62893-19-0

Basic information

• Product Name: Cefoperazone
• Synonyms: CEFOPERAZONE;CEFOPERAZONE ACID;(6r-(6-alpha,7-beta(r*)))--tetrazol-5-yl)thio)methyl)-8-oxo;-1-piperazinyl)carbonyl)amino)(4-hydroxyphenyl)acetyl)amino)-3-(((1-methyl-1h;cefoperazine;Cefobis：Cefogram;l~rdum;Perocef：Tomabef
• CAS NO: 62893-19-0
• Molecular Formula: C₂₅H₂₇N₉O₈S₂
• Molecular Weight: 645.67
• EINECS: 263-749-4
• Product Categories: Inhibitors
• Mol File: 62893-19-0.mol

Chemical Properties

• Melting Point: 169-171 C
• Appearance: white crystalline powder
• Density: 1.77 g/cm³
• Refractive Index: 1.819
• Storage Temp.: 2-8°C
• Solubility: DMSO (Slightly, Sonicated), Methanol (Slightly, Heated, Sonicated)
• PKA: pKa 2.6 (Uncertain)
• Merck: 14,1930
• CAS DataBase Reference: Cefoperazone(CAS DataBase Reference)
• NIST Chemistry Reference: Cefoperazone(62893-19-0)
• EPA Substance Registry System: Cefoperazone(62893-19-0)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22-36/37/38
• Safety Statements: 26-36
• RTECS: XI0373900
• Hazardous Substances Data: 62893-19-0(Hazardous Substances Data)

Usage

Uses

Used in Antibacterial Applications:
Cefoperazone is used as an antimicrobial agent for treating bacterial infections of various types. Its broad spectrum of antimicrobial action includes most clinically significant microorganisms, such as Gram-positive, Gram-negative, aerobic, and anaerobic bacteria. It is stable with respect to most beta-lactamases of Gram-positive and Gram-negative bacteria.
Cefoperazone is used as an antimicrobial agent for bacterial infections in the following areas:
1. Lower respiratory tract infections
2. Urinary and sexual tract infections
3. Bone and joint infections
4. Skin and soft tissue infections
5. Abdominal and gynecological infections
Used as a β-lactamase Inhibitor:
Cefoperazone acid is used as an antimicrobial β-lactamase inhibitor, which helps to enhance the effectiveness of other antibiotics by preventing their degradation by bacterial enzymes.
Synonyms and Brand Names:
Cefoperazone is also known by various synonyms, including cefazon, cefobid, cefobis, and many others. One of its brand names is Cefobid, which is manufactured by Pfizer.

Originator

Cefobid,Pfizer,W. Germany,1981

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).

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 α-(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.

InChI:InChI=1/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+/m0/s1

Upstream product

• 59703-00-3 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride 
• 74769-12-3 D-(-)-2-[(4-ethyl-2,3-dioxo-1-piperazinyl)amido]- 2-(4-hydroxyphenyl)acetic acid chloride 
• 957-68-6 7-Aminocephalosporanic acid 
• 62893-24-7 (R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid 
• 24209-38-9 (6R,7R)-7-amino-3-[(1H-1-methyltetrazol-5-yl)thio]methylceph-3-em-4-carboxylic acid 

Downstream Products

• 21917-76-0 2-methylthiazol-4-carbonitrile 
• 59378-87-9 pyrrolidine-3-carboxylic acid 
• 4911-70-0 2,3-dimethylpentan-2-ol 
• 3587-64-2 1-Methoxy-2-methylpropan-2-ol 
• 15925-30-1 5-hydroxy-4-oxopentanoic acid 
• 2749-59-9 1,3-dimethyl-5-pyrazolone 
• 109-94-4 formic acid ethyl ester 
• 62893-20-3 Cefobis 

Relevant articles and documents

New adaptation diseases of cefoperazone medicinal preparation for treating endometritis and other gynecological genital tract infections

The invention discloses new adaptation diseases of cefoperazone medicinal preparation for treating gynecological genital tract infections of gynecology department. The cefoperazone sodium provided bya specific raw material production process is extremely low in impurity content and remarkable in medicine effect, so that the quality of a preparation product is improved, the safety and effectiveness of the preparation product are guaranteed, and the invention provides the application of preparing the medicine for treating endometritis and other gynecological genital tract infections.

Preparation method of cefoperazone acid

The invention relates to a preparation method of cefoperazone acid. The preparation method comprises the following steps: (1) in a dichloromethane system, allowing 7-TMCA to react with a silanizationreagent at 20-70 DEG C, and carrying out silanization protection on the amino group and the carboxyl group; (2) in a dichloromethane body and a DMA system, allowing HO-EPCP salt to react with ethyl chloroformate at the reaction temperature of 20-70 DEG C under the action of a catalyst to prepare mixed anhydride; (3) adding the 7-TMCA after silanization protection into the mixed anhydride, reactingat 20-70 DEG C to obtain a reaction solution; (4) hydrolyzing the reaction solution, adding alkali to adjust the pH to be 5.5-7.5, layering, adding solvent into the water phase, adding acid to adjustthe pH to be 1.5-2.5, crystalizing and filtering to obtain cefoperazone acid. The method disclosed by the invention has the advantages that the product yield can be improved, S-isomer can be reduced,the residual solvent is reduced, the solvent is easy to recycle, the wastewater does not contain phosphorus and is easy to process.

Process for the preparation of keto acid [...]

The invention belongs to the field of medicine, and particularly relates to a preparation method of cefoperazone acid. The method comprises the following steps: with 7-ACA (amin-oeephalosporanic acid) and 1-methyl-5-tetrazole-thione as raw materials under catalysis of boron trifluoride acetonitrile, reacting to prepare 7-TMCA (7-Amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-3-cephem-4-carboxylicacid)hydrochloride; carrying out carboxyl and amino group protection on the 7-TMCA hydrochloride by using trimethylchlorosilane; and with the group-protected 7-TMCA hydrochloride prepared in the step (1), HO-EPCP ((2R)-2-[(4-Ethyl-2,3-dioxopiperazinyl)carbonyllamino]-2-(4-hydroxyphenyl)acetic acid) and benzotriazole diethyl phosphonate as raw materials, carrying out N-acylation reaction in a DMF (Dimethyl Formamide) solution under catalysis of triethylamine, so as to obtain the cefoperazone acid, wherein acyl chloride is prepared by reaction in absence of the HO-EPCP, the benzotriazole diethyl phosphonate is directly added to directly carry out acylation reaction on the HO-EPCP and the group-protected 7-TMCA hydrochloride. Thus, the preparation method is simple in reaction step, low in cost and high in purity.

Synthetic method of cefoperazone acid

The invention discloses a synthetic method of cefoperazone acid. The method comprises the steps of: reacting raw materials of 7-ACA and 1-methyl-5-mercapto tetrazole under the catalysis of boron trifluoride acetonitrile to obtain 7-ACT; dissolving the 7-ACT in a mixed solution of acetonitrile and N,O-(bis) trimethylsilyl acetamide to obtain a 7-ACT amino alkylate solution; mixing HO-EPCP, an organic solvent and a catalyst, adding phosphorus oxychloride for reaction at the temperature of -25 to -20 DEG C, wherein when the residue amount of HO-EPCP in the reaction solution is no more than 0.5%, the reaction is complete, so as to prepare a HO-EPCP acyl chloride solution; mixing and reacting 7-ACT amino alkylate solution with HO-EPCP acyl chloride solution, adding an aqueous solution of sodium bicarbonate after the reaction, standing foe stratification, filtering a lower layer material, adding water, crystallizing, filtering, washing and drying to obtain the cefoperazone acid. The method has the advantages of simpleness, high yield and stable intermediate.

NOVEL CRYSTALLINE CEFOPERAZONE INTERMEDIATE

The present invention relates to a crystalline form of an intermediate for cefoperazone of formula (1) and to a process for the preparation thereof by enzymatic condensation of a 3′-thiosubstituted β-lactam nucleus with a phenylglycine derivative.

Dioxo piperazine compounds

Certain cephalosporins having a heterocyclicthiomethyl group at the 3-position such as cefoperazone are prepared by reacting a solution of a 7-acylamidocephalosporanic acid having a free amino group as part of said acyl substituent with about an equi-molar amount of the thiolester STR1 wherein --S-Het is the desired conventional heterocyclicthio group which displaces the 3-acetoxy group of the starting acid and STR2 is the conventional acyl group which displaces a hydrogen on the free amino group which is part of the acyl substituent of the starting 7-acylamidocephalosporanic acid.