A Thorough Investigation of the Characteristic Phosphorus Couplings and 31P NMR Analysis in Attempts to Synthesize an Ifosfamide Analog Open Access
Wein, Emily P. (2011)
Abstract
Cancer remains one of the most prominent global health concerns
in today's society.
According to the International Journal of Cancer, there were an
estimated 12.7 million
newly reported cancer cases and 7.6 million cancer deaths in
2008.1 The Cancer Journal for
Clinicians indicated that, in the United States, one in four deaths
is caused by cancer.2 A
common treatment for cancer is the use of nitrogen mustard
chemotherapy treatments that
function by alkylating two different positions of a DNA strand,
causing intrastrand
crosslinks (ISCs) or kinks in the DNA structure, as well as
severing the base pairs from the
DNA backbone. These chemotherapy treatments, however, have severe
side effects due to
their lack of selectivity in the body and their inability to
differentiate between cancerous
and healthy dividing cells. This investigation focused on a
specific nitrogen mustard
chemotherapy drug, ifosfamide, in efforts to synthesize an
analog
of ifosfamide with the added functionality of a double bond in its
ring structure.
Once functionality is established in the ring, it opens the
possibility of attaching other
ligands to the double bond site on the ring, ligands that could
selectively bind the drug to
desired regions in the body.
1 Ferlay, Jacques, et. al. "Estimates of Worldwide Burden of Cancer
in 2008: GLOBOCAN 2008." International
Journal of Cancer. 15 December 2010, 127 (12),
2893.
2 Jemal, Ahmedin, et. al. "Cancer Statistics, 2008." Cancer Journal for Clinicians.
2008, 58, 71.
Table of Contents
Table of Contents
1.
Introduction………………………………………………………………………………….......1
2. Results and
Discussion………………………………………..
………………………...10
2.1 Ifosfamide
Characterization…………………………………..……………….…....10
2.2 Addition of Two Equivalents of
Chloroethylamine………………….…....17
2.3 Addition of Propargyl
Alcohol………………………………..………………,......18
2.4 Flash Chromatography and TLC
Difficulties……………………..……….....20
2.5 31P NMR Data and Exploring
Impurities……………………………..………..23
2.6 Cyclization
Attempts…………………………………………..……………………......30
3. Conclusion and Future
Research…………………………………..………………...42
4. Experimental
Section…………………………………………..…………………………..45
4.1 General
Procedures…….………………………………..
.
…………………………...45
4.2 Synthesis of N,N'-Bis(2-chloro-2-ethyl)phosphoramidic
chloride.46
4.3 Synthesis of
N,N'-Bis(2--chloro-2--ethyl)phosphoramidicpropargylic
ester……………………………………………………………………………………………….......46
4.4 Spectral Data for
Ifosfamide………………………………………………………...47
4.5 Initial Attempt at
Cyclization…………………………………………………..
....47
4.6 Secondary Attempt at
Cyclization………………………………………………...47
4.7 Final Attempt at
Cyclization……………………………………………..………..
.48
5.
References…………………………………………………………………………….…….....49
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