Deethylation

A cinnamoylamide, cinromide (44), is a long-acting anticonvulsant similar in its clinical effects to phenacetamide but is less hepatotoxic. The synthesis involves the straightforward amidation of acid via the intermediate acid chloride (SOCl 2) It appears that the drug is mainly deethylated in... 

The oxidation of OPs can bring detoxication as well as activation. Oxidative attack can lead to the removal of R groups (oxidative dealkylation), leaving behind P-OH, which ionizes to PO . Such a conversion looks superficially like a hydrolysis, and was sometimes confused with it before the great diversity of P450-catalyzed biotransformations became known. Oxidative deethylation yields polar ionizable metabolites and generally causes detoxication (Eto 1974 Batten and Hutson 1995). Oxidative demethy-lation (0-demethylation) has been demonstrated during the metabolism of malathion. 

Excretion of free atrazine in urine is consistent with the pattern of exposure, with maximal excretion rates at the end of the workshift and a rapid decrease after cessation of exposure. This pattern suggests that atrazine does not accumulate in the body (Catenacci et al., 1990). Atrazine metabolism gives rise to bi-dealkylated (80%), deisopropylated (10%), and deethylated (8%) metabolites, which are eliminated in urine over a period slightly longer... 

Other chlorotriazines (simazine, propazine, terbuthylazine) follow the same biotransformation pathway of atrazine therefore, urinary excretion of bi-dealkylated, deisopropylated, and deethylated metabolites is not compound specific. When simultaneous exposure to different chlorotriazines occurs, the unmodified compound measured in urine, even though it represents a minor portion of the absorbed dose, may be useful for a qualitative confirmation of exposure. 

Ethylisoeugenol and ethoxyanisole can be selectively demethylated or deethylated by use of potassium t-butoxide in the presence of 18-crown-6 (Eq. 56) [79]. 

Under solvent-free conditions only deethylation is observed whereas in the presence of ethylene glycol (EG), the selectivity is totally reversed and demethylation becomes the major process. In both, considerable increases in reaction rate were observed under the action of microwave irradiation when compared with classical heating (A) (Tab. 5.27). 

Tab. 5.28 Deethylation of 2-ethoxyanisole within 20 min under MW + PTC conditions (KOtBu 2 equiv. TDA-1 10%).

The liver, known as the chemical reactor of the body, serves to eliminate drugs and other compounds from the body. In one such process, lidocaine (a drag given to heart attack patients) may be converted either into MEGX by deethylation, or into hydroxylidocaine (OHLDD) by hydroxylation. Assuming that the liver may be represented by a CSTR, determine the... 

N-demethylation at the three N-methyl sites. In this regard, the 3-N-demethylation of caffeine to generate paraxanthine can serve as a particularly good in vivo indicator of the presence and activity of CYP1A2 (Fig. 4.7). In the case of phenacetin, CYP1A2 catalyzes N-deethylation to generate acetaminophen. Not unexpectedly, 1 A2 s selectivity toward heterocyclic aromatic substrates carries over to inhibitors of the enzyme. Furafylline (Fig. 4.7) is an example of a particularly potent 1A2 mechanism-based inhibitor. 

Carbinolamines are chemically unstable and, in the case of tertiary amines, dissociate to generate the secondary amine and aldehydes as products or eliminate water to generate the iminium ion. The iminium ion, if formed, can reversibly add water to reform the carbinolamine or add other nucleophiles if present. If the nucleophile happens to be within the same molecule and five or six atoms removed from the electrophilic carbon of the iminium ion, cyclization can occur and form a stable 5- or 6-membered ring system. For example, the 4-imidazolidinone is a major metabolite of lidocaine, which is formed in vivo or can be formed upon isolation of the A -deethyl metabolite of lidocaine if a trace of acetaldehyde happens to be present in the solvent used for extraction (116,118) (Fig. 4.52). 

Arylhydrocarbon (benzo[a]pyrene) hydroxylase, benzphetamine-N-demethylation, ethylmorphine-N-demethylation, ethoxycoumarin-0-deethylation and ethoxyresorufin-0-deethylation were performed by published procedures (31,32,33,34), but optimized for use with trout microsomes as described previously (30, 35). Hemoprotein P-450 was determined by the procedure of Estabrook et al. (36) to avoid spectral interference by hemoglobin. Microsomal protein content was estimated either by the method of Ross and Shatz (37) or Lowry et al. (38), using bovine serum albumin standards. 

In this study, we have utilized 2,2, 4,4 -tetrachlorobiphenyl and 3,3, 4,4 -tetrachlorobiphenyl as representative non-coplanar and coplanar isomers respectively. The 3,3, 4,4 -tetrachlordbi-phenyl isomer (0.3mmole/kg) induced ethoxycoumarin-and ethoxy-resorufin-O-deethylations in the rainbow trout to a similar extent as did Aroclor 1242 (Table III). However, the non-coplanar 2,2 -4,4 -tetrachlorobiphenyl was without effect upon any of the monooxygenase activities examined. Cytochrome P -450-like activity as determined by ethoxyresorufin-O-deethylation was increased by the planar 3,3, 4,4 -tetrachlorobiphenyl while cytochrome P-450-like activity (benzphetamine-N-demethylation) was unaffected. 

Ullrich, V. and Weber, P. The 0-deethylation of 7-ethoxycou-marin by liver microsomes. Hoppe-Seyler s Z. Physio 1 Chem. 

Burke, M.D. and Mayer, R.T. Ethoxyresorufin Direct fluori-metric assay of a microsomal O-deethylation which is preferentially inducible by 3-methylcholanthrene. Drug. Metab. Disp. (1974) 2 583-588. 

Fig. 4.3. Hydrolysis pathways in the metabolism of epicainide (4.29). Pathway a direct hydrolysis of the secondary amide function. Pathway b hydrolysis of the primary amide (4.30) formed by oxidative (V-dealkylation. Pathway c hydrolysis of the intermediary metabolite (4.31) formed by (V-deethylation and subsequent oxidation of the pyrrolidine moiety [17].

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. 

Fig. 4.6. Metabolic pathways of 4- [(diethylamino)aeetyl]amino -N-(2,6-dimethylphenyl)benzamide (4.140) in mice [86]. The metabolites formed by consecutive IV-deethylation (4.141 and 4.142) as well as of the parent compound are hydrolyzed at the amido bond to produce ameltolide (4.143).

Hydrocracking, 30 48-52 behavior, thermal, 29 269 catalytic, 26 383 deethylation, 30 50 demethylation, 30 50 metallocarbene formation, 30 51-52 of f -decane, 35 332-333 primary coal liquids, 40 57 procedure, 40 66-67 product distribution, 30 49 reactions, over perovskites, 36 311 suppression by sulfur, 31 229 zeolite-supported catalysts, 39 181-188... 

The catalysts for xylene isomerization with EB dealkylahon are dominated by MFI zeolite. The de-ethylation reaction is particularly facile over this zeolite. There have been several generations of catalyst technology developed by Mobil, now ExxonMobil [84]. The features in their patents include selectivation and two-catalyst systems in which the catalysts have been optimized separately for deethylation of EB and xylene isomerization [85-87]. The crystallite size used for de-ethylation is significantly larger than in the second catalyst used for xylene isomerization. Advanced MHAI is one example. The Isolene process is offered by Toray and their catalyst also appears to be MFI zeoUte-based, though some patents claim the use of mordenite [88, 89]. The metal function favored in their patents appears to be rhenium [90]. Bimetallic platinum catalysts have also been claimed on a variety of ZSM-type zeolites [91]. There are also EB dealkylation catalysts for the UOP Isomar process [92]. The zeolite claimed in UOP patents is MFI in combination with aluminophosphate binder [93]. 

The 2-phenyl derivative of 4-ethoxy-l-ethylpyrimidinium tetrafluoro-borate undergoes with liquid ammonia deethylation at N-1 as well as deethoxylation at C-4, a mixture of 4-ethoxy-2-phenylpyrimidine (18) and l-ethyl-4-imino-2-phenylpyrimidine (19), respectively, being obtained (Scheme IIL12) (77RTC183). 

Investigation of the deethylation with N-labeled ammonia showed that in 18 the label is incorporated for about 100% in the pyrimidine ring. Evidently the Sn(ANRORC) mechanism is operative in the replacement of the quaternary ring nitrogen by the amino nitrogen. The initial step in this deethylation reaction will probably be adduct formation on C-6, i.e., 17. Addition at C-2 is less likely because of the presence of the phenyl group at that position (Scheme III.12). 

Reaction of 4,6-diethoxy-l-ethylpyrimidinium tetrafluoroborate (21) showed similar behavior no N-deethylation, but deethoxylation at position 4 as well as at position 6 was observed, as indicated by the formation of the two isomeric products l,4-dihydro-6-ethoxy-l-ethyl-4-iminopyrimidine hydrogen tetrafluoroborate (23) and l,6-dihydro-4-ethoxy-l-ethyl-6-... 

The observation was made that the reaction of A -ethyl-4-ethoxypyrimi-dinium salts with liquid ammonia not only gives A -deethylation and deethoxylation products, but sometimes also yields 4(6)-(ethylamino) pyrimidines. For example, treatment of 6-ethoxy-l-ethyl-4-phenylpyrimi-dinium salt with liquid ammonia gives, besides the 6-imino- and the... 

The major degradation of atrazine in soil was its conversion to hydroxyatrazine by loss of the chlorine atom (2-5). Dealkylation also occurred with deethylation predominating over deisopropyla-tion (5,6). Only small amounts of the radioactivity of the ring labeled atrazine was converted to C02 by soil (6,8-10). Geller (11) found that the percentages of evolved "from C-labeled... 

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