Chapter 2: Novel Process for Synthesis of Armodafinil

Chapter 2
Novel Process for Synthesis of
Armodafinil

Novel Asymmetric Synthesis of Chiral Sulfoxides 34

Chapter 2: Novel Process for Synthesis of Armodafinil

Abstract

This chapter describes the synthesis of chiral sulfoxides by using the concept
of nucleophilic substitution on chiral “Sulfur”(S). It has less number of steps
easy reaction conditions and better yields. New process has been developed
for the synthesis of Armodafinil from diphenyl methane thiol which has a
commercial potential.

Figure-1. Retrosynthetic approach for Armodafinil

Novel Asymmetric Synthesis of Chiral Sulfoxides 35

Chapter 2: Novel Process for Synthesis of Armodafinil

2.1 Introduction

Modafinil is a racemic drug molecule and contains mixture of ‘S’ and ‘R’
enantiomers. Drug molecule Armodafinil, is nothing but the enantiomerically
pure isomer i.e. ‘R’ enantiomer of racemic molecule Modafinil. This drug is
approved in year 2007 by US FDA. Both Modafinil (Racemic compound) and
its Armodafinil (R-enantiomer) are central nervous system stimulants and this
is applicable to wakefulness to the patients those have excessive sleepiness.
Racemic Modafinil and Armodafinil molecules are linked for a low rate of
serum aminotransferase elevations during therapy but these are not
implicated in case of clinically apparent acute liver injury. Armodafinil ‘R’
isomer has better half-life upto 12-15 hours and ‘S’ isomer of Modafinil has
low half-life i.e. only 4 hours, many researchers expected to find that
Armodafinil (pure R-Modafinil) would have a longer half-life in the body
than racemic form Modafinil which contains 50% R-Modafinil and 50% S-
Modafinil.1-3

Figure-2. Modafinil and its isomers

Novel Asymmetric Synthesis of Chiral Sulfoxides 36

Chapter 2: Novel Process for Synthesis of Armodafinil

The application of single ‘R’ isomer of Modafinil is more beneficial over the
the use of unwanted ‘S’ enantiomer which leads to lower metabolic burden
on the patient body. Armodafinil and racemic Modafinil have similar
pharmacology, however the evidence suggests that Armodafinil is a more
appropriate kinetic approach for patients those have sleepiness disorder,
basically for the shift-work persons.

Modafinil drug available in the market in the dosage form of tablets of 100
and 200 mg under the brand name Provigil. The general dosage of Provigil in
adults is 200 mg once daily in the morning or a one hour before a work
shift. Armodafinil is available in the market with brand name Nuvigil and
dosage form is tablets of 50, 150 and 250 mg,4 the usual dose in adults being
150 to 250 mg once daily.

• Innovator: Teva Pharmaceuticals USA, Inc

• Brand: NUVIGIL® (Armodafinil)
• Tablet Strengths: 50, 150, 200 and 250 mg4
• Dosage Forms: Oral tablets
• Class: Schedule - IV
• Approval: USFDA approval - 2007

Mode of action:
Armodafinil is an indirectly considered as a dopamine receptor agonist
racemic Modafinil and Armodafinil bind in-vitro for the dopamine
transporter also it inhibit the dopamine reuptake. Armodafinil is useful for
the patient those have more histamine levels formed in hypothalamus and
increase the concentrations of norepinephrine and serofonin.4

Novel Asymmetric Synthesis of Chiral Sulfoxides 37

Chapter 2: Novel Process for Synthesis of Armodafinil

2.2 Drug Profile of Armodafinil

Name : Armodafinil
IUPAC Name : (–)-2-[(R)-(diphenylmethyl)sulfinyl] acetamide
Structure :

O O
S
(R) NH2

1
Armodafinil

Molecular Formula : C15H15NO2 S

Molecular Weight : 273.35
CAS No. : [112111-43-0]
Nature : White to off white, crystalline powder
Melting Point : 153-154°C
Therapeutic Activity : Wakefulness-promoting agent
Storage : Store in well- closed container

Novel Asymmetric Synthesis of Chiral Sulfoxides 38

Chapter 2: Novel Process for Synthesis of Armodafinil

2.3 Literature Review

Armodafinil 1 is represented in following manner in the literature,

Figure-3: Armodafinil structural representation

There are several routes available for synthesis of Armodafinil starting from
various raw materials like benzhydrol but most of the routes have more
number of steps. The synthetic routes available in the literature for synthesis
of Armodafinil 1 are as follows,

Louis approach (1990)5:

Louis et al have first disclosed following synthetic approach (Scheme-1) for
the synthesis of Armodafinil. Racemic benzyhdrylsulfinylacetic acid or
modafinic acid 1.1 resolved with (-)–alpha-methylbezylamine to get (-)
modafinic acid 1.2, which was further converted into methyl ester derivative
by during methyl sulfate and sodium bicarbonate. Isolated intermediate
converted into Armodafinil 1 by treating with ammonia.

Novel Asymmetric Synthesis of Chiral Sulfoxides 39

Chapter 2: Novel Process for Synthesis of Armodafinil

Scheme-1
Drawback of this method:
(-) Alpha methyl benzylamine is used as a resoluting agent for the resolution
of modafinic acid 1.2, because of this resolution 50% unwanted isomer is
wasted. Hence the overall yield is very low.

Thomas Prisinzano approach (2004)6:

T.Prisinzano et al have reported following two synthetic approaches, in first
approach racemic Modafinil is prepared from benzhydrol 2.1. The
preparation of Modafinil acid was achieved by reacting thioglycolic acid and
benzhydrol in presence of trifluoroacetic acid. The resultant acid further
converted into acetamide 2.3 which was oxidized with 30% hydrogen
peroxide in acetic acid to give racemic Modafinil 2.7 (Scheme-2).

Novel Asymmetric Synthesis of Chiral Sulfoxides 40

Chapter 2: Novel Process for Synthesis of Armodafinil

Scheme-2
In second approach benzhydrylsulfanylacetic acid 2.2 was converted into
ester 2.4 and further oxidized with 30% hydrogen peroxide to give racemic
modafinil acid 1.1. The isolated Modafinil acid 1.1 was resolved using alpha-
methylbezylamine and then separated into its isomer (-) and (+) using
fractional crystallization. Isomer 1.2 was then subjected to esterification

Novel Asymmetric Synthesis of Chiral Sulfoxides 41

Chapter 2: Novel Process for Synthesis of Armodafinil

followed by ammonolysis to give (R) isomer (1, Armodafinil) and undesired

(S) isomer 2.6 ( Scheme-2).
Drawback of this method:
In-line with Scheme-1, similar approach applied for the resolution, but here
absolute configuration of desired (R) modafinic acid is reported in the above
said literature.6

Antonia Osoria-Lozade approach (2004)7:

Antonia Osoria-Lozade et al have reported following synthetic approach for
the preparation of Armodafinil (Scheme-3).

O O
O
OH S S
HS OH H2SO4 O
OH

TFA EtOH

2.1 2.2 3.1

S
S
NH

O O S O O
S
O O S S
H2O2, MeOH N S N
S S
OH
NaOH DCC, DMAP,
CH2Cl2

(-) (+)
1.1 3.3
3.2

NH4OH, MeOH-CHCl3

O O O O
S S
NH2 NH2

1 2.6

(R) isomer (S) isomer

Armodafinil

Scheme-3

Novel Asymmetric Synthesis of Chiral Sulfoxides 42

Chapter 2: Novel Process for Synthesis of Armodafinil

Racemic modafinil acid (±) 1.1 was prepared from benzhydrol as per the
earlier synthetic method. As part of improvement for the preparation of
selective enantiomeric form of drug molecule Modafinil, here chiral
thiazolidinethione auxiliary was used. Both distereomeric thiazolidinethione
3.2, 3.3 was treated with chloroform-methanol and ammonium hydroxide to
afford (R) isomer i.e Armodafinil 1 and (S) isomer 2.6.

Drawback of this method:

Chiral thiazolidinethione auxiliary was used for the separation of two isomer
of Modafinic acid. The unwanted distereoisomer is wasted during synthesis
of Armodafinil.

Rebiere approach (2005)8:

Rebiere and coworkers have reported a process for the enantioselective
synthesis of the single enantiomer of Modafinil. In this approach metal chiral
ligand complex is used for the chiral synthesis. Acetamide 2.3 is treated with
metal complex Titanium isopropoxide and chiral ligand (+) diethyl-L-tartrate
is used along with oxidizing agent cumene hydroperoxide to get Armodafinil
1 (Scheme-4).

Scheme-4

Drawback of this method:

Metal complex titanium isopropoxide 1.0 mol is used for the reaction, which
is toxic in nature and non ecofriendly. The chiral ligand (+) diethyl-L-tartrate

Novel Asymmetric Synthesis of Chiral Sulfoxides 43

Chapter 2: Novel Process for Synthesis of Armodafinil

was used along with oxidizing agent cumene hydroperoxide which itself is
pyrophoric in nature.

H. F. Olivo approach (2005)9:

H.F. Olivo and co-workers have reported the enantiomerically pure synthesis
of Armodafinil using oxidative enzymes. Several type of microorganisms
having oxidative enzymes are responsible for oxidation of sulfoxides. In this
approach beauveria bassiana (AYCC-7159) and Escherichia Coli CHMO used for
the sulfoxidation synthesis. The enantiomeric excess (ee) of isolated
Armodafinil isomer is 22% and 25% with yield 67% and 31% respectively
(Scheme-5).

Scheme-5

Drawback of this method:

In this approach microorganism beauveria bassiana and Escherichia Coli CHMO
enzyme was used for the sulfoxidation synthesis. All these microorganisms
are expensive and not easily commercially available. The enantiomeric excess
(ee) of isolated Armodafinil is very low (~35%).

Moshkovitskaptson approach (2007)10:

Moshkovitskaptson et al reported a process for optical resolution of racemic
modafinic acid 1.1 comprising crystallization of racemic modafinic acid with
(R)-alpha naphthylethylamine to get (R) isomer of alpha naphthylethylamine

Novel Asymmetric Synthesis of Chiral Sulfoxides 44

Chapter 2: Novel Process for Synthesis of Armodafinil

and modafinic acid. Further resolved (R) modafinic acid 1.2 is converted into
Armodafinil 1 (Scheme-6).

Scheme-6

Drawback of this method:

In this method racemic modafinic acid was resolved by (R)-alpha
naphthylethylamine to get (R) isomer of modafinic acid 1.2. Because of this
resolution gets 50% atom economy and 50% gets wasted during synthesis.

Girish approach (2009)11:

Girish et al have developed different method for preparation of Armodafinil

from (R) modafinic acid. (R) modafinic acid 1.2 is reacted with isobutyl

Novel Asymmetric Synthesis of Chiral Sulfoxides 45

Chapter 2: Novel Process for Synthesis of Armodafinil

chloroformate to give mixed anhydride compound 7.1. The isolated

anhydride compound was further treated with ammonia gas to give desired
compound Armodafinil 1 with 83% yield (Scheme-7).

Scheme-7
Drawback of this method:
The chemistry described in above scheme-7 involved recation of chirally pure
R-isomer and isopropyl chloroformate to form anhydride derivative, thereby
increasing number of steps.

Kerstin approach (2012)12:

Kestin et al have developed a new approach for sulfoxidation using chiral
ligands such as vanadium and iron- catalyzed ligands along with hydrogen
peroxides.
The iron catalyzed oxidation of acetamide 2.3 by using ligand (b) as a
potential chiral precursor in Armodafinil preparation, having 45% yield with
enantiomeric excess is very low. The Schiff base ligand (a) used for the

Novel Asymmetric Synthesis of Chiral Sulfoxides 46

Chapter 2: Novel Process for Synthesis of Armodafinil

sulfoxidation in presence of hydrogen peroxide, but enantiomeric excess was

very poor (35%) (Scheme-8).

Scheme-8
Drawback of this method:
In this synthetic method, vanadium and iron- catalyzed ligands were used for
the sulfoxidation of Armodafinil. All these ligands are costly and not easily
commercially available as well as recovery of the ligands are very difficult.

Why need of new route for the synthesis of Armodafinil?

On the basis of following grounds there is need of new route for the synthesis
of Armodafinil.
1. Considering all the aspects of above reported methods, it is found that all
processes required costly resolving agents for resolution of modafinic acid.
2. Most of the synthetic methods lose 50% of molecule at the later stage, which
affect on atom economy of the molecule.
3. During asymmetric synthesis, costly ligand and metals are used which is
not feasible on the commercial scale of the molecule.

Novel Asymmetric Synthesis of Chiral Sulfoxides 47

Chapter 2: Novel Process for Synthesis of Armodafinil

3. Accordingly there remains a need for simple, cost effective and industrially
feasible process for Armodafinil.
4. Keeping in mind all the above issues, we have developed simplest and
robust methodology for Armodafinil synthesis from simple starting material
benzhydrol.

Novel Asymmetric Synthesis of Chiral Sulfoxides 48

Chapter 2: Novel Process for Synthesis of Armodafinil

2.4 Present Work:

2.4.1 Aim and Design of the Work

Our aim was to synthesize Armodafinil from benzhydrol and develop a new
intensified process. The literature methods have inherent problem of more
number of steps, costly raw material and critical reaction conditions. To
overcome these issues, there is a need for the development of alternative
methods using nucleophilic substitution on sulfur.

2.4.2 Design and Development:

We have considered an approach to synthesize Armodafinil employing
nucleophilic substitution strategy using cheap and readily available raw
materials. In proposed intensified process all the reaction conditions are
feasible and mild from industrial point of view. In this route less number of
steps will be required. All the reagents, conditions are easy to handle. The key
step in the process is the reaction of L-menthol derivative and nucleophilic
substitution on sulfur. A new general strategy for synthesis of Armodafinil is
disclosed in Scheme-9.

Novel Asymmetric Synthesis of Chiral Sulfoxides 49

Chapter 2: Novel Process for Synthesis of Armodafinil

Scheme-9

Based on the above general strategy we have planned following synthetic

scheme for the enantioselective synthesis of Armodafinil (Scheme-10).

Novel Asymmetric Synthesis of Chiral Sulfoxides 50

Chapter 2: Novel Process for Synthesis of Armodafinil

Scheme-10
The synthesis of Armodafinil is carried out in following reaction sequence
Step-I: Synthesis of diphenylmethanethiol
Step-II: Synthesis of diphenylmethanesulfinic chloride

Novel Asymmetric Synthesis of Chiral Sulfoxides 51

Chapter 2: Novel Process for Synthesis of Armodafinil

Step-III: Synthesis of (S)-(1R, 2R, 5R)-2-isopropyl-5-methylcyclohexyl

diphenylmethanesulfinate

Step- IV: Synthesis of (R)-methyl-2-(benzhydrylsulfinyl) acetate

Step-V: Synthesis of (R)-2-(benzhydrylsulfinyl) acetamide

Intermediates are represented in square bracket in Scheme-10 as these are not

isolated. After completion of the reaction we performed simple workup and
next step was carried out.

Novel Asymmetric Synthesis of Chiral Sulfoxides 52

Chapter 2: Novel Process for Synthesis of Armodafinil

2.5 Results and Discussion

In our effort to develop a simple and robust route for Armodafinil, we have
chosen benzhydrol, a commercially available starting material.

Preparation of diphenylmethanethiol 10.1:

It was found that one equivalent of Lawesson’s reagent 11.1 with respect to
benzhydrol in toluene was more efficient to achieve better yield than using
two equivalent of Lawesson’s reagent. The optimized reaction condition was
established (Table-1) with simple workup procedure (Scheme-11).

Scheme-11

Table-1: Optimized reaction condition

Raw Materials Mole Ratio
Benzhydrol(2.1) 1
Lawesson’s reagent 1 mole
Solvent Toluene (5 volume)
Time, Temp 2h at reflux
Yield 70%

The isolated product was characterized by mass and 1H-NMR.

Novel Asymmetric Synthesis of Chiral Sulfoxides 53

Chapter 2: Novel Process for Synthesis of Armodafinil

In Mass analysis, peak appeared at m/z = 199 (M-1) indicated that thiol was
prepared successfully. 1H-NMR and mass confirms the structure of desired
compound.

1H-NMR (400 MHz, CDCl3):

A doublet at δ 2.28-2.30 indicated the presence of -SH group in the molecule

and the doublet at δ 5.45-5.47 indicated the benzylic proton. The remaining 10
protons of aromatic ring appered in the region of δ 7.23-7.44. The structure
assigned to the compound thus is 10.1 and it is supported by mass analysis.

Preparation of Sulfinate derivative 10.3 and 10.4:

Diphenylmethane thiol was converted into diphenylmethane sulfinyl chloride

using acetic acid and sulfuryl chloride (SO2Cl2) at -40°C. Reaction mass was
stirred at ambient temperature for 2 h. After completion of reaction it was
quenched and standard work-up procedure furnished diphenylmethane
sulfinyl chloride 9.1 as an oil. This oil was carried forward for the preparation
of menthyl derivative 10.3 and 10.4 by using pyridine and L-menthol in
methanol as solvent but here the reaction ended up with methyl ester
derivative as a major product 12.1. The expected product was not formed in
this reaction (Scheme-12).

Novel Asymmetric Synthesis of Chiral Sulfoxides 54

Chapter 2: Novel Process for Synthesis of Armodafinil

Scheme-12

In another reaction THF was used as a solvent for the conversion of

diphenylmethane sulfinyl chloride 9.1 into menthyl diphenylmethane
sulfinate 10.3 and 10.4 at room temperature but reaction did not proceed at
all.
Due to unsuccessful efforts, it was thought to use DMF as a solvent for this
reaction. A solution of compound 10.1 in DMF was treated with SO2Cl2 in
acetic acid at -40°C. Reaction mixture was warmed to room temperature and
stirred for 12-15 h but there was no appreciable change in starting material.
The reaction temperature was further increased to 50-55°C and stirred for
additional 24 h. Reaction was complete, work-up procedure gave product as
an oil, but the desired product was obtained 10.3 and 10.4

Further this menthyl diphenylmethane sulfinate 10.3 and 10.4 was prepared
by another alternative method and the scheme is given below:

Following new route (Scheme-13) was proposed for the preparation of

targeted molecule Armodafinil 1.

Novel Asymmetric Synthesis of Chiral Sulfoxides 55

Chapter 2: Novel Process for Synthesis of Armodafinil

Scheme-13

Diphenyl methane was taken as a starting material for synthesis of sulfonyl

chloride derivative 13.2.

Diphenylmethane 13.1 was converted into Diphenylmethane sulfonyl

chloride 13.2 using sulfuryl chloride and n-BuLi under nitrogen atmosphere.

Novel Asymmetric Synthesis of Chiral Sulfoxides 56

Chapter 2: Novel Process for Synthesis of Armodafinil

Scheme-14.

Table 2: Optimized reaction condition

Raw Materials Mole ratio

Diphenylmethane (13.1) 1

Sulfuryl chloride 1.35 mole

n-BuLi 1.2 mole
Solvent Diethyl ether
Time 60 min

After the work-up this intermediate 13.2 was used as such for next reaction
for the preparation of racemic menthyl diphenylmethane sulfinate derivative.

The diphenylmethane sulfuryl chloride 13.2 was condensed with the L-

menthol in presence of triethylamine and triphenylphosphine to give two
isomers of sulfinate compound 10.3 and 10.4. These two isomers were well
separated by column chromatography.

Novel Asymmetric Synthesis of Chiral Sulfoxides 57

Chapter 2: Novel Process for Synthesis of Armodafinil

Scheme-15

Table 3: Optimized reaction condition

Raw Materials Mole ratio

Diphenylmethane sulfuryl chloride (13.2) 1

L-Menthol 1 mole
Triphenyl phosphine 1 mole
Triethylamine 10 mole
Solvent CH2Cl2
Time 60-120 min

After completion of reaction, the two isomers 10.3 and 10.4 were separated
easily on silica column chromatography. The desired isomer 10.4 was well
characterized by 1H-NMR, which is described below.

Novel Asymmetric Synthesis of Chiral Sulfoxides 58

Chapter 2: Novel Process for Synthesis of Armodafinil

1H-NMR (400 MHz, DMSO-d6):

Formation of compound 10.4 was confirmed by the appearance of singlet at δ

5.30 due to benzylic proton (Ar)2–CH in the molecule.

Preparation of (R)-methyl-2-(benzhydrylsulfinyl) acetate 1.3 :

The desired isomer 10.4 was further treated with methyl acetate and n-Butyl
lithium to get methoxy derivative i.e. (R)-methyl 2-(benzhydrylsulfinyl)
acetate 1.3.

Structure of the compound 10.4 was confirmed by mass, 1H-NMR and 13C-

NMR.

1H-NMR (400 MHz, CDCl3):

Formation of compound 1.3 was confirmed by the appearance of doublet at δ

Novel Asymmetric Synthesis of Chiral Sulfoxides 59

Chapter 2: Novel Process for Synthesis of Armodafinil

3.39-3.43 and doublet at δ 3.51-3.55 due to –CH2 protons in the molecule and
singlet at δ 3.73 confirmed the presence of methoxy group. Structure was
further supported by 13C-NMR, presence of peak at δ 165.7 confirmed the
ester group and peak at δ 53.9 revealed prescence of –OCH3 group.

Preparation of Armodafinil 1:

After the preparation of methoxy derivative 1.3 it was treated with ammonia
in methanol to end up with desired compound Armodafinil 1.

Scheme-16

Result:
The overall yield of designed route is 27%. The specific rotation of
synthesized Armodafinil matched with literature data [α]D22 = - 77.77° (c = 1.0,
CHCl3) [lit.6 [α] D 22 = - 76.6(c = 1.0, CHCl3].
The structure of compound 1 was also confirmed by mass, 1H-NMR and
chiral HPLC chromatogram showed single enantiomer with the purity 99.99%
(Refer Spectra no-12). This chiral purity and the specific rotation confirmed
the theory of inversion of configuration at ‘S’ during formation of
intermediate molecule 1.3.

Novel Asymmetric Synthesis of Chiral Sulfoxides 60

Chapter 2: Novel Process for Synthesis of Armodafinil

1H-NMR (400 MHz, CDCl3):

Formation of compound 1 was confirmed by the presence of doublet at δ 3.15-

3.18 and doublet at δ 3.46-3.50 due to –CH2 protons in the molecule. Singlet at
δ 5.98 and 7.11 is due to amide protons. Further 13C-NMR spectrum shows at
δ 166.3 indicated that the amide group is present.

Novel Asymmetric Synthesis of Chiral Sulfoxides 61

Chapter 2: Novel Process for Synthesis of Armodafinil

2.6 Conclusion

In summary, a simple and new route for the synthesis of Armodafinil was
developed. This route comprises cheaper raw material diphenyl methane
during the overall synthesis. The important attribute of this route is the use of
commercially available L-menthol, as an handle for chiral separation.

The key and important step of this route was nucleophilic reaction on
menthol attached sulfur derivative. Reaction of nucleophile with sulfur,
proceeds through the inversion of configuration. This was proved by the
chiral HPLC and the specific optical rotation at Armodafinil.

The used L-menthol can be recovered after nucleophilic reaction and easily
recycled during scale-up. In this route all the reagents, raw materials are safe
for handling purpose and reaction conditions are easily scalable.

In conclusion, nucleophilic substitution at the sulfur resulted in the inversion

of configuration, which was demonstrated by synthesizing Armodafinil.

Based on the reduced number of steps, cost efficient and novel route for the
synthesis of Armodafinil is established.

Novel Asymmetric Synthesis of Chiral Sulfoxides 62

Chapter 2: Novel Process for Synthesis of Armodafinil

2.7 Experimental Section:

Preparation of Diphenylmethane thiol (10.1):

SH

10.1

To a solution of benzhydrol (10 g, 0.054 mole) in toluene (50 ml) Lawesson’s

reagent (21.9 g, 0.054 moles) was slowly added and reaction mass stirred
under nitrogen atmosphere for 10-15 min. After that resultant reaction
mixture was slowly heated to reflux and further stirred for 2 h. Then after
completion of reaction, the mass was quenched with water (20 ml), and
stirred for 10 min. Both layers separated and organic layer was concentrated
under vacuum to give an oil (8.2 g, Yield 70%).
MS (ESI-TOF) (m/z) (Refer Spectra No-1): Calculated for C13H12S Molecular
Weight 200, Found 199 (M-1).

1H-NMR (400 MHz, CDCl3) (Refer Spectra No-2): δ = 2.28-2.30(d, J = 4.8Hz,

1H), 5.45-5.47(d, J = 4.8Hz, 1H), 7.23-7.44(m, 10H)

Synthesis of diphenylmethane sulfonyl chloride (13.2)

Novel Asymmetric Synthesis of Chiral Sulfoxides 63

Chapter 2: Novel Process for Synthesis of Armodafinil

To a chilled solution of diphenylmethane (25 g, 0.14 moles) in anhydrous

diethyl ether (150 ml), under nitrogen atmosphere, was added n-BuLi solution
(11.4g, 0.17 moles) in diethyl ether slowly in 15 min. Resultant reaction
mixture then was slowly added to sulfuryl chloride (15.7 ml, 0.19 moles) at -
40°C. After completion of reaction the remaining sulfuryl chloride and
solvent was evaporated under vacuum. In the left behind residue, was added
dichloromethane (262.5 ml) and the resulting solution then washed using
water (100ml X 2). The obtained organic layer further dried and evaporated to
get oil of diphenylmethane sulfonyl chloride compound 13.2 (22.5 g, yield:
57.0%).

Synthesis of (S)- (1R, 2R, 5R)-2-isopropyl-5-methylcyclohexyl

diphenylmethanesulfinate (10.4):

To a stirred solution of diphenylmethane sulfonyl chloride 13.2 (21 g, 0.078

moles), L-menthol (12.29 g, 0.078 moles) triethylamine (109 ml, 0.78 moles) in
dichloromethane (63 ml) was added, a solution of triphenylphosphine (20.45
g, 0.078 moles) in dichloromethane (21 ml) in a period of 60-65 min. After the
completion of recation, the resultant thick mass was filtered and mother
liquor was concentrated under vacuum to get (±)menthyl diphenylmethane
sulfinate as an oil (25.1 g, yield: 86%). Isomer (S) menthyl diphenylmethane
sulfinate 10.4 was separated easily and further purified on silica column
chromatography using ethyl acetate: cyclohexane as mobile phase (‘S’ isomer:
11.0 g).

Novel Asymmetric Synthesis of Chiral Sulfoxides 64

Chapter 2: Novel Process for Synthesis of Armodafinil

1H-NMR (400MHz, DMSO-d6) (Refer Spectra No-3): 0.71-1.00 (m, 13H), 1.29
– 1.37 (m, 1H), 1.48-1.61 (m, 2H), 1.80-1.83 (m, 1H), 2.15-2.21 (m, 1H), 3.11-3.23
(m, 1H), 5.30 (S, 1H), 7.32-7.52 (m, 10H).

Synthesis of (R)-methyl-2-(benzhydrylsulfinyl) acetate (1.3)

Methyl acetate (2.64 g, 0.035 moles) in tetrahydrofuran (33 ml) was slowly
added to a n-BuLi in hexane (1.2M) (35.54 ml, 0.042 moles) at -78°C. A
solution of menthyl diphenylmethane sulfinate compound 10.4 (11 g, 0.0297
moles) in THF was added at -78°C over a period of 30-35 min. Reaction mass
was stirred further for 2 h at temperature -60 to -78°C. It was slowly warmed
to ambient temperature, mixture mass quenched with aq. solution of
ammonium chloride to give a suspension. After quenching, water charged
into the mass and layers separated. The separated aqueous layer was
extracted with ethyl acetate. Combined organic layer was concentrated under
vacuum to get an solid. This solid was further purified on silica column
chromatography, using mobile phase ethyl acetate: cyclohexane to get pure
methyl (R)-methyl-2-(benzhydrylsulfinyl) acetate compound 1.3 (5.5 g, yield:
64%).

MS (ESI-TOF) (m/z) (Refer Spectra No-5): Calculated for C16H16O3S

Molecular Weight 288, Found 167 (M-121).

1H-NMR (400 MHz, CDCl3) (Refer Spectra No-6): δ = 3.39-3.43 (d, J = 14 Hz,
1H), 3.51 -3.55 (d, J = 14Hz, 1H), 3.73 (s, 3H), 5.21(s, 1H), 7.33-7.51(m, 10H).

Novel Asymmetric Synthesis of Chiral Sulfoxides 65

Chapter 2: Novel Process for Synthesis of Armodafinil

13C-NMR (100 MHz, CDCl3) (Refer Spectra No-7): δ= 165.7 (C=O), 135.13,
129.2, 128.7-128.4 (CH=CH), 71 (CH), 53.9 (OCH3) 52.6 (CH2) ppm

Preparation of Armodafinil (1):

Methanolic ammonia (15-20%, 50 ml) was charged in a round bottom flask at

25-30°C. A slurry of methyl (-) benzhydrylsulfinyl acetate 1.3 (5 g, 0.017
moles) in 20 ml methanol was prepared at 25-30°C and then it was slowly
added into the ammonical solution in 5-10 min. The reaction mass was further
stirred for 180-200 min at 25-30°C. A after completion of reaction, methanol
was removed by distillation under vacuum. Then to make a solution
dichloromethane (50 ml) was charged. The organic dichloromethane layer
washed using aqueous 5% sodium bicarbonate solution (25 ml). The aqueous
layer was extracted with dichloromethane (10 ml). The total organic layer was
again washed with water (25 ml) and then concentrated upto 5 volumes. Into
the left over mass diisopropyl ether (25 ml) was added and stirred further for
210 min. The solid was isolated by filtration, and washed using diisopropyl
ether to get crude Armodafinil. The crude solid was further dissolved in
dichloromethane (15 ml). Diisopropyl ether (25 ml) was added into the clear
solution. The resulting mass then stirred for 3 h. The solid isolated by
filtration and washed using diisopropyl ether to get purified Armodafinil 1
(4.2g; Yield 85%).

MS (ESI-TOF) (m/z) (Refer Spectra No-8): Calculated for C15H15NO2S

Molecular Weight 273, Found 167 (M-106)

Novel Asymmetric Synthesis of Chiral Sulfoxides 66

Chapter 2: Novel Process for Synthesis of Armodafinil

1H-NMR (400 MHz, CDCl3) (Refer Spectra No-9) : δ= 3.15-3.18 (d, J = 14.4
Hz, 1H), 3.46-3.50 (d, J =14.4 Hz, 1H), 5.28 (s, 1H), 5.98 (s, 1H), 7.11 (s, 1H),
7.28-7.52 (m, 10H) ppm.

13C-NMR (100 MHz, CDCl3) (Refer Spectra No-10): δ= 166.34 (C=O), 134.4,
134.07, 129.40, 129.38, 128.88, 128.76, 128.59 (CH=CH), 71.3(CH), 51.8(CH2)
ppm
IR (KBr, in cm-1) (Refer Spectra No-11): 3368, 3186, 1665, 1364, 1031 cm-1

HPLC Chiral purity (Refer Spectra No-12): 99.99%

Specific rotation: [α] D 22 = - 77.77° (c = 1.0, CHCl3) [lit.6 [α] D 22 = - 76.6° (c =

1.0, CHCl3].

MP: 152.7-153.2°C (lit.6, 153-154 °C).

Novel Asymmetric Synthesis of Chiral Sulfoxides 67

Chapter 2: Novel Process for Synthesis of Armodafinil

2.8 Spectra
1. Mass spectra of 10.1
2. 1H-NMR spectra of 10.1
3. 1H-NMR spectra of 10.4
4. 1H-NMR spectra of 10.4 (Elaborated part)
5. Mass spectra of 1.3
6. 1H-NMR spectra of 1.3
7. 13C-NMR spectra of 1.3
8. Mass spectra of 1
9. 1H-NMR spectra of 1
10. 13C-NMR spectra of 1
11. IR spectra of 1
12. Chiral HPLC chromatogram of 1

Novel Asymmetric Synthesis of Chiral Sulfoxides 68

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-1: Mass spectra of 10.1

Novel Asymmetric Synthesis of Chiral Sulfoxides 69

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-2: 1H-NMR spectra of 10.1

Novel Asymmetric Synthesis of Chiral Sulfoxides 70

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-3: 1H-NMR spectra of 10.4

Novel Asymmetric Synthesis of Chiral Sulfoxides 71

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-4: 1H-NMR spectra of 10.4 (Elaborated part)

Novel Asymmetric Synthesis of Chiral Sulfoxides 72

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-5: Mass spectra of 1.3

Novel Asymmetric Synthesis of Chiral Sulfoxides 73

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-6: 1H-NMR spectra of 1.3

Novel Asymmetric Synthesis of Chiral Sulfoxides 74

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-7: 13C-NMR spectra of 1.3

Novel Asymmetric Synthesis of Chiral Sulfoxides 75

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-8: Mass spectra of 1

Novel Asymmetric Synthesis of Chiral Sulfoxides 76

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-9: 1H-NMR spectra of 1

Novel Asymmetric Synthesis of Chiral Sulfoxides 77

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-10: 13C-NMR spectra of 1

Novel Asymmetric Synthesis of Chiral Sulfoxides 78

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-11: IR spectra of compound 1

Novel Asymmetric Synthesis of Chiral Sulfoxides 79

Chapter 2: Novel Process for Synthesis of Armodafinil

Spectra No-12: Chiral HPLC chromatogram of 1

Novel Asymmetric Synthesis of Chiral Sulfoxides 80

Chapter 2: Novel Process for Synthesis of Armodafinil

2.9 References

1. Robertson, P Jr.; Hellriegel ET. Clin Pharmakinet. 2003, 42, 123.

2. Nancy, Wong, Y.; Peter King, S.; Donna Simcoe, S.; Gorman J. Clin.
Pharmacol. 1999, 39, 281.
3. Wong, YN.; Simcoe, D.; Hartman, LN.; Laughton, WB; King SP;
McCormick; Grebow, PE. J. Clin. Pharmacol. 1999, 39, 30.
4. NUVIGIL (Package insert). Teva Pharmaceuticals USA, Inc U.S.
Approval: 2007.
5. Louis Lafon, Laboratories L. Lafon, France US 4,927,855; May 22,
1990.
6. Prisinzano, T.; Podobinski, J.; Tidgewell, K.; Luo, M.; Swenson, D.;
Tetrahedron: Asymmetry 2004, 15, 1053.
7. Osoria-Lozade, A.; Prisinzano, T.; Olivo, H. F. Tetrahedron:
Asymmetry 2004, 15, 3811.
8. Rebiere, F.; Duret Gerard; Part Laurence Cephalon France.; EP
1516869, March 23, 2005.
9. Olivo, H. F.; Osoria-Lozade, A.; Peeples, T. L.; Tetrahedron:
Asymmetry 2005, 16, 3507.
10. Moshkovitskaptson, R. Teva Pharmaceuticals USA, Inc.;
WO2007/103221, Sept 13, 2007.
11. Dixit, G.; Khile, A. S.; Pradhan, N.; Valgeirsson, J. Actavis Group
PTC EHS; WO 2009/024863, Feb 26, 2009.
12. Kerstin, A. Stingl; Katharina, M. W.; Svetlana, B. T. Tetrahedron,
2012, 68, 8493.

Novel Asymmetric Synthesis of Chiral Sulfoxides 81