Thesis
New methods for the synthesis of pharmaceutical azacycles
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2020
- Thesis identifier
- T16433
- Person Identifier (Local)
- 201658336
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- New methods for the synthesis of heterocyclic compounds are constantly required and sought after by the chemical industry. Specific heterocycles, including 1,2,3-triazoles and benzimidazoles are present in a multitude of pharmaceutical and agrochemical compounds. Contained within this thesis is the discovery, optimisation and exemplification of a highly general method for the synthesis of 1,2,3-triazoles and a new methodology for the synthesis of a specific class of benzimidazole. Chapter 1 concerns the synthesis of 1,2,3-triazoles. The state-of-the-art reaction to synthesise 1,2,3-triazoles uses high energy azides and alkynes, which require elaborate and lengthy synthetic procedures to incorporate these functional handles into the substrate. Moreover, the use of metal catalysts to furnish specific regioisomers of the 1,2,3-triazole product renders these reactions non-ideal from a financial, environmental and practical perspective. A new procedure has been designed which bypasses the use of azides and directly converts primary amines into 1,2,3-triazoles. The reaction is a 3-component coupling between α-ketoacetals, p-toluene sulfonylhydrazide and a primary amine and does not require a metal catalyst. Issues such as chemoselectivity, regiospecificity and scalability have all been addressed. An orthogonal set of conditions have been developed which allow for the chemoselective conversion of either aliphatic amines or aromatic amines into a 1,2,3-triazole depending on the utilised reaction conditions. The reaction has been exemplified multiple times to be highly efficient in the synthesis of 1,2,3-triazoles on a large scale in both batch and flow reactors. The reaction has been shown to give regiospecific access to 4-, 1,4-, 1,5-, 4,5-, 1,4,5- and 1-substituted systems and is often complete within less than 10 minutes. The desired triazoles can be isolated without chromatography in yields of up to 98% and the reaction has been exemplified on greater than 70 examples. Chapter 2 concerns the synthesis of 2-aminobenzimidazoles. Current methods to synthesise benzimidazoles largely rely on the use of 1,2-diaminobenzenes whereby a series of synthetic procedures furnish the benzimidazole. A new C–H functionalisation reaction to form 2-aminobenzimidazoles has been developed which directly targets the synthesis of this heterocycle in one-step from aryl-guanidines. High throughput screening and statistical Design of Experiments have enabled the discovery of an efficient system which uses a simple copper salt as a catalyst to mediate a C–H functionalisation event using pivalic acid as an additive. Empirical examination of this additive reveals that increased steric bulk around the carboxylate moiety plays a key role in delivering useful yields of the desired benzimidazole, providing a potential explanation as to why pivalic acid is an effective mediator. The developed methodology has been applied to the synthesis of Emedastine, a marketed pharmaceutical compound, in which the key step was performed on a gram-scale, highlighting the practical utility of the developed procedure.
- Advisor / supervisor
- Tomkinson, Nicholas C.O
- Resource Type
- Note
- Previously held under moratorium in Chemistry Department (GSK) from 17/06/2020 until 22/11/2022
- DOI
- Funder
- Embargo Note
Relations
Items
| Thumbnail | Title | Date Uploaded | Visibility | Actions |
|---|---|---|---|---|
|
|
File | 2022-12-15 | Embargo |