Late-stage C-H & N-H functionalisation of Benzodiazepines and other privileged scaffolds

Khan, Raysa (2018) Late-stage C-H & N-H functionalisation of Benzodiazepines and other privileged scaffolds. Doctoral thesis (PhD), University of Sussex.

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Abstract

This thesis focuses on developing efficient, atom-economic synthesis routes for functionalised 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one libraries. 1,4-Benzodiazepines (BZDs) are often referred to as “privileged scaffolds” due to their important biological activities; therefore, finding new efficient methods for synthesising such analogues is highly desirable in pharmaceutical and medicinal research.

Chapter 1 introduces the project detailing the biological importance and applications of BZDs. The classical synthetic routes towards BZDs and some of the limitations for efficient and rapid BZD-based library synthesis, followed by the aims of the project.

Chapter 2 presents a late-stage C-H activation method for synthesising ortho-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, including a library of over twenty novel analogues. The microwave-mediated palladium catalysed arylation method is also applicable to nordazepam (7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one), the active metabolite of diazepam. Further diversification of the compounds is achieved by N-alkylation and/or H/D exchange, which affords elaborated pharmaceuticals.

Chapter 3 describes an alternative catalytic visible light-mediated photoredox method for ortho-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones. The protocol uses aryldiazonium salts in refluxing methanol and showcases an interesting phenomenon known as the “nuisance effect” with 2- or 4-fluorobenzenediazonium salts. It results in both fluoroaryl and methoxyaryl- products, the latter result from a nucleophilic aromatic substitution (SNAr) on the fluorobenzenediazonium salt (nuisance effect). The results from biological tests of the benzodiazepine libraries against GABAA receptors indicated that the C-7 substituent is vital for activities in GABA and only the 7-chloro-benzodiazepines show any reasonable activities, although ortho arylation is detrimental to bioactivity. A computational DFT analysis of the reaction mechanism from our collaborators is also discussed in the Chapter.

Chapter 4 contains a brief overview of C-H functionalisation protols. Moreover, in this Chapter, the photoredox C-H activation method combined with the nuisance effect are extended to other privileged scaffolds. This Chapter describes the synthesis of small libraries of 2-phenylpyridines and 1-phenyl-2-pyrrolidinones. The nuisance effect proves to be effective in creating small arrays of compounds from a single reaction and in X-ray screening arrays for biological testing. A number of 1-phenyl-2-pyrrolidinone analogues display promising biological activities towards NUDT7, a peroxisomal coenzyme A diphosphatase of current interest.

Chapter 5 focuses on the synthesis of a series of N1-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones. The N-arylation occurs in one-step using a single 1,4-benzodiazepine precursor with unsymmetrical diaryliodonium salts in aqueous ammonia as a base.

Chapter 6 reports the scale-up synthesis of 6-(1H-indol-4-yl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-acetic acid methyl ester, TC-AC-28. This BZD derivative is a highly selective bromo and extra terminal (BET) bromodomain inhibitor and a useful epigenetic tool compound. The near gram-scale, seven-step synthesis of this key chemical probe compound enabled it to be available for researchers through Tocris, one of our industry sponsors, and where I spent 3 months as part of my CASE award.

Chapter 7 concludes the thesis and concentrates on future directions.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry
Depositing User: Library Cataloguing
Date Deposited: 27 Sep 2018 14:07
Last Modified: 27 Sep 2018 14:07
URI: http://sro.sussex.ac.uk/id/eprint/79061

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