Organic Process Research & Development 2009, 13, 854–856
An Investigation on Key Parameters that Influence the Synthesis of
(S)-(+)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine: A Key
Intermediate for Duloxetine
Sashikanth Suthrapu,† Somaiah Sripathi,† Raju Veeramalla,† Ramachandra Reddy Bojja,† and Venugopal Reddy Karnati*,‡
Department of Research and DeVelopment, Srini Pharmaceuticals Ltd., Plot No. 10, Type-C, Road No. 8, Film Nagar,
Jubilee Hills, Hyderabad-500033, Andhra Pradesh, India, and Department of Chemistry, Osmania UniVersity, Tarnaka,
Hyderabad- 500007, Andhra Pradesh, India
Abstract:
synthesis of duloxetine hydrochloride involves the condensation
of 8 with 1-fluoronaphthalene 9 in the presence of sodium
hydride/dimethylsulfoxide to yield (S)-(+)-N,N-dimethyl-3-(1-
naphthalenyloxy)-3-(2-thienyl)propylamine 10, which on hy-
drolysis with water affords (S)-(+)-N,N-dimethyl-3-(1-naph-
thalenyloxy)-3-(2-thienyl) propylamine 11. Demethylation of
11 with phenylchloroformate in the presence of diisopropyl-
ethylamine, followed by salt formation with conc. hydrochloric
acid6,7f in the presence of ethyl acetate afforded duloxetine
hydrochloride 1.
A similar synthetic approach is reported in the literature for
the key intermediate 11, which involves in situ generation using
different bases in combination with catalysts. However, the
given selectivity could not be reproduced in our laboratory when
the reaction was conducted under the literature conditions.7a-f
The usage of a hazardous base such as NaH in these processes
made them commercially nonattractive. In the recent modifica-
tion8 of this current process we have conducted the condensation
reaction in the presence of a catalytic amount of phase transfer
catalyst (PTC) to enhance the enantioselectivity of the desired
S-isomer 11 to more than 99%.
This document highlights the systematic study of influencing
factors such as temperature, base, catalyst, and solvent volume in
the synthesis of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-
thienyl)propylamine oxalate 11a, without affecting the chiral
purity.
Introduction
Duloxetine1,2 and the related class of compounds such as
fluoxetine, tomoxetine, etc. are important for treating psychiatric
disorders. Fluoxetine is selective inhibitor of serotonin in
serotonergic neurons; tomoxetine and nisoxetine are selective
inhibitors of norepinephrine in noradrenergic neurons, while
duloxetine is a dual inhibitor3 of serotonin (5-HT) and norepi-
nephrine (NE) reuptake and thus has a better pharmacological
profile as an antidepressant drug.
Serotonin and norepinephrine neurotransmitters are inti-
mately involved in a number of physiological and behavioral
processes, suggesting that duloxetine (with the ability to produce
robust increases of extracellular serotonin and norepinephrine
levels) is not only a highly efficient antidepressant agent for
treating psychiatric disorders but also can be used for treating
other symptoms such as alcoholism, stress urinary incontinence4
(SUI), fatigue, stroke, intestinal cystitis, obsessive compulsive
disorder, panic disorder, sleep disorder, sexual dysfunction, etc.
Discovery5 of the synthesis of duloxetine hydrochloride 1
is reported in Scheme 1, in which 2-acetyl thiophene 2 is reacted
with N,N-dimethylamine hydrochloride 3 and paraformaldehyde
4 in the presence of conc. hydrochloric acid to yield 3-(dimethyl
amino)-1-(thiophen-2-yl)propan-1-one hydrochloride 5, which
upon reduction with sodium borohydride in the presence of
ethanol affords 3-(dimethyl amino)-1-(thiophen-2-yl)propan-1-
ol 6. Resolution of 6 with (S)-(+)-mandelic acid affords
diastereomeric salt 7, which on hydrolysis with sodium hy-
droxide affords (S)-alcohol 8. The key intermediate 11 in the
Now we have taken up a comprehensive study of this
condensation reaction on enantioselectivity by employing dif-
ferent types of commercially available bases in the presence of
various catalysts in different solvents and at different temperatures.
Results and Discussion
It is known from the literature that there is a significant
change in the reactivity of different types of bases towards a
particular functional group.7a-f During the development of
duloxetine, we have screened several types of bases and found
that sodium hydroxide in the presence of PTC in dimethylsul-
foxide works well in this reaction, resulting in more than 99%
enantioselectivity of S-isomer 11a. The formation of desired
S-isomer 11a is extremely poor in other solvents such as
diglyme, toluene, and a mixture of solvents. The effects of
temperature, base, catalyst, and solvent volume on the enanti-
oselectivity of 11a are shown in Table 1.
* To whom correspondence should be addressed. Telephone: +91 9490783736.
E-mail: drkvr_ou@yahoo.com; kvgr1951@rediffmail.com.
† Srini Phramaceuticals Ltd.
‡ Osmania University.
(6) Berglund, R. A. U. S. Patent 5,362,886, 1994.
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Butchko, M. N.; Merschaert, A.; Moder, K. P. U. S. Patent Application
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Vol. 13, No. 5, 2009 / Organic Process Research & Development
10.1021/op800289h CCC: $40.75 2009 American Chemical Society
Published on Web 07/13/2009