An expedient synthesis of 3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one

Racemic 3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 2, was prepared in four steps utilizing a novel mercuric ion assisted ammonia displacement of an N-acyl alkylthioglycine amide 5.     

Nitration of 8-substituted 2,3-dihydro-1H-1,5-benzodiazepin-2-ones

The nitration of a number of 8-R-4-R-2,3-dihydro-1H-1,5-benzodiazepin-2-ones with substituents in the diazepin (4-R=CH₃, C₆H₅, and C₆H₄OCH₃-p) and benzene (8-R=Cl, Br) rings takes place in the 7 position. The presence in the benzene ring of a strong electron-donor substituent (methoxy group), by determining the direction of electrophilic substitution in the ortho position with respect to it, leads to the formation of 7- and 9-nitro isomers in a ratio of 43.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 551–554, April, 1978.     

Reactions of 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2,2-dioxide in Various pH Solutions

Diazepam ( 1 ) is a frequently prescribed hypnotic/anxiolytic drug worldwide. 7-Chloro-1,3-dihydro-l-methyl-5-phenyl-2H-1,4-benzodiazepin-2,2-dioxide ( 2 ) is an initial alkaline hydrolysis product of 1. The mechanisms in the conversion of 2 to 2-methylamino-5-chloro-α-(phenylbenzylidene)glycinate ( 3 ), 2-methylamino-5-chlorobenzophenone ( 4 ), and 1 in aqueous solutions with pH ranging from 0 to 12.2 is the subject of this report. Results of temperature-dependent hydrolysis kinetics and product identification indicated that: (1) in solutions with pH between 7 and 12.2, 2 underwent a ring-opening reaction to form 3; the rate decreased with increasing pH. (2) In solutions with pH between 2 and 7, 2 was rapidly converted to 3, followed by a pH-dependent conversion to 4 ; the rate increased with decreasing pH and became less sentitive to pH at pH ≤ 4.5. (3) In solutions with pH between 0 and 2, 2 was rapidly converted to 4 and 1; the percentage of 1 increased with decreasing pH. (4) A 2 containing one oxygen-18 atom lost 50% of its oxygen-18 following conversion to 1 in 1 M HCl. In addition to understanding the mechanism in the transformations of 2 in various pH solutions, this study established a simple and efficient method in the quantitative conversion of 1 to 4 and in the preparation of an oxygen-18-containing 1 at C2 position.     

Comparative study on the preparation of C(3)-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-ones

C(3)-Hydroxy-1,4-benzodiazepin-2-ones 1–3 have been prepared in high yields using a new, two step approach. In the first step, the 3-deoxy-precursors 4–6 were acetylated at C(3) using the redox-system lead tetraacetate and iodine, or potassium iodide, in acetic acid. The intermediary acetates 9–11 were quantitatively hydrolyzed into 1–3 in non-aqueous conditions, i.e. in a methanol-methylene chloride solvent mixture in the presence of sodium methoxide. Another route to the title compounds has been improved as follows. The yields of C(3)-bromination of compounds 4–6 has been significantly augmented in relation to the known methods using the strong trifluoroacetic acid in very dilute carbon tetrachloride solutions as a catalyst for NBS mediated bromination. The intermediary C(3)-bromo derivatives have been acetoxylated in situ, and compounds 9–11 have been isolated in over 80% yield. These compounds were solvolyzed into 1–3 as described above. The third part of this paper describes the search for feasible reaction conditions in the synthesis of 3 according to a known method (Scheme 1.); optimization of the yields in all steps was performed.     

Mass spectra of 3-arylidene-1H-2,3-dihydro-1,4-benzodiazepin-2-ones

The scheme of the fragmentation of arylidene derivatives of 5-phenyl-1,4-benzodiazepin-2-ones was established by means of high-resolution mass spectrometry. One of the principal fragmentation pathways of these compounds is cleavage of the 2C-3C and 4N-5C bonds to give two fragments. Depending on the substituents in the arylidene portion of the molecule, the charge is localized primarily on one or the other of these fragments. The mechanism of the formation of the [ArCH₂]⁺ ions observed in the mass spectra of all of the investigated compounds was established on the basis of the mass spectrum of the 1N-deuterium-labeled compound. The specific fragmentation pathways due to the ortho effect of the nitro group are discussed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1690–1696, December, 1976.     

Synthesis of 1,4-dihydro-4-methyl-1-phenyl-5H-1,3,4-benzotriazepin-5-ones

The synthesis of 1,4-dihydro-4-methyl-1-phenyl-5H-1,3,4-benzotriazepin-5-one ( 4a ) and its 8-chloro analog ( 4b ) is described. Attempted synthesis of the 2-methyl analog of 4a from 2-(phenylamino)benzoic acid 1-methylhydrazide ( 10 ) and triethyl orthoaeetate led only to the Schiff base intermediate, 2-(phenylamino)benzoic acid 2-(1-ethoxyethylidene)-1-methylhydrazide ( 11 ). Cyclization of 11 was attempted unsuccessfully with a variety of reagents. The intere?ting reaction products from the treatment of 11 with trifluoroacetic acid are described.     

Nuclear magnetic resonance of 1,4-benzodiazepines. II Stereochemistry of 1,3-dihydro-2H-1,4-benzodiazepin-2-ones by lanthanide shift reagents

The sterochemistry of some 1,3-dihydro-2H-1,4-benxodiazepin-2-ones, employed as psychotherapeutic agents, is deduced by proton magnetic resonance using the paramagnetic shift reagent Eu(fod)₃. the lanthanide induced shifts are computer simulated on the basis of the geometric parameters of the protons in different model structures, having intermediate conformations between a cycloheptadiene- and a cyclohepatatriene-like system. N-Desmethyldiazepam shows a conformational equilibrium between two pseudoboat forms, while the 1-alkyl substituted derivatives exist, at room temperature, in olny one boat cycloheptatriene-like conformation.     

New synthesis of 1,3-dihydro-1,4-benzodiazepin-2(2H)-ones and 3-amino-1,3-dihydro-1,4-benzodiazepin-2(2H)-ones: Pd-catalyzed cross-coupling of imidoyl chlorides with organoboronic acids

A new approach to the synthesis of 1,4-benzodiazepines and 3-amino-1,4-benzodiazepines, which employs the Pd-catalyzed cross-coupling reaction of an imidoyl chloride with an organometallic reagent as the key step, is described. A five-step synthesis of a key intermediate is described and it is shown that in only four further steps (three couplings and a TFA-mediated BOC-deprotection) a wide variety of N1-, C3-amino-, C5-carbon-, or nitrogen-substituted 1,4-benzodiazepines can be synthesized.     

Molecular-crystal structure of 5-methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one

5-Methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one, which is an antagonist of 5-aryl-1,2-dihydro-3H-1,4-benzodiazepin-2-ones, was subjected to a complete x-ray diffraction study. The crystals have monoclinic syngony witha = 11.456(5), b = 8.195(3), c = 9.257(4) Å, = 93.10(3) °, and space group P2₁/b. The nonplanar molecules (with a boat conformation) form cyclic dimers by means of NH...O hydrogen bonds (2.937 Å) in the vicinity of the center of symmetry (0, 0, 1/2). Replacement of the phenyl ring in the 5 position by a less bulky methyl group does not lead to appreciable changes in the geometry and conformation of the heteroring. It is assumed that the substituent in the 5 position plays a role in determining the character of the pharmacological action of 1,4-benzodiazepines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 985–988, July, 1982.     

Nitration of 7- and 8-methyl-4-R-1H-2, 3-dihydro-1,5-benzodiazepin-2-ones

4-R-8-Methyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones are nitrated in the 7 position, whereas their 7-methyl analogs are nitrated in the 1, 8, or 9 position. The nitration of 4,8-dimethyldihydrobenzodiazepinone proceeds as primary substitution at the N₁ atom of the amide group. The resulting N₁-nitroamide undergoes prototropic rearrangement to the 9-nitro isomer in strongly acidic media.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 122–126, January, 1978.     

Die Bestimmung des Psychotherapeutikums Valium (Diazepam = 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2 H-1,4-benzodiazepin-2-on) im Blut

Ohne Zusammenfassung     

Formylation of 4-aryl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones

The formylation of 8-chloro- and 8-methoxy-4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones with the Vilsmeier reagent leads to 3-dimethylaminomethylene derivatives which, in the case of the 8-chloro derivative, have been converted by hydrolysis in acetic acid into 8-chloro-3-formyl-4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones.Translated from Khimiya Geterotsiklicheskaya Soedinenii, No. 9, pp. 1262–1265, September, 1984.     

Synthesis of 4-Pyridyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones

4-Pyridyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones were obtained by the condensation of ethyl nicotinoyl- or isonicotinoylacetates with o-phenylenediamine. Alkylation of the pyridylbenzodiazepinones with ethyl iodide under phase-transfer catalysis conditions occurred at the amide nitrogen of the heterocycle, whereas in nitromethane it occurred at the nitrogen of the pyridine substituent. Bromination with N-bromosuccinimide occurred at position 3 of the heterocycle. Pyridyldibenzodiazepinones underwent thermal rearrangement to derivatives of vinylbenzimidazole.