Description
As was already stated, and which is visible from the scheme of synthesis, moxalactam contains a dihydrooxazine ring instead of the dihydrothiazine ring common to all
cephalosporins, and thus this compound cannot be formally numbered with cephalosporins,
cephamicins, or penicillins; however, in terms of pharmacological action, it is related to all
three of the antibiotics listed above, and it is classified as a third-generation cephalosporin.
Moxalactam is resistant to the action of beta-lactamase, penicillinase, and cephalosporinase, which are produced by Gram-negative and Gram-positive bacteria. Many strains of a number of microorganisms that possess multiple resistance to other antibiotics—
semisynthetic penicillins, cephalosporins, and aminoglycosides—are sensitive to moxalactam.
This drug is used for infections of the respiratory organs, urinal tract, abdominal cavity,
as well as for gynecological infections, infections of the bones, joints, skin, soft tissues,
and for gonorrhea. Synonyms of this drug are latamoxef, festamoxin, moxacef, moxam,
and many others.
Synthesis
Moxalactam, 7|?[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7|á-methoxy-
3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxa-dethia-3-cefem-4-carboxylic acid (32.1.2.98), is
synthesized in a multi-stage synthesis from 6-APA, which is acylated by benzoylchloride in
the presence of triethylamine to give 6-benzoylpenicillin (32.1.2.85). The carboxyl group
of this compound is protected by a reaction with diphenyldiazomethane, to form the
3-diphenylmethyl ester of 6-benzoylpenicillin (32.1.2.86). Oxidation of this product with
molecular chlorine under basic conditions gives the S-oxide of the 3-diphenylmethyl ester of
6-benzoylpenicillin (32.1.2.87). Upon reacting this with triphenylphosphine, the expected
reduction of sulfoxide to sulfide does not occur, but rather the thiazine ring is opened, causing sulfur to be released while also resulting in its simultaneous substitution with oxygen and
subsequent formation of a cyclic iminoester (32.1.2.88). Chlorinating the double bond of this
product with chlorine and subsequent treatment of obtained dichloro derivative with sodium
bicarbonate gives a chloromethyallyl derivative (32.1.2.89), which upon reaction with potassium iodide substitutes the chlorine with iodine, forming an iodomethylallyl derivative
(32.1.2.90), and finally, hydrolyzing this product in dimethylsulfoxide in the presence of copper(I) oxide forms the corresponding allylic alcohol (32.1.2.91).
Upon heating this in the
presence of boron trifluoride¨Cdiethyl etherate, it recyclizes back to form an oxazine ring and
the reverse transformation of the cyclic iminoester into the amide form (32.1.2.92). The exocyclic double bond of the resulting product undergoes chlorination and subsequent treatment
of the product with a base using 1,7-diazabicyclo-[4.5.0]undec-6-ene (DBU), gives the
3-chloromethyl derivative (32.1.2.93). Reacting this with tert-butyl hypochlorite, obviously
to make an N-chloro derivative, and then with lithium methoxide, after acidification and treatment with sodium thiosulfate gives diphenylmethyl ester of 7|?-benzoylamido-7
|á-methoxy-3-(chloromethylyl)-1-oxa-dethia-3-cefem-4-carboxylic acid (32.1.94). Reacting
this with the sodium salt of 5-mercapto-1-methyl-tetrazol gives the diphenylmethyl ester of
7|?-benzoylamido-7|á-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxa-dethia-3-cefem-
4-carboxylic acid (32.1.95). Debenzoylation of this product and subsequent treatment with
phosphorous pentachloride in pyridine and then with methanol and diethylamine gives the
diphenylmethyl ester of 7|?-amino-7|á-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cefem-4-carboxylic acid (32.1.2.96). Acylating this compound with the mixed
anhydride synthesized from mono-diphenylmethyl ester of (4-hydroxyphenyl)malonic acid
and oxalylchloride in the presence of triethylamine gives the bis-diphenylmethyl ester protection on both carboxyl groups of the desired product (32.1.2.97). Finally, removing the
indicated protecting groups from both carboxyls by boiling it with trifluoroacetic acid in
toluene gives the desired moxalactam (32.1.2.98)
