Benzodiazepines, reduction reductive acetylation

The fused-ring benzodiazepines (34) have been reductively acetylated electrochemically in acetonitrile at -2.35 V the products were cyclo-propanotetrahydroquinoxalines [79JCS(CC)761] (Scheme 30). 

In acetonitrile some 1,5-benzodiazepine derivatives, prepared by condensation of o-phenylenediamine with 4,6-dimethylbicyclo[3.3.1]nona-3,6-diene-2,8-dione, have been reductively acetylated to substituted barbaralanes [344]. 

Neither the oxide nor the amidine function are in fact required for activity. Treatment of the oxime, 7, with chloro-acetyl chloride in the presence of sodium hydroxide proceeds directly to the benzodiazepine ring system (14)(the hydroxyl ion presumably fulfills a role analogous to methylamine in the above rearrangement). Reduction of the N-oxide function of 14 leads to diazepam (15). ... 

Derivatives of 1-methyl-3//-l,4-benzodiazepine-2,5(l/I,4/I)dione (193) were synthesized by ring closure of substituted 2-(A-chloro-acetyl-A-methylaminoJbenzamides with sodium methoxide in methanol.209 Treatment of 193 with lithium aluminum hydride led to reduction of both carbonyl groups.209 The parent tetrahydro system (194) has been prepared by reaction of the tosylate (195) with 1,2-dibromoethane followed by hydrolysis.210 The preparation of 194 by another route had previously been noted.204 Reaction of 194 with formaldehyde or benzaldehyde gave a compound formulated as 196 (R = H or C6H5).210 Hydrolysis of 196 (R = C6H5) with 0.1 N hydrochloric acid gave 194 while 196 (R = H) was not hydrolyzed at this acidity. 

Clonazepam, U5P. Clonazepam S-(2-chlorophenyl)-3-dihydro-7-nitro-2//-1,4-benzodiazpin-2-one (iCIonopin). partially selective at benzodiazepine allosteric binding sites on GABAa receptors, is useful in ab.sence seizures and in myoclonic seizures. Tolerance to the anticonvulsant effect often develops, a common problem with the benzodiazepines. Metabolism involves hydroxylation of the 3 position, followed by glucuronidation and nitro group reduction, followed by acetylation. 

Clonazepam (8) is almost completely absorbed after oral dosing (96) with an average max of 2-4 h. As with other 7-nitro benzodiazepines, the major metabolic pathway for clonazepam is reduction of the nitro group, acetylation of the resulting amine, and elimination of the acetamide. Hydroxylation of clonazepam or of 7-amino clonazepam to give the 3-hydroxy derivatives represents minor metabolic pathways. The elimination half-life of clonazepam is 20-30 h (97), and no active metabolites are produced. 

Hydroxyamino)benzodiazepine (90) is acylated on oxygen upon reaction with acid chlorides (acetyl or benzoyl chloride) or isocyanates (methyl isocyanate) in the cold. On heating with acetic anhydride at 100°C, there is an oxido-reductive rearrangement to give the 3-acetoxy-2-methylamino derivative (91) (Scheme 14). This is considered to proceed by isomerization of the nitronium ion formed by cleavage of the N—O bond to the 3-carbonium ion which is trapped by the nucleophile (acetate) <80AP(313)926>. A similar mechanism is used to explain the formation of the 3-(l-imidazolyl) derivative (92) on reaction of (90) with carbonyl diimidazole. 

Benzodiazepines are metabolized through a variety of hydroxylation, desalkylation, reduction, and acetylation reactions, followed in many cases by conjugation to glucuronic acid prior to excretion. The most common specimens for the analysis of benzodiazepines are urine, blood, serum/plasma, and liver. Prior to liquid-liquid or SPE, samples should be hydrolyzed. 

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See also in sourсe #XX -- [ ]

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