Advisor(s)

Graham Jones

Contributor(s)

Jason Katz, Philip W. Le Quesne

Date of Award

2009

Date Accepted

4-2009

Degree Grantor

Northeastern University

Degree Level

M.S.

Degree Name

Master of Science

Department or Academic Unit

College of Arts and Sciences. Department of Chemistry and Chemical Biology.

Keywords

Chemical biology, Pharmaceutical

Subject Categories

Fluorine, Pharmaceutical chemistry

Disciplines

Chemistry

Abstract

Fluorine has a long history as an important and useful tool in the development of new pharmaceuticals. Fluorine is able to modulate physical properties like solubility and facilitate stronger binding interactions within the binding pocket, while also having the added benefit in that one of its isotopes, 18F, can be employed as a radiotracer for PET and SPECT imaging. Thus, there is a renewed need for technologies that allow fluorine to be easily introduced into pharmaceutical agents to take advantage of the many benefits available.

During the course of a recent medicinal chemistry program there was a need to be able to install a difluoroketone moiety. Currently, the best viable option for reaching this objective was using Percy's difluorostannane derivative, which was coupled to respective aromatic rings through Stille coupling conditions.1, 2 Since removal of tin during the purification steps can be problematic, and is a known neurotoxin, a boron based alternative was explored. Herein I present the work of the optimization, scope and application of the Suzuki-Miyaura coupling of a novel potassium trifluoroborate salt with various aryl halide coupling partners. This work identified our agent as an effective and efficient precursor for difluoroketone substituted compounds, and viable alternative to the analogous tin reagent.

The fluorodenitration reaction has been developed as a routine way to install nucleophilic fluorine onto aromatic rings. This technology was adopted to microwave acceleration for the use in the synthesis of radio-labeled pharmaceuticals. This method decreased reaction time dramatically and allowed the radioactive fluorine to be installed well within its half-life of 110 min. This procedure worked well for compounds already containing a nitro group, but due to its reactive nature difficulties arose when trying to carry out a full synthesis with a nitro group present. Thus, time was dedicated to exploring a recently published nitrodehalogenation reaction, but under microwave conditions.3 After determining the optimum reaction conditions, this method was applied to series of substituted aryl-halides. With these two technologies in hand it would be possible to carry out two sequential microwave reactions to obtain the final radio-labeled pharmaceutical agent.

Document Type

Master's Thesis

Rights Information

copyright 2009

Rights Holder

Blair T. Lapointe


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