New synthesis of donepezil through palladium-catalyzed hydrogenation approach

Article abstract of DOI:10.1080/00397910500334231

A new, economical, and efficient process has been developed for large-scale synthesis of donepezil 1, an anti-Alzheimer's drug. The process involves palladium-catalyzed hydrogenation of (2E)-5,6-dimethoxy-2-(pyridin-4- ylmethylene)indan-1-one 6 to provide 5,6-dimethoxy-2-(piperidin-4-ylmethyl) indan-1-one 8 as a key step. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500334231

This article was downloaded by: [Texas Technology University]
On: 29 September 2014, At: 05:24
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
New Synthesis of Donepezil Through
Palladium‐Catalyzed Hydrogenation Approach
Chandrashekar R. Elati a , Naveenkumar Kolla a , Subrahmanyeswara Rao
Chalamala a , Pravinchandra J. Vankawala a , Venkataraman Sundaram a
Himabindu Vurimidi b & Vijayavitthal T. Mathad a
,
a Department of Research and Development , Dr. Reddy's Laboratories Ltd. ,
Hyderabad, Andhra Pradesh, India
b Institute of Science and Technology, J. N. T. University , Hyderabad,
Andhra Pradesh, India
Published online: 15 Aug 2006.
To cite this article: Chandrashekar R. Elati , Naveenkumar Kolla , Subrahmanyeswara Rao Chalamala ,
Pravinchandra J. Vankawala , Venkataraman Sundaram , Himabindu Vurimidi & Vijayavitthal T. Mathad
(2006) New Synthesis of Donepezil Through Palladium‐Catalyzed Hydrogenation Approach, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:2,
169-174, DOI: 10.1080/00397910500334231
To link to this article: http://dx.doi.org/10.1080/00397910500334231
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 36: 169–174, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500334231
New Synthesis of Donepezil Through
Palladium-Catalyzed Hydrogenation
Approach
Chandrashekar R. Elati, Naveenkumar Kolla,
Subrahmanyeswara Rao Chalamala,
Pravinchandra J. Vankawala, and Venkataraman Sundaram
Department of Research and Development, Dr. Reddy’s Laboratories Ltd.,
Hyderabad, Andhra Pradesh, India
Himabindu Vurimidi
Institute of Science and Technology, J. N. T. University, Hyderabad,
Andhra Pradesh, India
Vijayavitthal T. Mathad
Department of Research and Development, Dr. Reddy’s Laboratories Ltd.,
Hyderabad, Andhra Pradesh, India
Abstract: A new, economical, and efficient process has been developed for large-scale
synthesis of donepezil 1, an anti-Alzheimer’s drug. The process involves palladium-
catalyzed hydrogenation of (2E)-5,6-dimethoxy-2-(pyridin-4-ylmethylene)indan-1-
one 6 to provide 5,6-dimethoxy-2-(piperidin-4-ylmethyl)indan-1-one 8 as a key step.
Keywords: Anti-Alzheimer’s drug, donepezil, economic synthesis, palladium-
catalyzed hydrogenation
Received in India July 11, 2005
DRL-IPD Communication No. 006.
Address correspondence to Vijayavitthal T. Mathad, Department of Research and
Development, Dr. Reddy’s Laboratories Ltd., IPD, Unit-III, Bollaram, Hyderabad
502 325, Andhra Pradesh, India. Tel.: þ91 8458 279485; Fax: þ91 8458 279619;
E-mail: vijayavitthalm@drreddys.com
169

170
C. R. Elati et al.
INTRODUCTION
Alzheimer’s disease, the most common cause of dementia, is a neurodegen-
erative disorder characterized by a progressive deterioration of memory and
cognition.[1] Among the group of clinically useful marketed acetyl cholin-
esterase inhibitors, donepezil 1 is one of the promising agents for the
treatment of this type of disease. It is effective for the treatment of various con-
ditions involving memory loss, such as Alzheimer’s disease and other neuro-
degenerative disorders.[2]
Sugimoto and coworkers[3] accomplished the synthesis of 1 with an
overall yield of 27.4%, where in the aldol condensation of 5,6-dimethoxy-
indan-1-one 2, 1-benzyl piperidine-4-carboxaldehyde 4 served as a key step
of synthesis to yield 5, which upon debenzylation resulted donepezil 1
(Scheme 1). This process has additional obstacles for the large-scale pro-
duction because of subzero temperature requirements (2788C) and
hazardous chemicals such as n-butyl lithium.
Several other syntheses of 1 have been reported,[4] which are either too
long or contain unacceptable operations and thus are not suitable for large-
scale preparation. Stephen Lensky[5] reported an efficient three-step
synthesis for 1 involving hydrogenation of pyridine analogue 7 using
expensive platinum oxide (Scheme 2, path A). This process was found to be
highly expensive because of the high cost of platinum oxide. Attempts to
replace platinum oxide with less expensive 5% palladium carbon always
resulted in debenzylated products 8 and 11.
In our approach 8 is identified as the suitable intermediate to prepare
donepezil 1. Reported synthesis[4a] of 8 involves five stages with much less
overall yield and is commercially not feasible for large-scale production.
Interestingly, no attempts were made in the literature to reduce the pyridine
moiety of the potential and cheaply available intermediate 6.
Here in we report an economic and efficient synthesis[6] (Scheme 2, path B)
for donepezil 1. The first step of our synthesis commenced from commercially
available 5,6-dimethoxy-indan-1-one 2, which was condensed with isonicoti-
naldehyde 3 in a modification of a literature procedure[5] to furnish the known
intermediate 6 in 95.8% yield. With 6 in hand, hydrogenation of pyridine
ring[7] was attempted utilizing palladium carbon. Two major impurities
9 and 10 (Fig. 1) were observed as a result of a competitive side reaction of
Scheme 1. Reagents and conditions: a ¼ n-BuLi/THF/2788C/2 h, b ¼ 10%
PD-C/THF/rt/6 h.

Donepezil Synthesis
171
Scheme 2. a ¼ P-TSA/toluene/reflux/5 h; b ¼ benzyl bromide/acetonitrile/reflux/
2 h; c ¼ PtO2/MeOH/rt/24 h; d ¼ 5% Pd-C/MeOH-HAc/60–658C/6.5–7.0 h; e ¼
benzyl bromide/IPA : MeOH (1 : 1)/60–658C/11–12 h.
carbonyl moiety. With systematic screening of reaction conditions (reaction
temperature, reaction time, hydrogen pressure, choice of solvent, etc.) the
best result was obtained by hydrogenating 6 in methanol under a hydrogen
pressure of 3.5–4.0 kg/cm2 at 60–658C for 6–7 h to accomplish 8 with
90% yield and 98.5% purity by HPLC. Finally in the last step, which
involves benzylation of 8, we learned that the nature of solvent and quantity
of benzylbromide plays critical role in controlling obvious competitive
dibenzyl product 12. Our approach to understanding this benzylation
chemistry began witha literature-reported procedure[4a] (benzyl bromide,
IPE, 60–658C, triethanolamine) that resulted in poor yield (19.5%) with
dibenzylated impurity 12 (.15% by TLC). We tried solvents such as
acetone, dichloromethane, acetonitrile, isopropylether, and dichloromethane,
but they produced poor yields. Interestingly, usage of a 1 : 1 mixture of isopro-
pylalcohol–water produced exclusively dibenzyl impurity 12. Among the set
of solvents screened treatment of 8 with 1 eq. of benzyl bromide/sodium
Figure 1. Observed process impurities.

172
C. R. Elati et al.
carbonate in ethanol or 1 : 1 mixture of isopropanol–methanol produced
fruitful results with satisfactory yield (65%) of 1, as well facilitated ejecting
an unwanted dibenzyl by-product as a filterable solid from the reaction
mass. The spectroscopic data of our process samples 8 and 1 were well in
agreement with those reported previously.[4a]
In summary, we present an economically competitive synthesis of donepezil
1, which was obtained from 5,6-dimethoxy-indan-1-one 2 in three steps with
overall yield of 56.0% using commercially available and less expensive raw
materials and reagents. Although the moderate yield of the final step affected
the overall yield of the process, the hydrogenation of (2E)-5,6-dimethoxy-2-
(pyridin-4-ylmethylene)indan-1-one 6 in 90% yield employing less-expensive
palladium carbon reduced the overall cost by twofold from that of the
platinum oxide process.[5] To the best of our knowledge, our approach is the
most economically advantageous among all the reported syntheses because of
its yields and less-expensive raw materials and reagents.
EXPERIMENTAL
Experimental Procedure for 6
A mixture of compounds 2 (100.0 g, 0.52 mol), 3 (78.0 g, 0.728 mol), and
p-toluene sulfonic acid (138.4 g, 0.804 mol) in toluene (1250 mL) were
heated to reflux using a water separator for 6 h. The resulting solid was
filtered and slurried in 10% NaHCO3 solution (1200 mL) and filtered. The
filter cake was washed with water (1000 mL) and dried at 808C to afford
pure 6 as pale yellow solid (140.0 g, 95.6%, 99.64% purity by HPLC).
Note
Initially hydrogenation of 6 was carried out using 5% Pd-C in neat acetic acid
at 60–658C and a hydrogen pressure of 4.0 kg/cm2 for 16 h. HPLC analysis of
the product yielded under these conditions recorded a content of 1.37% and
22.42% of 9 and 10 respectively. Interestingly, only impurity 9 was
observed (18.9% by HPLC) when methanol was used as solvent in the
presence of 1.2 eq. of acetic acid in these reaction conditions. Further optim-
ization of time (6–7 h) and temperature (60–658C) enabled these two impu-
rities to be controlled to a level of ,0.25% by HPLC.
Experimental Conditions for 8
The hydrogenation experiments were carried out in a clean and dry autoclave.
The appropriate quantities of 6, solvent, acetic acid, and the catalyst were

Donepezil Synthesis
173
added. Before heating the autoclave to the required temperature, it was repeat-
edly purged first with nitrogen and then with hydrogen at room temperature in
the absence of agitation. Once the required temperature was reached,
hydrogen pressure was applied to obtain the desired pressure of hydrogen.
As the reaction proceeded, the consumed hydrogen was replenished so as to
maintain a constant pressure in the autoclave.
Experimental Procedure for 8
A mixture of compound 4 (100.0 g, 0.35 mol), 5% palladium on activated
carbon (25.0 g), acetic acid (25.6 g, 0.42 mol), and methanol (1800 mL)
were heated to 60–658C at a hydrogen pressure of 4.0 kg/cm2 for 7.0 h.
Reaction was monitored until the content of 11 complied to a limit of 5–
10% by TLC. After cooling the flask to room temperature, the catalyst was
filtered off, the solvent was removed under vaccum, and the residue was
dissolved in water (1000 mL). The aqueous solution was treated with dichlor-
omethane (3 ꢀ 200 mL), basified to a pH of ꢀ13.0, and extracted with
dichloromethane (3 ꢀ 300 mL). Dichloromethane was dried and evaporated
under vacuum and treated with n-heptane (500 mL) to afford a crystalline
5,6-dimethoxy-2-(piperidin-4-ylmethyl)indan-1-one 8 (92.0 g, 90.0%, 98.5%
purity by HPLC).
Experimental Procedure for 1
A mixture of compound 8 (150 g, 0.519 mol), sodium carbonate (33.0 g,
0.311 mol), and 1 : 1 mixture of isoproponal and methanol (1500 mL) were
heated to 60–658C. Benzyl bromide (88.74 g, 0.518 mol) was added slowly,
and the mixture was stirred at 60–658C for 11 h. After cooling the flask to
room temperature, the unwanted by-product 12 was filtered off, and water
(1650 mL) was added to the filtrate. Then the pH of the aqueous solution
was adjusted to 7.5–8.2 and was extracted with toluene (5 ꢀ 750 mL). The
combined organic phases were distilled and treated with toluene–petether
(150 : 300 mL) to precipitate donepezil free base as a white crystalline solid
(128 g, 65.0%, 97.5% purity by HPLC).
ACKNOWLEDGMENT
The authors thank management of Dr. Reddy’s Laboratories Ltd. for
supporting this work. Cooperation from the project colleagues is highly
appreciated.

174
C. R. Elati et al.
REFERENCES
1. (a) Altman, H. J. Alzheimer’s Diseases Problems, Prospects and Perspectives;
Plenum Press: New York, 1987; (b) Durnett, S. B.; Fibiger, H. C. Prog. Brain
Res. 1993, 98, 413–420.
2. (a) Enz, A.; Amstutz, R.; Boddeke, H.; Gmelin, G.; Malanowski, J. Prog. Brain Res.
1993, 98, 431–438; (b) Millard, C. B.; Broomfield, C. A. J. Neurochem. 1995, 64,
1909–1918.
3. (a) Sugimoto, H.; Iimura, Y.; Yamanishi, Y.; Yamatsu, K. J. Med. Chem. 1995, 38,
4821–4829; (b) Hachiro, S.; Yutaka, T.; Kunizou, H.; Norio, K.; Youichi, L.;
Atsushi, S.; Yoshiharu, Y.; Hiroo, O.; Shin, A.; Takashi, K.; Atsuhiko, K.;
Michiko, K.; Kiyomi, Y. US patent, 4,895,841, 1990.
4. (a) Devries Keith, M. WO patent 22584, 1997; (b) Gutman, L. A.; Shkolnik, E.;
Tishin, B.; Nisnevich, G.; Zaltzman, I. WO patent 09483, 2000; (c) Yoichi, I.
US patent 6,252,081, 2001.
5. Stephen, L. US patent 5,606,064, 1997.
6. Manne, S.; Sajja, E.; Mathad, V. T.; Elati, R. R. C.; Podichetti, A.; Kolla, N. US
patent 0143121A1, 2004.
7. Augustine, R. L. Heterogeneous Catalysis for the Synthetic Chemist 1996,
421–424.