A-dealkylation

The feedstock is usually extracted toluene, but some reformers are operated under sufftciendy severe conditions or with selected feedstocks to provide toluene pure enough to be fed directiy to the dealkylation unit without extraction. In addition to toluene, xylenes can also be fed to a dealkylation unit to produce benzene. Table 20 Hsts the producers and their capacities for manufacture of benzene by hydrodealkylation of toluene. Additional information on hydrodealkylation is available in References 50 and 52. 

The fate of the dinitroaniline herbicides in soil is extremely complex and many metabolites have been identified. Golab and Althaus reported 28 metabolites identified in a degradation study of trifluralin in soil. Major degradation products of dinitroaniline herbicides were formed by nitro reduction, A-dealkylation (mono-dealkylated and completely dealkylated) and the ring formation of benzimidazole. 

Phenacyl-3-phenyl-l,2-dihydroquinoxaline (208) gave 2-phenylquinoxaline (HC1, MeOH, H20, reflux, 15 min 53% acetophenone also isolated as its dinitrophenylhydrazone. Note that this is a passenger deacylation in the course of a dealkylation).782... 

It should be noted that the preparation of complexes (RNC)AuCN can be carried out via very special routes. Thus AuCN reacts with Mel to give (MeNC)AuCN. This reaction involves an interesting A-alkylation of an Au(i)-bound cyanide group.219 Other (RNG)AuGN complexes were obtained from the reaction of K[AuC14] with the isocyanide in methanol. Examples are the compounds (L)Au2(CN)2 with L = l,8-diisocyano-/>-menthane or 2,5-diisocyano-2,5-dimethyl-hexane. The reactions proceed with a dealkylation of an isocyanide in the coordination sphere of a gold(m) center to produce free cyanide (Scheme 53).201... 

UNIDAK A process for extracting naphthalene from reformer residues in petroleum refining. It includes a dealkylation stage to convert the naphthalene homologues to naphthalene. 

Peptidylglycine a-amidating monooxygenase (PAM) Pituitary, heart Oxidative A-dealkylation... 

When Tonnesen et al. used an immersion lamp giving emission wavelengths between 240 and 600 nm, the same four photodegradation products were obtained from solutions of hydroxychloroquine (313) in water or isopropanol. Compounds (314) to (317) all derived from A-dealkylations. It was particularly noted that no photodechlorinated products were obtained in this work [181]. 

It is interesting to note that the A1 -alkylbenzodiazepines can be analysed by a method that involves photodealkylation. The compounds are acid-hydrolysed to benzophenones and run on a plate to separate primary and secondary amines. The plate is then exposed to UV light for 10-15 min, which causes A-dealkylation, and run in the second dimension to identify the primary aminobenzophenones [230]. 

Quaternary fluorinated alkyl ammonium compounds The fluorine-containing cationic surfactants of quat type with the general formula C F2 , 1-S02-NH-CH2-CH2-CH2-N (CH3)3 X (n = 8) (Fig. 2.12.1(d)) were examined by FIA—MS using APCI and ESI in the positive and negative modes. The APCI(- -/—) ionisation resulted in a dealkylation at the nitrogen with ions at m/z 585 or 583, respectively. The alkyl chain of this compound contained the moiety C8Fi7. The ions generated under APCI conditions were characterised as dealkylation products—m/z 585 [M — CH2]+ or m/z 583 [M — H— CH3] —as reported in the literature [35,37]. 

In Fig. 19(6) the formation of a hydrogen bond is envisaged followed by the attachment of the positive P atom to the negative site and elimination of HF (fig. 19 (c)). Reversal, when possible,3 is represented in fig. 19(d). The inhibitor is of course hydrolysed at the end of the reaction. It may well be that (i 0)2P0(0H) is not actually recoverable, but that the regeneration process involves, first of all, a dealkylation which then facilitates the removal of the phosphate moiety from the enzyme.4... 

The simplest structures in this series are A-methyl- and A-ethylbenz-amide (4.73 and 4.74, respectively). When administered intraperitoneally in rats, these amides yielded methylamine and ethylamine, respectively, plus benzoic acid, which was detected in the urine as hippuric acid [47]. An alternative metabolic pathway is possible, involving A-dealkylation to the primary amide followed by hydrolysis its contribution, if any, must be minor, since benzamide levels in urine were negligible. 

A simple example in this class with which to begin is A,A-diethyl-m-to-luamide 0V,/V-dicthyl-3-mcthylbenzamidc, DEET, 4.82), an extensively used topical insect repellant. The hydrolysis product 3-methylbenzoic acid was detected in the urine of rats dosed intraperitoneally or topically with DEET. However, amide hydrolysis represented only a minor pathway, the major metabolites resulting from methyl oxidation and A-dealkylation [52], Treatment of rats with /V,/V-dicthylbcnzamidc (4.83), a contaminant in DEET, produced the same urinary metabolites as its secondary analogue, A-ethylbenzamide (see Sect. 4.3.1.2). This observation can be explained by invoking a metabolic pathway that involves initial oxidative mono-A-deethylation followed by enzymatic hydrolysis of the secondary amide to form ethylamine and benzoic acid [47], Since diethylamide was not detected in these experiments, it appears that A,A-diethylbenzamide cannot be hydrolyzed by amidases, perhaps due to the increased steric bulk of the tertiary amido group. 

The hepatic injury caused by iproniazid could also be due to the formation of the toxic metabolite hydrazine by A-dealkylation followed by hydrolysis. Indeed, A-dealkylation is a main route in the metabolism of iproniazid, with plasma levels of hydrazine in rabbits three- to sixfold higher than after isoniazid [188],... 

In contrast to the A-monosubstituted carbamates, the A,A-disubstituted analogues (8.124 and 8.125, R = R R"NCO R = Me or Et R" = Me, Et, i-Pr, etc.) proved very stable at pH 7.4 in both buffer and plasma, with less than 5% degradation in 4 d. In fact, these compounds were potent inhibitors of plasma cholinesterase (EC 3.1.1.8), with K values ranging from 600 to 3 nM. Although these carbamates were stable in plasma, they underwent rapid bioactivation in liver, as demonstrated with mouse and rat liver microsomes. For example, the A,A-dimethylcarbamate (8.124, R = Me2NCO) was bioactivated in rat liver microsomes with t1/2 of ca. 30 min. Two routes of bioactivation were postulated, namely direct carboxylesterase-catalyzed hydrolysis, and cytochrome P450 mediated A-dealkylation to a more labile A-monosubstituted carbamate. 

As in carboxylic esters it is possible to substitute alkoxy groups of Fischer-type carbene complexes by non-carbon nucleophiles, such as other alcohols [73,214,218], enols [219], aliphatic amines [43,64,66,220-224], aniline [79], imines [225], or pyrroles [226]. Strong nucleophiles can also lead to a dealkylation of methoxy-substituted carbene complexes (5 2 at the methyl group, [227]), in the same way as methyl esters can be cleaved by nucleophiles such as iodide. Carbon... 

In the presence of hydroxy or perhydroxy radicals generated from Fenton s reagent, atrazine undergoes oxidative dealkylation in aqueous solutions (Kaufman and Kearney, 1970). Major products identified by GC/MS included deisopropylatrazine (2-chloro-4-ethylamino-6-amino-s-triazine), 2-chloro-4-amino-6-isopropylamino-5-triazine, and a dealkylated dealkylatrazine (2-chloro-4,6-diamino-s-triazine) (Kaufman and Kearney, 1970). 

Insect steroid metabolism has two biochemically distinctive components dealkylation of phytosterols to cholesterol and polyhydroxylation of cholesterol to ecdysone. We will focus on the first of these. Lacking the ability to synthesize sterols de novo, insects instead have evolved a dealkylation pathway to convert plant sterols to cholesterol(7-10). The dealkylation pathways are apparently absent in most other higher and lower organisms, which can convert mevalonate to squalene and thence into sterols( ). Specific insecticides are possible based on these biochemical differences. 

Variability in metabolism A subset (approximately 7%) of the population is devoid of CYP2D6, the enzyme responsible for the formation of the 5-hydroxymethyl metabolite of tolterodine. The identified pathway of metabolism for these individuals ( poor metabolizers ) is by dealkylation via cytochrome P450 3A4 (CYP3A4) to A/-dealkylated tolterodine. The remainder of the population is referred to as extensive metabolizers. Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite. 

Another route to the bicyclic phosphazenes is through a dealkylation-cum-transannular attack in the reactions of N4P4CI8 with the bulky diben-zylamine biyclic phosphazenes are formed where the bridgehead is an amino substituent which has underwent a dealkylation [67]. 

Investigation of the in vitro metabolism of delavirdine is accomplished using mouse, rat, dog, monkey, rabbit, and human liver microsomes. The primary metabolite observed is the A-dealkylated delavirdine 26. Another primary metabohte observed is the hydroxy-lation of the pyridine ring at C-6 (compound 27). The primary metabolism is by CYP3A4 and also CYP2D6. Delavirdine reduces the activity of CYP3A4, thereby inhibiting its own metabolism. 

Kinetic parameters of metabolism of fluorinated analogues of propanolol by a cytochrome enzyme (recombinant CYP1A2) have been determined. They clearly indicate that the A/-dealkylation was almost tenfold lower for the A/-CH2CF3... 

Metabolism of the anti-malarial amodiaquine provides quinone-imine, which is an electrophilic metabolite responsible for hepatotoxicity and agranulocytosis. These side effects have severely restricted the clinical use of amodiaquine. The replacement of the phenolic hydroxyl by a fluorine prevents from oxidation process. Then, the A/-dealkylation becomes the major process. This has led to further refinements, with the preparation of the A/-f-butyl analogue, a compound which resists towards metabolic side-chain cleavage and has an excellent in vitro and in vivo profile (Fig. 15) [56]. 

Kinetic parameters of metabolism of fluorinated analogues of propanolol by cytochrome enzyme (recombinant CYP1A2) have been determined. They clearly indicate that the A-dealkylation process was 10-fold lower for the N—CH2CF3 compound with respect to propanolol itself. Hydroxylation of the naphthalene ring process is not observed in the case of propanolol but it becomes the major process with the fluoro analogue (Figure 3.13)." The same decreased metabohsm trend has also been observed with lower pKa values for CYP2D6 cytochrome enzyme." ... 

One of the more common pathways for the metabolic transformation of tertiary amines involves A -dealkylation to a secondary amine. The observation that those products often show the same biological activity as the parent dmg in many cases confounds the issue of the identity of the chemical species responsible for the drug s action. The fact that the dealkylation product of disobutamide shows antiarrhythmic activity in its own right prompted the synthesis of the acetyl derivative of that secondary amine this agent may be considered a latent form of the active metabohte. This compound is prepared by first repeating the penultimate step in the disobutamide synthesis using (Af-benzyl-Af-isopropyl)-2-chloroethylamine instead of the diisopropyl intermediate. The product from that reaction (56-1) is then hydrolyzed to the... 

Benzodiazepines undergo extensive and complex metabolism. They are excreted mainly in the urine, largely in the form of several metabolites. Biotransformation processes include mainly hydroxylation and A-dealkylation reactions, whereas the end-products include both free and conjugated compounds (116). Chlordiazepoxide, for example, is metabolized to oxazepam and other metabolites and, depending on its dosage, urine may contain significant concentrations of oxazepam (117). 

The transalkylation of fm-alkylbenzenes follows a different route, since they have no abstractable benzylic hydrogen. They were shown to transalkylate by a dealkylation-transalkylation mechanism with the involvement of free ferf-alkyl cations. The exceptional ability of fcrt-alkyl groups to undergo transalkylation led to the extensive utilization of these groups, especially the fm-butyl group, as positional protective groups in organic synthesis pioneered by Tashiro.223... 

Many substances can be partially oxidized by oxygen if selective catalysts are used. In such a way, oxygen can be introduced in hydrocarbons such as olefins and aromatics to synthesize aldehydes (e.g. acrolein and benzaldehyde) and acids (e.g. acrylic acid, phthalic acid anhydride). A selective oxidation can also result in a dehydrogenation (butene - butadiene) or a dealkylation (toluene -> benzene). Other molecules can also be selectively attacked by oxygen. Methanol is oxidized to formaldehyde and ammonia to nitrogen oxides. Olefins and aromatics can be oxidized with oxygen together with ammonia to nitriles (ammoxidation). 

Oxidative reactions at carbon predominate in the biotransformation of cyclic amiiies, and an important consequence of this is often the cleavage of the carbon-nitrogen bond. For example, A-dealkylation of N- alkyl substituted pyrrolidine (or piperidine, morpholine, etc.) involves an initial oxidative attack at the a- alkyl carbon atom to yield an N hydroxyalkyl derivative (carbinolamine), which is then metabolized to a secondary amine and the corresponding aldehyde. The metabolic conversion of nicotine to nornicotine (30 see Scheme 3) probably involves this mechanism, although the iminium ion (31) has also been suggested as an intermediate in the biotransformation (76JMC1168). Carbinolamines are unstable intermediates and have been identified only in a few cases, e.g. A-hydroxymethylcarbazole... 

Thiophene-2-carbaldehyde has become extremely cheap and easily available through the Vilsmeier formylation of thiophene. The reactions of thiophene substrates with several iminium salts have been investigated (B-76MI31400). 3-Phenylthiophene gives 4-phenylthiophene-2-carbaldehyde with chloromethylene iminium ion. In the case of 2-methoxy-5-methylthiophene, a dealkylation takes place above 50-70 °C. If the intermediate iminium salt (91) is formed at 20 °C and then hydrolyzed, the aldehyde (92) is obtained. 

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