A polarographic study of the hydrolysis of 1,4-benzodiazepines and its analytical applications

The mechanism of hydrolysis of flurazepam (Dalmane) and six of its metabolites was investigated in mildly acidic solution (pH 0–2) by differential pulse polarography. Simultaneous determinations of the “parent” compound(s) and hydrolytic degradation product(s) are possible because of the different reduction potentials. The kinetic results can be explained if the hydrolytic reaction is considered reversible; this is important for evaluation of the hydrolysis and absorption of 5-(o-fluorophenyl)-1,4-benzodiazepines in the stomach. The rate constants and the pK_a values corresponding to protonation of the azomethine groups are shown to be correlated. Appropriate kinetic data for other 1,4-benzodiazepines make it possible to evaluate the effects of certain substituents on the rate of hydrolysis and on the peak potentials of the “parent” compounds and their hydrolytic degradation products. The results of the kinetic investigations can be used for the identification of an isolated 5-(o-fluorophenyl)-1,4-benzodiazepine or identification of any 1,4-benzodiazepine studied here which exhibits some degree of acid hydrolysis within 24 h.     

An anomalous reaction of 7-chloro-2-hydrazono-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine with sodium acetate and 1,1′-carbonyldiimidazole

The addition of 7-chloro-2-hydrazono-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine 3 to a mixture of sodium acetate and 1,1′-carbonyldiimidazole 1 at room temperature gave, in moderate yields, carbonyl-1,1′-bis[7-chloro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-ylidene hydrazone] 7 instead of the expected 2-acetylhydrazono-7-chloro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine 4 .     

Me3SiCl-promoted intramolecular cyclization of aromatic compounds tethered with N,O-acetals leading to the facile preparation of 1,4-benzodiazepine skeletons

The Me₃SiCl-promoted intramolecular aminomethylation of a novel type of N,O-acetals, which were prepared via a facile three-step synthesis from N-alkylaniline derivatives and N-alkyl-2-oxazolidinones that leads to the production of pharmaceutically useful 1,4-benzodiazepine skeletons with a variety of functional groups is described. This method was successfully applied to the facile preparation of both tricyclic benzodiazepine derivatives and a 1,4-benzoxazepine derivative via 7-exo-trig cyclization.     

Convergent syntheses of carbon-13 labeled midazolam and 1′-hydroxymidazolam

For the purpose of drug interaction studies, the stable-isotope labeled [¹³C₃]midazolam and its metabolite, 1′-hydroxy-[¹³C₃]midazolam were synthesized in four and five steps in overall yields of 25.5% and 14.2%, from 7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine, respectively, by a convergent synthesis, in which a key imidazoline ring formation was achieved by the facile reaction of [¹³C]2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine with varying ethyl imidate hydrochlorides. The scrambling of C-3 and C-4 labeling in intermediate diamine, and consequently in the final products, as well as the formation of a Δ^4,5 isomer of 1′-hydroxy-[¹³C₃]midazolam was observed and explained.     

1,4-Benzodiazepines and their cyclic homologs and analogs

The dependence of the IR and PMR spectral characteristics of 12 compounds of the 1,2-dihydro-3H-1,4-benzodiazepine series on structural and sterochemical factors was studied. Information in favor of concepts regarding the pseudoboat conformation as the primary one for this type of 1,4-benzodiazepine derivative was obtained.     

Synthesis of 1,4-benzodiazepine-1-carbothioamides,bicyclic analogues of the TIBO-type anti-HIV agents

A series of N'-substituted 1,4 -benzodiazepine-1-carbothioamides 2a-j were prepared by reacting the precursor 1,4-benzodiazepine 11 with the corresponding N-substituted isothiocyanates 2a-i or with sodium thiocyanate-trifluoroacetic acid (2j) . Despite the structural ressemblance of these molecules with the potent TIBO-type anti-HIV compound R82150, 2a-j displayed no anti-HIV activity in vitro.     

Versatile synthesis of chiral 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines as novel scaffolds for peptidomimetic building

The stereocontrolled synthesis of phenylalanine and tryptophan derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives is described. This new methodology involves a modified Strecker reaction of N-Boc protected amino aldehydes and methyl anthranilate, reduction of the resulting α-amino nitriles, and lactamization. The resulting 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines were further functionalized at position 4 by alkylation or acylation reactions. One of these new tryptophan-derived 1,4-benzodiazepines showed significant selective binding affinity at cholecystokinin CCK₁ receptors (IC₅₀=156.5±33.2 nM).     

A new strategy for the synthesis of 1,4-benzodiazepine derivatives based on the tandem N-alkylation-ring opening-cyclization reactions of methyl 1-arylaziridine-2-carboxylates with N-[2-bromomethyl(phenyl)]trifluoroacetamides

A new method for the synthesis of novel 1,4-benzodiazepine derivatives has been established from a one-pot reaction of methyl 1-arylaziridine-2-carboxylates with N-[2-bromomethyl(aryl)]trifluoroacetamides. The reaction proceeds through the N-benzylation and highly regioselective ring-opening reaction of aziridine by bromide anion followed by Et3N-mediated intramolecular nucleophilic displacement of the bromide by the amide nitrogen. The easy availability of starting materials, simple and convenient synthetic procedure, and formation of functionalized 1,4-benzodiazepine scaffold ready for further chemical manipulations render this strategy useful in synthetic and medicinal chemistry.     

Diazepines I. A new synthesis of 6-phenyl-4H-imidazo[1,2-a] [1,4] benzodiazepines

6-Phenyl-4H-imidazo[1,2-a][1,4]benzodiazepines are obtained on reaction of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine with α-bromoketones. In the cases of 3-bromo-2-butan-one and of 3-bromo-2-pentanone, 2-alkylimidazobenzodiazepine but not 1,2-dialkyl compound is the major product. A mechanism for the imidazole ring formation is presented.     

Synthesis of 5-amino-2,3-dihydro-1H-1,4-benzodiazepines

A number of 5-amino-2,3-dihydro-lH-1,4-benzodiazepines (II) have been prepared from the reaction of 5-methylmercapto-2,3-dihydro-1H-1,4-benzodiazepine (I) with amines. Another alternate approach based on the cyclodehydration of the ureic compounds (IV) was unsuccessful. The synthesis of I was accomplished by methylation of the 1,2,3,4-tetrahydro-5H-5-thioxo-1,4-benzodiazepine (VI) with dimethyl sulfate in methanol-dioxane. Another attempted method for the synthesis of I is also presented. J. Heterocyclic Chem., 14, 985 (1977)     

Synthetic Strategies Applicable in the Synthesis of Privileged Scaffold: 1,4-Benzodiazepine

The development of new synthetic approaches to the 1,4-benzodiazepine ring system and their further elaboration have provided access to a broad range of functionalized derivatives. In this review an attempt has been made to summarize those synthetic strategies involved for the synthesis of privileged scaffold 1,4-benzodiazepine over time.     

Chiral diphenylthiophosphoramides: a new class of chiral ligands for the silver(I)-promoted enantioselective allylation of aldehydes

Chiral C₂-symmetric diphenylthiophosphoramides 1 and 2 were prepared in high yields from the reaction of diphenylthiophosphinic chloride with (1R,2R)-(−)-1,2-diaminocyclohexane and (1R,2R)-(+)-1,2-diphenylethylenediamine, respectively. Another novel chiral ligand 4 was prepared from reaction of diphenylthiophosphinic chloride with (R)-(+)-1,1′-binaphthyl-2,2′-diamine using butyllithium as a base. They were used as catalytic chiral ligands in the silver(I)-promoted enantioselective allylation reaction of aldehydes with allyltributyltin.     

The synthesis of bicyclic 1,2,3,4-tetrahydro-1,4-benzodiazepin-5-ones from 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxide precursors

Sulfinylation of o-nitrobenzamide and subsequent hetero Diels-Alder reaction gave a series of 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxides. The 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxides undergo a ring opening reaction with phenyl magnesium bromide to give allylic sulfoxides, which, after [2,3]-sigmatropic rearrangement and desulfurisation, furnish unsaturated vicinal N-(o-nitrobenzoyl)-1,2-amino alcohols. Oxidation of the alcohol and reductive ring closure gave a series of bicyclic 1,2,3,4-tetrahydro-1,4-benzodiazepin-5-ones, a subset of the ‘privileged’ 1,4-benzodiazepine structure. A 4-hydroxy-1,2,5-benzothiadiazepin-1,1-dioxide was synthesised by the same route starting from o-nitrobenzenesulfonamide.     

Synthesis of 1,2,3,4,8,9,10,11-octahydro-[1,4] diazepino[6,5,4-jk ]earbazole and related compounds

1,2,3,4,8,9,10,11-Octahydro[1,4]diazepino[6,5,4-jk]earbazole (VIa) was synthesized from 2,3,4,5-tetrahydro-1H-benzodiazepine (la) via the route shown in Scheme 1. Other compounds which were prepared similarly are 3-acetyl-6-chloro-1,2,3,4,8,9,10,11-octahydro[1,4]diazepino-[6,5,4-jk]carbazole(Vb) and 3-methyl-1,2,3,4,8,9,10,11-octahydro[1,4]diazepino[6,5,4-jk]carb-azole (VIII). Chemical transformations which were carried out with VI and 3-acetyl-1,2,3,4,8,9, 10,11-octahydro[1,4]diazepino[6,5,4-jk]carbazole (Va) are also described.     

C2-Symmetric diphenylphosphoramide and diphenylthiophosphoramide derived from (1R,2R)-1,2-diaminocyclohexane as ligands for the titanium(IV) alkoxide-promoted addition of diethylzinc to aldehydes

Chiral C₂-symmetric diphenylphosphoramide 4 and diphenylthiophosphoramide 5 were prepared from the reaction of diphenylphosphinic chloride and diphenylthiophosphinic chloride with (1R,2R)-(−)-1,2-diaminocyclohexane in the presence of diisopropylethylamine in high yields. They were used as chiral ligands in the catalytic asymmetric addition reaction of diethylzinc to aldehydes in the presence of titanium(IV) isopropoxide to give the corresponding sec-alcohols in 70–83% ee with an (R)-configuration and in 40–50% ee with an (S)-configuration, respectively.     

2-Methyl-1,4-naphthoquinones containing 3-[N-(ω-mercaptoalkyl)alkanamide] chains: synthesis, self-assembling, and electrochemical properties

2-Methyl-1,4-naphthoquinone derivatives containing 3-[N-(ω-mercaptoalkyl)alkanamide] chains were synthesized from ω-bromoalkylamine salts of 2-methyl-3-carboxyalkyl-1,4-naphthoquinones in the presence of N,N′-dicyclohexylcarbodiimide at ambient temperature, and then transformed into the corresponding mercapto derivatives. Their self-assembling and electrochemical properties on gold were studied. The influence of an intrachain amide group on the structure and electron transfer properties of self-assembled monolayers were evaluated by comparison with analogous ester and alkyl chain-containing 2-methyl-1,4-naphthoquinones.     

1,4-Benzodiazepines III . Cyclization paths of hexaminium salts of 2-chioroacetamido-5-ehlorobenzophenone and its N-methyl derivative

This study reports the isolation and characterization of hexaminium salts of 2-chloroacetamido-5-chlorobenzophenone (I) and of 2-(N-methyl)chloroacetamido-5-chlorobenzophenone (II). The 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (VI) and 7-chloro-1,3-dihydro-1-meth-yI-5-phenyl-2H-1,4-benzodiazepin-2-one (VII), respectively are of pharmacodynamic importance. Based on chromatographic separation of some intermediates, and on spectrophotometric monitoring of cyclizations I → VI and II → VII, respectively, two different pathways for these reactions have been proposed. Since the slowest step in the reaction sequence II → VII follows the quasi first order rate law, intramolecular nucleophilic attack of the benzophenone carbonyl group on the hexamine moiety proved to be decisive for the cyclization (scheme II). However, cyclization I → VI seems to incorporate quite different solvolytic pathways in addition to one corresponding to the sequence II → VII. Isolated 4-imidazolidinone intermediates N,N' -methylene-bis[3-{2 -benzoyl-4-chIoro)phenyI]-4-imidazolidinone(III), and 3-(2 -benzoyl-4′-chlorophenyI)-4-imidazolidinone hydrochloride (IV) recyclize into the 1,4-benzodiazepine VI. The optimal reaction conditions have been found to be between pH 6-7.     

Synthesis of triazolo[4,3-d], tetrazolo[1,5-a] -and quinazolino[3,2-d] [1,4] benzodiazepines

Treatment of 5-methylmercapto-1,4-benzodiazepine (I) with hydrazine hydrate gave the 5-hydrazino derivative (II, R = H) which, in turn, was conveniently cyclized to the title compounds. Another method for the synthesis of triazolo [4,3-d] [1,4] benzodiazepines (III) is also described.     

Chiral 1,4-benzodiazepines. XII. Conformation in a solution of 7-chloro-5-phenyl-3(S)methyl-1,3-dihydro-2H-1,4-benzodiazepine

Deuterium labeled congeners of 7-chloro-5-phenyl-3(S)-methyl-1,3-dihydro-2H-1,4-benzodiazepine ( 8 ), i.e., compounds 9 and 16-18 were prepared and their lis-nmr spectra run. For computational studies compounds 9 and 16 were chosen. The results of lis measurements revealed that 16 is present in more than 97% in the boat-like conformation I (Scheme 3).     

Schmidt Reaction on 2-Aryl-1,2,3,4-tetrahydro-4-quinolone

Synthesis and stereochemistry of 2-aryl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one and 2-aryl-2,3-dihydro-4H-tetrazolo [1,5-d]-1H-1,4-benzodiazepine is reported by the Schmidt reaction on 2-aryl-1,2,3,4-tetrahydro-4-quinolone.