Cefoperazone Chemical Properties

Melting point:

169-171 C

Density 

1.77±0.1 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

DMSO (Slightly, Sonicated), Methanol (Slightly, Heated, Sonicated)

form 

Solid

pka

pKa 2.6 (Uncertain)

color 

White to Off-White

Merck 

14,1930

InChI

InChI=1S/C25H27N9O8S2/c1-3-32-8-9-33(21(39)20(32)38)24(42)27-15(12-4-6-14(35)7-5-12)18(36)26-16-19(37)34-17(23(40)41)13(10-43-22(16)34)11-44-25-28-29-30-31(25)2/h4-7,15-16,22,35H,3,8-11H2,1-2H3,(H,26,36)(H,27,42)(H,40,41)/t15-,16-,22-/m1/s1

InChIKey

GCFBRXLSHGKWDP-XCGNWRKASA-N

SMILES

N12[C@@]([H])([C@H](NC([C@H](NC(N3CCN(CC)C(=O)C3=O)=O)C3=CC=C(O)C=C3)=O)C1=O)SCC(CSC1N(C)N=NN=1)=C2C(O)=O

CAS DataBase Reference

62893-19-0(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xn

Risk Statements 

20/21/22-36/37/38

Safety Statements 

26-36

RTECS 

XI0373900

HS Code 

29419000

Cefoperazone Usage And Synthesis

Description

Cefoperazone has a C-7 side chain reminiscent of piperacillin's and also possesses the C-3 side chain (MTT ) that often is associated with the bleeding and alcohol intolerance problems among patients taking cephalosporins. Its useful activity against pseudomonads partly compensates for this, although it is not potent enough to be used as a single agent against this difficult pathogen. The C-7 side chain does not convey sufficient resistance to many β-lactamases, although the addition of clavulanic acid or sulbactam would presumably help.

Chemical Properties

white crystals

Originator

Cefobid,Pfizer,W. Germany,1981

Uses

Antibacterial.

Uses

Cefoperazone also has a broad spectrum of antimicrobial action, including most clinically significant microorganisms: Gram-positive, Gram-negative, aerobic, and anaerobic. It is stable with respect to most beta-lactamases of Gram-positive and Gram-negative bacteria.
Cefoperazone is used for bacterial infections of the lower respiratory tract, urinary and sexual tracts, bones, joints, skin, soft tissues, abdominal, and gynecological infections. Synonyms of this drug are cefazon, cefobid, cefobis, and many others.

Uses

Cefoperazone acid is an antimicrobial β-lactamase inhibitor.

Definition

ChEBI: A semi-synthetic parenteral cephalosporin with a tetrazolyl moiety that confers beta-lactamase resistance.

Manufacturing Process

To a suspension of 3.0 g of 7-[D-(-)-α-amino-p-hydroxyphenylacetamido]-3- [5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-?3-cephem-4-carboxylic acid in 29 ml of water was added 0.95 g of anhydrous potassium carbonate. After the solution was formed, 15 ml of ethyl acetate was added to the solution, and 1.35 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was added to the resulting solution at 0°C to 5°C over a period of 15 minutes, and then the mixture was reacted at 0°C to 5°C for 30 minutes. After the reaction, an aqueous layer was separated off, 40 ml of ethyl acetate and 10 ml of acetone were added to the aqueous layer, and then the resulting solution was adjusted to a pH of 2.0 by addition of dilute hydrochloric acid. Thereafter, an organic layer was separated off, the organic layer was washed two times with 10 ml of water, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 10 ml of acetone, and 60 ml of 2-propanol was added to the solution to deposit crystals. The deposited crystals were collected by filtration, washed with 2- propanol, and then dried to obtain 3.27 g of 7-[D-(-)-α-(4-ethyl-2,3-dioxo)-1- piperazinocarbonylamino)-p-hydroxyphenylacetamido]-3-[5-(1-methyl- 1,2,3,4-tetrazolyl)thiomethyl]-?3-cephem-4-carboxylicacid, yield 80.7%. The product forms crystals, MP 188°C to 190°C (with decomposition).

brand name

Cefobid (Pfizer).

Therapeutic Function

Antibiotic

Antimicrobial activity

A semisynthetic parenteral cephalosporin. It is unstable, losing activity on storage even at –20°C. A formulation with sulbactam is available in some countries.
It exhibits moderate activity against carbenicillin-sensitive strains of Ps. aeruginosa. Activity against Burk. cepacia and Sten. maltophilia is unreliable. It is much less stable to enterobacterial β-lactamases than most other cephalosporins of groups 4–6 and consequently has unreliable activity against many species, including β-lactamase-producing strains of H. influenzae and N. gonorrhoeae. It is active against Achromobacter, Flavobacterium, Aeromonas and associated non-fermenters. Past. multocida is extremely susceptible (MIC <0.01–0.02 mg/L). It exhibits modest activity against most Gram-negative anaerobes, but not B. fragilis. Sulbactam increases activity against many, but not all, enterobacteria and non-fermenters, and almost all B. fragilis.
A 2 g intravenous infusion achieves a peak plasma concentration of 250 mg/L. The plasma half-life is 1.5–2 h. Over 85% is bound to plasma proteins. It achieves therapeutic concentrations in tissue and inflammatory exudates. Variable low levels are found in the sputum up to 1.5% of simultaneous serum levels. Penetration into CSF is unreliable even in the presence of meningeal inflammation.
The bile is a major route of excretion, accounting for almost 20% of the dose. About 20–30% is eliminated in urine, almost entirely by glomerular filtration. Clearance is effectively unchanged by renal failure or dialysis.
Side effects associated with the methylthiotetrazole side chain have been reported. Diarrhea has been notable in some studies. Marked suppression of fecal flora, with the appearance of C. difficile, has occasionally been found. There is a 5–10% incidence of mild transient increases in liver function tests. Its potential toxicity and the availability of compounds with better β-lactamase stability and more reliable antipseudomonal activity have undermined its popularity.

Synthesis

Cefoperazone, (6R,7R)-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazincarboxamido)-2-(p-hydroxyphenyl)acetamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo- 5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.84), is synthesized by acylating 7-amino-3-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-3-cefem-4-carboxylic acid (32.1.2.24) with a mixed anhydride synthesized from ethyl chloroformate and |á-(4-ethylpiperazin-2, 3-dion-1-carbonylamino)-4-hydroxyphenylacetic acid (32.1.2.83), which in turn is synthesized from 4-ethylpiperazin-2,3-dion-1-carboxylic acid (32.1.1.29) and the sodium salt of 4-hydroxyphenylglycine.

References

[1]. kato y1,takahara s,kato s,kubo y,sai y,tamai i,yabuuchi h,tsuji a. involvement of multidrug resistance-associated protein 2 (abcc2) in molecular weight-dependent biliary excretion of beta-lactam antibiotics.drug metab dispos.2008 jun;36(6):1088-96. doi: 10.1124/dmd.107.019125. epub 2008 mar 13.
[2]. craig wa,gerber au. pharmacokinetics of cefoperazone: a review. drugs.1981;22suppl 1:35-45.

Cefoperazone(62893-19-0)Related Product Information

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