Latamoxef (or moxalactam) is an

oxacephem An oxacephem is a β-lactam molecule similar to a cephem, but with an oxygen substituted for the sulfur. They are synthetic compounds not seen in nature, generally used as β-lactam antibiotic β-lactam antibiotics (beta-lactam antibiotics) a ...

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy, ...

usually grouped with the

cephalosporin The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus '' Acremonium'', which was previously known as ''Cephalosporium''. Together with cephamycins, they constitute a subgroup of β-lactam antibioti ...

s. In oxacephems such as latamoxef, the

sulfur Sulfur (or sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formul ...

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 we ...

atom. Latamoxef has been associated with prolonged

bleeding time Bleeding time is a medical test done on someone to assess their platelets function. It involves making a patient bleed, then timing how long it takes for them to stop bleeding using a stopwatch or other suitable devices. The term template bleed ...

, and several cases of

coagulopathy Coagulopathy (also called a bleeding disorder) is a condition in which the blood's ability to coagulate (form clots) is impaired. This condition can cause a tendency toward prolonged or excessive bleeding (bleeding diathesis), which may occur sp ...

, 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 Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects of ...

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 Diphenylmethanol is the organic compound with the formula (C6H5)2CHOH. Also known as benzhydrol, it is a white solid and the parent member of a large class of diaryl alcohols. Preparation Diphenylmethanol may be prepared by a Grignard reaction b ...

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 ...

) is S-chlorinated and treated with base whereupon the intermediate

sulfenyl chloride In organosulfur chemistry, a sulfenyl chloride is a functional group with the connectivity , where R is alkyl or aryl. Sulfenyl chlorides are reactive compounds that behave as sources of . They are used in the formation of and bonds. According ...

fragments (to 2). Next, displacement with

propargyl alcohol Propargyl alcohol, or 2-propyn-1-ol, is an organic compound with the formula C3H4O. It is the simplest stable alcohol containing an alkyne functional group. Propargyl alcohol is a colorless viscous liquid that is miscible with water and most pol ...

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 A Lindlar catalyst is a heterogeneous catalyst that consists of palladium deposited on calcium carbonate or barium sulfate which is then poisoned with various forms of lead or sulfur. It is used for the hydrogenation of alkynes to alkenes (i.e. ...

) and then epoxidized with

mCPBA ''meta''-Chloroperoxybenzoic acid (mCPBA or ''m''CPBA) is a peroxycarboxylic acid. A white solid, it is used widely as an oxidant in organic synthesis. mCPBA is often preferred to other peroxy acids because of its relative ease of handling. mC ...

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 volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a chlorinating reagent, with approximately per year bein ...

and

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, 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, weakl ...

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. Most ...

. Displacement with

PPh3 Triphenylphosphine (IUPAC name: triphenylphosphane) is a common organophosphorus compound with the formula P(C6H5)3 and often abbreviated to P Ph3 or Ph3P. It is widely used in the synthesis of organic and organometallic compounds. PPh3 exists ...

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 Cephamycins are a group of β-lactam antibiotics. They are very similar to cephalosporins, and the cephamycins are sometimes classified as cephalosporins. Like cephalosporins, cephamycins are based upon the cephem nucleus. Unlike most cephalospor ...

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 carbapene ...

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 Nickel (III) oxide is the inorganic compound In chemistry, an inorganic compound is typically a chemical compound that lacks carbon–hydrogen bonds, that is, a compound that is not an organic compound. The study of inorganic compounds is a subf ...

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 The T. Marzetti Company is the Specialty Food Group of the Lancaster Colony Corporation. T. Marzetti produces numerous salad dressings, fruit and vegetable dips, frozen baked goods and specialty brand items. It is the largest food and beverage c ...

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