Synthesis and determination of the absolute stereochemistry of the enantiomers of adrafinil and modafinil

Article abstract of DOI:10.1016/j.tetasy.2004.10.019

Both enantiomers of modafinil, adrafinil, modafinic acid and ethyl modafinate were prepared from the diastereomers formed by reacting racemic β-sulfinyl carboxylic acid with (4R)-phenyl-thiazolidinethione. The absolute stereochemistry of the sulfoxide group was confirmed via X-ray analysis of one of the thiazolidinethione diastereomers.

Full text of DOI:10.1016/j.tetasy.2004.10.019

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3811–3815
Synthesis and determination of the absolute stereochemistry
of the enantiomers of adrafinil and modafinil
Antonio Osorio-Lozada, Thomas Prisinzano and Horacio F. Olivo*
Division of Medicinal & Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, IA 52242-1112, USA
Received 7 October 2004; accepted 15 October 2004
Abstract—Both enantiomers of modafinil, adrafinil, modafinic acid and ethyl modafinate were prepared from the diastereomers
formed by reacting racemic b-sulfinyl carboxylic acid with (4R)-phenyl-thiazolidinethione. The absolute stereochemistry of the sulf-
oxide group was confirmed via X-ray analysis of one of the thiazolidinethione diastereomers.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
stereomeric salt resolution of a b-sulfinyl carboxylic acid
with each of the two enantiomers of a-methylbenzyl-
amine.8 This method provided the enantiomeric forms
of b-sulfinyl carboxylic acid 4 in less than 21% yield
and 44%, respectively. In order to improve the prepara-
tion of both enantiomeric forms of modafinil and adra-
finil, we selected a chiral thiazolidinethione auxiliary to
carry out a chemical resolution of the b-sulfinyl carb-
oxylic acid. The chiral auxiliary was selected to provide
two enantiomerically pure synthetic intermediates in one
single operation. Herein, we report our results and also
confirm the absolute stereochemistry of the enantio-
meric forms via X-ray analysis of one of the diastereo-
meric thiazolidinethione derivatives.
Modafinil [Provigil] ( )-1 is a psychostimulant used in
the treatment of narcolepsy.1 Adrafinil [Olmifon] ( )-
2, the hydroxamic acid derivative of modafinil, is cur-
rently in phase III clinical trials for the same disorder.
Recent work has suggested that 1 and 2 might also be
effective treatments for ADHD as well as treating opi-
oid-induced sedation.2,3 The exact mechanisms through
which ( )-1 and ( )-2 exert their effects are currently
unclear. However, its mechanism of action appears
different from that of other CNS stimulants such as
d-amphetamine.4–6 Given their unique pharmacological
properties, clinical work has begun to explore the utility
of these agents as pharmacological treatments for stimu-
lant dependence.7
2. Results and discussion
O
S
O
O
S
O
We selected an aminoacid-derived thiazolidinethione as
the chiral auxiliary for the resolution of a racemic mix-
ture of b-sulfinyl carboxylic acid 4 based on our experi-
ence with these versatile molecules (Scheme 1).9
Diastereomeric mixtures with chiral thiazolidinethiones
can be easily separated by column chromatography
because of their different Rf values, their yellow colour
and also the ability to recycle the silica gel. These chiral
auxiliaries have also proved superior to others, because
they are easily displaced by several nucleophilic
reagents.10
NH2
NHOH
Modafinil 1
Adrafinil 2
Modafinil 1 and adrafinil 2 each possess a stereogenic
sulfoxide group, however, they are marketed as racemic
materials. Recently, Prisinzano et al. reported the dia-
Chiral thiazolidinethione auxiliary (ꢀ)-3,11 derived from
phenyl glycine, was coupled with racemic sulfinyl carb-
oxylic acid 4 (Scheme 1),12,13 and the two diastereomeric
*
Corresponding author. Tel.: +1 319 335 8849; fax: +1 319 335
8766; e-mail: horacio-olivo@uiowa.edu
0957-4166/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.10.019

3812
A. Osorio-Lozada et al. / Tetrahedron: Asymmetry 15 (2004) 3811–3815
S
S
S
O
S
O
O
O
S
O
O
S
DCC, DMAP
S
NH
OH
S
N
S
N
+
+
CH2Cl2
88%
(-)-(R)-3
Scheme 1. Resolution of b-sulfinyl carboxylic acid 4.
( )-4
(-)-5
(-)-6
products were easily separated by column chromatogra-
phy. An X-ray crystallographic analysis of diastereomer
(ꢀ)-5 showed the absolute stereochemistry of the sulfinyl
group to be R (Fig. 1).14 Thus, the stereochemistries of
the sulfinyl groups in the two diastereomers were un-
equivocally assigned as illustrated in Scheme 1.
thione 5 was treated with a solution containing a mix-
ture of chloroform–methanol and ammonium hydroxide
(78:20:2) (Scheme 2). The reaction was monitored by
TLC; when no more starting material was observed,
the solvent was evaporated and the resulting mixture
of chiral auxiliary and modafinil separated by silica gel
column chromatography. Modafinil (ꢀ)-(R)-1 was ob-
tained in very good yield while chiral thiazolidinethione
was also recovered. The same thiazolidinethione 5 was
then treated with hydroxylamine hydrochloride to yield
adrafinil (+)-(R)-2 in 91% yield. It is noteworthy that
this method provides the desired targets directly from
the diastereomeric thiazolidinethiones and the chiral
auxiliaries can be recovered and recycled. Thiazolidine-
thione 5 was also hydrolyzed and esterified to show its
synthetic versatility. Adrafinil (+)-(R)-2 was also ob-
tained from ethyl modafinate (ꢀ)-(R)-7 in moderate
yield (75%).
′
C10
C13
′
C11
′
C9
C14
02
C12
03
S3
′
C6
C15
′
C8
′
C4
C4
C2
C16
C11
′
C7
′
C6
C7
C5
C5
C10
C9
′
C2
C8
In the same manner, the addition of ammonia to diastereo-
meric thiazolidinethione 6 yielded modafinil (+)-(S)-1,
while the addition of hydroxylamine to compound 6 fur-
nished adrafinil (ꢀ)-(S)-2, both in excellent yields
(Scheme 3). Hydrolysis of thiazolidinethione 6 delivered
Figure 1. X-ray crystal structure of compound (ꢀ)-5.
With both diastereomers in hand, our efforts shifted to
the preparation of adrafinil. Diastereomeric thiazolidine-
S
O
O
S
O
S
O
S
a or b or c or d
S
N
R
+
S
NH
(-)-(R)-1 R= NH2, 88%
(-)-5
(-)-(R)-3
(+)-(R)-2 R= NHOH, 91%
(-)-(R)-4 R= OH, 98%
(-)-(R)-7 R= OEt, 96%
b
Scheme 2. Synthesis of (R)-modafinil and (R)-adrafinil. Reagents: (a) CHCl3–MeOH–NH4OH (78:20:2); (b) NH2OH–HCl, Et3N, THF–H2O;
(c) LiOH, THF–H2O; (d) DCC, EtOH.
S
O
O
S
O
S
O
S
a or b or c or d
S
N
R
+
S
NH
(+)-(S)-1 R= NH2, 97%
(-)-6
(-)-(R)-3
(-)-(S)-2 R= NHOH, 68%
(+)-(S)-4 R= OH, 87%
(+)-(S)-7 R= OEt, 91%
b
Scheme 3. Synthesis of (S)-modafinil and (S)-adrafinil. Reagents: (a) NH4OH–MeOH–CHCl3 (78:20:2); (b) NH2OH–HCl, Et3N, THF–H2O;
(c) LiOH, THF–H2O; (d) DCC, EtOH.

A. Osorio-Lozada et al. / Tetrahedron: Asymmetry 15 (2004) 3811–3815
3813
modafinic acid (+)-(S)-7, and esterification furnished
ethyl modafinate (+)-(S)-7.
165.4(C), 138.5 (C), 135.3 (C), 13.41 (C), 129.65
(2CH), 129.29 (2CH), 129.16 (2CH), 129.07 (2CH),
128.93 (2CH), 128.72 (CH), 128.67 (CH), 128.57 (CH),
125.4(2CH), 71.8 (CH), 69.71 (CH), 57.5 (CH ), 37.2
2
3. Conclusions
(CH2); IR m 1677, 1495, 1450, 1357, 1304, 1248, 1170,
1158, 1045cmꢀ1
452.0813, obsd 452.0821.
;
ES HRMS m/z (M+H)+ calcd
In summary, we have prepared both enantiomers of
modafinil, adrafinil, modafinic acid and ethyl modafi-
nate employing a chemical resolution of a diastereo-
meric mixture formed by reacting racemic b-sulfinyl
carboxylic acid with a chiral thiazolidinethione. The
absolute stereochemistry of the sulfoxide group was
confirmed via X-ray analysis of one of the thiazolidine-
thione diastereomers. Thiazolidinethiones were shown
to be easily displaced by ammonia and hydroxylamine
providing modafinil and adrafinil in one operation. This
strategy will be useful to prepare other analogues to fur-
ther explore the pharmacological activity of these com-
pounds. The biological evaluation of these single
enantiomeric compounds is currently underway and will
be reported in due course.
4.2.2.
(diphenylmethanesulfinyl)acetamide (ꢀ)-6. Rf 0.24(3:2,
(ꢀ)-[(4R)-Phenyl-2-thioxo-thazolidine-3-yl]-(S)-
petroleum ether/ethyl acetate); mp 69ꢁC (dec);
22
½aŠ ¼ ꢀ216:5 (c 1.0, CHCl3); 1H NMR (CDCl3): d
D
7.49–7.29 (15H, m), 6.17 (1H, d, J = 8.1Hz), 5.07 (1H,
s), 4.55 (1H, d, J = 16.0Hz), 4.28 (1H, d, J = 16.0Hz),
3.96 (1H, dd, J = 11.2, 8.1Hz), 3.09 (1H, dd, J = 11.2,
1.1Hz); 13C NMR (CDCl3): d 202.6 (C), 165.8 (C),
138.5 (C), 135.7 (C), 133.9 (C), 129.77 (2CH), 129.40
(2CH), 129.23 (2CH), 129.01 (2CH), 128.94(2CH),
128.89 (CH), 128.77 (CH), 128.61 (CH), 125.7 (2CH),
71.5 (CH), 69.6 (CH), 59.7 (CH2), 37.3 (CH2); IR m
3063, 3028, 3004, 1694, 1495, 1451, 1299, 1160, 1046,
743, 697cmꢀ1; ES HRMS m/z (M+H)+ calcd 452.0813,
obsd 452.0818.
4. Experimental
4.2.3. (ꢀ)-(R)-(Diphenylmethanesulfinyl)acetamide (ꢀ)-
(R)-1. A mixture of chloroform–methanol, ammonium
hydroxide (78:20:2, 5mL) was added directly to thiazo-
lidinethione (ꢀ)-5 (179mg, 0.396mmol). The solution
was stirred until the yellow colour disappeared and
TLC did not show the presence of starting material.
The solvent was evaporated and the residue purified
by column chromatography (2.5 · 12.5cm) eluting with
a gradient of 1–4% methanol in dichloromethane. Moda-
finil was obtained as a white solid: 95mg (88% yield).
Rf 0.30 (5% methanol in dichloromethane); mp 158–
4.1. General remarks
Melting points were determined on Thomas Hoover
apparatus. Optical rotations were measured on a Jasco
P-1020 polarimeter at room temperature. NMR spectra
were recorded in a Bruker Avance-300 spectrometer. IR
spectra were recorded on a Nicolet-210 spectrophoto-
meter. HRMS was conducted by Dr. Blake Watkins at
the University of Mississippi.
22
1
4.2. Coupling of thiazolidinethione 3 and carboxylic acid 4
159ꢁC; ½aŠ ¼ ꢀ79 (c 1.0, CHCl3); H NMR (CDCl3):
D
d 7.51–7.48 (2H, m), 7.45–7.32 (8H, m), 7.07 (1H, br
s), 5.88 (1H, br s), 5.24(1H, s), 37.4 (1H, d,
J = 14.2Hz), 3.14 (1H, d, J = 14.2Hz); 13C NMR
(CDCl3): d 166.5 (C), 134.7 (C), 134.3 (C), 129.62
(2CH), 129.58 (2CH), 129.1 (2CH), 128.98 (3CH),
128.8 (CH), 71.6 (CH), 52.0 (CH2); IR 3383,
3314, 3257, 3191, 1690, 1617, 1495, 1376, 1027,
702cmꢀ1; ES HRMS m/z (M+Na)+ calcd 296.0721,
obsd 296.0713.
A
solution of (ꢀ)-(R)-phenylthiazolidinethione
(410.2mg, 2.1mmol) in dichloromethane (15mL) was
treated with racemic modafinic acid (548.6mg,
2.0mmol). 4-Dimethylaminopyridine (45mg, 0.37
mmol) and 1,3-dicyclohexylcarbodiimide (454mg,
2.2mmol) were then added under a nitrogen atmos-
phere. The solution was stirred overnight. The reaction
was quenched with a 2M solution of hydrochloric acid
(20mL) and extracted with diethyl ether (2 · 25mL).
The combined organic layers were washed with a satd
solution of NaHCO3 and brine, dried over Na2SO4, fil-
tered and concentrated. The residue was purified by
chromatography on silica gel (5 · 13cm) eluting with
petroleum ether–ethyl acetate (3:2). Thiazolidinethione
5 was obtained as a yellow solid: 403mg (44.5% yield)
with thiazolidinethione 6 was obtained as a yellow foam:
395mg (43.5% yield).
4.2.4. (+)-(S)-(Diphenylmethanesulfinyl)acetamide (+)-
(S)-1. The title compound was obtained in 97% yield
from compound (ꢀ)-6 following the same procedure
22
as above. ½aŠ ¼ þ81 (c 1.0, CHCl3).
D
4.2.5. (+)-(R)-(Diphenylmethanesulfinyl)acetohydroxamic
acid (+)-(R)-2. To a solution of hydroxylamine-hydro-
chloride (578.6mg, 8.3mmol) in a mixture of THF–H2O
(10mL, 5:1) was added triethylamine (1.5mL,
10.7mmol). The mixture was stirred for 15min, filtered
through a small plug of cotton and added to a solution
of thiazolidinethione (ꢀ)-5 (376.1mg, 0.83mmol). The
solution was stirred until no more starting material
was observed by TLC. The solution was concentrated
and the residue purified by column chromatography
on silica gel (2 · 13cm), eluting with a gradient using
2–6% methanol in dichloromethane. Adrafinil was
4.2.1. (ꢀ)-[(4R)-Phenyl-2-thioxo-thazolidine-3-yl]-(R)-
(diphenylmethanesulfinyl)acetamide (ꢀ)-5. Rf 0.38 (3:2,
petroleum ether/ethyl acetate); mp 134–136ꢁC (dec);
22
1
½aŠ ¼ ꢀ230:4 (c 0.99, CHCl3); H NMR (CDCl3): d
D
7.53–7.27 (15H, m), 6.13 (1H, dd, J = 8.1, 1.2Hz), 5.20
(1H, s), 5.10 (1H, d, J = 14.2Hz), 4.13 (1H, d,
J = 14.2Hz), 3.93 (1H, dd, J = 11.2, 8.1Hz), 3.09 (1H,
dd, J = 11.2, 1.2Hz); 13C NMR (CDCl3): d 202.7 (C),

3814
A. Osorio-Lozada et al. / Tetrahedron: Asymmetry 15 (2004) 3811–3815
isolated as a slightly brown solid: 218.5mg (91% yield).
Rf 0.42 (10% MeOH in CHCl3); mp 159–160ꢁC;
(C), 134.0 (C), 129.8 (2CH), 129.4 (2CH), 128.9
(4CH), 128.7 (CH), 128.6 (CH), 71.6 (CH), 62.2
(CH2), 54.4 (CH2), 14.2 (CH3); IR 3061, 3029, 2983,
2932, 1732, 1495, 1451, 1286, 1053cmꢀ1; ES HRMS
m/z (M+Na)+ calcd 325.0874, obsd 325.0874.
22
D
½aŠ ¼ þ14( c 0.85, CH3OH); 1H NMR (CD3OD): d
7.56–7.51 (4H, m), 7.44–7.32 (6H, m), 5.40 (1H, s),
3.41 (1H, d, J = 13.7Hz), 3.23 (1H, d, J = 13.7Hz);
13C NMR (CD3OD): d 163.5 (CO), 137.2 (C), 135.6
(C), 130.9 (2CH), 130.3 (2CH), 129.9 (2CH), 129.8
(2CH), 129.6 (2CH), 72.1 (CH), 54.0 (CH2); IR
3209, 3027, 1686, 1656, 1496, 1451, 1061, 1005,
703cmꢀ1; ES HRMS m/z (M+Na)+ calcd 312.0670,
obsd 312.0659.
4.2.10. (+)-(S)-Ethyl (diphenylmethanesulfinyl)acetate
(+)-(S)-7. The title compound was obtained in 87%
yield from compound (ꢀ)-6 following the same proce-
22
dure as above.½aŠ ¼ þ56:2 (c 1.0, CHCl3).
D
4.2.6. (ꢀ)-(S)-(Diphenylmethanesulfinyl)acetohydroxamic
acid (ꢀ)-(S)-2. The title compound was obtained in
22
Acknowledgements
98% yield from compound (ꢀ)-6 following the same
Financial support for this work was provided by the
National Science Foundation (CHE-0111292 and
EEC-0310689). We thank Mr. John Podobinski for the
preparation of compound 4 and Dr. Dale Swenson for
obtaining the crystallographic analysis of compound
(ꢀ)-5. We are indebted to Dr. Blake Watkins (Univer-
sity of Mississippi) for obtaining all the HRMS.
procedure as above. ½aŠ ¼ ꢀ14( c 1.0, CH3OH).
D
4.2.7. (ꢀ)-(R)-(Diphenylmethanesulfinyl)acetic acid (ꢀ)-
(R)-4. A 0.1M THF/H2O (2.5:1) solution of LiOH
(15mL, 1.5mmol) was added to thiazolidinethione imide
(ꢀ)-5 (180mg, 0.398mmol) at 0ꢁC. The solution was
then stirred at room temperature until no imide was ob-
served by TLC. Water (15mL) was added to solution
and washed with dichloromethane (4 · 10mL). The
aqueous solution was acidified (1mL of concd HCl)
and extracted with ethyl acetate (2 · 25mL). The organ-
ic layer was dried over Na2SO4, filtered and concen-
trated. The title compound was obtained as an
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amorphous solid: 105mg (96% yield). Rf 0.21 (10%
22
MeOH in CHCl3); mp 118–120ꢁC; ½aŠ ¼ ꢀ41:7 (c
D
0.85, CH3OH); 1H NMR (CDCl3): d 7.56–7.51 (4H,
m), 7.44–7.32 (6H, m), 5.40 (1H, s), 3.41 (1H, d,
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22
as above. ½aŠ ¼ þ39:3 (c 1.0, CH3OH).
D
4.2.9. (ꢀ)-(R)-Ethyl (diphenylmethanesulfinyl)acetate
(ꢀ)-(R)-7. A solution of thiazolidinethione imide (ꢀ)-
5 (242mg, 0.53mmol) in ethanol (10mL), was treated
with dicyclohexylcarbodiimide (166.2mg, 0.80mmol)
and 4-dimethylaminopyridine (6mg, 0.05mmol). The
solution was stirred until the yellow colour disappeared
and TLC showed no more starting material. The solvent
was evaporated, and the residue purified by column
chromatography on silica gel (2 · 12cm), eluting with
petroleum ether–ethyl acetate (55:45). The ethyl ester
(ꢀ)-7 was eluted after the phenyl-thiazolidinethione
´
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a white paste: 158.4mg (98%
yield). Rf 0.23 (7:3, petroleum ether–ethyl acetate);
22
mp 84–85ꢁC; ½aŠ ¼ ꢀ58:5 (c 0.85, CHCl3); 1H
NMR (CDCl3): d D7.52–7.46 (4H, m), 7.43–7.30 (6H,
m), 5.20 (1H, s), 4.20 (2H, q, J = 7.2Hz), 3.51 (1H, d,
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