Synthesis of 2,3,4,5,6Pentasubstituted1,4dihydropyridines antihypertensive agents and Some Spectrosc

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Synthesis of 2,3,4,5,6-Pentasubstituted-1,4-dihydr
opyridines (antihypertensive agents) and Some
Spectroscopic Properties Part II

• ?Nicole Franklin
• ?John Rippy
• ?Dr. William E. Solomons

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Objectives of Research

• Study the Knoevenagel and modified Hantzsch
  syntheses of substituted 1,4-dihydropyridines.
• To obtain pure modified-Hantzsch products with
  various substituents on the aromatic ring.
• Obtain and study the spectroscopic properties of
  these specifically substituted 1,4-dihydropyridine
  s.
• Experiment with Microwave Reactions.

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Accomplishments of previous study by John Rippy
and Dr. Solomons

• Obtained a pure product with the most simple
  Hantzsch reaction.
• Other compounds were synthesized but were impure
  and at low yields
• Compounds were detected by GC-MS.
• Mass spectral fragment mechanisms were
  postulated.

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What do Calcium Channel Blockers do in the body?

• Calcium channel blockers relax smooth muscles in
  blood vessels causing vasodilation, blocking
  blood vessel spasms and lowering blood pressure.
• They have been utilized in medicine extensively
  for the treatment of hypertension and certain
  types of angina.

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Common Calcium Channel Blockers
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More Calcium Channel Blockers
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Why is the study of 1,4-dihydropyridines
IMPORTANT?

• The prototype of 1,4-dihydropyridines,
  nifedipine, is an effective drug but has some
  undesirable clinical features.
• Several attempts have been made to introduce
  other drugs in this class with improved
  pharmacokinetic and pharmaco-dynamic properties.
• Changes in the substitution patterns at C-3, C-4
  and C-5 positions of nifedipine alter activity
  and tissue selectivity.

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Hantzsch Synthesis used by John Rippy
? The dihydropyridine is completed in one
reaction.
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NEW Synthesis of the 1,4-Dyhydropyridines

• Began with the Knoevenagel Reaction to synthesize
  the benzylidene compound.
• Took this product and reacted it with methyl
  3-aminocrotonate to form the substituted
  1,4-dihydropyridines.
• These two reactions together are modifications of
  the Hantzsch synthesis.

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NEW Synthesis Continued

• The Energy necessary to cause the reactions to
  take place was attempted in 2 different ways
• Refluxing in Organic Solvents
• Microwaves

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Knoevenagel Reaction (I II)
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Modified Hantzsch Reaction
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SUCCESSFUL Reactions
m.p. 191.8-193.3
Performed using a homemade microwave oven
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Our very own MICROWAVE OVEN
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SUCCESSFUL Reactions Continued
m.p. 200.4-203.5
m.p. 203.5-205.0
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SUCCESSFUL Reactions Continued
m.p.
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UNSUCCESSFUL Reaction
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Mass Fragmentation of NO2 Substituted Product
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Proton NMR of Fluoro-Substituted Dihydropyridine
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Carbon 13 of F-Substituted Dihydropyridine
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Splitting Effects of the Fluoro-substituted
product
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Carbon 13 of F-Substituted Dihydropyridine
Splitting of the 123.5-123.6ppm peak
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IR of F-Substituted Dihydropyridine
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Proton NMR of Bromo-Substituted Dihydropyridine
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Carbon 13 of Bromo-Substituted Dihydropyridine
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Proton NMR of Chloro-Substituted Dihydropyridine
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Carbon 13 of Chloro-Substituted Dihydropyridine
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NMR of 4-NO2 Substituted Dihydropyridine
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CONCLUSIONS

• ? Obtained pure products of the F, Br, Cl,
  substituted dihydropyridines.
• ? From a microwave reaction, a pure product was
  obtained.
• ? Obtained Proton NMR and Carbon 13 of these
  compounds. FT-IR was obtained for some compounds.

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Acknowledgements

• The University of Tennessee at Martin Department
  of Chemistry
• Dr. William E. Solomons
• Dr. Devenyi, Dr. Thomas, Dr. Harmon, Dr. Osborn
  and Gary Mansfield