of nitrogen oxides and sulfur oxides.

Description

Aztreonam is the first member of the monobactam class of antibiotics to be introduced into the world market. It possesses high β-lactamase stability and moderately good activity against gram negative aerobes such as E. coli, S. marcescens, -9 Proteus Providencia, Salmonella, g. influenzae, E. gonorrhea, and &. pneumonia. While somewhat less potent against Pseudomonas aeruginosa, it is nonetheless one of the better β-lactams against this species. It has poor activity against gram positive organisms.

Chemical Properties

White Crystalline Powder

Originator

Squibb (USA)

Manufacturing Process

This mixture was sterilized for 15 minutes at 121°C at 15 lbs/inch2 steam pressure prior to use. The fermentation flasks were incubated at 25°C for 40 to 45 hours on a of rotary shaker. A 250 liter batch of Agrobacterium radiobacter A.T.C.C. No. 31700 is fermented in a 100 gallon steel vessel with a media and operating conditions described below. Culture of Agrobacterium radiobacter grown out on agar slants, pH 7.3 consisted of yeast extract (1 g), beef extract (1 g), NZ amine A (2 g), glucose (10 g), agar (15 g) in 1000 ml distilled water. Loopful of surface growth from agar slant was used as the source of incolumn. Medium of oatmeal (20 g), tomato paste (20 g) tapped water to 1000 ml, pH 7, was sterilized for 15 min at 121°C at 15 lbs/inch2 steam pressure prior to use. 100 ml of the medium, containing incolumn is incubated at 25°C for about 24 hours on a rotary shaker. It was added to a mixture of yeast extract (5 g), glucose (10 g) in 1 L distilled water and incubated for about 42 hours at 25°C in 100 gallon stainless steel fermentation vessel. During incubation, the broth is agitated at 155 r.p.m. and aerated at rate of 10.0 cubic feet per minute. An antifoam agent (Ucon LB625, Union Carbide) was added as needed. The fermentation beer was adjusted to pH 4 with aqueous HCl and calls separated by centrifugation. The supernatante (200 L) was extracted with 40 L of 0.05 m cetyldimethylbenzyl ammonium chloride in dichloromethane and extract concentrated in vacuo to 5.5 L. The concentrate was then extracted with solution of 177 g of sodium thiocyanate in 2 L of water, adjusting the mixture of pH 4.35 with phosphoric acid. The aqueous extract was concentrated in vacuo to 465 ml and added to 1840 ml of methanol. Solids are filtrated yielded 194 g of crude solid product. It was dissolved and chromatographed on a 5x106.5 cm column of Sephadex G-10 three times and after concentrating in vacuo gave 3.5 g of crude antibiotic M53 (azetreonam) which was chromatographed at first on QAE Sephadex A- 25 (liner gradient, prepared from 2.5 L of water and 2.5 L of 0.25 M sodium nitrate). Then the residue (fractions 26-75) gave M53 (natrium salt) after evaporation. It was triturated with methanol and the souble fraction, 0.40 g was chromatographed on a 2.5x20 cm column of Diaion HP20AG, eluting at 2 ml per minute with water and collecting 20 ml fractions. Fractions 26-75 gave 51.9 mg of antibiotic M53 (sodium salt).

Brand name

Azactam (Bristol-Myers Squibb);PRIMBACTAM.

Therapeutic Function

Antibiotic

Antimicrobial activity

Concentrations (mg/L) inhibiting 50% of other organisms are: Aeromonas spp., 0.1;Acinetobacter spp., 16; Mor. catarrhalis, 0.1; Burkholderia cepacia, 2; and Yersinia spp., 0.1. Synergy has been shown with gentamicin, tobramycin and amikacin against 52–89% of strains of Ps. aeruginosa and gentamicin-resistant Gram-negative bacteria.

General Description

Azactam (aztreonam for injection, intravenous or intramascular)contains the active ingredient aztreonam, which is amember of the monobactam class of antibiotics. A true antibiotic,aztreonam was originally isolated from cultures ofthe bacterium Chromobacterium violaceum. Now, the antibioticis prepared by total synthesis. Monobactams possessa unique monocyclic β-lactam nucleus, and are structurallyunlike other β-lactams like the penicillins, cephalosporins,carbapenems, and cephamycins. The β-lactam arrangementof aztreonam is unique, possessing an N-sulfonic acid functionality.This group activates the β-lactam ring towardattack. The side chain (3-position) aminothiazolyl oximemoiety and the 4-methyl group specify the antibacterialspectrum and β-lactamase resistance.The mechanism of action of aztreonam is essentially identicalto that of other β-lactam antibiotics. The action of aztreonamis inhibition of cell wall biosynthesis resulting from ahigh affinity of the antibiotic for penicillin binding protein 3(PBP-3). Unlike other β-lactam antibiotics, aztreonam doesnot induce bacterial synthesis of β-lactamases. The structureof aztreonam confers resistance to hydrolysis by penicillinasesand cephalosporinases synthesized by most Gramnegativeand Gram-positive pathogens. Because of theseproperties, aztreonam is typically active against Gram-negativeaerobic microorganisms that resist antibiotics hydrolyzedby -lactamases. Aztreonam is active against strains that aremultiply-resistant to antibiotics such as cephalosporins, penicillins,and aminoglycosides. The antibacterial activity ismaintained over a broad pH range (6–8) in vitro, as well as inthe presence of human serum and under anaerobic conditions.Aztreonam for injection is indicated for the treatment ofinfections caused by susceptible Gram-negative microorganism,such as urinary tract infections (complicated and uncomplicated),including pyelonephritis and cystitis(initial and recurrent) caused by E. coli, K. pneumoniae, P.mirabilis, P. aeruginosa, E. cloacae, K. oxytoca, Citrobactersp., and S. marcescens. Aztreonam is also indicated for lowerrespiratory tract infections, including pneumonia and bronchitiscaused by E. coli, K. pneumoniae, P. aeruginosa, H.influenzae, P. mirabilis, S. marcescens, and Enterobacterspecies. Aztreonam is also indicated for septicemia causedby E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis, S.marcescens, and Enterobacter spp. Other infections respondingto aztreonam include skin and skin structure infections,including those associated with postoperative wounds andulcers and burns. These may be caused by E. coli, P.mirabilis, S. marcescens, Enterobacter species, P. aeruginosa,K. pneumoniae, and Citrobacter species. Intra-abdominalinfections, including peritonitis caused by E. coli,Klebsiella species including K. pneumoniae, Enterobacterspecies including E. cloacae, P. aeruginosa, Citrobacterspecies including C. freundii, and Serratia species includingS. marcescens. Some gynecologic infections, including endometritisand pelvic cellulitis caused by E. coli, K. pneumoniae,Enterobacter species including E. cloacae, and P.mirabilis also respond to aztreonam.

Biochem/physiol Actions

Aztreonam is a monobactam antibiotic used primarily to treat gram-negative bacterial infections. It is an older compound being re-examined as a therapeutic agent because of increasing carbapenem resistance in aerobic Gram-negative bacilli and because aztreonam is stable to Ambler class B metallo-β-lactamases. It is used alone or more commonly in combination with β-lactamase inhibitors such as avibactim.

Pharmacokinetics

Cmax 1 g intravenous: 90 mg/L end infusion 1 g intramuscular: 46 mg/L after 1 h Plasma half-life: 1.7 h Volume of distribution: 0.18 L/kg Plasma protein binding: 56% Absorption and distribution Oral bioavailability is less than 1%. Peak concentrations above the median MIC for most Gram-negative pathogens are achieved in most tissues and body fluids after 1 g intramuscular or intravenous doses. Metabolism and excretion It is not extensively metabolized, the most prominent product, resulting from opening the β-lactam ring, being scarcely detectable in the serum and accounting for about 6% of the dose in the urine and 3% in the feces. It is predominantly eliminated in the urine, where 58–72% appears within 8 h. Less than 12% is eliminated unchanged in the feces, suggesting low biliary excretion.

Clinical Use

Urinary tract infections, including pyelonephritis and cystitis Lower respiratory tract infections, including pneumonia and bronchitis caused by Gram-negative bacilli Septicemia Skin and skin structure infections, including postoperative wounds, ulcers and burns Intra-abdominal infections, including peritonitis Gynecological infections, including endometritis and pelvic cellulitis

Side effects

Local reactions occasionally occur at the injection site. Systemic reactions include diarrhea, nausea and/or vomiting and rash (1–1.3%). Neutropenia was seen in 11.3% of the pediatric patients younger than 2 years. Pseudomembranous colitis has been reported. There are no reactions in patients with immunoglobulin E (IgE) antibodies to benzylpenicillin or penicillin moieties. It is rarely cross-reactive with other β-lactam antibiotics and is weakly immunogenic.

Safety Profile

Moderately toxic by severalroutes. An experimental teratogen. Other experimentalreproductive effects. When heated to decomposition itemits toxic fumes of NOx and SOx.

Synthesis

Aztreonam, (Z)-2[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]cabamoyl]methylen]amino]oxy]-2-methylpropionoic acid (32.1.4.9), is synthesized from tert-butyloxycarbonylthreonine, which is reacted with O-benzylhydroxylamine in the presence of dicyclohexylcarbodimide and 1-hydroxybenzotriazole, to form the benzyl hydroxamide derivative (32.1.4.1). This product undergoes a reaction with triphenylphosphine and ethyl azodicarboxylate, which results in the cyclodehydration of the product to (3S-trans)-N-benzyloxy-3-tert-butyloxycarbonylamino-4-methyl-azetidinone (32.1.4.2). Debenzylating this by hydrogen reduction using a palladium on carbon catalyst forms (3S-trans)-N-hydroxy-3-tertbutyloxycarbonyl-amino-4-methyl-azetidinone (32.1.4.3). The hydroxyl group in this compound is removed by reducing it with titanium trichloride, which forms azetidinone (32.1.4.4). Removing the tert-butyloxycarbonyl protection using trifluoroacetic acid and subsequent acylation of the resulting product with the benzyl chloroformate gives (3S-trans)-benzyloxycarbonylamino-4-methylazetidinone (32.1.4.5). Sulfonating this product with a mixture of sulfur trioxide and dimethylformamide gives the corresponding N-sulfonic acid. Turning the resulting Nsulfonic acid into a potassium salt by reacting it with potassium hydrophosphate, followed by replacing the potassium cation with a tetrabutylammonium cation by reacting it with tetrabutylammonium sulfate gives the product (32.1.4.6). Reducing this with hydrogen using a palladium on carbon catalyst gives 3-amino-4-methyl-monobactamic acid (32.1.4.7). Acylating this with (Z) 2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino] 4-thiazoleacetic acid in the presence of dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole gives the diphenylmethyl ester of the desired aztreonam (32.1.4.8), which is hydrolyzed to aztreonam (32.1.4.9) using trifluoroacetic acid.It is believed that the methyl group at position 4 increases the stability of the beta-lactam ring with respect to most beta-lactamases, and at the same time it does not induce formation of beta-lactamase as cephalosporins and imipenems do.

Veterinary Drugs and Treatments

Aztreonam is a monobactam antibiotic that may be considered for use in small animals for treating serious infections caused by a wide variety of aerobic and facultative gram-negative bacteria, including strains of Citrobacter, Enterobacter, E. coli, Klebsiella, Proteus, Pseudomonas and Serratia. The drug exhibits good penetration into most tissues and low toxic potential and may be of benefit in treating infections when an aminoglycoside or a fluoroquinolone are either ineffective or are relatively contraindicated. Any consideration for using aztreonam must be tempered with the knowledge that little clinical experience or research findings have been published with regard to target species. Aztreonam has also been used to treat pet fish (koi) infected with Aeromonas salmonocida.

Drug interactions

Potentially hazardous interactions with other drugs Possibly enhanced anticoagulant effect of coumarins.

Metabolism

Aztreonam is not extensively metabolised. The principal metabolite, SQ-26992, is inactive and is formed by opening of the beta-lactam ring; it has a much longer half-life than the parent compound. Aztreonam is excreted as unchanged drug with only small quantities of metabolites, mainly in the urine, by renal tubular secretion and glomerular filtration. Only small amounts of unchanged drug and metabolites are excreted in the faeces.

Synthetic route

(3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid (80082-65-1) + (Z)-2-<<<1-(2-amino-4-thiazolyl)-2-<(2-benzothiazolyl)thio>-2-oxoethylidene>amino>oxy>-2-methyl propanoic acid 1,1-dimethylethyl ester (89604-92-2) → azthreonam (78110-38-0)

Conditions	Yield
Stage #1: (3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid; (Z)-2-<<<1-(2-amino-4-thiazolyl)-2-<(2-benzothiazolyl)thio>-2-oxoethylidene>amino>oxy>-2-methyl propanoic acid 1,1-dimethylethyl ester With pyridine In acetonitrile at -5℃; for 4h; Stage #2: With nitric acid at 35℃; for 2h; pH=1; Solvent; Reagent/catalyst; Temperature;	86.9%

(Z)-2-[[[1-(2-amino-4-thiazolyl)-2-(3-oxido-1H-benzotriazol-1-yl)-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid methanesulfonate (1:1) salt (139714-28-6) + (3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid (80082-65-1) → azthreonam (78110-38-0)

Conditions	Yield
Stage #1: (Z)-2-[[[1-(2-amino-4-thiazolyl)-2-(3-oxido-1H-benzotriazol-1-yl)-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid methanesulfonate (1:1) salt; (3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid With triethylamine In ethanol; water at -6 - -3℃; for 3h; Stage #2: With hydrogenchloride In ethanol; water at -3 - 0℃;	81%

[3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (330944-50-8) → azthreonam (78110-38-0)

Conditions	Yield
With hydrogenchloride; water at 0 - 65℃; for 4.75h;	72%
With water; trifluoroacetic acid at 0 - 63℃; for 1 - 21.75h;	63%
With hydrogenchloride In water at 60℃; for 5h;

3-<<(2-amino-4-thiazolyl)-<<1-(diphenylmethoxycarbonyl)-1-methyl ethoxy>-imino>-acetyl>-amino>-4-methyl-2-oxoazetidi-ne-1-sulfonic acid (123539-91-3) → azthreonam (78110-38-0)

Conditions	Yield
With methoxybenzene; trifluoroacetic acid In dichloromethane

2-[1-(2-Amino-thiazol-4-yl)-2-(diphenoxy-phosphoryloxy)-2-oxo-eth-(Z)-ylideneaminooxy]-2-methyl-propionic acid benzhydryl ester → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2O 2: trifluoroacetic acid, anisole / CH2Cl2 View Scheme

aztreonam + 6,7-Dihydroxy-2,3-quinolinedicarboxylic anhydride → azthreonam (78110-38-0)

Conditions	Yield
In water; N,N-dimethyl-formamide; acetonitrile

azthreonam dipotassium salt → azthreonam (78110-38-0)

Conditions	Yield
With hydrogenchloride In methanol; water
With hydrogenchloride In methanol; water

water (7732-18-5) + 3-<<(2-amino-4-thiazolyl)-<<1-(diphenylmethoxycarbonyl)-1-methyl ethoxy>-imino>-acetyl>-amino>-4-methyl-2-oxoazetidi-ne-1-sulfonic acid (123539-91-3) → azthreonam (78110-38-0)

Conditions	Yield
With trifluoroacetic acid In acetone-denatured alcohol; ethanol; dichloromethane; methoxybenzene

(Z)-2-Amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]-imino]-4-thiazoleacetic acid (80542-76-3) → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dicyclohexyl-carbodiimide / N,N-dimethyl-formamide / 2 h / 30 °C 2.1: methoxybenzene / dichloromethane / 1 h / 0 - 3 °C 3.1: triethylamine / water; methanol / 0 °C / pH 8 - 8.5 3.2: 10 °C / pH 1.3 View Scheme
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; dicyclohexyl-carbodiimide / acetonitrile / 3 h / 20 - 24 °C 1.2: 15 h / 20 °C 2.1: methanesulfonic acid; methoxybenzene / dichloromethane / 5 h / 0 °C 3.1: triethylamine / ethanol; water / 3 h / -6 - -3 °C 3.2: -3 - 0 °C View Scheme

(Z)-2-[[[1-(2-amino-4-thiazolyl)-2-(3-oxido-1H-benzotriazol-1-yl)-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid diphenylmethyl ester methanesulfonate (1:1) salt (139714-26-4) → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: methanesulfonic acid; methoxybenzene / dichloromethane / 5 h / 0 °C 2.1: triethylamine / ethanol; water / 3 h / -6 - -3 °C 2.2: -3 - 0 °C View Scheme

2-{[(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethylidene]amino]oxy}-2-methylpropionic acid benzhydryl ester → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: methoxybenzene / dichloromethane / 1 h / 0 - 3 °C 2.1: triethylamine / water; methanol / 0 °C / pH 8 - 8.5 2.2: 10 °C / pH 1.3 View Scheme

2-amino-4-[(1-carboxy-1-methyl-ethoxyimino)-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl)-methyl]-thiazol-3-ium methanesulfonate (477528-80-6) + (3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid (80082-65-1) → azthreonam (78110-38-0)

Conditions	Yield
Stage #1: 2-amino-4-[(1-carboxy-1-methyl-ethoxyimino)-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl)-methyl]-thiazol-3-ium methanesulfonate; (3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid With triethylamine In methanol; water at 0℃; pH=8 - 8.5; Stage #2: With hydrogenchloride In methanol; water at 10℃; pH=1.3;	174.2 g

C16H22N4O7SSi*ClH → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / N,N-dimethyl-formamide; ethyl acetate / 0.02 h / 10 °C 1.2: 10 °C 2.1: triethylamine / water; methanol / 0 °C / pH 8 - 8.5 2.2: 10 °C / pH 1.3 View Scheme

2-amino-α-[(1-carboxy-1-methylethoxy)imino]-4-thiazoleacetic acid → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide / 0.25 h / 50 °C 1.2: 3 h / -5 - 5 °C 2.1: triethylamine / N,N-dimethyl-formamide; ethyl acetate / 0.02 h / 10 °C 2.2: 10 °C 3.1: triethylamine / water; methanol / 0 °C / pH 8 - 8.5 3.2: 10 °C / pH 1.3 View Scheme

3-(3-amino-2-methyl-4-oxo-azetidine-1-sulfonyloxy)-2,2-dimethylpropionic acid ethyl ester methanesulfonic acid salt → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 0 °C 2.1: dichloromethane / 20 °C 2.2: 0.5 h 3.1: carboxylesterase 1 (CES1) / acetonitrile / 0.5 h / 37 °C / pH 4.7 / Enzymatic reaction View Scheme

4-((((2S,3S)-3-amino-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-3,3-dimethylbutyl pivalate mesylate → azthreonam (78110-38-0) + 3,3-dimethyltetrahydrofuran (15833-75-7) + Trimethylacetic acid (75-98-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 0 °C 2.1: dichloromethane / 20 °C 2.2: 0.5 h 3.1: sodium dihydrogenphosphate / water-d2; [D3]acetonitrile / 1.17 h / 37 °C / Enzymatic reaction View Scheme

4-((((2S,3S)-3-amino-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-3,3-dimethylbutyl pivalate mesylate → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 0 °C 2.1: dichloromethane / 20 °C 2.2: 0.5 h 3.1: carboxylesterase 1 (CES1) / acetonitrile / 0.03 h / 37 °C / pH 4.7 / Enzymatic reaction View Scheme

5-((((2S,3S)-3-amino-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-4,4-dimethylpentanoate mesylate → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 0 °C 2.1: dichloromethane / 20 °C 2.2: 0.5 h 3.1: carboxylesterase 1 (CES1) / acetonitrile / 0.33 h / 37 °C / pH 4.7 / Enzymatic reaction View Scheme

5-((((2S,3S)-3-amino-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-4,4-dimethylpentanoate mesylate → γ,γ-dimethyl-δ-valerolactone (1679-55-6) + 5-hydroxy-4,4-dimethylpentanoic acid (1148130-26-0) + azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 0 °C 2.1: dichloromethane / 20 °C 2.2: 0.5 h 3.1: sodium dihydrogenphosphate / water-d2; [D3]acetonitrile / 19 h / 37 °C / Enzymatic reaction View Scheme

(Z)-2-(2-aminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxy)iminoacetic acid (86299-47-0) → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 0 °C 2.1: dichloromethane / 20 °C 2.2: 0.5 h 3.1: carboxylesterase 1 (CES1) / acetonitrile / 0.5 h / 37 °C / pH 4.7 / Enzymatic reaction View Scheme

C24H37N5O10S2*C2HF3O2 → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dichloromethane / 20 °C 1.2: 0.5 h 2.1: carboxylesterase 1 (CES1) / acetonitrile / 0.5 h / 37 °C / pH 4.7 / Enzymatic reaction View Scheme

2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid trifluoroacetic acid salt → azthreonam (78110-38-0)

Conditions	Yield
With carboxylesterase 1 (CES1) In acetonitrile at 37℃; for 0.5h; pH=4.7; Enzymatic reaction;	28 %Chromat.

4-((((2S,3S)-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-3,3-dimethylbutyl pivalate trifluoroacetate → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dichloromethane / 20 °C 1.2: 0.5 h 2.1: carboxylesterase 1 (CES1) / acetonitrile / 0.03 h / 37 °C / pH 4.7 / Enzymatic reaction View Scheme
Multi-step reaction with 2 steps 1.1: dichloromethane / 20 °C 1.2: 0.5 h 2.1: sodium dihydrogenphosphate / water-d2; [D3]acetonitrile / 1.17 h / 37 °C / Enzymatic reaction View Scheme

2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-4-(pivaloyloxy)butoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid trifluoroacetate → azthreonam (78110-38-0) + 3,3-dimethyltetrahydrofuran (15833-75-7) + Trimethylacetic acid (75-98-9)

Conditions	Yield
With sodium dihydrogenphosphate In [D3]acetonitrile; water-d2 at 37℃; for 1.16667h; Mechanism; Enzymatic reaction;

2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-4-(pivaloyloxy)butoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid trifluoroacetate → azthreonam (78110-38-0)

Conditions	Yield
With carboxylesterase 1 (CES1) In acetonitrile at 37℃; for 0.0333333h; pH=4.7; Enzymatic reaction;	> 95 %Chromat.

ethyl 5-((((2S,3S)-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-4,4-dimethylpentanoate trifluoroacetate → azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dichloromethane / 20 °C 1.2: 0.5 h 2.1: carboxylesterase 1 (CES1) / acetonitrile / 0.33 h / 37 °C / pH 4.7 / Enzymatic reaction View Scheme

ethyl 5-((((2S,3S)-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-4,4-dimethylpentanoate trifluoroacetate → γ,γ-dimethyl-δ-valerolactone (1679-55-6) + 5-hydroxy-4,4-dimethylpentanoic acid (1148130-26-0) + azthreonam (78110-38-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dichloromethane / 20 °C 1.2: 0.5 h 2.1: sodium dihydrogenphosphate / water-d2; [D3]acetonitrile / 19 h / 37 °C / Enzymatic reaction View Scheme

2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((5-ethoxy-2,2-dimethyl-5-oxopentyl)oxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid trifluoroacetate → azthreonam (78110-38-0)

Conditions	Yield
With carboxylesterase 1 (CES1) In acetonitrile at 37℃; for 0.333333h; pH=4.7; Enzymatic reaction;	90 %Chromat.

2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((5-ethoxy-2,2-dimethyl-5-oxopentyl)oxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid trifluoroacetate → γ,γ-dimethyl-δ-valerolactone (1679-55-6) + 5-hydroxy-4,4-dimethylpentanoic acid (1148130-26-0) + azthreonam (78110-38-0)

Conditions	Yield
With sodium dihydrogenphosphate In [D3]acetonitrile; water-d2 at 37℃; for 19h; Mechanism; Enzymatic reaction;

L-lysine (56-87-1) + azthreonam (78110-38-0) → aztreonam lysinate (827611-49-4)

Conditions	Yield
In water at 0 - 5℃; Conversion of starting material;	77%
In water at 0 - 5℃; Conversion of starting material;	62%
In water for 0.1h; pH=4.34; Cooling with ice;	56%
In water at 0 - 5℃; Conversion of starting material;

ethanol (64-17-5) + azthreonam (78110-38-0) → aztreonam ethyl ester

Conditions	Yield
With 4-pyrrolidin-1-ylpyridine; triethylamine; diisopropyl-carbodiimide at 0 - 32℃; for 48h; Reagent/catalyst;	71.6%

azthreonam (78110-38-0) → (2S,3S)-2-{2-(2-Amino-thiazol-4-yl)-2-[(Z)-1-carboxy-1-methyl-ethoxyimino]-acetylamino}-3-sulfoamino-butyric acid

Conditions	Yield
With citrate buffer at 35℃; Rate constant; other aqueous buffer;
With Zn2+-Tris In water at 35℃; Rate constant; other metal ions;

azthreonam (78110-38-0) → C12H14N3O5S(1-)*Na(1+)

Conditions	Yield
With phosphoric acid In water at 35℃; Rate constant; various pH;

azthreonam (78110-38-0) → aztreonam

Conditions	Yield
With water at 59.85℃; Kinetics; Thermodynamic data; Further Variations:; Temperatures;

azthreonam (78110-38-0) → [2S-[2α,3β(Z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, 2-[(1,4-dihydro-6,7-dihydroxy-4-oxo-3-quinolinyl)carbonyl]hydrazide, monopotassium salt

Conditions	Yield
In N-methyl-acetamide

Upstream product

• 123539-91-3 3-<<(2-amino-4-thiazolyl)-<<1-(diphenylmethoxycarbonyl)-1-methyl ethoxy>-imino>-acetyl>-amino>-4-methyl-2-oxoazetidi-ne-1-sulfonic acid 
• 330944-50-8 [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid 
• 80951-91-3 aztreonam 
• 7732-18-5 water 
• 80542-76-3 (Z)-2-Amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]-imino]-4-thiazoleacetic acid 
• 139714-26-4 (Z)-2-[[[1-(2-amino-4-thiazolyl)-2-(3-oxido-1H-benzotriazol-1-yl)-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid diphenylmethyl ester methanesulfonate (1:1) salt 
• 139714-28-6 (Z)-2-[[[1-(2-amino-4-thiazolyl)-2-(3-oxido-1H-benzotriazol-1-yl)-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid methanesulfonate (1:1) salt 
• 80082-65-1 (3S-trans)-3-Amino-4-methyl-2-oxo-1-azetidinesulfonic acid 
• 477528-80-6 2-amino-4-[(1-carboxy-1-methyl-ethoxyimino)-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl)-methyl]-thiazol-3-ium methanesulfonate 
• 102507-85-7 2-amino-α-[(1-carboxy-1-methylethoxy)imino]-4-thiazoleacetic acid 
• 89604-92-2 (Z)-2-<<<1-(2-amino-4-thiazolyl)-2-<(2-benzothiazolyl)thio>-2-oxoethylidene>amino>oxy>-2-methyl propanoic acid 1,1-dimethylethyl ester 
• 86299-47-0 (Z)-2-(2-aminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxy)iminoacetic acid 

Downstream Products

• 80951-91-3 aztreonam 

Relevant articles and documents

Novel crystal form of compound for treating bacterial infection and preparation method thereof

The invention belongs to the field of medicines, and discloses a new crystal form of a compound for treating bacterial infection and a preparation method thereof. Specifically, the invention discloses a new crystal form of an aztreonam compound and a preparation method thereof. The novel aztreonam crystal form disclosed by the invention is different from the prior art, and an X-ray powder diffraction pattern measured by using Cu-K alpha rays is as shown in Figure 1. According to the invention, the pH value is adjusted in sections after the purified water is added, so that the problem that triethylamine easily exceeds the standard is solved, and meanwhile, the novel aztreonam crystal form with good stability, low solvent residue and low impurity content is prepared and is suitable for industrial mass production.

An improved method for the synthesis of Aztreonam

The invention provides an improved synthetic method of aztreonam. According to the improved synthetic method, alpha-(2-aminothiazole-4-yl)-alpha-[(tert-butoxycarbonyl)-propoxyimino)] acetic acid mercaptobenzothiazole ester, and (2S, 3S) 3-amino-2-methyl-4-oxoazetidine sulfonic acid are taken as reaction intermediates; an organic amine is used as a catalyst; and a mixed acid water solution of formic acid and an organic acid is used for removing tertiary butyl protecting group so as to obtain aztreonam. Separation of the intermediates is not necessary, operation is simple and convenient, deprotection method is mild, yield is high, and product purity is high.

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