Industrially scalable synthesis of anti-alzheimer drug donepezil

Article abstract of DOI:10.14233/ajchem.2017.20716

This paper describes a simple, efficient and industrially scalable total synthesis of donepezil hydrochloride. The article also reported the X-ray studies of the 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one, an intermediate in the synthesis of donepezil. The crystal structure analysis of 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one shows that it crystallizes in monoclinic class under the space group P121/c1 with cell parameters, a = 17.2992(7) ?, b = 10.1999(4) ?, c = 11.9539(5) ?, β = 103.450(2)°, V = 2051.42(15) ?³ and Z = 4.

Full text of DOI:10.14233/ajchem.2017.20716

Asian Journal of Chemistry; Vol. 29, No. 9 (2017), 1999-2004
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2017.20716
Industrially Scalable Synthesis of Anti-alzheimer Drug Donepezil
1,*
2
3
1
SANTOSH L. GAONKAR , Y.F. NADAF , DINESH BILEHAL and NITINKUMAR S. SHETTY
1
2
3
Department of Chemistry, Manipal Institute of Technology, Manipal University, Manipal-576 104, India
Department of Physics and Research Center, Maharani Science College for Womens, Bangalore-560 001, India
Department of Chemistry, Reva University, Bangalore-560 064, India
*
Corresponding author: E-mail: gaonkarslg@rediffmail.com
Received: 17 April 2017; Accepted: 11 June 2017;
Published online: 15 July 2017;
AJC-18483
This paper describes a simple, efficient and industrially scalable total synthesis of donepezil hydrochloride. The article also reported the
X-ray studies of the 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one, an intermediate in the synthesis of donepezil. The
crystal structure analysis of 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one shows that it crystallizes in monoclinic
class under the space group P121/c1 with cell parameters, a = 17.2992(7) Å, b = 10.1999(4) Å, c = 11.9539(5) Å, β = 103.450(2)°, V =
3
2
051.42(15) Å and Z = 4.
Keywords: Donepezil, Alzheimer’s disease, X-ray diffraction.
with benzyl bromide followed by reduction with platinum
dioxide gives donepezil. US 2006/0122227A1 reported the
reaction of N-protected 4-methyl-piperidine with 2-alkoxy-
carbonyl-5,6-dimethoxy-indan-1-one to yield 4-[2-alkoxycarbonyl-
5,6-dimethoxy-indan-1-on-2-yl)methyl]-N-protected-piperidine,
deprotecting the above molecule to yield 4-[2-alkoxycarbonyl-
5,6-dimethoxy-indan-1-on-2-yl)methyl] piperidine which on
treatment with benzyl chloride, followed by hydrolysis and
decarboxylation yields donepezil. WO 97/22584 discloses the
process for the preparation of donepezil. Indanone was reacted
with 4-substituted piperidine derivative which on Mannich
reaction followed by cyclization produces donepezil. WO 2006/
070396-A1 discloses a process where Indanone was condensed
with pyridine 4-carboxaldehyde, which is reacted with the
peracid to make N-oxide followed by ring reduction using Pd/
C and N-benzylation to yield donepezil. WO 2005/076749
A2 discloses a process where pyridine 4-carboxaldehyde was
INTRODUCTION
Alzheimer’s disease, a type of dementia has no cure, over
the time leads to death. It is a chronic neurodegenerative
disease, commonly starts slowly and gets worse over time [1].
The symptoms of this disease are the gradual progress of
absent-mindedness, trouble in language, mutism and perplexity
[
2]. Stepwise deterioration in remembrance and consciousness
is the symptomatic course of the ailment [3].Scientists believe
thatAlzheimer’s disease may result from a deficiency of neuro-
transmitters present in brain nerves. Donepezil is an oral medication
for Alzheimer’s disease [4]. It belongs to cholinesterase
inhibitors class of drugs with fewer side effects [5-8]. Donepezil
inhibits acetylcholinesterase [9], an enzyme responsible for the
destruction of acetylcholine, a neurotransmitter [10]. Research
on donepezil began in 1983 with its first Phase I clinical trial
in 1989 [11]. Besides, it has studied in patients with Down’s
syndrome, multiple sclerosis and schizophrenia.
4
reduced with NaBH , reacted with benzyl bromide, reduction
In most of these patents, indanone was used as the starting
material for the preparation of donepezil HCl. US Patent US
of aldehyde group to corresponding alcohol using NaBH ,
resulting primary alcohol was converted to primary chloride,
which was reacted with 5,6-dimethoxy indanone and finally
4
4
,895,841 described that indanone was reacted with aldehyde
by aldol condensation by using a base like LDA at -80 °C and
heating the reaction mixture at room temperature to conduct
dehydration which is reduced by Pd/C to yield donepezil. EP
alkene reduction using PtO yields donepezil base. WO 2007/
2
077443 discloses a process for preparing donepezil by using
condensation of aldehyde and indanone, followed by hydro-
genation. This process mainly covers preparation of aldehyde
by Darzen reaction. Further to our studies on active pharmaceutical
ingredients and biologically active heterocycles [12-16], we
report herein industrially scalable, efficient total synthesis of
0
296560B1 discloses 1-indanon-2-yl-phosphonate with an
aldehyde (Wittig reaction), which was reduced with Pd/C. US
,606,064 discloses a process where indanone was condensed
with N-benzyl pyridine-4-carboxaldehyde, which on treatment
5

2
000 Gaonkar et al.
Asian J. Chem.
donepezil hydrochloride by using safe reagents and experi-
mental conditions. To confirm the product and to study the
structural conformation details, the crystal structure of 2-(1-
benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one,
an intermediate in the synthesis of donepezil is also reported.
19 g, 0.10 mol) in methanol (8 mL) is stirred under inert
atmosphere at room temperature. Slowly add NaOH flakes
(12.8 g, 0.32 mol) followed by N-benzyl-piperidine-4-carbox-
aldehyde (4, 20.2 g, 0.10 mol) to the reaction mixture. The
mixture was stirred at room temperature for 3 h and progress
of the reaction was monitored by TLC (hexane:ethyl acetate;
EXPERIMENTAL
1
:1). Once the reaction is complete, the solid formed was
The melting points were ascertained on Thomas-Hoover
apparatus and remain uncorrected. Infrared(KBr) spectra were
recorded on Shimadzu 8300 Fourier transform infrared spectro-
meter. H and C NMR spectra (400 and 100 MHz respectively)
were recorded on a BrukerAM spectrometer in DMSO solution
with TMS as an internal standard. ESI mass spectra were recorded
on anAgilent 6520 ESIQTOF instrument at ionization potential
of 110V. HPLC analysis was performed on Shimadzu LC-20AD
using a C18, 150 mm × 4.6 mm reversed phase column with a
filtered, washed with 5 % acetic acid and then with methanol
and dried. The obtained solid (34 g) was taken into a round
bottom flask and refluxed with DMF (50 mL). Gradually cooled
to room temperature and stirred for 2 h, filtered the solid
formed, wash with chilled methanol to afford a pale yellow
crystalline solid 6 (32.0 g, 84 %); m.p.: 175-177 °C.
1
13
l-Benzyl-4-[(5,6-dimethoxyl-indanon)-2-yl]methyl
piperidine hydrochloride (donepezil hydrochloride) (8):
Charge 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxy-
indan-1-one (6, 25 g, 0.066 mol) and methanol (150 mL) into
SS autoclave under inert atmosphere. Charge methane sulfonic
acid (8 g) to the above reaction mass and stir for 30 min. Charge
activated Raney nickel (1 g). The autoclave was flushed with
nitrogen gas and then applied hydrogen gas pressure (15 psi)
and hydrogenated for 15 h at room temperature.After comple-
tion of the reaction, the catalyst was filtered through hyflo
bed. The filtrate was neutralized with sodium carbonate (10 g)
and the solid was filtered. Methanol was removed under vacuum
and the residue left was charged with water (5 vol). The product
was extracted with toluene (2 × 100 mL), washed with water,
dried over anhydrous sodium sulfate. Toluene extract was treated
with decolorizing carbon for 1 h, filtered through hyflo bed
and toluene was removed under vacuum to get donepezil base
as an oily product. It was dissolved in isopropyl alcohol (50
mL). Decolorizing carbon treatment is given again to isopropyl
alcohol layer at 50 °C for 1 h. Carbon was filtered through hyflo
bed and the clear filtrate was taken into round bottom flask.
Under stirring isopropyl-HCl was added dropwise and pH was
adjusted to 2-3. The temperature was raised to 70-75 °C and
gradually cooled to room temperature and the product formed
was filtered. The wet product was slurried with hot isopropyl
alcohol, filtered and dried under vacuum to get donepezil HCl
(8) as white crystalline solid to yield 22.8 g (85 %). m.p.: 229-
5
µm particle size with detection at 230 nm in water/acetonitrile/
perchloric acid (75:25:0.1 v/v) and the flow rate of 1 mL/min.Thin
layer chromatography (TLC) was conducted on 0.25 mm silica
gel plates (60F254, Merck).Visualization was made with ultraviolet
light (UV. R-340).
N-Benzyl ethyl isonipecotate (2): Ethyl isonipecotate (1,
5
0 g, 0.31 mol) was dissolved in toluene (150 mL) in a round
bottom flask, charged with potassium carbonate (60 g, 0.43
mol) and stirred for 15 min. Benzyl chloride (42 g, 0.31 mol)
was charged and the reaction mass was refluxed for 4 h at
1
00 °C. Upon completion of the reaction as marked by TLC
(
hexane:ethyl acetate; 2:1), the reaction mass was cooled to
room temperature and quenched with water (100 mL), stirred
and the organic phase was separated. The aqueous phase was
again extracted with toluene (100 mL). Combined organic
phase was washed twice with saturated brine solution (50 mL).
Remove toluene in vacuo to obtain N-benzyl ethyl isonipecotate
(
2, 6.97 g, 91 %) as a yellow liquid.
N-Benzyl piperidine alcohol (3): Charge toluene (100
mL) in a round bottom flask along with vitride (26 g, 0.12
mol) in an inert atmosphere. N-Benzyl ethyl isonipecotate (2,
4
0 g, 0.16 mol) was added slowly in portions to the reaction
mass. The mixture was stirred at room temperature for 2 h.
After completion of the reaction the mass was quenched with
chilled water. Toluene phase was separated and dried over
anhydrous sodium sulfate. Toluene was removed under vacuum
to get N-benzyl piperidine alcohol (3, 26.9 g, 82 %).
-1
231 °C. HPLC purity: 99.8 %; IR (KBr, νmax, cm ) 3588, 3371,
2925, 1683, 1592, 1501, 1455, 1315, 1266, 1217, 1119, 1039, 700;
1
H NMR (500 MHz, DMSO-d ) δ: 1.48-1.5 (m, 1H), 1.82-2.10
6
N-Benzyl piperidine-4-carboxaldehyde (4): A round
bottom flask was charged with oxalyl chloride (16.2 g, 0.12
mol), dichloromethane (150 mL) and anhydrous dimethyl sulfoxide
(m, 6H), 2.63-2.68 (m, 4H), 3.28 (dd, J = 8, 17.6 Hz, 1H), 3.38-
3.42 (m, 2H), 3.9 (s, 3H), 3.96 (s, 3H), 4.12-4.19 (m, 2H),
6.85 (s, 1H), 7.12 (s, 1H), 7.44-7.63 (m, 3H), 10.3 (s, 1H, HCl);
13
(20 mL). Stir the reaction mixture mass in a cryo bath at -70 °C
C NMR (125 MHz, DMSO-d ) δ: 206.8, 155.8, 149.6, 148.8,
6
for 15 min. The resulting mixture is charged dropwise with N-
benzyl piperidine alcohol 3 (20 g, 0.097 mol), along with
triethylamine (24.6 g, 0.24 mol) and continued stirring for the
next 15 min. After that, the mass is allowed to attain room
temperature overnight, then diluted with dichloromethane (100
mL) and quenched with cold water. The organic layer was
washed subsequently with 5 % HCl solution, brine solution, 5
131.5, 130.1, 129.2, 128.8, 128.2, 107.3, 104.4, 61.0, 56.2, 56.1,
52.4, 52.2, 44.2, 38.1, 34.0, 32.1, 29.4, 28.4; MS (ESI) m/z
+
380 [M +1].
X-ray data collection: A specimen of C24
H
27NO was used
3
for the X-ray crystallographic analysis. A single crystal of the
title compound with dimensions 0.10 mm × 0.10 mm × 0.01 mm
was used for X-ray diffraction study. The X-ray intensity data
were measured. The total exposure time was 1.44 h. The frames
were integrated with the Bruker SAINT software package using
a narrow-frame algorithm [17]. Data were corrected for absorption
effects using the multi-scan method (SADABS). The ratio of
minimum to the maximum apparent transmission was 0.868.
%
sodium bicarbonate solution and dried over sodium sulfate.
Toluene was removed in vacuo to afford N-benzyl piperidine-
-carboxaldehyde (4, 19.2 g, 96 %).
-(1-Benzylpiperidin-4-ylmethyliden)-5,6-dimethoxy-
indan-1-one (6): A solution of 5,6-dimethoxy-indanone (5,
4
2

Vol. 29, No. 9 (2017)
Industrially Scalable Synthesis of Anti-alzheimer Drug Donepezil 2001
The structure was solved and refined using the Bruker SHELXTL
Software Package [18], using the space group P121/c1, with
5,6-dimethoxyindan-1-one. Sodium hydroxide is employed
in the reaction as a base to avoid the use of more expensive or
toxic reagents as promoters such as lithium diisopropylamide
(LDA), alkali-metal alkoxide such as sodium methoxide, triethyl-
amine, diisopropyl ethyl amine, pyridine, piperidine. Reduction
of 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-
Z = 4 for the formula unit, C24
H
27NO . The structure was deposited
3
at the Cambridge Crystallographic Data Centre with CCDC
No. 982818.
RESULTS AND DISCUSSION
1
-one to donepezil was carried out using Raney nickel in the
The synthetic scheme for the synthesis of donepezil
hydrochloride is as shown in Scheme-I. Ethyl isonipecotate
1) is condensed with benzyl chloride to afford N-benzyl ethyl
presence of methane sulfonic acid in methanol medium.
Methane sulfonic acid was used to convert aldol type product
formed during the reaction of 5,6-dimethoxy-indanone and N-
benzylpiperidine-4-carboxaldehyde in the presence of NaOH.
Methane sulfonic acid dehydrates aldol type product into 2-
(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-
one which undergoes reduction to donepezil. The title compound
(
isonipecotate (2). Potassium carbonate is used to abstract the
HCl generated during the reaction course. N-Benzyl ethyl
isonipecotate (2) is reduced to corresponding N-benzyl piperidine
alcohol (3) using vitride as reducing agent. Vitride, also called
sodium bis(2-methoxyethoxy)aluminum hydride is a powerful
reducing agent with comparable characteristics to lithium
aluminium hydride. However, it selectively reduces esters to
alcohols and is freely soluble in aromatic hydrocarbons like
toluene. The high solubility and non-pyrophoric qualities of
this reagent are beneficial compared to lithium aluminium hydride.
In contrast with lithium aluminum hydride, its solutions show
better moisture stability and are superior in thermal stability as
well. N-Benzyl piperidine alcohol (3) undergoes swern oxidation
to provide N-benzyl piperidine-4-carboxaldehyde (4) using
oxalyl chloride, dimethyl sulfoxide and triethylamine. To avoid
possible side reaction, the reaction was carried out at low temper-
ature. The reaction conditions are best suited for the oxidation
of acid-sensitive alcoholic group, which might decompose
under the acidic conditions of conventional methods. The
reaction between 5,6-dimethoxy-indanone and N-benzyl-
piperidine-4-carboxaldehyde ia carried out in methanolic
NaOH solution to gave 2-(1-benzylpiperidin-4-ylmethyliden)-
1
13
synthesized was characterized by H NMR, C NMR, mass
1
13
spectra and elemental analyses. H NMR, C NMR showed all
the characteristic peaks in expected region. Mass spectra indicate
+
the peak at m/z 380 (M +1), which corresponds to molecular
ion of donepezil base. The HPLC purity of the product was
more 99.6 % by the validated method. Significant advantages
of the present invention are higher purity, better yields and the
industrially scalable synthesis.
Crystal structure analysis: Fig. 1 displays ORTEP diagram
of the compound 6 at 50 % probability with atom numbering
while Fig. 2. depicts the packing diagram of the title compound.
Crystal data and structure refinements details are given in
Table-1. The data integration using a monoclinic unit cell
yielded a total of 10391 reflections to a maximum θ angle of
22.76° (0.92 Å resolution), of which 2753 were independent
(average redundancy 3.774, completeness = 99.8 %, Rint = 2.72
2
%, Rsig = 3.03 %) and 1999 (72.61 %) were greater than 2σ(F ).
The final cell constants of a = 17.2992(7) Å, b = 10.1999(4)
Ph
Ph
Ph
H
N
N
N
Vitride
DMSO/TEA
(COCl)2
N
Benzyl chloride
K2CO3
Toluene
Toluene
COOEt
CH OH
3
COOEt
2
4 CHO
1
2
Ph
MeO
N
(
1) NaOH, MeOH
2) H SO4
MeO
N
Ph
+
(
O
2
MeO
(
3) DMF
O
MeO
6
5
4
CHO
MeOH
Raney Ni
Methane sulfonic acid
HCl
MeO
N
Ph
O
IPA, IPA/HCl
MeO
N
Ph
O
MeO
8
7
MeO
Donepezil HCl
Donepezil base
Scheme-I: Scheme for the synthesis of donepezil hydrochloride

2
002 Gaonkar et al.
Asian J. Chem.
TABLE-1
X-RAY CRYSTALLOGRAPHY DATA COLLECTION AND STRUCTURE REFINEMENT
Chemical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C H NO
3
377.47
296(2) K
0.71073 Å
Monoclinic
P121/c1
Independent reflections
Coverage of independent reflections 99.8 %
Absorption correction
Structure solution technique
Structure solution program
Refinement method
2753 [R(int) = 0.0272]
2
4
27
Multi-scan
Direct methods
SHELXS-97 (Sheldrick, 2008)
2
Full-matrix least-squares on F
Unit cell dimensions
a = 17.2992(7) Å; α = 90°
b = 10.1999(4) Å; β = 103.450(2)°
c = 11.9539(5) Å; γ = 90°
Refinement program
Function minimized
Data/restraints/parameters
Goodness-of-fit on F
SHELXL-97 (Sheldrick, 2008)
2
2 2
Σw(F -F )
o
c
2753/0/255
1.065
3
2
Volume
2051.42(14) Å
Z
4
∆/σmax
0.017
3
Density (calculated)
1.222 Mg/cm
Final R indices
1999 data; I>2σ(I); R1 =
0.0419, wR2 = 0.1099
-
1
Absorption coefficient
F(000)
0.080 mm
All data; R1 = 0.0639,
wR2 = 0.1328
2
2
o
2
808
Weighting scheme
w = 1/[σ (F ) + (0.0778P) +
2
o
2
0.0000P] where P = (F +2F )/3
c
-
3
Theta range for data collection 1.21 to 22.76°
Index ranges
Largest diff. peak and hole
RMS deviation from mean
0.137 and-0.170 eÅ
0.043 eÅ
-
3
-18 ≤ h ≤ 18; -11≤ k ≤ 11;
10 ≤ l ≤ 12
10391
-
Reflections collected
TABLE-2
ATOMIC COORDINATES AND EQUIVALENT ISOTROPIC ATOMIC DISPLACEMENT PARAMETERS (Å )
2
x/a
y/b
z/c
U/eq
x/a
y/b
z/c
U/eq
O1
O2
O3
N1
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
0.80970(9) 0.96545(15) 0.90332(13)
0.85014(9) 0.74549(14) 0.99827(13)
0.14335(10) 0.68052(15) 0.90971(14)
0.38696(10) 0.17040(16) 0.74707(16)
0.0709(5)
0.0671(5)
0.0774(5)
0.0581(5)
0.0845(8)
0.0531(6)
0.0539(6)
0.0499(6)
0.0591(6)
0.0537(6)
0.0624(6)
0.0595(6)
0.0655(7)
0.0666(7)
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22
C23
C24
0.42967(14)
0.49180(13)
0.53612(15)
0.59466(16)
0.61010(18)
0.87004(15)
0.90516(13)
0.2812(2)
0.2431(2)
0.1313(2)
0.0997(3)
0.1808(3)
0.6247(2)
0.8008(2)
0.7135(2)
0.65040(19)
0.6767(2)
0.6210(3)
0.5380(3)
0.0567(2)
0.94790(17)
0.0671(7)
0.0559(6)
0.0717(7)
0.0856(8)
0.0896(9)
0.0908(9)
0.0520(6)
0.0530(6)
0.0488(6)
0.0658(7)
0.0657(7)
0.0769(8)
0.0926(9)
0.0559(6)
0.78256(15)
0.88274(13)
0.0888(2)
0.9243(2)
0.8523(2)
0.89556(18)
0.93340(13) 0.99287(19) 0.84446(17)
0.00684(13)
0.07146(12)
0.9388(2)
0.9965(2)
0.84261(16)
0.79333(18)
0.97730(13) 0.74782(19) 0.94465(18)
0.02796(12) 0.81810(19) 0.89136(17)
0.13671(13) 0.89541(19) 0.82202(17)
0.29760(13)
0.33807(13)
0.50814(15)
0.56729(19)
0.10728(14)
0.9855(2)
0.1044(2)
0.3231(2)
0.2923(3)
0.7825(2)
0.6828(2)
0.6465(2)
0.5664(2)
0.5113(2)
0.87862(18)
0.21032(14)
0.24634(12)
0.29677(14)
0.33723(13)
0.9061(2)
0.0222(2)
0.1001(2)
0.2145(2)
0.80991(19)
0.76545(19)
0.8650(2)
0.8230(2)
U(eq) is defined as one-third of the trace of the orthogonalized U tensor
ij
TABLE-3
BOND LENGTHS (Å)
O1-C2
1.355(2)
1.361(2)
1.226(2)
1.463(3)
0.96
0.96
1.419(3)
0.93
1.500(3)
0.97
1.319(3)
1.492(3)
1.520(3)
0.98
O1-C1
1.429(3)
C10-H10A
C11-C12
C11-H11B
C12-C13
C13-H13
C14-H14
C15-H15
C16-H16B
C17-C18
C18-H18
C20-C21
C20-H20B
C21-H21B
C22-H22
–
0.97
1.501(3)
0.97
1.369(3)
0.93
0.93
0.93
0.96
1.369(3)
0.93
1.514(3)
0.97
C10-H10B
0.97
0.97
O2-C17
O3-C24
N1-C21
C1-H1A
C1-H1C
C2-C17
C3-H3
C4-C5
C5-H5A
C6-C7
O2-C16
N1-C11
N1-C10
C1-H1B
C2-C3
C3-C4
C4-C19
C5-C6
C5-H5B
C6-C24
C7-H7
C8-C9
C9-C10
C9-H9B
1.419(2)
1.456(3)
1.460(3)
0.96
1.371(3)
1.390(3)
1.375(3)
1.509(3)
0.97
1.484(3)
0.93
1.525(3)
1.505(3)
0.97
C11-H11A
C12-C22
C13-C14
C14-C15
C15-C23
C16-H16A
C16-H16C
C18-C19
C19-C24
C20-H20A
C21-H21A
C22-C23
C23-H23
–
1.373(3)
1.373(3)
1.365(4)
1.355(4)
0.96
0.96
1.396(3)
1.461(3)
0.97
0.97
1.376(3)
0.93
C7-C8
C8-C20
C8-H8
0.97
0.93
–
C9-H9A
0.97
–
2
Å, c = 11.9539(5) Å, β = 103.450(2)°, volume = 2051.42(14)
final anisotropic full matrix least-squares refinement on F with
255 variables converged at R1 = 4.19 %, for the observed data
and wR2 = 13.28 % for all data. The goodness-of-fit was 1.065.
3
Å , are based upon the refinement of the XYZ-centroids of
2
468 reflections above 20 σ(I) with 4.67° < 2θ < 40.69°. The

Vol. 29, No. 9 (2017)
Industrially Scalable Synthesis of Anti-alzheimer Drug Donepezil 2003
TABLE-4
BOND ANGLES (°)
C2-O1-C1
117.56(17)
C17-O2-C16
C11-N1-C10
O1-C1-H1A
H1A-C1-H1B
H1A-C1-H1C
O1-C2-C3
C3-C2-C17
C2-C3-H3
C19-C4-C3
C3-C4-C5
C4-C5-H5A
C4-C5-H5B
H5A-C5-H5B
C7-C6-C5
C6-C7-C8
C8-C7-H7
C7-C8-C9
C7-C8-H8
C9-C8-H8
C10-C9-H9A
C10-C9-H9B
H9A-C9-H9B
N1-C10-H10A
N1-C10-H10B
117.61(18)
110.03(17)
109.5
109.5
109.5
125.1(2)
120.8(2)
120.5
120.15(19)
128.17(19)
111.1
C12-C11-H11A
C12-C11-H11B
C22-C12-C13
C13-C12-C11
C12-C13-H13
C13-C14-C15
C15-C14-H14
C23-C15-H15
O2-C16-H16A
H16A-C16-H16B
H16A-C16-H16C
O2-C17-C18
108.8
108.8
N1-C11-H11B
H11A-C11-H11B 107.7
108.8
C11-N1-C21
C21-N1-C10
O1-C1-H1B
O1-C1-H1C
H1B-C1-H1C
O1-C2-C17
C2-C3-C4
C4-C3-H3
C19-C4-C5
C4-C5-C6
C6-C5-H5A
C6-C5-H5B
C7-C6-C24
C24-C6-C5
C6-C7-H7
C7-C8-C20
C20-C8-C9
C20-C8-H8
C10-C9-C8
C8-C9-H9A
C8-C9-H9B
N1-C10-C9
C9-C10-H10A
C9-C10-H10B
N1-C11-C12
111.35(18)
109.94(17)
109.5
109.5
109.5
114.10(19)
119.1(2)
120.5
111.67(19)
103.23(17)
111.1
117.6(2)
121.9(2)
119.3
120.1(3)
120.0
120.3
109.5
109.5
109.5
125.8(2)
119.7(2)
120.5
121.4(2)
128.7(2)
109.3
109.3
108.0
109.5
109.5
C22-C12-C11
C12-C13-C14
C14-C13-H13
C13-C14-H14
C23-C15-C14
C14-C15-H15
O2-C16-H16B
O2-C16-H16C
H16B-C16-H16C
O2-C17-C2
120.5(2)
121.4(2)
119.3
120.0
119.4(3)
120.3
109.5
109.5
109.5
114.5(2)
118.9(2)
120.5
109.97(19)
111.55(18)
109.3
109.3
110.54(19)
109.5
109.5
121.2(2)
119.4
119.8
127.1(2)
106.56(19)
111.1
109.1
111.1
C18-C17-C2
C17-C18-H18
C4-C19-C18
C17-C18-C19
C19-C18-H18
C4-C19-C24
123.8(2)
108.43(19)
116.6
113.02(18)
108.74(17)
108.2
111.72(19)
109.3
109.3
127.52(19)
126.7(2)
116.6
110.26(19)
108.2
108.2
109.3
109.3
107.9
C18-C19-C24
C21-C20-H20A
C21-C20-H20B
H20A-C20-H20B
N1-C21-H21A
N1-C21-H21B
H21A-C21-H21B
C12-C22-H22
C15-C23-C22
C22-C23-H23
O3-C24-C6
C21-C20-C8
C8-C20-H20A
C8-C20-H20B
N1-C21-C20
C20-C21-H21A
C20-C21-H21B
C12-C22-C23
C23-C22-H22
C15-C23-H23
O3-C24-C19
C19-C24-C6
108.1
119.4
120.3(3)
119.8
126.3(2)
110.83(18)
109.5
109.5
109.5
109.5
H10A-C10-H10B 108.1
N1-C11-H11A 108.8
113.97(18)
TABLE-5
2
ANISOTROPIC ATOMIC DISPLACEMENT PARAMETERS (Å )
U11
U22
U33
U23
U13
U12
O1
O2
O3
N1
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22
C23
C24
0.0642(11)
0.0657(11)
0.0773(11)
0.0582(11)
0.0764(18)
0.0538(14)
0.0621(15)
0.0592(14)
0.0674(15)
0.0584(15)
0.0657(16)
0.0551(14)
0.0721(16)
0.0680(16)
0.0636(15)
0.0550(14)
0.0792(17)
0.084(2)
0.0714(11)
0.0637(10)
0.0498(10)
0.0478(10)
0.0802(18)
0.0538(13)
0.0480(13)
0.0478(13)
0.0541(13)
0.0479(13)
0.0533(14)
0.0549(13)
0.0571(14)
0.0546(14)
0.0479(13)
0.0453(13)
0.0617(15)
0.0667(17)
0.083(2)
0.0882(19)
0.0504(13)
0.0395(11)
0.0419(12)
0.0662(15)
0.0685(15)
0.0646(15)
0.087(2)
0.0806(11)
0.0755(11)
0.1101(14)
0.0736(13)
0.097(2)
0.0155(9)
0.0154(8)
0.0082(9)
0.0243(9)
0.0241(9)
0.0088(9)
-0.0070(8)
0.0062(9)
0.0319(10)
0.0260(10)
0.0209(15)
0.0109(11)
0.0095(11)
0.0100(11)
0.0151(12)
0.0173(12)
0.0187(13)
0.0223(12)
0.0317(13)
0.0300(14)
0.0276(14)
0.0175(12)
0.0384(15)
0.0389(18)
0.0571(19)
0.0286(16)
0.0109(11)
0.0116(12)
0.0108(11)
0.0215(13)
0.0257(13)
0.0270(16)
0.0512(19)
0.0144(12)
-0.0045(9)
0.0175(15)
-0.0003(11)
0.0058(10)
-0.0008(10)
0.0057(11)
-0.0036(10)
-0.0022(11)
0.0015(12)
-0.0057(12)
-0.0074(12)
0.0028(12)
0.0020(11)
0.0101(13)
-0.0051(16)
-0.0298(18)
0.0472(17)
-0.0005(10)
0.0006(10)
-0.0051(10)
-0.0104(12)
-0.0022(13)
0.0145(15)
0.0053(16)
-0.0049(11)
-0.0055(9)
0.0217(15)
-0.0020(12)
-0.0010(12)
-0.0087(11)
-0.0078(12)
-0.0062(12)
-0.0005(12)
-0.0021(12)
-0.0016(12)
-0.0022(12)
-0.0029(12)
-0.0071(11)
0.0088(14)
0.0058(15)
-0.0238(18)
-0.0051(15)
-0.0119(12)
-0.0057(11)
-0.0074(11)
-0.0107(12)
-0.0073(12)
-0.0049(14)
-0.0184(19)
-0.0058(12)
0.0510(13)
0.0499(13)
0.0418(13)
0.0562(14)
0.0568(14)
0.0695(16)
0.0722(16)
0.0744(16)
0.0833(17)
0.0941(19)
0.0689(16)
0.0839(18)
0.114(2)
0.094(2)
0.109(2)
0.106(2)
0.0821(18)
0.0564(14)
0.0636(15)
0.0540(14)
0.0635(14)
0.0634(15)
0.0761(18)
0.115(2)
0.0485(13)
0.0547(14)
0.0499(13)
0.0705(16)
0.0701(16)
0.094(2)
0.089(2)
0.0645(16)
0.0434(13)
0.0597(14)
2
2
*2
*
*
The anisotropic atomic displacement factor exponent takes the form: -2σ [h a U11 + ... + 2 h k a b U ]
12
3
–
The largest peak in the final difference electron density synthesis
1.222 g/cm and F(000), 808 e based on the final model.
Positional coordinates of all the atoms, anisotropic atomic
displacement and hydrogen atomic coordinates along with
–
3
–
3
was 0.137 e /Å and the biggest hole was-0.170 e /Å with an
-
3
RMS deviation of 0.043 e /Å . The calculated density was

2
004 Gaonkar et al.
Asian J. Chem.
TABLE-6
HYDROGEN ATOMIC COORDINATES AND ISOTROPIC ATOMIC DISPLACEMENT PARAMETERS (Å )
2
x/a
y/b
z/c
U/eq
0.127
0.127
0.127
0.065
0.071
0.071
0.075
0.071
0.079
0.079
0.08
x/a
y/b
z/c
U/eq
H1A
H1B
H1C
H3
H5A
H5B
H7
-0.1808
-0.2690
-0.2207
-0.0812
0.0891
0.0537
0.2432
0.2032
0.2632
0.3366
0.2975
0.3698
0.4550
0.3917
0.1564
0.1077
0.0851
0.0744
0.0802
0.0085
-0.1662
0.0788
0.1320
0.0429
0.2752
0.2603
0.3297
0.3392
0.8863
0.8653
0.7711
0.8115
0.8288
0.7108
0.8313
0.7246
0.9138
0.9109
0.7820
0.8884
0.7820
0.6650
H13
H14
H15
0.5264
0.6238
0.6497
-0.1202
-0.1731
-0.0830
-0.0077
0.3376
0.2647
0.3712
0.2982
0.4787
0.5779
–
0.0756
0.0230
0.1596
-0.4403
-0.4033
-0.3641
-0.3337
-0.0774
-0.0559
0.0776
0.1648
0.3993
0.3484
–
0.7334
0.6399
0.5001
1.0035
1.0890
1.1172
0.9774
0.7196
0.6152
0.5954
0.6050
0.5464
0.4554
–
0.086
0.103
0.108
0.136
0.136
0.136
0.064
0.079
0.079
0.079
0.079
0.092
0.111
–
H16A
H16B
H16C
H18
H20A
H20B
H21A
H21B
H22
H8
H9A
H9B
H10A
H10B
H11A
H11B
0.08
0.08
0.08
H23
–
ACKNOWLEDGEMENTS
The authors gratefully acknowledge to Manipal Institute
of Technology, Manipal, India for laboratory facilities/financial
support and Karnatak University, Dharwad for XRD analysis.
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1
1
Fig. 2. Packing diagram of the title compound
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1
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