Benzodiazepin-2-one derivatives

The directed sorting approach has been widely applied both in industry and in academia. Two examples are detailed in this chapter. Some other recently published examples include a benzopyran library synthesized using the Nanokan system,15 libraries derived from phenolic amino acid scaffolds prepared with the Accutag system,16 and libraries of l,5-benzodiazepine-2-one derivatives.17... 

Fig. 12. Sequence spaces for the sequence/structure shown in the right column, (a) Sequence for ssRNA of length 3 with monomers G and A only, (b) Part ofthe sequence space for the 1,4-benzodiazepin-2-one derivative library constructed in Ref. 156. For clarity, not all neighbor relations are shown with lines in this figure. Points which differ at one site are called 1-mutant neighbors. For example, the points marked o are all 1-mutant neighbors of the point marked .

I. Im, T. R. Webb, Y. D. Gong, J.-I. Kim, J.-C. Kim, Solid phase synthesis of tetrahydro-l,4-benzodiazepine-2-one derivatives as a beta-turn peptidomimic library,/. Comb. Chem. 2004, 6, 207-213. 

Vitamin D3 [5] Benzodiazepin-2-one derivatives [6] Method Ascending, one-dimensional development in a trough eham ber. The layer was conditioned for 30 min at 0% relative humidity after the samples had been applied. 

Cyclopropyl-l,5-benzodiazepin-2-ones 4 are converted into 3-chloro derivatives 5 by the action of, V-chlorosuccinimide in contrast, A-bromosuccinimide provides 4-(l -bromoallyl)bcnzo-diazepinones 6 with opening of the cyclopropane ring.269... 

Benzodiazepin-2-ones are converted efficiently into the 3-amino derivatives by reaction with triisopropylbenzenesulfonyl (trisyl) azide followed by reduction <96TL6685>. Imines from these amines undergo thermal or lithium catalysed cycloaddition to dipolarophiles to yield 3-spiro-pyrrolidine derivatives <96T13455>. Thus, treatment of the imine 50 (R = naphthyl) with LiBr/DBU in the presence of methyl acrylate affords 51 in high yield. 

Diazepam From a chemical point of view, diazepam, 7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one (5.1.2), is the most simple of all of the examined derivatives of l,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one (5.1.1), is methylated by dimethylsulfate, which leads to the formation of diazepam (5.1.2). 

Mild alkaline hydrolysis of (186 R = Me) gave the l,4-benzodiazepin-2-one 4-oxide. Grignard reagents react with the nitrone (152 R = R1 = H) and similar compounds to give the 4-hydroxy-5-phenyl derivative (77ACS(B)70l). 

In similar studies, the reduction potentials of 1,2-benzothiazole derivatives in DMF were correlated to antimycotic activity [166], and those of 1,3,5,7-substituted-1,3-dihydro-2H-l, 4-benzodiazepin-2-ones and benzodiazepine-2-thiones in dimethylformamide (DMF)-water solutions were correlated to inhibition of orientation reactions and to protection from electric shock [167]. 

The preferred tautomer of the products derived from the condensation reaction of phenylenediamine with cyclic /3-keto esters (Scheme 5) is highly dependent on the structure of the /3-ketoester <2005JHC1001>. H and 13C NMR analysis of the l,5-benzodiazepin-2-one 34, formed from methyl 2-oxocyclohexanecarboxylate under micro-wave conditions, indicated the presence of the C(4)-N(5) imine <2005JHC1001>. In contrast, the products arising from condensation with methyl 2-oxocyclopentanecarboxylate and methyl l-alkyl-4-oxopiperidine-3-carboxylates were found to be in the enamine form 35. 

The direct azidation of l,4-benzodiazepin-2-ones with trisyl azide provided access to 3-amino derivatives after reduction of the intermediate azide in a process that is compatible with a range of N-l and C-5 substituents (Scheme 15) <1996TL6685>. This protocol offers a convenient alternative to the reduction of a C-3 oxime, obtained by reaction of the l,4-benzodiazepin-2-one with isoamyl nitrite, which requires more vigorous conditions... 

Heating imines derived from 3-amino-l,4-benzodiazepin-2-ones with iV-methylmaleimide in boiling toluene provided adducts derived from the stereospecific cycloaddition of the resonance-stabilized azo-methine ylide 45, formed by a 1,2-prototropic rearrangement, in 82-89% yield (Scheme 16) <1996T13455>. The relative stereochemistry was established by analysis of H NMR NOE data and comparison with the single crystal X-ray structure of an analogous compound. 

Condensation of an amino acid-derived anilide and a /3-ketoamide afforded l,4-benzodiazepin-2-ones in which the initially formed imine tautomerizes to an exocyclic enamide (Scheme SO) <2001TL3227>. Only the (Z)-isomer of the enamide was isolated, assigned based on NOE data, and presumably reflecting stabilization by an intramolecular H-bond between the ring NH and exocyclic amide carbonyl. 

Acetylated derivatives of Baylis-Hillman adducts derived from ethyl acrylate and aromatic and heteroaromatic aldehydes are synthetically accessible three-carbon fragments that readily react with phenylenediamine under the influence of base to provide l,4-benzodiazepin-2-ones in good overall yield, as depicted in Scheme 71 <2006S4205>. 

Substituted derivatives of 3-amino-5-phenyl-l,4-benzodiazepin-2-one continue to be a rich source of compounds that display a diverse range of biological properties. The 2-fluorophenylurea 166 is an inhibitor of respiratory syncytial virus (RSV) that appears to act by inhibiting the nucleocapsid (N) protein <2006JME2311, 2007JME1685>. This compound is the first orally active inhibitor of RSV to be advanced into clinical studies. 

Nitration of l,3-dihydro-5-phenyl-2/f-l,4-benzodiazepin-2-one led to 7-nitro derivatives while 7-substituted compounds were nitrated in the 5-phenyl substituent.204 Nitration of the corresponding 7-un-substituted 1,3,4,5-tetrahydro compound, however, occurs in the 5-phenyl substituent.214... 

An intriguing enantioselective preparation of substituted quaternary 1,4-benzodiazepin-2-one scaffolds has been reported by Carlier et al. <03JA11482>. Enantioselective alkylation is used to prepare chiral products 64 (e.g. R = H R = Me, PhCH2 R = Me2CH) from non-racemic glycine-derived 1,4-benzodiazepinones. If the N1 substituent is sufficiently large (e.g. an isopropyl group) then the stereochemistry at the 3-position of the 3-substituted 1,4-benzodiazepinones is transmitted to the product despite the loss of chirality at C-3 on intermediate enolate anion formation. 

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