Synthesis of some 7-α-carboxyethyl-1,3-dihydro-(2H)-1,4-benzodiazepin-2-ones

1,4-Benzodiazepin-2-ones possessing an α-carboxyethyl group in 7-position (21-25) were prepared from a key compound, 2-amino-5-α-carboxyethylbenzophenone (8) or from its O-benzyl derivative 14 , using methods developed previously. An optimized route to 8 starting from 2-nitro-5-chlorobenzophenone ( 1 ), as well as some unsuccessful attempts are described. Compound 8 was deaminated into racemic α-(3-benzoyl)-phenylpropionic acid ( 9 ), a well-known antiinflammatory agent.     

Nitration products of substituted 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones

Highly substituted, novel, 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones were obtained by direct nitration of the corresponding mono- or di-substituted 5-phenyl-1,4-benzodiazepines. Substituent effects and the orientation of aromatic substituents in the nitration products are discussed. The single-crystal X-ray structural data for one of these products, 18 , is given.     

Synthesis of 2-amino-3-hydroxy- and of 2,3-diamino-3H-1,4-benzodiazepines

A new synthesis of 7-chloro-2,3-diamino-5-phenyl-3H-1,4-benzodiazepines is described, which allows for the preparation of compounds bearing the same or different substituents at the 2 and 3 positions, starting from 2-amino-7-chloro-3-hydroxy-5-phenyl-3H-1,4-benzodiazepines.     

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.     

Novel application of Leuckart-Wallach reaction for synthesis of tetrahydro-1,4-benzodiazepin-5-ones library

A novel and efficient strategy has been developed to synthesize privileged tetrahydro-1,4-benzodiazepines with excellent yields and purities; this synthetic pathway was established by the revitalization of the Leuckart-Wallach (LW) reaction via solid-phase synthesis.     

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.     

Communication: polymer-assisted solution-phase synthesis of 4,5-dihydro-1,4-benzoxazepin-3(2H)-ones

The polymer assisted solution phase (PASP) synthesis of 4,5-dihydro-1,4-benzoxazepin-3(2H)-ones is described. Using salicylic aldehydes, alpha-bromo acetic acid esters, and primary amines as broadly variable building blocks, the target molecules were obtained in a straightforward manner. The use of polymer bound reagents and scavengers greatly simplified workup, and avoided the use of protecting groups. A small library was prepared, showing the feasibility of the synthetic concept for the generation of larger sets of screening compounds.     

Enantioselective synthesis of diversely substituted quaternary 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones

Benzodiazepines are privileged scaffolds in medicinal chemistry, but enantiopure examples containing quaternary stereogenic centers are extremely rare. We demonstrate that installation of the di(p-anisyl)methyl (DAM) group at N1 of 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones derived from enantiopure proteinogenic amino acids allows retentive replacement of the C3-proton via a deprotonation/trapping protocol. A wide variety of carbon and nitrogen electrophiles function well in this reaction, providing the corresponding quaternary benzodiazepines with excellent enantioselectivity. Deprotonation/trapping experiments on a pair of diastereomeric 1,4-benzodiazepine-2,5-diones provide evidence for a key role of conformational chirality in these enantioselective reactions. Acidic removal of the DAM group is fast and high-yielding and can be performed selectively in the presence of a N-Boc indole. Thus the synthesis of quaternary benzodiazepines with diverse N1 functionality can now be accomplished.     

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)     

Parallel synthesis of 1,3-dihydro-1,4-benzodiazepine-2-ones employing catch and release

An efficient solid-phase method has been developed for the parallel synthesis of 1,3-dihydro-1,4-benzodiazepine-2-one derivatives. A key step in this procedure involves catching crude 2-aminobenzoimine products 4 on an amino acid Wang resin 10. Mild acidic conditions then promote a ring closure and in the same step cleavage from the resin to give pure benzodiazepine products 12. The 2-aminobenzoimines 4 can be synthesized from either 2-aminobenzonitriles 1 and Grignard reagents 2 or from iodoanilines 5 and nitriles 7 allowing a range of diversification. Further diversification can be introduced to the benzodiazepine products by N-alkylation promoted by a resin bound base and alkylating agents 13.     

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.     

A convenient synthesis of 3,4-dihydro-1,4-benzoxazin-2-ones

3,4-Dihydro-1,4-benzoxazin-2-one was prepared for the first time by catalytic hydrogenation of 4-benzyl-3,4-dihydro-1,4-benzoxazin-2-one. A simple and efficient synthesis of 4-benzyl- and 4-alkyl-3,4-dihydro-1,4-benzoxazin-2-one derivatives from ethyl 2-(2-hydroxyphenylamino)acetate and aldehydes is described. Some considerations regarding the reactivity of 3,4-dihydro-1,4-benzoxazin-2-ones are given.     

Expedient one-pot synthesis of novel chiral 2-substituted 5-phenyl-1,4-benzodiazepine scaffolds from amino acid-derived amino nitriles

An efficient and stereocontrolled synthesis of phenylalanine- and tryptophan-derived 5-phenyl-1,4-benzodiazepines is described. This new methodology involves, as a key step, the synthesis of 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepines by a one-pot cyano reduction and reductive cyclization of the appropriate amino nitrile, which were obtained via a modified Strecker reaction of N-protected alpha-amino aldehydes with 2-aminobenzophenone and trimethylsilyl cyanide. The subsequent reduction of these 2,3-dihydro-1H-1,4-benzodiazepines, followed by regioselective alkylation or acylation at position 4, led to 2,4-disubstituted-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine.     

A facile large scale synthesis of optically active 3-amino-5-(2-pyridyl)-1,4-benzodiazepin-2-one derivatives

A facile method for the synthesis of 3-amino-5-(2-pyridyl)-1,4-benzodiazepin-2-ones (8) mediated by benzotriazole is described. The synthesis and optical resolution of the product by fractional crystallisation proceeds in high yield, under mild conditions and without recourse to toxic reagents or chromatographic separations and hence is amenable to the large scale preparation of these important precursors to potent CCK receptor ligands.     

New synthesis of 7-bromo-1, 3-dihydro-3-hydroxy-5-(2′-pyridyl)-2H-1,4-benzodiazepin-2-one

A new synthesis of 7-bromo-1,3-dihydro-3-hydroxy-5-(2′-pyridyl)-2H-1,4-benzodiazepin-2-one ( 5 ) is described. Starting from bromazepam ( 3 ), C(3) acylation with lead tetraacetate/potassium iodide in acetic acid affords 4 , while its mild hydrolysis according to our recently described method (5) gives 5 . Improved hexamine cyclization of 1 into 3 , via quaternary hexaminium salt 2 , is discussed, and identification of the intermediates 7 and 8 is performed. Compound 5 undergoes on melting, or on brief heating in glacial acetic acid, the thermal rearrangement into quinazolin-2-aldehyde ( 13 ), the structure of which is confirmed by oxidation into the ester 14 , which in turn was hydrolyzed to the acid 15 . The same compound ( 5 ) rearranges on heating with manganese(III) acetate in acetic acid into the 3-amino-2-quinolone derivative 6 . On heating in glacial acetic acid in the presence of lead tetraacetate/potassium iodide (or iodine), compound 4 , in addition to giving the aldehyde 13 , ester 14 and acid 15 rearrangement products, affords 1,2-dihydroquinazolin-2-carboxylic acid 16 .     

Solid phase synthesis of tetrahydro-1,4-benzodiazepin-2-ones

A novel solid phase route to tetrahydro-1,4-benzodiazepin-2-ones is described which involves construction of a core template in solution followed by diverse derivatization on solid phase.     

A facile synthesis of novel 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-ones

A facile synthesis of novel 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-ones is described. The synthesis was developed on solid phase and was applied to provide a series of analogs in good yield. The key reactions are acylation of a cysteine derivative with 2,4-dichloropyrimidine-5-carbonyl chloride followed by cyclization to generate a 6-arylmethyl-7-carboxamido-2-chloro-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one, which is further derivatized with an amine to give the desired 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one.     

An efficient approach to chiral C8/C9-piperazino-substituted 1,4-benzodiazepin-2-ones as peptidomimetic scaffolds

A promising way to interfere with biological processes is through the modulation of protein-protein interactions by means of small molecules acting as peptidomimetics. The 1,4-benzodiazepine scaffold has been widely reported as a peptide-mimicking, pharmacogenic system. While several synthetic pathways to C6-8 substituted benzodiazepines have been disclosed, few 1,4-benzodiazepines substituted at C9 have been reported. Herein, we describe a versatile approach to introduce cyclic, protonatable functionality at C8/C9. Introduction of the piperazine system at C8 and C9 gave access to a unique functionalization of the versatile benzodiazepine skeleton, broadening tailoring options on the benzofused side of the molecule, and the possibility of discovering novel peptidomimetics potentially able to modulate protein-protein interactions. Coupling of activated amino acids with poorly reactive anilines under mild conditions, while avoiding racemization, gave easy access to these compounds. Efficient amino acid activation was obtained by exploiting the rapid formation of acid chlorides under low temperature and acid/base free conditions, using triphenylphosphine and hexachloroacetone. This procedure successfully resulted in high reaction yields, did not produce racemization (ee > 98%, as demonstrated by using chiral solvating agents), and was compatible with the acid sensitive protecting groups present in the substrates.     

Traceless solid-phase synthesis of 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinoline-2-ones

A traceless solid-phase route to 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinazolin-2-ones is described. N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was tethered to Rink resin via its carboxylic group. The protected amine was coupled with an organic acid after Alloc-deprotection and the arylfluorine was displaced with a primary amine to generate a resin-bound aniline with two diversity points. The aniline was released via cleavage to produce the desired products in high yield and purity.     

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.