Oxidative N-dealkylation

In the second example, N-dealkylation, oxidation of the carbon next to the nitrogen leads to a carbinolamine. This spontaneously leads to formaldehyde and an amine. The mechanism involves loss of a proton with electrons moving toward the electronegative nitrogen atom. The negative charge on the nitrogen is neutralized due to the addition of a proton from the environment. 

Secondary and Primary Amines. Secondary amines (cither patent compounds or metabolites) are susceptible to oxidative N-dealkylation. oxidative deamination, and N-oxi-dation reactions. - As in tertiary aminc.s. N-dealkylation of secondary amines proceeds by the carbinolamine path-... 

N-dealkylation Oxidative deamination Oxidation of deaminated product to benzoic acid... 

Aromatic hydroxylation at C-4 N-dealkylation Oxidative deamination Oxidation of deaminated product to naphthoxylactic acid Conjugation with glucuronic acid O-dealkylation... 

Oxidation of alcohol, carbonyl and acid functions, hydroxylation of aliphatic carbon atoms, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic and sulfur, oxidative N-dealkylation, oxidative O- and S-dealkylation, oxidative deamination, other oxidative reactions... 

Chlordiazepoxide 1 5-30 N-Dealkylation Oxidation Desmethylchlordiazepoxide Demoxepam DMDZ 96... 

Oxidative O-dealkylation of ethers is a common metabolic reaction with a mechanism of dealkylation analogous to that of N-dealkylation oxidation of the a-carbon, and subsequent decomposition of the unstable hemiacetal to an alcohol (or phenol) and a carbonyl product... 

Flurazepam (Dal mane ) 8 10-30 15-30 Oxidation N-dealkylation Hydroxyethylflurazepam Flurazepam aldehyde N-DAF High risk of hangover and residual effects... 

A great number of transformations has been performed on narceine imide (116) by Czech researchers. Oxidation with potassium permanganate in acetone or with nitric acid caused the cleavage of the alkaloid, giving rise to hemipinic imide (127). A similar result was noted by Rdnsch (129,130) during Lemieux-Johnson oxidation of ene lactam 152 (129,130) in this reaction the basic component (156) was isolated as well. The use of hydrogen peroxide in acetone converted 116 to (Z)-narceine imide N-oxide, which under the action of acetic anhydride underwent N-dealkylation (135). 

Quazepam (Doral) 2 39 7.5-15 Oxidation, N-dealkylation 2-Oxo-quazepam, N-desalkylflurazepamc... 

Aryl and alkyl hydroxylations, epoxide formation, oxidative dealkylation of heteroatoms, reduction, dehalogenation, desulfuration, deamination, aryl N-oxygenation, oxidation of sulfur Oxidation of nucleophilic nitrogen and sulfur, oxidative desulfurization Oxidation of aromatic hydrocarbons, phenols, amines, and sulfides oxidative dealkylation, reduction of N-oxides Alcohol oxidation reduction of ketones Oxidative deamination... 

Scheme 2. Simplified scheme for oxidative N-dealkylation incorporating a cytochrome P-450 perferryl oxygen intermediate and substrate radicals.

Nicotine Resolution of racemates N-Demethylation, pyrrole oxidation N-Dealkylation, pyrrole oxidation, iminium formation... 

N-dealkylation, O-dealkylation, oxidative dehalogenation, and oxidation of aryl and alkyl methyl groups. 

FIGURE 4.50 Cytochrome P450-catalyzed oxidative N-dealkylation of Mdocaine. 

An example of N-dealkylation of an amine adjacent to a tertiary carbon can be found in the metabolism of synthetic opiod, alfentanil. The CYP3A4-catalyzed oxidation of the opiod alfentanil follows two major pathways (119) N-dealkylation to form no-ralfentanil and cleavage of the spiro center to generate N-phenylproprionamidc. Moreover,... 

FIGURE 4.57 Examples (/V-rncthylcarbazole, N,N-dimethylaniIinc, N,/V-dimethylbenzamide, iV-methylbenzamidine, and /V,/V-dimcthylnitrosamine) of cytochrome P450-catalyzed oxidative N-dealkylation. 

It is clear from the literature that, while N-oxides and N-hydroxylated compounds are observable metabolites of amines, they are nowhere near as prevalent as metabolites resulting from N-dealkylation. They appear to only become more significant when N-dealkylation is not an option (157). A caveat of this conclusion however is that N-hydroxy compounds are not all that stable, particularly in vivo, where they can be reduced back to the amine or further oxidized to even less stable compounds. It may be that,... 

Breck GD, Trager WF. Oxidative N-dealkylation a mannich intermediate in the formation of a new metabolite of lidocaine in man. Science 1971 173(996) 544-546. 

Seto Y, Guengerich FP. Partitioning between N-dealkylation and N-oxygenation in the oxidation of N, N-dialkylarylamines catalyzed by cytochrome P450 2B1. J Biol Chem 1993 268(14) 9986-9997. 

The major metabolites of lidocaine formed from this part of the molecule are the amine (16), which is further oxidized to the para-phenol, N-dealkylation of the parent drug with loss of acetaldehyde to form the secondary amine, and a second N-dealkylation to form the primary amine (structure not shown). Although there are only a few major metabolites of lidocaine, with sensitive analytical methods it is likely that hundreds of minor metabolites could be detected. 

The stepwise oxidation of alkylamine, which leads to N-dealkylation, generates nitrones that form tightly bound complexes with the heme iron [48]. These heme iron complexes give rise to characteristic changes in the UV-Vis spectrum of the CYP. 

Tertiary arylacetamides appear to undergo hydrolysis to a very limited extent only. Hydrolysis of the synthetic opioid fentanyl (4.117) to despropa-noylfentanyl (4.118) was a very minor pathway in humans [76], No metabolites resulting from amide hydrolysis were detected for the fentanil analogues alfentanil (4.119) and sufentanil (4.120) [77], for which oxidative N-dealkylation was the main metabolic pathway. 

These and other interesting results allow quantitative insight into the rate of breakdown of N-(hydroxymethyl) compounds (i.e., carbinolamines (hemi-aminals)), the reaction mechanisms of which we examined in Sect. 8.7.3 (see, in particular, Fig. 8.20) [80 - 82], These carbinolamines, we recall, are major metabolic intermediates in oxidative N-dealkylation reactions resulting from cytochrome P450 catalyzed hydroxylation of the C-atom adjacent to the... 

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