Latamoxef (or moxalactam) is an oxacephem antibiotic usually grouped with the . In oxacephems such as latamoxef, the sulfur atom of the cephalosporin core is replaced with an oxygen atom.
Latamoxef has been associated with prolonged bleeding time, and several cases of coagulopathy, some fatal, were reported during the 1980s.
It has been described as a third-generation cephalosporin.
Synthesis
Oxa-substituted third generation cephalosporin antibiotic (oxacephalosporin).
The
benzhydrol ester of 6-Aminopenicillanic acid (6-APA) is S-chlorinated and treated with base whereupon the intermediate sulfenyl chloride fragments (to
2). Next, displacement with propargyl alcohol in the presence of
zinc chloride gives predominantly the stereochemistry represented by diastereoisomer
3. The side chain is protected as the phenylacetylamide; the triple bond is partially reduced with a 5% Pd-CaCO3 (
Lindlar catalyst) and then epoxidized with
mCPBA to give
4. The epoxide is opened at the least hindered end with 1-methyl-1
H-tetrazole-5-thiol to put in place the future C-3 side chain and give intermediate
5. Jones oxidation followed in turn by ozonolysis (reductive work-up with zinc-AcOH) and reaction with SOCl2 and
pyridine give halide
6. The stage is now wet for intramolecular
Wittig reaction. Displacement with PPh3 and Wittig olefination gives 1-oxacephem
7. Next a sequence is undertaken of side chain exchange and introduction of a 7-methoxyl group analogous to that which is present in
cephamycins and gives them the enhanced
beta-lactamase stability. First
7 is converted to the imino chloride with PCl5 and then to the imino methyl ether (with
methanol) and next hydrolyzed to the free amine (
8). Imine formation with 3,5-di-t-butyl-4-hydroxybenzaldehyde is next carried out leading to
9. Oxidation with nickel(III) oxide gives iminoquinone methide
10, to which methanol is added in a conjugate sense and in the sterechemistry represented by formula
11. The imine is exchanged with Girard's reagent T to give
12, and this is acylated by a suitable protected arylmalonate, as the hemiester hemiacid chloride so as to give 11. Deblocking with aluminium chloride and anisole gives moxalactam
14.
