Cephalosporins reactions

Alkylation of a cephalosporin. Reaction of the ester (1) with methyl fluorosulfonate gives the optically active sulfonium salt (2) formed with inversion at Cg. This is the first report of an S-alkylated penam or cepham. The... 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

Other Reactions. The reaction of Thydioxybenzaldehyde with sodium cyanide and ammonium chloride, Strecker synthesis, yields /J-hydroxyphenylglycine [938-97-6] a key intermediate in the manufacture of semisynthetic penicillins and cephalosporins (see Antibiotics, p-LACTAMs). 

The P-lactam antibiotics ate produced by secondary metaboHc reactions that differ from those responsible for the growth and reproduction of the microorganism. In order to enhance antibiotic synthesis, nutrients must be diverted from the primary pathways to the antibiotic biosynthetic sequences. Although most media for the production of penicillins and cephalosporins are similar, they ate individually designed for the specific requkements of the high yielding strains and the fermentation equipment used. 

The cephalosporins generally cause few side effects (80,132,219—221). Thrombophlebitis occurs as a result of intravenous administration of all cephalosporins. Hypersensitivity reactions related to the cephalosporins are the most common side effects observed, but these are less common than found with the penicillins. Clinically only about 5—10% of patients with allergic reactions to the penicillins manifest the same reactions to the cephalosporins, and data would contradict any tme cross-reactivity to cephalosporins in patients who have previously reacted to penicillin (80,132,219). 

Although immediate reactions of anaphylaxis, bronchospasm, and urticaria have been reported, most commonly patients exhibiting an adverse reaction develop a maculopapular rash, usually after several days of therapy. They may also develop fever and eosinophilia (80,219). Cefoperazone (34) and ceftriaxone (39), having greater biUary excretion than other cephalosporins, are associated with an increased risk of diarrhea, which may be caused by selection of cytotoxin producing stains of Clostridium difficile (219). 

Generally, nephrotoxicity is not a problem. Some cephalosporins, especially those with the 3-methylthiotetrazole side chain, such as moxalactam (48), show a tendency to promote bleeding. This appears to be due to a reduction in the synthesis of prothrombin and can be a problem especially in elderly patients, patients with renal insufficiency, or patients suffering from malnutrition (219). The same side chain seems to promote a disulfiramlike reaction in patients consuming alcohol following a cephalosporin dose (80,219). 

Cephalosporin 5-oxides and penicillin 5-oxides (221) can be converted into isothiazol-3-ones (222) by the action of bases. These reactions proceed via an intermediate azetidinonesulfenic acid (223 Scheme 37) (77SST(4)339). Attempts to prepare /3-lactam compounds from isothiazoles have, as yet, been unsuccessful (81X2181). 

An intermolecular carbenoid reaction followed by intramolecular displacement of acetate gives the clavulanic acid derivative (112) in one step from 4-acetoxyazetidin-2-one (91) (80CC1257). Carbene-induced reactions of penicillins and cephalosporins have been reviewed (75S547, 78T1731). 

Because the integrity of the dihydrothiazine ring and its C-4 carboxyl substituent is crucial to useful antimicrobial activity, reactions involving this part of the cephalosporin molecule are usually undesirable. The possibilities for sulfur oxidation or alkylation, substitution at C-2 which is adjacent to both sulfur and a double bond, double bond isomerization and addition reactions, and the influence of a free carboxylic acid must all be considered in designing reactions to selectively modify other cephalosporin functionalities. 

Early attempts to produce cephalosporin analogs by varying the 7-acylamino substituent were frustrated because, in contrast to previous experience with penicillins, a good method for producing the necessary 7-amino compound (33a) could not be found. This problem was finally solved when it was discovered that diazotization of the a-aminoadipyl residue produces an iminolactone (33b) which can be hydrolyzed to the free amine in good yield. Subsequently an improved procedure was developed which involves silylation of the carboxyl groups followed by reaction with phosphorus pentachloride to yield iminochloride (33c)... 

At Smith Kline French a general approach to cephalosporin and penicillin nuclear analogs was developed that utilizes a monocyclic /3-lactam (59) with the correct cis stereochemistry as a key intermediate. This is prepared by reaction of the mixed anhydride of azidoacetic acid and trifluoroacetic acid with imine (58) followed by oxidative removal of the dimethoxybenzyl group. This product could be further elaborated to intermediate (60) which, on reaction with a -bromoketones, provides isocephalosporins (61). These nuclear analogs displayed antibacterial properties similar to cephalosporins (b-79MI51000). 

Ceftiofur (57) differs from the preceding cephalosporin derivatives in that it ha.s a thioester moiety at C-3. This can be introduced by displacement of the C-3 acetyl group of 7-aminocepha-losporanic acid (40) with hydrogen sulfide and esterification with 2-furylcarboxylic acid to give synthon 5reacted with trimethylsilylated oximinoether derivative 55 (itself obtained from the corresponding acid by reaction with dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole) to produce, after deprotecting, ceftiofur (57) [18]. 

Meanwhile a stirred suspension of phosphorus pentachloride (14.99 g, 0.072 mol) in dry di-chloromethane (150 ml) was cooled to 0°C, and N,N-dimethylacetamide (27.5 ml) was added. The resulting solution was recooled to -10°C and 2-fur-2-yl)-2-methoxyiminoaceticacid (syn-isomer) (12.17 g, 0.072 mol) was added. The mixture was stirred at -10°C for 15 minutes and crushed ice (35 g) was added. The mixture was stirred at 0°C for 10 minutes, whereafter the lower dichloromethane phase was added over 10 minutes to the cephalosporin solution prepared above, cooled to -10°C so that the reaction temperature rose steadily to 0°C. The mixture was stirred at 0°C to 2°C for 1 hour, whereafter the cooling bath was removed and the reaction temperature allowed to rise to 20°C over 1 hour. The reaction mixture was then added slowly to 2 N hydrochloric acid (100 ml) diluted with cold water (1.15 C) at 5°C. The pH of the two-phase mixture was adjusted to below 2 with 2 N hydrochloric acid (10 ml), and the mixture was stirred and recooled to 5°C. The solid which precipitated was filtered, washed with dichloromethane (100 ml) and water (250 ml), and dried in vacuo at 40°C overnight to give the title compound (22.04 g, 86.6%). 

Discuss uses, general drug action, adverse reactions, contraindications, precautions, and interactions associated with the cephalosporins. 

Discuss ways to promote an optimal response to therapy, how to manage common adverse reactions, special considerations related to administration, and important points to keep in mind when educating patients about the use of the cephalosporins. 

The most common adverse reactions seen with administration of the cephalosporins are gastrointestinal disturbances, such as nausea, vomiting, and diarrhea Hypersensitivity (allergic) reactions may occur with administration of the cephalosporins and range from mild to life threatening. Mild hypersensitivity reactions include pruritus, urticaria, and skin rashes. More serious hypersensitivity reactions include S teveils-Johnson syndrome (fever, cough, muscular aches and... 

Other adverse reactions that may be seen with administration of the cephalosporins are headache, dizziness, nephrotoxicity (damage to the kidneys by a toxic substance), malaise, heartburn, and fever. Intramuscular (IM) administration often results in pain, tenderness, and inflammation at the injection site Intravenous (IV) administration has resulted in thrombophlebitis and phlebitis. 

---