Synthesis of Tricyclic 4-Chloro-pyrimido[4,5-b][1,4]benzodiazepines

Abstract

[reaction: see text] A novel methodology was developed for the efficient synthesis of 4-chloro-pyrimido[4,5-b][1,4]benzodiazepines. The key is the intramolecular Friedel-Crafts cyclization of 5-amino-4-(N-substituted)anilino-6-chloropyrimidine with either a carboxylic acid or its derivatives to construct the 4-chloro-pyrimido[4,5-b][1,4]benzodiazepine core. Subsequent nucleophilic substitution allows the introduction of one more diversity point in the target molecules. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.

Synthesis of novel tricyclic 4‐chloro‐7,8,10,11‐tetrahydro‐5H‐benzo[e]pyrimido[4,5‐b][1,4]diazepin‐9(6H)‐ones

“…The reactions with aliphatic aldehydes (entries 1-3) proceeded at room temperature to generate the desired products in moderate yields. Various functional groups ranging from electron-donating (methyl or methoxy; entries 4-6) to electron-withdrawing groups (halo, cyano, or nitro; entries [8][9][10][11][12][13][14] were tolerated under the reaction conditions. The Results presented in Table 2 seem to suggest that both electronic and steric effects may affect the yields when benzaldehydes were used.…”

“…As part of our program to prepare heterocyclic libraries, we developed a series of methodologies to rapidly access various heterocyclic scaffolds with benzodiazepine as the core [10][11][12][13][14][15]. These methodologies entail Bischler-Napieralski cyclization reactions and iminium cyclization reactions as the key transformation steps.…”

Easy synthesis of new series of pteridine analogs: di- and tetra-hydropyrimido[4,5-d]pyrimidines via 5-pyrimidinecarbaldehydes

“…On account of the pharmaceutical interest in these compounds, the development of highthroughput methodologies for the synthesis of novel pyrimidine-fused heterocyclic scaffolds is in continuous expansion. [15][16][17][18][19] It has become widely accepted that many classical reactions perform better under microwave irradiation than by conventional heating methods. [20][21][22][23][24] Microwave irradiation has been used to carry out a wide range of reactions in short times, with high yields and regioselectivity, and frequently without the need of solvents.…”

Concise Palladium-Catalyzed Synthesis of Dibenzodiazepines and Structural Analogues

“…Such transformations typically require harsh conditions, purification after each synthetic step, and the use of protecting groups. 1b–c, 5c, 6 Most previously reported synthetic pathways require reduction of a NO 2 group, and have limited functional group compatibility, whereas coupling of substrates with two free NH 2 groups leads to a mixture of products. Thus there is a need for an efficient, concise, and general protocol to provide access to a diverse range of dibenzodiazepine derivatives.…”