Latamoxef (or moxalactam) is an oxacephem antibiotic usually grouped with the cephalosporins. In oxacephems such as latamoxef, the sulfur atom of the cephalosporin core is replaced with an

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...

atom. Latamoxef has been associated with prolonged bleeding time, and several cases of coagulopathy, some fatal, were reported during the 1980s. Latamoxef is no longer available in the United States. As with other cephalosporins with a methylthiotetrazole side chain, latamoxef causes an antabuse reaction when mixed with alcohol. Additionally, the methylthiotetrazole side chain inhibits γ-carboxylation of glutamic acid; this can interfere with the actions of vitamin K. It has been described as a third-generation cephalosporin.

Synthesis

Oxa-substituted third generation cephalosporin antibiotic (oxacephalosporin). Moxalactam synthesis

The benzhydrol ester of 6-Aminopenicillanic acid (

6-APA 6-APA ((+)-6-aminopenicillanic acid) is a chemical compound used as an intermediate in the synthesis of β-lactam antibiotics. The major commercial source of 6-APA is still natural penicillin G: the semi-synthetic penicillins derived from 6-APA a ...

) 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 Zinc chloride is the name of inorganic chemical compounds with the formula ZnCl2 and its hydrates. Zinc chlorides, of which nine crystalline forms are known, are colorless or white, and are highly soluble in water. This salt is hygroscopic and e ...

gives predominanntly 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 Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately Volatility (chemistry), volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a Halogenation, chlorinating reagen ...

and

pyridine Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a ...

give halide 6. The stage is now wet for intramolecular

Wittig reaction The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide called a Wittig reagent. Wittig reactions are most commonly used to convert aldehydes and ketones to alkenes. Mos ...

. 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 Beta-lactamases, (β-lactamases) are enzymes () produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems ( ertapenem), although carbap ...

stability. First 7 is converted to the imino chloride with

PCl5 Phosphorus pentachloride is the chemical compound with the formula PCl5. It is one of the most important phosphorus chlorides, others being PCl3 and POCl3. PCl5 finds use as a chlorinating reagent. It is a colourless, water-sensitive and moist ...

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 Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms hexahydrate with the formula , containing six water molecules of hydration. Both are colourless crystals, but samples are often contam ...

and anisole gives moxalactam 14.

References

Acetaldehyde dehydrogenase inhibitors Cephalosporin antibiotics Tetrazoles Sulfides Carboxylic acids Lactams Ethers Propionamides Phenols Oxygen heterocycles {{antibiotic-stub