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Title: Derivatisation of nucleosides, nucleotides and their analogues in a ball mill
Author: Ravalico, Francesco
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2013
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Vibrating ball mill enabled chemoselective acylation of primary amines (including nucleoside analogues) within ten minutes using avoiding undesirable solvents which are typically employed for such reactions (e.g., DMF). A model reaction between propargylamine and the N-hydroxysuccinimidyl ester of p-phenylazobenzoic acid was optimised with respect to the milling frequency, equivalents of propargylamine, and the equivalents and strength of additional base / catalyst. Under optimised conditions, synthesis of amides in the presence of primary and a secondary alcohol functions was achieved in high to excellent yields (65 - 94%). The addition of ethyl acetate was found to both significantly accelerate reaction rates using solid substrates and enhance chemoselectivity. Overall, the optimised methods demonstrated to have significant practical advantages over conventional solvent- approach including greater yields; higher chemoselectivity and easier product separation. Atom-efficient pyrophosphate coupling between adenosine 5'-phosphoromorpholidate and 5'- riboside mono-, di-, or tri-phosphates was achieved using liquid-assisted grinding in a ball mill. This methodology avoided the use of anhydrous pyridine, dmf or formamide and thereby enabled the use of commercially-available donors and acceptors (as their alkali or alkaline earth metal salts) without extensive pre-reaction processing to generate organic-soluble materials. A dramatic reduction in reaction times (to 90 minutes) did not prejudice the yields (50 - 87% HPLC yield) a rapid purification using reversed-phase HPLC was facilitated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available