GREEN SYNTHESIS: NAPROXENNate ShawSteve Schlitzer

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.

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

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%

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

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%

‘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

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%

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%

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.

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

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.

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.

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