The Chemistry and Spectroscopy of Substituted 1,4Dihydropyridines Calcium Channel Blockers

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The Chemistry and Spectroscopy of Substituted
1,4-Dihydropyridines(Calcium Channel Blockers)

• John Rippy
• Dr. William E. Solomons
• University of Tennessee at Martin
• Chemistry Department

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The Goals of the Project

• I. To study the Hantzsch synthesis and the
  spectroscopic properties of substituted
  1,4-dihydropyridines.
• II. To turn these observations into a basic
  research project.
• III. To write syntheses from these experiments
  which will be useful for undergraduate organic
  synthesis teaching laboratories.
• IV. To publish a Journal of Chemical Education
  article.

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What are Calcium Channel Blockers?

• Na, K, and Ca ions cross membranes through
  channels causing
• Polarization and depolarization of nerve cells.
• Contraction and relaxation of muscle tissue.
• Ca ions pass through channels to excite smooth
  muscle contraction in blood vessels.
• Calcium channel blockers relax smooth muscles in
  blood vessels causing vasodilation, blocking
  blood vessel spasms and lowering blood pressure.

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Characteristics of Calcium Channels

•  Highly Selective
• Ca 0.95 Å, Na 0.99 Å
• Selectivity 10001
•   Allow 1,000,000 Ca ions to pass per second
  when excited.
• Ubiquitous in excitable cells.
•       The substituted 1,4-dihydropyridines block
  calcium channels associated with smooth
  muscle contraction particularly in the blood
  vasculature.
•  
• Mechanisms of Permeation and Selectivity in
  Calcium Channels, B. Corry, T. W. Allen, S.
  Kuyucak, and S.-H. Chang, Biophysical Journal
  2001, 195-214

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Diagram of a calcium channel.

• Model calcium channel and reservoirs
•  A. The three-dimensional channel model is
  generated by rotating the curves about the
  central axis by 180?. The positions of two of
  the four glutamate groups are shown by the
  squares, and the inner end of two of the four
  mouth dipoles by the diamonds. The other two
  groups lie into and out of the page. The
  intracellular end of the channel is on the left
  and the extracellular side on the right.
•  B. The channel is enclosed with cylindrical
  reservoirs on either side representing the
  intracellular and extracellular baths.

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What are some calcium channel blockers?
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More calcium channel blockers.
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What is the Hantzsch reaction?
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Mechanism for Hantzsch Reaction
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Unsuccessful attempts at the Hantszch synthesis.

• First Reaction

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Other attempts involved primary organic amines
with similar results.

• n-butyl amine was also attempted.
• Our results, and the literature, show that the
  ring will not close with primary amines.

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First successful reaction.
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We then reduced the concentrations by 50
yielded similar results.Reduced concentration
by another 50 obtained a solid product.
Recrystallized well from CH3CN good spectral
qualities.
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Additional successful reactions.
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Spectroscopic properties of the first product
Proton NMR
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Infrared Spectrum
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Mass spectrum of unsubstituted aryl.
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Mass Spectrum for o-nitro.
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Mass spectral interpretation for o-nitro.
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2-Nitro Fragmentations

• Other 2-nitro fragments at 224 and 192 presumably
  arise as shown previously.

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Conclusions

• Obtained a pure product with the most simple
  Hantzsch reaction.
• Obtained impure products for 2-nitro and 3-chloro
  phenyl substituents which could be detected by
  GC-MS.
• Obtained impure products utilizing microwave
  synthesis and must improve the technique.
• Wrote possible mass fragmentation mechanisms for
  Hantzsch products.

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Acknowledgements

• The Chemistry Department at UTM for
• 1. Facilities
• 2. Equipment
• 3. Chemicals
• Lana Ferrell