Clark, Peter David (2007) Synthesis of drug intermediates in carbon dioxide. PhD thesis, University of Nottingham.
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 (PhD)|
|Uncontrolled Keywords:||supercritical carbon dioxide, drug synthesis, chemoselective N-debenzylation, diastereoselective hydrogenation, green chemistry|
|Faculties/Schools:||UK Campuses > Faculty of Science > School of Chemistry|
|Deposited By:||Ms. K EVANS|
|Deposited On:||12 Apr 2011 09:48|
|Last Modified:||12 Apr 2011 09:59|
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