Synthesis of drug intermediates in carbon dioxide

Clark, Peter David (2007) Synthesis of drug intermediates in carbon dioxide. PhD thesis, University of Nottingham.

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Abstract

The application of supercritical C0₂(scC0₂) as a solvent for the synthesis of fine and bulk chemicals has been well documented; however its application as a solvent for the synthesis of pharmaceuticals is yet to be exploited fully. To address this issue, two synthetically important reactions have been investigated in scC0₂; chemoselective N-debenzylation and diastereoselective hydrogenation.

Chapter 3 details the study of catalytic N-debenzylation in the presence of sensitive functional groups (COMe and Cl). It has been shown that selective N-debenzylation in the presence of a carbonyl (COMe) is difficult to achieve due to the high operating temperatures that are required to facilitate continuous flow debenzylation. N-debenzylation in the presence of chloro- substituents was also investigated. Dechlorination can be a major problem during this reaction however several different strategies were developed to suppress dechlorination including:

(i) the correct selection of catalyst support; (ii) selective poisoning of a Pd catalyst;

(iii) the addition of acids, such as H₂S0₄ to the reactant stream; (iv) the use of an aprotic co-solvent, such as THF.

Chapter 4 covers progress made on the diastereoselective hydrogenation of the pharmaceutical intermediate, rac-sertraline imine. It has been shown that the hydrogenation reaction can be performed with excellent levels of chemo- and diastereoselectivity (cis:trans ratio of 97:3, 0.7 % by-product formation) by performing the reaction as a continuous flow process in the presence of scC0₂

All details of the apparatus, experimental and synthetic procedures are reported in Chapter 2.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Poliakoff, M.
Keywords: supercritical carbon dioxide, drug synthesis, chemoselective N-debenzylation, diastereoselective hydrogenation, green chemistry
Subjects: Q Science > QD Chemistry > QD450 Physical and theoretical chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 11912
Depositing User: EP, Services
Date Deposited: 12 Apr 2011 08:48
Last Modified: 24 Sep 2016 13:11
URI: http://eprints.nottingham.ac.uk/id/eprint/11912

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