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Green Chemistry
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DOI: 10.1039/C6GC02623K
Green Chemistry
COMMUNICATION
Efficient Atom and Step Economic (EASE) Synthesis of Smart Drug
Modafinil
Received 00th January 20xx,
Accepted 00th January 20xx
a,b
a
a,b
a,b,†
Shivam Maurya , Dhiraj Yadav , Kemant Pratap and Atul Kumar
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract
:
Modafinil, 2-[(Diphenylmethyl)sulfinyl]acetamide qualitative in nature but it does not define the clear matrices.
6
,7
(
MOD) is a key psychostimulant drug used for treatment of Therefore various simple matrices have been intercepted
narcolepsy and other sleep disorders with very low addiction which have the basic parameters of these twelve principles like
liability. Recently, MOD has been clinically investigated for the step economy, atom economy, mass intensity & E–factor etc.
treatment of cocaine addiction and used by astronauts in long- In this perspective we wish to report synthesis of smart drug
term space missions. We have developed smart synthetic strategy
for Smart Drug Modafinil. An efficient atom and step economic
Modafinil using smart chemistry-green chemistry with
application of green chemistry matrix.
(
EASE) synthesis has been done by direct reaction of benzhydrol
Various approaches have been proposed in the literature to
synthesize Modafinil and its analogues such as in US Pat. No.
and 2-mercaptoacetamide using recyclable heterogeneous
catalyst Nafion-H along with post- sulphoxidation. This protocol
exhibits improved green chemistry matrix. We have also
developed a superior pre-sulfoxidation approach for Modafinil.
4
177290, 2-(benzhydryl thio) acetic acid is prepared by first
reacting benzhydrol with thiourea and 48% hydrobromic acid,
then adding sodium hydroxide and chloroacetic acid. The
reaction of 2-(benzhydryl thio)acetic acid with thionyl chloride
in benzene affords 2-(benzhydryl thio)-acetyl chloride, which is
1
Smart drug, Modafinil {1,2-[(diphenyl methyl) sulfinyl]
acetamide} is utilized clinically as awake promoting agent for
2
the treatment of narcolepsy and other sleeping disorders.
8
,3,4
treated with ammonia to give 2-(benzhydrylthio) acetamide .
In US Pat. No. 4098824, Bromo diphenyl methane is reacted
with thiourea to give diphenyl methanthiol, which is then
reacted with chloroacetic acid to give 2-(benzhydryl thio)acetic
acid or with chloroacetonitrile to give 2-(benzhydyl
Modafinil has significant advantages over traditional anti-
narcoleptic drugs such as amphetamine and methylphenidate
as it rarely promotes abusive tendencies and exhibits reduced
peripheral and central side-effects. As it is used for narcolepsy
and enhances cognition independent of its known effects in
sleep disordered populations therefore considered as the first
well-validated pharmaceutical nootropic agent. Recently
9
thio)acetonitrile . Both compounds can be transformed in to 2-
(benzhydryl thio) acetamide by known methods. In EP528172,
Benzhydrol is reacted with mercaptoacetic acid in
trifluoroacetic acid to give 2-(benzhydrylthio)acetic acid, which
Modafinil entitled as the best example of “smart drug” or
1
1
0
is then converted to 2-(benzhydryl thio) acetamide . In CA131
299268, Chlorodiphenyl methane is reacted with 2-ethyl
mercaptoacetate to give ethyl 2-(benzhydryl thio)acetate form
“
dose of intelligence”.
:
The green chemistry started with an idea that chemists are
highly creative profession but one of its profession to make the
5
earth more pleasant using “Smart Chemistry”. At the silver
1
1
which compound (II) is subsequently obtained . In US
004/0106829A1, 2-(benzhydryl thio) acetamide has been
prepared from chlorodiphenyl methane and thiourea utilizing
2
jubilee of this science we have achieved some milestones and
the concept is now honoured in both academia and industry.
Although useful, the twelve principles of green chemistry are
1
2
KI, NaOH and followed by chloroacetamide in DMSO . In US
007/0015836A1, 2-(benzhydryl thio) acetic acid is subjected
firstly to oxidation then followed by the treatment of dimethyl
2
1
3
a.
sulphate in basic media.
Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute,
Sector 10, Jankipuram extension, Sitapur Road, P.O. Box 173, Lucknow 226031,
India.
Academy of Scientific and Innovative Research, New Delhi 110001, India.
It is ascertained that above mentioned methods require the
recovery of different intermediates and the use of costly and
toxic reagents. Therefore there is the need to develop a
method for the preparation of Modafinil devoid of previously
b.
†
Electronic Supplementary Information (ESI) available: [Experimental section,
E-mail: dratulsax@gmail.com/atul_kumar@cdri.res.in
1
13
characterization of compounds, copies of H and C NMR spectra for compounds,
See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
Green Chemistry, 2016, 00, 1-4 | 1
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