Cefamandole

Description

Cefamandole is also known as cephamandole. It is a parenterally administered broad-spectrum cephalosporin antibiotic. The pharmacological action and indications for use of cefamandole is analogous to that of cefuroxime and cefamandole. Synonyms of this drug are mandoxef, kefandol, kefadol, and many others.

Chemical Properties

Off-White Foam

Originator

Mandokef,Lilly,W. Germany,1977

Uses

Intermediate for the oreparation of Phenylephrine Glucuronide.

Uses

Cefamandole is a second-generation cephalosporin antibiotic with antibacterial activity. It is a labelled metabolite of Deprenyl (D288641) (Selegiline).

Application

Cefamandole was synthesized by Eli Lilly & Co. in 1972. It shows strong activity against Proteus (indole-positive) species, Enterobacter, and Citrobacter, against which the earlier cephalosporins, such as cephalothin and cefazolin, are inactive. The nafate (sodium salt of the O-formyl ester) has been used in the United States and Europe, and the sodium salt of cefamandole has been used in Japan by injection.

Definition

ChEBI: Cefamandole is a cephalosporin compound having (R)-mandelamido and N-methylthiotetrazole side-groups. It has a role as an antibacterial drug. It is a cephalosporin and a semisynthetic derivative. It is a conjugate acid of a cefamandole(1-).

Manufacturing Process

To 21.6 kg (17.8 l) of 98% formic acid was added 1.14 kg (7.5 mols) of D-(-)- mandelic acid and the reaction mixture was heated for 4 hours at 70°C with stirring. The excess formic acid was evaporated off in vacuo and the residual syrup was dissolved in 6 l of benzene. The solution was washed twice with 6 l portions of water and was dried over magnesium sulfate. The drying agent was filtered and washed with 1.5 l of benzene, the washes being added to the filtrate. The dried filtrate was evaporated in vacuo to obtain the D-(-)- mandelic acid formate ether as a syrup. The product can be crystallized from cyclohexane to yield material melting at about 55°C to 58°C.
The mandelic acid formate ester obtained as a syrup as described above is stirred for 2 hours with 2.9 kg (~1.75 l) of thionyl chloride at a temperature of about 70°C. The excess thionyl chloride is removed by evaporation and the residual green solution is vacuum distilled. The product, O-formyl mandeloyl chloride, distills over at 127°C to 130°C (15 mm) or at 108°C to 112°C (7 mm).
To 13 l of ethyl acetate were added 85.1 g (2.59 mols) of 7-amino-3-(1- methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and 1,361 g (10.37 mols) of monotrimethylsilyl acetamide, and the mixture was stirred at 50°C until a clear solution was obtained. The solution was cooled to 20°C and 514 g (2.59 mold of O-formyl mandeloyl chloride was added at a rate such that the temperature of the reaction solution was maintained between about 20°C to 25% with ice-cooling.
The reaction mixture was stirred for 1.5 hours at about room temperature after the addition of the mandeloyl chloride was completed. Five liters of water were then added to the reaction mixture and the diluted mixture was stirred for about 10 minutes. The organic layer was separated and was washed twice with water. The combined washes are extracted with 1.5 l of ethyl acetate and the extract is combined with the washed organic layer. The whole was dried over magnesium sulfate, filtered and evaporated in vacuo on a 25°C water bath to yield 1,460 g of product, 7-(D-2-formyloxy-2- phenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4- carboxylic acid, as a yellow foam.
The product was dissolved in 5 l of acetone and the solution was mixed with a solution of 430 g (2.59 mols) of sodium 2-ethylhexanoate in 5.4 l of acetone. The combined solutions were seeded and stirred in an ice bath for 1.5 hours. The crystalline precipitate of sodium 7-(D-2-formyloxy-2-phenylacetamido)-3- (1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate was filtered and washed with 5 l of acetone. The crystalline salt was dried overnight in a vacuum oven at 40°C to yield 1,060 g (80%)of product, melting at 182°C to 184°C.

brand name

Mandol (Lilly).

Therapeutic Function

Antibiotic

Antimicrobial activity

A semisynthetic cephalosporin supplied as the nafate, an antibacterially inactive ester hydrolyzed in the body to cefamandole. It is active against common pathogenic bacteria , but there is considerable strain variation in susceptibility. It is somewhat more stable than other group 1 agents to enterobacterial β-lactamases. Acinetobacter, Serratia and Pseudomonas spp. are often resistant. Some anaerobic Gram-negative rods are susceptible but B. fragilis is resistant.
A 1 g intramuscular dose achieves a plasma concentration of 20–35 mg/L after 1 h. It is widely distributed in body tissues. CSF levels are poor in the absence of meningeal inflammation. Therapeutically effective concentrations (c. 9 mg/kg) are found in bone after an intravenous dose of 2 g. Protein binding is 65–80%.
Renal excretion with a plasma half-life of around 50 min is mainly by both glomerular and tubular routes. A small amount is excreted in the bile and concentrations around 150–250 mg/L are found in T-tube bile following a 1 g intravenous dose. Only about 5% is removed by hemodialysis.
Cefamandole is one of the analogs containing the methylthiotetrazole side chain associated with bleeding . Rare renal damage or enhancement of existing renal damage has been described. Thrombophlebitis on intravenous administration is relatively common.
Experience in the treatment of a variety of infections and for surgical prophylaxis has been mixed and it is no longer recommended.

General Description

Cefamandole is a semisynthetic second-generation, β-lactam, wide-spectrum cephalosporin antibiotic with bactericidal activity. It is active against many strains resistant to other cephalosporins, such as Enterobacter species and indole-positive Proteus species. It is used for the treatment of serious infections caused by susceptible strains of microorganisms. In pharmaceutical products, cefamandole may be employed as cefamandole sodium (CAS number 30034-03-8, EC number 250-009-0, molecular formula C18H 17N6NaO5S2) or (when used parenterally) the formate ester prodrug cefamandole nafate (CAS number 42540-40-9, EC number 255-877-4, molecular formula C19H17N6NaO6S2).

Synthesis

Cefamandole, 7-D-mandelamido-3-[[(1-methyl-1H-tetrazol-5-yl)thio] methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.25), is synthesized from 7-aminocephalosporanic acid.
Protecting free amino group in 7-aminocephalosporanic acid by formylation with formic acid in the presence of acetic anhydride produces 7-formamidocephalosporanic acid (32.1.2.23). The acetoxy group of this compound is replaced by a reaction with 1-methyl- 1,2,3,4-tetrazol-5-thiol, after which the N-formyl protection is removed by hydrochloric acid, giving 7-amino-3-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-3-cefem-4-carboxylic acid (32.1.2.24). Reacting this with a mixed anhydride synthesized from mandelic acid and phosgene gives the desired cefamandole (32.1.2.25).