The preparation of potential antiviral agents

Abstract

My thesis is adequately described by the title Preparation of Potential Antiviral Agents and this work has been devoted to the synthesis of two candidate compounds.The first target molecule is the heterocyclic pyrimidine analogue of the antioxidant and antiherpetic agent 3,5-di-t-butyl-4-hydroxytoluene (BHT) which is more correctly called 2,6-di-t-butyl-4-methylphenol. Attention was later turned to the synthesis of 3'-azido-5-t-butyl-2',3'-dideoxyuridine which is the 5-t-butyl analogue of 3'-azido-3'-deoxythymidine (AZT), the only antiviral agent approved for clinical use in patients with AIDS.Very few organic compounds have been approved for medical use for the treatment of antiviral borne diseases. However, increased public support for research in development of antiviral agents has led to clinical testing of an expanding array of synthetic drugs. A brief review of antiviral chemotherapy is outlined in Chapter 1.Chapter 2 deals with approaches to the synthesis of the heterocyclic analogue of BHT, namely, 4,6-di-t-butyl-5-hydroxy-2-methylpyrimidine. Two variations of the Principal Type Synthesis of pyrimidines were adopted. In the first approach the requisite β-di-carbonyl component contained a protected hydroxyl group which was destined to be the 5-hydroxy substituent. In the other approach a t-butylated component was transformed into a key intermediate which was a sterically hindered 5-bromopyrimidine. In both strategies, 4(6)-halogeno replacement by a t-butyl group was effected using higher order lithium organocuprate reagents.The remaining chapters are devoted to the synthesis of the t-butyl analogue of 3'-azido-3'-deoxythymidine (AZT). Chapter 3 discusses approaches to the synthesis of a 3-azido-2,3-dideoxy-β-D-erythro-pentofuranoside derivative which may be used to directly alkylate the heterocyclic base. Starting from 2-deoxy-α,β-D-erythro-pentose both a 1-O-methyl- and a 1-chloro-derivative of 2-deoxy-3,5-di-O-p-toluoyl-α,β-D-erythro-pentofuranose were prepared.Chapter 4 details how the syntheses of the known 5-isopropyl- and 5-t-butylthiouracils were improved. The successful preparation of the latter involved the condensation of a β-aldehydo ester with thiourea and this was followed by hydrolysis to t-butyluracil. This was found to be more advantageous than the t-butylation of a 5-bromouracil derivative.Chapter 5 describes the successful synthesis of the 5-t-butyl-2'-deoxyuridine with the β:α anomeric ratio improved to 12:1. An X-ray structural determination was carried out on a protected derivative of the β-anomer of this uridine.Chapter 6 gives details of a number of approaches to the synthesis of the 3'-azido-5-t-butyl-2',3'-dideoxyuridine, the second target molecule, together with the final successful synthesis on a small scale which involved a 2,3'-anhydronucleoside as a key intermediate.Chapter 7 comments upon the electron impact mass spectra of some of the compounds obtained in this work and shows that they are consistent with literature data.Chapter 8 is devoted to the Experimental Section of this thesis.