Efficient and industrially viable synthesis of donepezil

Article abstract of DOI:10.1080/00397910701471477

An efficient, economically viable process has been developed for large-scale preparation of donepezil HCl (1), an anti-Alzheimer's agent. The process involves the condensation of 5,6-dimethoxy-1-indanone (3) and 1-benzyl-4-piperidinecarboxaldehyde (4) in the presence of alkalimetal carbonates at elevated temperature to yield 1-benzyl-4-[(5,6-dimethoxy-1- indanone)-2-yidenyl] methyl piperidine (2), the key intermediate in the synthesis of donepezil. Hydrogenation of 2 yields donepezil. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701471477

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Efficient and Industrially Viable Synthesis of
Donepezil
R. Janaki Rama Rao a , A. K. S. Bhujanga Rao a & Y. L. N. Murthy b
a Natco Research Centre, Natco Pharma Limited , Hyderabad, Andhra
Pradesh, India
b Department of Organic Chemistry , Andhra University , Visakhapatnam,
Andhra Pradesh, India
Published online: 30 Aug 2007.
To cite this article: R. Janaki Rama Rao , A. K. S. Bhujanga Rao & Y. L. N. Murthy (2007) Efficient and
Industrially Viable Synthesis of Donepezil, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:17, 2847-2853, DOI: 10.1080/00397910701471477
To link to this article: http://dx.doi.org/10.1080/00397910701471477
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Synthetic Communicationsw, 37: 2847–2853, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701471477
Efficient and Industrially Viable Synthesis
of Donepezil
R. Janaki Rama Rao and A. K. S. Bhujanga Rao
Natco Research Centre, Natco Pharma Limited, Hyderabad, Andhra
Pradesh, India
Y. L. N. Murthy
Department of Organic Chemistry, Andhra University, Visakhapatnam,
Andhra Pradesh, India
Abstract: An efficient, economically viable process has been developed for large-scale
preparation of donepezil HCl (1), an anti-Alzheimer’s agent. The process involves the
condensation of 5,6-dimethoxy-1-indanone (3) and 1-benzyl-4-piperidinecarboxalde-
hyde (4) in the presence of alkalimetal carbonates at elevated temperature to yield
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yidenyl] methyl piperidine (2), the key
intermediate in the synthesis of donepezil. Hydrogenation of 2 yields donepezil.
Keywords: anti-Alzheimer’s agent, aqueous alkali metal carbonates, condensation,
donepezil, economically viable
INTRODUCTION
Donepezil HCl (1) is a memory-enhancing drug useful in the treatment of
Alzheimer’s disease. Alzheimer’s disease, the most common cause of
dementia, is a neurodegenerative disorder characterized by a progressive
deterioration of memory and cognition.[1] Donepezil HCl (1) is one of the
most promising agents among the acetyl cholinesterase inhibitors.
Donepezil HCl was introduced by Japanese pharmaceutical company Eisai.
Received in India November 4, 2006
Address correspondence to A. K. S. Bhujanga Rao, Natco Research Centre, Natco
Pharma Limited, B-13, Industrial Estate, Sanath Nagar, Hyderabad 500 018, Andhra
Pradesh, India. E-mail: nrc@natcopharma.co.in
2847

2848
R. J. R. Rao, A. K. S. B. Rao, and Y. L. N. Murthy
CHEMISTRY
Sugimoto and coworkers[2] described the synthesis of donepezil with an
overall yield of 27.4%, which involves the condensation of 5,6-dimethoxy-
1-indanone (3) and 1-benzyl-4-piperidinecarboxaldehyde (4) in the presence
of n-BuLi as base, at 2788C in tetrahydrofuran/hexamethylphosphoric
triamide (THF/HMPTA) solvents under anhydrous conditions (Scheme 1).
The resulting compound (2) is isolated by column chromatography, hydrogen-
ated over palladium carbon in THF solvent, followed by conversion to hydro-
chloride to afford donepezil hydrochloride (1). In this method, the donepezil
base is also isolated by column chromatography.
The process described is not suitable for large-scale production, because
of subzero temperature requirements (2788C) and use of raw materials such
as BuLi, diisopropylamine, and THF/HMPTA that are either expensive,
hazardous, or toxic. Anhydrous conditions are required to protect n-BuLi
from moisture. Isolations of compounds 2 and 1 involve column chromato-
graphy, which is time-consuming and limits the batch size.
The other process reported for condensation of 5,6-dimethoxy-1-
indanone (3) and 1-benzyl-4-piperidinecarboxaldehyde (4) employs sodium
methoxide in THF solvent.[3] This process also has disadvantages such as
the moisture-sensitive nature of sodium methoxide.
Gutman and his coworkers[4] established a new method for preparation of
donepezil (1) (Scheme 2) using dimethyl-(4-pyridylmethylene)malonate (5)
and 3,4-dimethoxy benzylchloride as key intermediates. The preparation of
Scheme 1. Reagents and conditions: a ¼ n-BuLi/THF/HMPTA, 2788C, 2 h;
b ¼ H2-10% Pd-C/THF, 258C, 6 h; c ¼ HCl-EtOAc.

Synthesis of Donepezil
2849
Scheme 2. Reagents and conditions: a ¼ H2-10% Pd-C/AcOH, 608C; b ¼ benzyl
chloride/Na2CO3, 60–658C, 12 h; c ¼ 60% NaH/3,4-dimethoxy benzylchloride/
THF, reflux; d ¼ KOH, reflux; e ¼ P2O5/methanesulphonic acid, 55–658C.
intermediate dimethyl-(4-pyridyl methylene)malonate (5) involves the raw
material 4-pyridinecarboxaldehyde, which is expensive and not readily
available. The process is lengthy, and column chromatography is employed
to isolate donepezil, thus rendering the process industrially unviable.
Iimura and coworkers[5] invented a novel method for the preparation of
donepezil (1) (Scheme 3). The process involves the condensation of 5,6-
dimethoxy-2-ethoxycarbonyl-1-indanone (6) with 4-pyridylmethyl chloride,
in the presence of sodium hydride, followed by decarbalkoxylation, benzyla-
tion, and ring reduction of quaternary salt with platinum oxide. This process is
also beset with the following disadvantages: 4-Pyridylmethyl chloride is a
lachrymator and is not readily available. The preparation of this intermediate
involves 4-picoline-N-oxide, which is hygroscopic. C-Acetylation of
4-picoline-N-oxide, hydrolysis, and chlorination are experimental conditions
that cannot be handled easily at a plant level. The condensation reaction
between 6 and 4-pyridylmethyl chloride requires anhydrous conditions.
Hydrogenation of the quaternary salt 7 requires expensive PtO2 catalyst.
Chandrasekhar and his coworkers[6] prepared donepezil by condensing
5,6-dimethoxy-1-indanone (3) with 4-pyridinecarboxaldehyde (8) followed
by catalytic hydrogenation and benzylation (Scheme 4). 4-Pyridinecarboxal-
dehyde is expensive and not commercially available, and benzylbromide used
for benzylation is a severe lachrymator, posing difficulties on large scale.

2850
R. J. R. Rao, A. K. S. B. Rao, and Y. L. N. Murthy
Scheme 3. Reagents and conditions: a ¼ 60% NaH/4-pyridylmethyl chloride;
b ¼ KOH/MeOH, reflux; c ¼ benzyl bromide/CH3CN, reflux; d ¼ H2-PtO2, 258C.
Several other syntheses of donepezil have been reported,[7] which are
either too long or contain unacceptable operations and thus are not suitable
for plant-scale operations.
We have focused primarily on the Sugimoto process of condensation of
5,6-dimethoxy-1-indanone (3) and 1-benzyl-4-piperidinecarboxaldehyde (4)
(Scheme 1) to improve and render it economically viable. Alkalimetal carbon-
ates are chosen as base instead of n-BuLi, and aqueous aliphatic alcohols are
chosen as reaction media. Reaction is carried out at reflux temperatures, and
hydrogenation of compound 2 is carried out in methanol instead of THF.
Scheme 4. Reagents and conditions: a ¼ TsOH/toluene, reflux, 5 h; b ¼ H2-5%
Pd-C/MeOH-HOAc, 60–658C, 6.5–7.0 h; c ¼ benzyl bromide/IPA: MeOH (1:1),
60–658C, 11–12 h.

Synthesis of Donepezil
2851
Thus we report herein an excellent synthetic method for condensation of
commercially available 5,6-dimethoxy-1-indanone (3), with 1-benzyl-4-
piperidenecarboxaldehyde (4), in the presence of potassium carbonate, in
aqueous methanol medium at reflux temperature (Scheme 5).
The alkylidene derivative (2) is isolated by a simple crystallization
technique with no need to carry out column chromatography. Yields are in
the range of 75–80%, and purity of the product is .96% by high performance
liquid chromatography (HPLC). This purity is sufficient to proceed to the next
stage (hydrogenation).
Donepezil is prepared by carrying out hydrogenation of 2 with 10%
palladium carbon as catalyst in methanol solvent at 258C for 2 h. Here also
the product is isolated without involving column chromatography.
Afterhydrogenationofthe intermediate 2, thin-layerchromatography(TLC)
of the reaction mass shows two polar impurities (9 and 10) in about 2% level.
In summary, we present an economically and industrially viable synthesis
of donepezil HCl, which is obtained from 5,6-dimethoxy-1-indanone (3) in
two steps by employing commercially available, less expensive, nontoxic
raw materials by simplified experimental conditions and isolation procedures.
EXPERIMENTAL
Preparation of 1-Benzyl-4-[(5,6-dimethoxy-1-indanone)2-ylidenyl]
methyl-piperidine (2)
5,6-Dimethoxy-1-indanone (3, 61 g, 0.32 mol) was dissolved in methanol
(610 ml) under stirring at a temperature of 45–508C. The solution was
heated to reflux temperature. Aqueous potassium carbonate solution
(potassium carbonate 305 g (2.20 mol), water 305 ml) was added to the
reaction mass dropwise over 30–40 min. After an additional 20 min of
stirring, 1-benzyl-4-piperidinecarboxaldehyde (4, 83.08 g, 0.409 mol) was
added dropwise to the reaction mass. The pale brown suspension was main-
tained at a bath temperature of 758C for a period of 2.5 h.
Scheme 5. Reagents and conditions: a ¼ potassium carbonate, water/methanol,
reflux, 2.5 h; b ¼ H2-10% Pd-C/MeOH, 258C, 2 h, 1.5 N aqueous HCl.

2852
R. J. R. Rao, A. K. S. B. Rao, and Y. L. N. Murthy
The reaction mass was then cooled to room temperature, diluted with
water (640 ml), and extracted with CH2Cl2 (600 ml ꢀ 2). The combined
organic layer was washed with demineralized water (600 ml ꢀ 2), and
the separated organic layer was dried over anhydrous sodium sulphate. The
solvent was evaporated under reduced pressure to afford a brown solid. The
solid was recrystallized in CH2Cl2/isopropylether to yield an off-white
solid (92 g, 77%), mp 170–1748C.
Data
IR (KBr): y 3003 (aromatic C-H), 2929 (aliphatic C-H), 1690 (.C55O), 1647
(C55C), 1603 (aromatic C55C). 1H NMR (200 MHZ, CDCl3): d 1.6–1.8
(m, 5H), 2.0–2.2 (m, 2H), 2.3–2.4 (m, 1H), 2.9–3.0 (m, 2H), 3.5 (s, 2H),
3.6 (s, 2H), 3.9 (s, 3H), 4.0 (s, 3H), 6.7 (d, 1H), 6.9 (s, 1H), 7.3–7.4
(m, 5H). 13C NMR (200 MHZ, CDCl3): d 29.2, 31.0, 37.0, 52.8, 55.76,
55.90, 63.17, 104.60, 106.95, 126.61, 127.82, 128.76, 131.41, 135.31,
137.94, 139.36, 144.15, 149.12, 154.92, 192.00. Mass (m/e) ¼ 378.3
(M þ 1), 271.1, 188.1.
Preparation of Donepezil HCl (1)
The compound 2 obtained (30 g, 0.079 mol) in methanol (600 ml) and 10%
palladium carbon (3.0 g) was hydrogenated at room temperature and 1 atm
for 2 h. Thin-layer chromatography (TLC) was checked for completion of
reaction. The reaction mixture was filtered through a hyflow bed, and the
filtrate was distilled off at temperatures less than 608C under reduced
pressure to yield a yellow product (31 g).
To this crude material, 1.5 N aqueous HCl (140 ml) was added and stirred
for 15 min at room temperature. To this cloudy liquid, demineralized water
(95 ml) was added and stirred for another 15 min at room temperature. The
aqueous phase was extracted with EtOAc (2 ꢀ 65 ml), and the organic layer
was discarded. The aqueous phase was extracted with CHCl3 (2 ꢀ 190 ml).
The organic layer was washed with demineralized water (2 ꢀ 190 ml). The
aqueous layer was discarded. The organic layer was dried over anhydrous
Na2SO4. The solvent was evaporated at temperatures less than 608C
under reduced pressure to yield an off-white foamy solid [25 g, donepezil
HCl (1)].
The obtained solid was recrystallized in MeOH/isoprpoylether (1:1,
75 ml). After 1 h of stirring at 58C, the product was filtered off, washed
with isopropylether (100 ml), and dried in vacuum at 30 mm for 6 h
at room temperature to afford donepezil HCl (21.6 g, 65%, 99.8% HPLC
purity).

Synthesis of Donepezil
Data
2853
IR (KBr): y 3588.7 (.N-H), 3004.5 (aromatic C-H), 1684.6 (.C55O), 1316
and 1266.1 (-OCH3). 1H NMR (200 MHZ, CDCl3): d 1.2–1.4 (m, 4H), 1.6–
1.8 (t, 2H), 1.8–2.1 (m, 3H), 2.6–3.0 (m, 4H), 3.2–3.4 (dd, 1H), 3.45–3.55
(s, 2H), 3.9 (s, 3H), 4.0 (s, 3H), 6.9 (s, 1H), 7.2 (s, 1H), 7.3–7.4 (m, 5H).
13C NMR (200 MHZ, CDCl3): d 31.66, 32.87, 33.14, 34.27, 38.52, 45.25,
53.58, 55.83, 55.96, 63.21, 104.13, 107.16, 126.59, 127.84, 128.87, 129.03,
138.28, 148.42, 149.15, 155.16, 207.27. Mass (m/e): 380.1 (M þ 1), 362.2,
288.1, 243.1, 172.1.
ACKNOWLEDGMENT
The authors thank the management of Natco Pharma Ltd. for supporting this
work. The technical service from the analytical division of Natco Research
Centre is gratefully acknowledged.
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