In the Laboratory edited by
The Microscale Laboratory
R. David Crouch Dickinson College Carlisle, PA 17013-2896
Keeping Your Students Awake: Facile Microscale Synthesis of Modafinil, a Modern Anti-Narcoleptic Drug
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Evangelos Aktoudianakis, Rui Jun Lin, and Andrew P. Dicks* Department of Chemistry, University of Toronto, Ontario, Canada, M5S 3H6; *
[email protected] Undergraduate organic laboratories are invaluable for teaching essential techniques and concepts to aspiring chemists. Keeping the class alert and awake during laboratory sessions poses a different challenge altogether. A successful approach is to have students generate compounds having “real-world relevance” to inspire them and expedite their learning (1). This article outlines an uncomplicated organic synthesis experiment that showcases a prevalent modern antinarcoleptic drug (2). Limited practical skills are required yet students profit greatly from the mechanistic, stereochemical, and spectroscopic concepts discussed. Additionally, a central nervous system (CNS) stimulant with significant appeal and societal impact is synthesized. Laboratory instructors should note that modafinil is listed on Schedule IV of the Controlled Substances Act in the United States (3). As such, any potential adopter of this experiment must verify with appropriate authorities that preparation of modafinil is permitted under local regulations.1 Modafinil, 2-(diphenylmethylsulfinyl)acetamide (Figure 1), is a psychostimulant approved in 1998 by the United States Food and Drug Administration for treatment of narcolepsy (4). Narcolepsy is a debilitating neurological disor-
Figure 1. Enantiomers of (±)-modafinil.
der characterized by chronic sleepiness and a marked disorganization of sleep and awake patterns (5). Six people per ten thousand (0.06%) in Western Europe and North America are affected in this manner (6). Modafinil affords significant advantages over traditional anti-narcoleptic drugs such as amphetamine and methylphenidate as it rarely promotes abusive tendencies (7) and exhibits reduced peripheral and central side-effects (8). The compound exerts its biological activity via a mechanism different from other CNS stimulants (9) although its precise mode of action is still being vigorously researched. Modafinil contains a chiral sulfoxide moiety but is prescribed as a racemate and marketed in the United States by Cephalon under the name Provigil (10). The tetrahedral sulfur atom acts as a chirality center (being surrounded by two dissimilar carbon atoms, an oxygen atom and an electron lone pair; Figure 1). Unlike most analogous trisubstituted amines that undergo umbrella-like inversion at the nitrogen atom, sulfoxides are configurationally stable (11). Racemic modafinil is easily prepared from 2-(diphenylmethylthio)acetamide 1 by peracid oxidation (Scheme I) (12). While almost all undergraduates appreciate that carbon is regularly a chirality center due to its tetravalent nature, fewer recognize that heteroatoms including nitrogen, phosphorus, and sulfur can also act as chirality centers. Moreover very few organic textbooks, articles, or laboratory experiments address the concept of sulfur as a chirality center (11, 13). In 2003 (±)-modafinil was thrust into mainstream media when United States athlete Kelli White tested positive for the stimulant at the World Track and Field Championships (14). The following year the World Anti-Doping Agency added (±)-modafinil to the list of banned substances based on its ability to increase athletic alertness (15). As many of our students are (ab)users of a common anti-narcoleptic (caffeine), we felt preparation of (±)-modafinil would spark increased laboratory enthusiasm.
Scheme I. Synthesis of (±)-modafinil by sulfide oxidation.
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In the Laboratory
Synthetic Overview To a 10-mL Erlenmeyer flask is added 2-(diphenylmethylthio)acetamide2 (0.776 mmol), 30% aqueous hydrogen peroxide (0.916 mmol), and acetic acid (1 mL). The mixture is stirred and heated in a water bath at 50 ⬚C. Reaction progress is monitored by TLC at 20-minute intervals. Upon reaction completion (60–90 minutes) the mixture is cooled to room temperature before addition of water to the flask to form a white precipitate. The product is further cooled on ice before the crude solid is isolated by vacuum filtration. Recrystallization from aqueous methanol and thorough drying typically yields ∼120 mg of (±)-modafinil (∼57%), mp 159–162 ⬚C (lit. 162–163 ⬚C; ref 2). The product is further characterized by 1H NMR and IR spectroscopy.
Figure 2. 1H NMR Spectrum of (±)-modafinil (CDCl3, 200 MHz).
Hazards The experiment presented does not pose any significant hazards to students but standard undergraduate laboratory handling procedures should be followed. All work should be undertaken in a fumehood and gloves, laboratory coat, and goggles should be worn at all times. Aqueous hydrogen peroxide (30%) is an oxidizing agent and can explode when heated. All organic solvents used (acetic acid, ethyl acetate, and methanol) are flammable. Concentrated aqueous ammonia is corrosive and a lachrymator. 2-(Diphenylmethylthio)acetamide is a skin irritant. It is stressed to students that all of their synthetic sample must be handed in to the demonstrator at the end of the laboratory session (reported masses are checked). Discussion The transformation of 2-(diphenylmethylthio)acetamide (1, Scheme I) to (±)-modafinil 2 is stimulating to undergraduates on several experimental and theoretical levels. From a practical perspective, students appreciate the controlled oxidation of a sulfide to a sulfoxide with little or no formation of “over-oxidized” sulfone 3. They can comment on reaction parameters such as quantity of oxidizing agent, temperature, and time, which all control the observed outcome. As a consequence students are reminded of the importance of moni-
toring reaction progress via thin-layer chromatography. While sulfide oxidation is often not covered in many organic chemistry curricula, the reaction mechanism is analogous to the more familiar peracid oxidation of alkenes to epoxides (Scheme II) (16). Peracetic acid is the likely oxidizing agent formed by oxidation of acetic acid by hydrogen peroxide (12). Analysis of the proton NMR spectrum of (±)-modafinil presents an opportunity to observe the effects of a diastereotopic environment. The two methylene protons are geminally coupled and appear as a pair of doublets at δ3.14 and δ3.48 with J = 14.5 Hz (Figure 2). Students can rationalize that these protons are adjacent to the sulfur chirality center and are thus diastereotopic, causing them to exhibit different chemical shifts and couple to one other (17). For comparison purposes the 1H NMR spectrum of sulfide 1 is distributed to the class. The sulfide lacks a chiral environment causing the two methylene protons to be equivalent and manifested as a singlet at δ3.05.2 The absence of chirality in sulfone 3 also leads to a singlet for the methylene protons at δ3.74 (17). This provides an unambiguous means via proton NMR for students to confirm their product identity. Infrared spectroscopy is readily utilized to identify the sulfoxide S⫽O stretch in (±)-modafinil at 1033.6 cm᎑1. This differs significantly from that observed for sulfone stretching (two bands between 1100–1350 cm᎑1) (18).
Scheme II. Mechanism of sulfide oxidation by peracetic acid.
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The preparation and measurement of absolute stereochemistry for the two modafinil enantiomers has recently been reported (2, 19). Students research this methodology with a view to understanding concepts of asymmetric synthesis (by diastereomeric mixture resolution and microbial oxidation approaches) and absolute configuration determination. This has gained special significance of late with news that Cephalon has filed a New Drug Application seeking approval to market Nuvigil (armodafinil), a single-isomer form of modafinil, the (R)-enantiomer (20). This is in part to offset potential loss of revenue from Provigil as generic (±)-modafinil is scheduled to become available in the near future. Conclusion The synthesis and analysis of racemic 2-(diphenylmethylsulfinyl)acetamide, (±)-modafinil, is suitable as a midlevel undergraduate organic laboratory experiment. The product is easily synthesized, purified, and characterized using standard practical techniques. The reaction furnishes occasion to examine an exciting and relevant pharmaceutical having an important real-world application. In doing so students learn that sulfur can act as a stereocenter in organic molecules. Generating (±)-modafinil provokes lively debates concerning the societal impact of prescription anti-narcoleptics. Acknowledgments We thank students enrolled in a second-year undergraduate Research Opportunity Program (ROP 299Y). We are grateful to the Xerox Research Center of Canada for a Chemistry Undergraduate Scholarship (RJL) and the Department of Chemistry, University of Toronto for a Chemistry Lecturer Scholar Fund. W
Supplemental Material
Instructions for the students, notes for the instructor, synthesis of 2-(diphenylmethylthio)acetamide, and spectra are available in this issue of JCE Online. Notes 1. Many readers of this Journal are in countries with laws that are very different to those in the United States. Instructors are advised to contact the pertinent Drug Enforcement Administration (or equivalent organization) for advice. 2. 2-(Diphenylmethylthio)acetamide is synthesized by the instructor by adapting a literature procedure (21). Full details and spectra are provided in the accompanying Supplemental Material.W
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Literature Cited 1. For recent examples, see: (i) Stabile, R. G.; Dicks, A. P. J. Chem. Educ. 2004, 81, 1488–1491. (ii) Stabile, R. G.; Dicks, A. P. J. Chem. Educ. 2003, 80, 1439–1443. (iii) Donahue, C. J.; D’Amico, T.; Exline, J. A. J. Chem. Educ. 2002, 79, 724–726. 2. Prisinzano, T.; Podobinski, J.; Tidgewell, K.; Luo, M.; Swenson, D. Tetrahedron: Asymmetry 2004, 15, 1053–1058. 3. United States Drug Enforcement Administration Drug Scheduling Home Page. http://www.dea.gov/pubs/scheduling.html (accessed Sep 2006). 4. O’Connor, A. Wakefulness Finds A Powerful Ally. The New York Times, June 29, 2004, p F1. 5. Scammell, T. E. Ann. Neurol. 2003, 53, 154–166. 6. Becker, P. M.; Schwartz, J. R.; Feldman, N. T.; Hughes, R. J. Psychopharmacology 2004, 171, 133–139. 7. Gold, L. H.; Balster, R. L. Psychopharmacology 1996, 126, 286–292. 8. Teitelman, E. Am. J. Psychiatry 2001, 158, 1341. 9. Ferraro, L.; Antonelli, T.; O’Connor, W. T.; Tanganelli, S.; Rambert, F. A.; Fuxe, K. Biol. Psychiatry 1997, 42, 1181–1183. 10. Provigil Home Page. http://www.provigil.com/patient/home.aspx (accessed Sep 2006). 11. Morris, D. G. In Stereochemistry; Royal Society of Chemistry: Cambridge, 2001; p 91. 12. Wade, L. G., Jr. In Organic Chemistry, 5th ed.; Pearson: Upper Saddle River, NJ, 2003; p 617. 13. An article describing chiral sulfonium compounds: Davenport, D. A. J. Chem. Educ. 1981, 58, 682–683. 14. Canadian Broadcasting Corporation (CBC) Sports Online: Drugs And Sport. http://www.cbc.ca/sports/indepth/drugs/stories/ modafinil_faq.html (accessed Sep 2006). 15. (i) World Anti-Doping Agency (WADA) 2005 Prohibited List Of Substances. http://www.wada-ama.org/rtecontent/document/ list_book_2005_en.pdf (accessed Sep 2006). (ii) Kaufman, K. R. Br. J. Sports. Med. 2005, 39, 241–244. 16. Overberger, C. G.; Cummins, R. W. J. Am. Chem. Soc. 1953, 75, 4250–4253. 17. Chatterjie, N.; Stables, J. P.; Wang, H.; Alexander, J. G. Neurochem. Res. 2004, 29, 1481–1486. 18. Field, L. D.; Sternhell, S.; Kalman, J. R. Organic Structures From Spectra, 2nd ed.; Wiley: New York, 2000; p 17. 19. (i) Osorio–Lozada, A.; Prisinzano, T.; Olivo, H. F. Tetrahedron: Asymmetry, 2004, 15, 3811–3815. (ii) Olivo, H. F.; Osorio–Lozada, A.; Peeples, T. L. Tetrahedron: Asymmetry 2005, 16, 3507–3511. 20. Cephalon Files New Drug Application For Nuvigil. http:// phx.corporate-ir.net/phoenix.zhtml?c=81709&p=irolnewsArticle&ID=690724&highlight= (accessed Sep 2006). 21. Fornaroli, M.; Velardi, F.; Colli, C.; Baima, R. Process For The One-Pot Synthesis Of Modafinil. U.S. Pat. Appl. Publ. US 2004106829, June 3, 2004.
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