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
A labelled metabolite of Deprenyl (D288641) (Selegiline).
Uses
Cefamandole is a second-generation cephalosporin antibiotic with antibacterial activity.
Uses
Intermediate for the oreparation of Phenylephrine Glucuronide.
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).
