green chemistry synthesis of naproxen
TRANSCRIPT
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GREEN SYNTHESIS: NAPROXENNate ShawSteve Schlitzer
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Chemical Properties• Chemical Formula: C14H14O3; • MW: 230.3 g/mol• Half-Life: 12 to 24 hours• Brand names: Aleve, Naprosyn, Anaprox• Usually sold as the sodium salt naproxen.
• Propionic acid class (same as ibuprofen)• Odorless, white to off-white crystalline substance. Lipid soluble, practically insoluble in water in low pH and freely soluble in water at high pH.
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Mechanism of Action• Naproxen works by blocking the effects of chemicals in
your body, called cyclo-oxygenase enzymes, which help produce prostaglandins.
• Prostaglandins are produced at sites of injury or damage, causing pain and inflammation. Blocking cyclo-oxygenase enzymes results in fewer prostaglandins, thus reducing pain and inflammation.
• Does not follow typical Michaelis-Menten kinetics like most drugs – Biphasic Kinetics.
Bowalgha, K. et al. J. Clin. Pharmacol. 2005 Oct. 60(4): 423
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First Large Scale Synthesis – 1969Performed by I. Harrison at Syntex
Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roszkowski, A.; Tomolonis, A.; Fried, J. H. J. Med. Chem. 1970, 13, 203.Agar, D. Handbook of Chiral Chemicals, 2nd Ed; CRC Press: 2003.
4 Steps Total Overall Yield: 48%
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Harrison Method - Problems• Utility of the Friedel-Crafts acylation, with the drawback of the reagent AlCl3• Recall as in Ibuprofen Synthesis, Hydrated Aluminum
Chloride is disposed of in landfills.• This Friedel-Crafts Acylation is non-regiospecific, also
producing the 1-isomer which is removed through crystallization.
• Other Harmful Reagents:• Nitrobenzene• Sodium Hydride• Methyl Iodide
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Syntex Method - Improved• Patented in 1972 at industrial scale.
Tsuchihashi, G; Kitajima, K; Mitamura, S.Optically active 1-aromatic-group-substituted-1-alkanones and methods for their manufacture. EP 0067698 A2, Dec 22 1972. Schlomer, G. Optically Active alpha-substituted alryl ketones and their preparation and their use in preparing alpha-arlalkanoic acids. EP 0081993 A2, Jun 6 1973.
5 Total Steps, Overall Yield 58%
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‘72 Syntex Synthesis - Drawbacks• Stoichiometric amount of ZnCl was required for napthylzinc coupling reaction.• Large volumes of byproduct ZnOH were landfilled.
• The yield of coupling reaction was low (50-60%).
• Two undesirable side products in coupling reaction:• Reduction – 2-methoxynapthalene (Nerolin- Volatile!)• Radical Coupling – Highly insoluble Napthyl dimer -
Landfilled
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Modern Syntex Synthesis• Developed in 1976 and utilized till patent expiration in
1993.
Overall Scheme:Arnold, R. A.; Matthews, G. J. Ger. 2,805,488, Aug 17, 1978.Resolution Procedure:Holton, P. G. U.S. 4,515,811, May 7, 1985
5 Total StepsOverall Yield: 66%
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Atom Economy Analysis - SyntexReagent Used in Naproxen Unused in Naproxen
Formula MW Formula MW Formula MW
C10H8O 114.2 C10H7O 113.2 H 1.0
Br2 160.0 - - Br2 160.0
NaHSO3 104.0 - - NaHSO3 104.0
CH3Cl 50.4 CH3 14.9 Cl 35.5
Mg 24.3 - - Mg 24.3
H4C3O2MgClBr
211.6 H4C3O2 72.0 MgClBr 139.6
C14H31NO5 293.4 - - C14H31NO5 293.4
Total Naproxen Waste
H47C28NO11
NaMg2Cl2Br3
957.9 C14H14O3 230.3 H33C14NO8
NaMg2Cl2Br3
726.6
Overall Atom Economy of 23%
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Improvements in Modern Syntex Method
• Issues in first manufacturing process associated with napthylzinc coupling reaction.• Eliminated Zinc waste• Minimized formation of dimer and Nerolin
• Coupling Reaction yield increased from <50% in 1984 to >90% in 1993.
• 98% of N-octylglucamine recoverable per cycle. • Considering this, Atom Economy jumps to 34%.
• However…• Bromination and the coupling reaction still produce high volumes of
waste.
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Schlitzer/Shaw Adapted Synthesis
Acetic Anhydride Substitution:Schuster, H., Hoelderich, W. App. Cat. 350(1), 1-5; 2008 .Carbonylation: Seayad, A. et al. Cat. Let., 61, 99-103; 1999
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Atom Economy – Proposed SynthesisReagent Used in Naproxen Unused in Naproxen
Formula MW Formula MW Formula MW
C10H7OCH3 158.2 C10H6OCH3 157.2 H 1.0
C4H6O3 102.1 CH3CO 43.0 C2H3O2 59.1
H2 2.0 H2 2.0 - -
CO 28.0 CO 28.0 - -
C14H31NO5 293.4 - - C14H31NO5 293.4
Total Naproxen Waste
C30H49NO10 583.7 C14H14O3 230.3 C16H35NO7 353.5
Overall Atom Economy of 39%, 77% when 98% resolving agent recovered.
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Conclusion - Green Chemistry• Safer Solvents and Auxiliaries:
• Use of Sulfolane, as well as Gaseous Reagents (H2, CO; Steps 2 and 3).
• Catalyst: SiO2, Raney Nickel, Paladium catalyst, Tosylic acid, LiCl virtually all recoverable.
• Green waste – Acetic Acid (step 1)• Potential Recyclability?
• Atom economy:. Syntex 29% compared to 39%.• Avoid use of Halogens and Alkali metals if possible.
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References• Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roszkowski, A.; Tomolonis, A.; Fried,
J. H. J. Med. Chem. 1970, 13, 203.• Agar, D. Handbook of Chiral Chemicals, 2nd Ed; CRC Press: 2003. • Tsuchihashi, G; Kitajima, K; Mitamura, S.Optically active 1-aromatic-group-
substituted-1-alkanones and methods for their manufacture. EP 0067698 A2, Dec 22 1972.
• Schlomer, G. Optically Active alpha-substituted alryl ketones and their preparation and their use in preparing alpha-arlalkanoic acids. EP 0081993 A2, Jun 6 1973.
• Arnold, R. A.; Matthews, G. J. A Process for preparing a 2-arylpropionic Acid. Ger. 2,805,488, Aug 17, 1978.
• Holton, P. G. Process for the resolution of d, 1 2-(6-methoxy-2-napthyl)propionic acid. U.S. 4,515,811, May 7, 1985
• Schuster, H., Hoelderich, W. The Acylation of 2-methoxynapthalene with Acetic Anhydride over Nafion/Silica Composites and BEA Zeolites containing Lewis Acid Sites. App. Cat. 350(1), 1-5; 2008 .
• Seayad, A. et al. Highly Efficient Catalyst System for the Synthesis of 2-Aryl-Propionic Acids by Carbonylation. Cat. Let., 61, 99-103; 1999
• Harrington, P.J., Lodewijk, E. Twenty Years of Naproxen Technology. Organic Procc. Research & Development. 1, 72-76. 1997