A Revision Synthesis of Modafinil [2-(diphenylmethylsulfinyl)acetamide]

Nicole A. Shipley
1
, James J. Kiddle
2

Department of Chemistry, Western Michigan University, Kalamazoo, MI 49008
Narcolepsy is a debilitating neurological disorder which is characterized by chronic
sleepiness and is marked to be disorganization of sleep and wake patterns. Every
six out of ten thousand people in Western Europe and North America are affected
by this disorder. Modafinil (Provigil) is approved by the Food and Drug
Administration for the treatment of narcolepsy. It is commonly used in opposition to
Ritalin, however Ritalin has an associated dependency issue. Modafinil, a
central nervous system stimulant, has reported to have little abuse potential.
Modafinil has the ability to act like wake-promoting sympathomimetic agents which
includes amphetamine. At relevant pharmacological concentrations modafinil lacks
binding ability to receptors for sleep/wake regulation, which includes the ones used
for norepinephrine and serotonin. The precise mechanism of action of modafinil is
unknown and is presently being researched. Modafinil contains a chiral sulfoxide
moiety but is prescribed as a racemate. In collaboration with faculty from the
Psychology department at Western Michigan University we were to synthesize
modafinil for behavioral studies with animals. Therefore a large scale of pure
modafinil was synthesized.























































ACKNOWLEDGEMENTS
REFERENCES
RESULTS AND DISCUSSION
Figure 3. Alternate steps used to produce ()modafinil.
(H NMR spectra)


http://www.arzneistoffe.net/Modafinil.html
http://commons.wikimedia.org/wiki/File:Modafinil.svg
http://www.chemicalbook.com/ChemicalProductPropertyENCB6491138.htm
http://pubs.acs.org/doi/abs/10.1021/ed083p1832
http://provigil.com/patient/home.aspx

Aktoudianakis, E; Lin, R.; Dicks, A. (2006)
Keeping Your Students Awake-Facile
Microscale Synthesis of Modafinil, A Modern Anti-Narcoleptic.
Junior Chemistry Education 83 (12) 1832.



Figure 1. Enantiomers of ()-modafinil.
INTRODUCTION
The tetrahedral sulfur atom acts as a chiral 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.
Scheme III. Mechanism of sulfide oxidation by peracetic acid.
Scheme I .Synthesis Of 2-(diphenylmethylthio)acetamide

Cl
H2N
S
NH2
+
KI,H2O,Heat
30%aq. NaOH
Cl
NH2
O
2-chloroacetamide,
triethylamine
(3 hrs)
Benzhydral chloride
Thiourea
1
2-(diphenylmethylthio)acetamide
NH2
S
O
56%Yield
Scheme II. Synthesis Of Racemic Modafinil by Sulfide Oxidation
H2O2
CH3COOH
50 C, 90 min
2
2-(diphenylmethylsulfinyl)acetamide
() modafinil
NH2
S
O
excess H2O2,
CH3COOH
50 C, overnight
NH2
S
O O
3
2-(diphenylmethylsulfonyl)acetamide
() modafinil
O
O
NH2
S
O O
NH2
S
O
H
O
O
1
2-(diphenylmethylthio)acetamide
CH3COOH +
NH2
S
O O
2
NH2
S
O
O
NH2
S
O
O
(R) (S)
Figure 2. Product After Recrystallization
(H NMR spectra)

The initial target of this synthesis was to prepare the 2-(diphenylmethylthio)acetamide (1) (Scheme I). The
reaction of benzyhydral chloride and thiourea are reacted with potassium iodide, water, heat, 30% sodium
hydroxide, 2-chloroacetamide and triethylamine. The procedure required the 2-(diphenylmethylthio)
acetamide (1) to be recrystallized to remove any impurities with methanol:water solution 60:40 . After
recrystallization (Figure 2) the H NMR spectrum of the synthesized 2-(diphenylmethylthio)acetamide (1)
provides evidence that the recrystallization did not purify the compound. In addition recrystallization
significantly reduced the percent yield from 78.3-79.2% to 56%. If the compound were pure it would only
show peaks at the following locations (ppm): 3.05 (s, 2H), 5.18 (s, 1H), 6.53 (s, 1H), 7.21-7.44(m, 10H).
In preparing () modafinil (2) the procedure used acetic acid and hydrogen peroxide to form peracetic
acid to react with 2-(diphenylmethylthio)acetamide (1) to form () modafinil (2) . The summation of
experimentations of Scheme II eventually lead us to use of commercially available peracetic acid to
obtain a more pure molecule of () modafinil (2). Over oxidation of the sulfone product can be seen if
occurs at the peak (ppm):3.7-3.8 in aH NMR spectrum of () modafinil (2) . To produce pure 2-(diphenylmethylthio)acetamide (1) elimination of the recrystallization
step and 2-(diphenylmethylthio)acetamide (1) was then purified via column
chromatography using dichloromethane:ether 80:20 as an eluent with the stationary
phase (silica gel). After testing several of the fractions from the column using thin layer
chromatography the fractions where able to be identified that contained 2-
(diphenylmethylthio)acetamide (1). Once 2-(diphenylmethylthio)acetamide (1) was
isolated it was oxidized with peracetic acid. The oxidation process was extended to three
hours due to lack of desired product () modafinil (Figure 1).
With the procedure we used and modified through experimentation a new procedure
was developed that increased the percent yield from 56% to 78.3-79.2%. We
encountered a few problems that lead to the removal of the recrystallization step and the
use of column chromatography was performed to purify 2-(diphenylmethylthio)acetamide
(1) . Over- oxidation could have occurred but would have showed up at 3.7-3.8 (ppm),
this did not occur in our experiment. The peak at 1.5 (ppm) is a water peak that was not
fully removed during the rotovep procedure. After a precise and confident procedure was
perfected then we were able to upscale the reaction and sythesize12gs of pure ()
modafinil.
CONCLUSIONS
FUTURE WORK
Various methods are available for the asymmetric oxidation of sulfides to
chiral sulfoxides. One future direction for this project will be the synthesis of
the two enantiomers of modafinil. These species will be useful for future
studies since it is well documented that enantiomers of chiral substances
have unique biological activities.
This research was supported in part by a grant to Western Michigan
University from the Howard Hughes Medical Institute through the
Undergraduate Science Education Program.

I would also like to acknowledge and thank the following people:
James J. Kiddle Ben Strong
Cathy Northcutt Agozie Oyeamalu
Renee Schwartz Janie Toth
Way2Go Science Camp Carlen Smith
Brad Thayer
FUTURE ExpeRTS
The Howard Hughes medical Institute's Experiencing Research
Teaching Science project will be a valuable asset to my future career
researching and teaching science. Experiencing diverse teaching
methods that involved inquiry and direct teaching styles had provided
several experiences that I will be able to reference back to and use or
avoid in my teaching style that I will develop with experience.
Participating in the programs laboratory hands-on research improved
my knowledge and experience of experimentational procedures, their
uses, and how to evaluate/produce/categorize conclusions of expected
or unexpected results. Problems with procedures or unexpected results
that are encountered during experimentation can be further addressed, it
could lead to a dead end or to something new and valuable. In my future
teaching I will be confident in the methods I use and with the ability to
acknowledge and accept that problems in experimentation occur that
can be beneficial or inconsequential.