JV-Demethylation

Projean, D., P.E. Morin, T.M. Tu, and J. Ducharme, Identification of CYP3A4 and CYP2C8 as the major cytochrome P450s responsible for morphine jV-demethylation in human liver microsomes,... 

The same group also studied the transformation of vindoline by Strep-tomyces albogriseolus A17178 and again were able to isolate two metabolites, 3-acetonyldihydrovindoline ether (42) and jV-demethyl vindoline (44) (49-51). The major product of metabolism 42 contained 56 mass units more than... 

Bromination of JV-demethyl-20(lV)-conenine (3a) in the presence of sodium carbonate gave the tribromo-derivative (3b).3 The reaction of (3a) with chlorinating agents under a variety of conditions gave the trichloro-derivative (3c) together with... 

Where isotopically labelled compounds are employed as tracers, biological isotope effects may be encountered. There have been several reports of primary isotope effects in the metabolism of deuterated drugs (for review see [403] and in general, metabolic rate is slower when a bond to deuterium rather than to hydrogen is cleaved during metabolism. Such effects have been observed, for example in the hydroxylation of butobar-bitone [404] and in the JV-demethylation of morphine [405]. A marked deuterium isotope effect has been reported in the 3-hydroxylation of cotinine-d2 (27). In this case a kn/ko ratio of about 6 was determined by... 

Axelrod, J. The enzymatic JV-demethylation of narcotic drugs. J. Pharmacol. Expt. Therap. 1956, 117, 322—330. 

Three new methods for the preparation of nortropine (5) have been reported.23 All three routes involve JV-demethylation by means of ethyl chloroformate, e.g. from tropine acetate (6). 

Another type of rearrangement involving 1,5-asymmetric induction is the ketene aza-Claisen rearrangement, used in the stereoselective synthesis of intermediate 16, a common precursor for the synthesis of monoterpene alkaloids (-)-a-skytanthine, (-)-jV-demethyl-<5-skytamhine, and (+ )-epidihydrotecomanine 649. 

With the exception of sceletenone and its close relatives, which will be discussed in Section IV,A,7, the remaining extant members of this subgroup are simple relatives of the four alkaloids mesembrine, mesembrenone, mesembranol, and mesembrenol, and include the known base (—)-mesem-brane, which has been demonstrated to occur in S. namaquense (22). The majority of these bases are either O- or JV-demethylated compounds derived from the four above-mentioned alkaloids discussion of these compounds will be confined to representative examples which illustrate general features of the methods used in the elucidation of their structures. 

Epoxidation of cyclohexene by MovO(TPP)X-Bu 02H has been reported.131 Demethylation of JV,A -dimethylaniKne by Fem(TPP)Cl-PhIO offers a model for P-450-catalyzed JV-dealkylation reactions.132 The aziridine formation from acylimino Mn(Por) and alkene may be taken for the nitrogen analogue of the oxygen transfer reaction (Scheme 32).133... 

In a study of the Hofmann-Loffler reaction, the jV-chloro-amine (8a) was irradiated in trifluoroacetic acid solution and underwent photolysis to yield the pyrrolidine (9a) together with the 205-isomer (9b) in a ratio 8 1. The starting amine (8b) was prepared by hydrogenation of (8c), followed by von Braun demethylation and hydrolysis of the JV-cyano-amine (8d) which was so formed. The n.m.r. spectrum of (8b) and of related amines in the presence of lanthanide shift reagents was discussed.10... 

Recent studies by Baciocchi et al. on kinetic deuterium isotope effect profiles and substituent effects in the oxidizing N-demethylation of iV,JV-dimethylanilines catalyzed by tetrakis (pentafluorophenyl)porphyrin also supports the electron-transfer mechanism and exclude the hydrogen-atom transfer mechanism in such processes [218]. 

The final step in methanogenesis is the reductive demethylation of CH3-S-CoM to CH4. This reduction involves two reactions CH3-S-C0M is reduced with jV-7-mercaptoheptanoylthreonine phosphate (H-S-HTP) (Fig. 2B) as electron donor to yield CH4 and a heterodisulfide of H-S-CoM and H-S-HTP (CoM-S-S-HTP) (Reaction 7, Table 2). This reaction is catalyzed by CH3-S-C0M reductase [70-72] which contains a nickel porphinoid, factorF430, as prosthetic group (Fig. 2C) (for a recent review see Friedmann et al. [73]). The subsequent reduction of the heterodisulfide with H2 to yield H-S-HTP and H-S—CoM (Reaction 8, Table 2) is catalyzed by CoM-S-S-HTP-dependent heterodisulfide reductase. The enzyme is an iron-sulfur protein containing FAD as prosthetic group [74]. The physiological electron donor for the heterodisulfide reductase is not known. 

Oxidative cydization, 321 Oxidative decarboxylation, 101, 280 Oxidative demethylation, 431432 Oxidative methyladon, 431 JV-Oxides, 20, 372 4(5,5(3-0 xidochoIestane-3-one, 97,98 Oxocrinine, 499... 

Oxidative demethylation of A -alkyl-JV-methylanilines with nitrone [258] proceeds via intermediates having a N-O-N subunit. A [2.3]sigmatropic rearrangement leads to the decomposition. 

Alprazolam (C4-hydroxylation), lidocaine (JV-deethylation), erythromycin (N-demethylation), midazolam (Cl -hydroxylation), testosterone (C6j3-hydroxylation)... 

In the mass spectral fragmentation pattern of 3/ -N-demethyl-5a-20(jV)-conene (22), after [2H] labelling in positions 2 and 4, it was demonstrated that hydrogen transfer occurred from C-2 to C-4, giving an insight into the mechanism leading to ions a, characteristic of 3-amino-steroids 14... 

Introduction of more than two nitro groups into jV,A-dimethylaniline is no longer a smooth reaction demethylation and JV-nitration lead eventually to iV-methyl-2,4,6,Af-tetranitroaniline which is used as an explosive under the name Tetryl . 

In an attempt to mimic an enzymatic demethylation process, nitroxide photolysis has been used as a method for oxidizing the C-4 jS-methyl group of 4,4-dimethylcholestanone.158 Further applications have been published of the photolysis of jV-nitrosoamides in the presence of oxygen to the synthesis of nitrate esters having functionalized methyl and methylene groups.180... 

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