64485-93-4

Basic information

• Product Name: Cefotaxime sodium
• Synonyms: Cefotaxime：Claforan;FIR-756;(6R,7R)-7-[[(Z)-(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[(acetyloxy)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt;(6R,7R)-7α-[2-(2-Amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetylamino]-3-(acetoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt;Cefotaxime sodium salt,Cefotaxim sodium salt;Cefotaxime Sodium (350 mg);Cefotaxime Sodium (250 mg)J0C189901ug/mg(ai);Cefotaxime Sodium (250 mg)
• CAS NO: 64485-93-4
• Molecular Formula: C₁₆H₁₆N₅O₇S₂*Na
• Molecular Weight: 477.45
• EINECS: 264-915-9
• Product Categories: Pharmaceutical intermediate;CLAFORAN;antibiotic;Pharmaceutical;API;Antibiotics for Research and Experimental Use;beta-Lactams (Antibiotics for Research and Experimental Use);Biochemistry;Antibiotic Explorer;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds
• Mol File: 64485-93-4.mol

Chemical Properties

• Melting Point: 162-163 C
• Appearance: white to yellow/powder
• Density: 1.8 g/cm³
• Refractive Index: 61 ° (C=1, H2O)
• Storage Temp.: 2-8°C
• Solubility: H2O: aqueous solutions of pH 4.3-6.2 are stable up to 3 weeks at
• Water Solubility: Soluble in water.
• Stability: Stable. Incompatible with strong oxidizing agents.
• Merck: 14,1933
• BRN: 5711411
• CAS DataBase Reference: Cefotaxime sodium(CAS DataBase Reference)
• NIST Chemistry Reference: Cefotaxime sodium(64485-93-4)
• EPA Substance Registry System: Cefotaxime sodium(64485-93-4)

Safety Data

• Hazard Codes: Xn,Xi
• Statements: 42/43
• Safety Statements: 22-36/37-60-45-37-24
• WGK Germany: 2
• RTECS: XI0250000
• Hazardous Substances Data: 64485-93-4(Hazardous Substances Data)

Usage

Uses

1. Used in Pharmaceutical Industry:
Cefotaxime sodium is used as a broad-spectrum antibiotic for treating various types of bacterial infections. It is particularly effective against gram-negative bacteria, with the notable exception of pseudomonas and penicillin-resistant strains of streptococcus pneumoniae.
2. Used in Medical Treatment:
Cefotaxime sodium is used as an effective antibacterial agent for treating infections of the bones, joints, skin, respiratory tract, and blood stream. It acts as a beta-lactamase resistant antibiotic, providing a valuable option for treating infections that are resistant to other types of antibiotics.
3. Used in Quality Control:
Cefotaxime sodium serves as a pharmaceutical secondary standard, offering a convenient and cost-effective alternative for the preparation of in-house working standards in pharmaceutical laboratories and manufacturers. This helps ensure the quality and efficacy of the final product, contributing to the overall safety and effectiveness of the medication.

Originator

Claforan,Hoechst-Roussel,W. Germany,1980

Manufacturing Process

A solution of 8 g of sodium bicarbonate in about 20 ml of ethanol was progressively added to 45.55 g of pure 3-acetoxymethyl-7-[2-(2-amino-4- thiazolyl)-2-methoxyiminoacetamido]-ceph-3-eme-4-carboxylic acid in 100 ml of distilled water and another 80 ml of ethanol and 4.5 g of activated carbon were added thereto. The mixture was stirred for 5 minutes and was filtered. The filter was rinsed with ethanol and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in 100 ml of ethanol and evaporated to dryness again. The residue was dissolved in 100 ml of methanol and the solution was poured into 2 l of acetone. The mixture was vigorously stirred and was vacuum filtered. The recovered product was rinsed with acetone and then ether and dried under reduced pressure to obtain 43.7 g of a white product which rehydrated in air to obtain a final weight of 45.2 g of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2- methoxyiminoacetamido]-ceph-3-eme-4-carboxylate.

Therapeutic Function

Antibiotic

Biological Activity

mic: <0.1 μg/ml for s. pneumoniaecefotaxime is a cephalosporin antibiotic.the cephalosporins, a class of β-lactam antibiotics originally derived from the fungus acremonium, are indicated for the prophylaxis and treatment of infections caused by bacteria susceptible to this particular form of antibiotic.

Biochem/physiol Actions

Cefotaxim inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs) which inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls. As a result, bacteria lyse due to cell wall autolytic enzymes.

Clinical Use

Cefotaxime (Claforan) was the first third-generationcephalosporin to be introduced. It possesses excellentbroad-spectrum activity against Gram-positive and Gramnegativeaerobic and anaerobic bacteria. It is more activethan moxalactam against Gram-positive organisms. Manyβ-lactamase–producing bacterial strains are sensitive to cefotaxime,including N. gonorrhoeae, Klebsiella spp., H. influenzae,S. aureus, and E. cloacae. Some, but not all,Pseudomonas strains are sensitive. Enterococci and Listeriamonocytogenes are resistant.The syn-isomer of cefotaxime is significantly more activethan the anti-isomer against β-lactamase–producing bacteria.This potency difference is, in part, because of greaterresistance of the syn-isomer to the action of β-lactamases.The higher affinity of the syn-isomer for PBPs, however,may also be a factor.Cefotaxime is metabolized in part to the less active desacetylmetabolite. Approximately 20% of the metaboliteand 25% of the parent drug are excreted in the urine. Theparent drug reaches the cerebrospinal fluid in sufficient concentrationto be effective in the treatment of meningitis.Solutions of cefotaxime sodium should be used within 24hours. If stored, they should be refrigerated. Refrigerated solutionsmaintain potency up to 10 days.

Veterinary Drugs and Treatments

In the United States, there are no cefotaxime products approved for veterinary species but it has been used clinically in several species when an injectable 3rd generation cephalosporin may be indicated.

in vitro

previous studies found that the in-vitro activity of cefotaxime against staphylococcus au reus has ranged from 0.8 g to 8 μg/ml with 50% of isolates inhibited by 2 μg/ml and 90% by 4 μg/ml. moreover, it was found that methicillin resistant s. aureus were resistant to cefotaxime with mic values above 64 μg/ml. the cefotaxime mics against s. pneumoniae were found to be below 0.1 μg/ml, with 90% inhibited by 0.04 μg/ml. cefotaxime has also been shown to have excellent activity against haemophilus injluenzae, such as β-lactamase-containing strains [1].

in vivo

an in-vivo study with the mouse model of vibrio vulnificus infection was conducted to evaluate the efficacies of therapy with minocycline or cefotaxime alone and in combination. results indicated that combination therapy with cefotaxime and minocycline was distinctly more advantageous than therapy with the single antibiotic regimen for the treatment of severe vibrio vulnificus infections [2].

references

[1] neu hc. the in vitro activity, human pharmacology, and clinical effectiveness of new beta-lactam antibiotics. annu rev pharmacol toxicol. 1982;22:599-642.[2] chuang yc, ko wc, wang st, liu jw, kuo cf, wu jj, huang ky. minocycline and cefotaxime in the treatment of experimental murine vibrio vulnificus infection. antimicrob agents chemother. 1998 jun;42(6):1319-22.[3] schleupner cj, engle jc. clinical evaluation of cefotaxime for therapy of lower respiratory tract infections. antimicrob agents chemother. 1982 feb;21(2):327-33.

InChI:InChI=1/C16H17N5O7S2.Na/c1-6(22)28-3-7-4-29-14-10(13(24)21(14)11(7)15(25)26)19-12(23)9(20-27-2)8-5-30-16(17)18-8;/h5,10,14H,3-4H2,1-2H3,(H2,17,18)(H,19,23)(H,25,26);/q;+1/b20-9+;/t10-,14-;/m1./s1

Synthetic route

cefotaxime (63527-52-6) → cefotaxime sodium salt (64485-93-4)

Conditions	Yield
With sodium hydrogencarbonate In ethanol Substitution;	95.4%
With sodium isooctanoate; sodium sulfite In water; acetone at 5 - 10℃; for 0.5h;	95%
With triethylamine; sodium 2-ethylhexanoic acid In methanol; ethyl acetate	88.7%

cefotaxime (60846-21-1, 63527-52-6, 63527-53-7) → cefotaxime sodium salt (64485-93-4)

Conditions	Yield
With sodium acetate trihydrate In water; acetone

7-Aminocephalosporanic acid (957-68-6) → cefotaxime sodium salt (64485-93-4)

Conditions	Yield
Stage #1: 7-Aminocephalosporanic acid In water; acetone at 10℃; for 10h; Large scale; Stage #2: With sodium hydroxide In water; acetone at 10 - 15℃; pH=9.5; Temperature; pH-value; Large scale;

2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid (91868-79-0) + (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (36923-17-8) → cefotaxime sodium salt (64485-93-4)

Conditions	Yield
Stage #1: 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid With dmap; dicyclohexyl-carbodiimide In ethanol at 20℃; for 0.5h; Stage #2: With 1-hydroxy-pyrrolidine-2,5-dione In ethanol at 20℃; for 0.5h; Stage #3: (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Further stages;	2.59 g

2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid (91868-79-0) → cefotaxime sodium salt (64485-93-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 2.5 h / 2 - 25 °C 2: N,O-bis-(trimethylsilyl)-acetamide / acetonitrile / 1 h / -5 - 0 °C 3: sodium sulfite; sodium isooctanoate / water; acetone / 0.5 h / 5 - 10 °C View Scheme

silver nitrate + cefotaxime sodium salt (64485-93-4) → C32H32Ag2N10O14S4

Conditions	Yield
In methanol for 1h; Reflux;	77%

water (7732-18-5) + tin(ll) chloride + cefotaxime sodium salt (64485-93-4) → Sn(2+)*Cl(1-)*C16H16N5O7S2(1-)*H2O

Conditions	Yield
at 20℃; for 6h;	72%

furane-2-monocarboxylic acid (4741-45-1) + cefotaxime sodium salt (64485-93-4) → ceftiofur (80370-57-6)

Conditions	Yield
With methanesulfonic acid In acetonitrile at 20℃; for 3h;	25%

O-benzylhydoxylamine hydrochloride (2687-43-6) + cefotaxime sodium salt (64485-93-4) → C23H24N6O7S2

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water pH=4.5;	24%

N-methyl-O-allylhydroxylamine hydrochloride + cefotaxime sodium salt (64485-93-4) → C20H24N6O7S2

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water pH=4.5;	24%

O-allylhydroxylamine hydrochloride (38945-21-0) + cefotaxime sodium salt (64485-93-4) → C19H22N6O7S2

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water pH=4.5;	16%

O-benzyl-N-methylhydroxylamine hydrochloride (71925-14-9) + cefotaxime sodium salt (64485-93-4) → C24H26N6O7S2

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water pH=4.5;	14%

cefotaxime sodium salt (64485-93-4) → 2-<<(2-amino-4-thiazolyl)((Z)-methoxyimino)acetyl>amino>acetoaldehyde (104301-63-5) + (Z)-4-Acetoxy-2-amino-3-mercaptomethyl-but-2-enoic acid

Conditions	Yield
With sodium hydroxide at 95℃; for 0.416667h;

cefotaxime sodium salt (64485-93-4) → (E)-3-Acetoxymethyl-2-imino-4-(7-nitro-benzo[1,2,5]oxadiazol-4-ylsulfanyl)-but-3-enoic acid

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aq. NaOH / 0.42 h / 95 °C 2.1: Na2B4O7*10H2O / H2O 2.2: H2O; acetone / 0.5 h / 25 °C View Scheme

1-Cyclopropyl-4-thiopyridone (101234-94-0) + cefotaxime sodium salt (64485-93-4) → (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(1-cyclopropylpyridinium-4-yl)thiomethyl]-ceph-3-em-4-carboxylate

Conditions	Yield
With sodium iodide In water; acetone; acetonitrile

2,4,6-Trinitrophenol (88-89-1) + cefotaxime sodium salt (64485-93-4) → C16H16N5O7S2(1-)*C6H3N3O7*Na(1+)

Conditions	Yield
In methanol at 20℃; for 2h;

3,6-dichloro-2,5-dihydroxy-1,4-benzoquinone (87-88-7) + cefotaxime sodium salt (64485-93-4) → C16H16N5O7S2(1-)*Na(1+)*C6H2Cl2O4

Conditions	Yield
In methanol at 20℃; for 2h;

2,3-dicyano-5,6-dichloro-p-benzoquinone (84-58-2) + cefotaxime sodium salt (64485-93-4) → C16H16N5O7S2(1-)*Na(1+)*C8Cl2N2O2

Conditions	Yield
In methanol at 20℃; for 2h;

7,7',8,8'-tetracyanoquinodimethane (1518-16-7) + cefotaxime sodium salt (64485-93-4) → C16H16N5O7S2(1-)*Na(1+)*C12H4N4

Conditions	Yield
In methanol at 20℃; for 2h;

copper(II) sulfate (7758-99-8) + cefotaxime sodium salt (64485-93-4) → Cu(2+)*C16H16N5O7S2(1-)*Na(1+)

Conditions	Yield
In aq. acetate buffer at 60℃; for 0.666667h; pH=5.5; pH-value; Concentration; Temperature; Solvent;

cadmium sulfate + cefotaxime sodium salt (64485-93-4) → Cd(2+)*C16H16N5O7S2(1-)*Na(1+)

Conditions	Yield
In aq. buffer at 40℃; for 0.666667h; pH=11; pH-value; Concentration; Temperature; Solvent;

cefotaxime sodium salt (64485-93-4) → C16H16N5O7S2(1-)*Na(1+)*0.25H2O

Conditions	Yield
With water In methanol	80.87 g

Upstream product

• 60846-21-1 (6R)-3-acetoxymethyl-7t-[2-(2-amino-thiazol-4-yl)-2-(Z)-methoxyimino-acetylamino]-8-oxo-(6rH)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
• 60846-21-1 cefotaxime 
• 91868-79-0 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetic acid 
• 36923-17-8 (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
• 63527-52-6 cefotaxime 
• 957-68-6 7-Aminocephalosporanic acid 

Downstream Products

• 80370-57-6 ceftiofur 

Relevant articles and documents

Cefotaxime sodium pharmaceutical preparation, and application thereof in treatment of new salmonella infection indications including typhoid and paratyphoid

The invention provides a cefotaxime sodium, and a preparation method, a cefotaxime sodium preparation and application thereof. The mass content of the cefotaxime sodium is 98% or above, and the cefotaxime sodium also comprises impurities A, B and C. The preparation method comprises the following steps: firstly, reacting methoxyiminoacetic acid with an activating agent to obtain an active ester intermediate; reacting 7-ACA with the active ester intermediate under a temperature control condition, and performing acid regulation and crystallization to obtain cefotaxime acid; carrying out a salifying reaction on cefotaxime acid and a salifying agent in a salifying solvent, and separating out to obtain the cefotaxime sodium. The cefotaxime sodium is low in impurity content, beneficial to long-term storage and placement, good in quality stability and better in clinical curative effect and safety, and can be used for treating salmonella infections including typhoid and paratyphoid.

Cefotaxime sodium preparation method

The invention provides a cefotaxime sodium preparation method. The method is characterized in that after an active group of 7-aminocephalosporanic acid is protected by a silanization reagent, subjecting to condensation reaction with AE-active ester to generate cefotaxime acid containing a protecting group; after deprotection of the cefotaxime acid containing the protecting group under the action of a deprotection agent, sequentially subjecting to aqueous-phase acidification and crystallization to obtain cefotaxime acid; subjecting the cefotaxime acid to salification and solvent crystallizationto obtain a pure product of cefotaxime sodium. In a whole technical process, a product degradation process is reduced, product quality is evidently improved, product market competitiveness is improved, and medication safety is further guaranteed.

1/4 water cefotaxime sodium compound

The invention discloses a 1/4 water cefotaxime sodium compound and a preparation method thereof. The cefotaxime sodium per mole contains 1/4 mole of water. The 1/4 water cefotaxime sodium compound obtained has good particle size distribution, good fluidity, low impurity content, thermodynamic stability and wide application prospects.

Cefotaxime sodium compound prepared by fluid mechanics principle and preparation of cefotaxime sodium compound

The invention discloses a cefotaxime sodium compound prepared by the fluid mechanics principle and a preparation of the cefotaxime sodium compound, namely efotaxime sodium for injection. A 'research, development and industrialization project of high-end medicine product refining and crystalizing technologies' acquires the second prize of 2015 National Science and Technology Progress Award, and the fluid mechanics principle belongs to one of the high-end medicine product refining and crystalizing technologies. The cefotaxime sodium compound is measured by X-ray powder diffraction, and the main feature peaks indicated by diffraction angles 2theta in the spectrum of the cefotaxime sodium compound is 9.24 degrees, 18.65 degrees, 20.65 degrees, 25.10 degrees and 28.42 degrees. The cefotaxime sodium compound is high in purity, low in impurity content, good in flowability and good in stability.

A method for preparing Cefotaxime

The invention discloses a preparation method of cefotaxime sodium. Ceftizoxime acid used as the initial raw material reacts with anhydrous sodium acetate to generate the cefotaxime sodium. In such process, purified water, butanol and acetone are selected as crystallizing solvents to control the mixing speed and crystallization temperature in the crystallization process, so that the finally obtained cefotaxime sodium has favorable flowability and can satisfy the subpackaging requirements in production. Various quality indexes of the obtained cefotaxime sodium conform to the requirements for medicinal standard, and thus, the cefotaxime sodium can satisfy the demands for clinical application.

Synthesis method of cefotaxime sodium

The invention relates to a synthesis method of cefotaxime sodium. The method includes the steps that with an acetone-water solution as a solvent, 7-ACA and AE-active ester are subjected to a stirring reaction for 5-15 min; then, a sodium hydroxide solution is added with stirring for a reaction, obtained reaction liquor is filtered and then crystallized with acetone, and the product cefotaxime sodium is obtained. By the adoption of the one-step synthesis method, the reaction yield is high, product quality is stable, and the operation process is simple and convenient; moreover, no amine intermediate reactant or cosolvent is used, so that production safety is high.

PROCESS FOR PREPARATION OF CEFOTAXIME ACID AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

A process for the preparation of cefotaxime acid of formula (IV) and pharmaceutically acceptable salt thereof, such as cefotaxime sodium of formula (I) is provided, which comprises condensing the compound of formula (II) with the compound of formula (III) and using aqueous glyme or aqueous cellosolve as the solvent.

Process for the production of cefotaxime sodium

A process for the production of 7-[2-(2-amino-4-thiazolyl)-2-syn-methoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (Cefotaxime) in aqueous isopropyl alcohol is provided. The synthesis provides the product in greater than 99 % HPLC purity.

Process for preparing cephalosporins with salified intermediate

Cephalosporins may be conveniently prepared by a process in which 7-ACA is silylated, acylated, desilylated and then salified to give an intermediate which is eventually cyclized with thiourea.

PROCESS FOR THE PREPARATION OF CEPHEM CARBOXYLIC ACIDS

The invention relates to processes for the preparation of cephem carboxylic acids. More particularly, it relates to the preparation of ceftriaxone and cefotaxime and pharmaceutical compositions that include the ceftriaxone and cefotaxime.