Latamoxef

Latamoxef

Systematic (IUPAC) name
(6R,7R)-7-{[carboxy(4-hydroxyphenyl)acetyl]amino}-7-methoxy-3-{[(1-methyl-1H-tetrazol-5-yl)thio]methyl}-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Routes of administration	Intramuscular, intravenous
Pharmacokinetic data
Protein binding	35 to 50%
Metabolism	Nil
Biological half-life	2 hours
Excretion	Mostly renal, unchanged; also biliary
Identifiers
CAS Number	64952-97-2 Y
ATC code	J01DD06 (WHO)
PubChem	CID: 47499
DrugBank	DB04570 N
ChemSpider	43215 Y
UNII	VUF6C936Z3 Y
KEGG	D08109 Y
ChEBI	CHEBI:599928 N
ChEMBL	CHEMBL74632 Y
Chemical data
Formula	C20H20N6O9S
Molecular mass	520.474 g/mol
SMILES O=C2N1/C(=C(\CO[C@@H]1[C@]2(OC)NC(=O)C(c3ccc(O)cc3)C(=O)O)CSc4nnnn4C)C(=O)O
InChI InChI=1S/C20H20N6O9S/c1-25-19(22-23-24-25)36-8-10-7-35-18-20(34-2,17(33)26(18)13(10)16(31)32)21-14(28)12(15(29)30)9-3-5-11(27)6-4-9/h3-6,12,18,27H,7-8H2,1-2H3,(H,21,28)(H,29,30)(H,31,32)/t12?,18-,20+/m1/s1 Y Key:JWCSIUVGFCSJCK-CAVRMKNVSA-N Y
NY (what is this?)  (verify)

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 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).

File:Moxalactam synthesis.svg

Moxalactam synthesis: (excerpt from Lednicer book 3)

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 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-1H-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 peroxide 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.