A new commercially viable synthetic route for donepezil hydrochloride: Anti-Alzheimer's drug

Article abstract of DOI:10.1248/cpb.58.1157

An economical new process has been developed for the synthesis of donepezil hydrochloride (1) an anti-Alzheimer's drug. The process involves Darzen reaction of pyridine-4-carboxaldehyde and 2-bromo-5,6-dimethoxy indanone affording epoxide 5,6-dimethoxy-3-(pyridine-4-yl)spiro[indene-2,2′-oxiran] -1(3H)-one (4) as a key intermediate. The one-pot deoxygenation of 4 and hydrogenation of the aryl moiety in high yield improved the overall yield of the process.

Full text of DOI:10.1248/cpb.58.1157

September 2010
Regular Article
Chem. Pharm. Bull. 58(9) 1157—1160 (2010)
1157
A New Commercially Viable Synthetic Route for Donepezil
Hydrochloride: Anti-Alzheimer’s Drug
Shailendra Kumar DUBEY,*,a Manita KHARBANDA,a Sushil Kumar DUBEY,a and
b
Chandra Shekhar MATHELA
a Chemical and Pharma Research Department, Jubilant Organosys Limited; C-26, Sector-59, UP-201301, India: and
b Department of Chemistry, Kumaun University; Nainital, Uttarakhand-263002, India.
Received March 31, 2010; accepted June 8, 2010; published online June 17, 2010
An economical new process has been developed for the synthesis of donepezil hydrochloride (1) an anti-
Alzheimer’s drug. The process involves Darzen reaction of pyridine-4-carboxaldehyde and 2-bromo-5,6-
dimethoxy indanone affording epoxide 5,6-dimethoxy-3-(pyridine-4-yl)spiro[indene-2,2؅-oxiran]-1(3H)-one (4) as
a key intermediate. The one-pot deoxygenation of 4 and hydrogenation of the aryl moiety in high yield improved
the overall yield of the process.
Key words donepezil hydrochloride; improved process; deoxygenation; epoxide; benzylation
Donepezil hydrochloride (E2020) alongside with galanta- proved solubility and hence employ lower volume of solvents
mine and rivastigmine is a piperidine-based drug developed for the synthesis of donepezil.
specifically for Alzheimer’s disease (AD) by Eisai Pharma-
In this contribution, we report a convenient and reliable
ceuticals (Aricept).1) It belongs to a class of acetylcholin- process, which is novel, economical, high yielding and is
esterase (AchE) inhibitors having N-benzylpiperidine and an industrially applicable for the synthesis of donepezil hy-
indanone moiety which shows longer and more selective ac- drochloride.
tion.2—9) It is the second drug approved by US-FDA for the
The first step of our synthetic strategy commences from
treatment of mild to moderate Alzheimer’s disease.10) On a commercially available 2-bromo-5,6-dimethoxy indanone 2
large-scale, donepezil hydrochloride 1 is being synthesized which undergoes Darzens condensation19—21) with pyridine-
from alkylidene or arylidene-2-indanone formed by Aldol 4-carboxaldehyde 3 in the presence of a suitable base afford-
condensation chemistry as key intermediates (Sugimoto and ing the epoxy intermediate 4 as diastereomers (Chart 1)
co-workers)11,12) followed by catalytic reduction affording 1 along with dehydrated side product 5, formed as a result of
with an overall yield of 27%. The process suffered from sev- competitive side reaction. An optimization of the reaction
eral disadvantages such as the use of unacceptable process process to minimize the formation of 5 was performed by
solvent like hexamethyl phosphoric amide (HMPA), forma- screening nature of base, reaction temperature and reaction
tion of side products during catalytic reduction and the need solvents (Table 1). It is quite evident from the table that con-
of column chromatography to remove the unwanted side densation requires strong nucleophilic organic base and
products. Stephen Lensky13) designed an efficient and scala- lower temperature. Among various bases examined for the
ble three-step synthesis involving N-benzylation of arylidene reaction, nBuLi and KOtBu showed significant formation of 4
intermediate to form a quaternary salt which was subse- in tetrahydrofuran (THF). Dehydration product 5 was the
quently hydrogenated with PtO2 to afford the target skeleton only product for reactions employing NaH (Table 1, entries
1. Though, Stephen Lensky process involves only three 1—4). Other solvents at various temperatures failed to elimi-
chemical transformations for the synthesis of 1, it is not eco- nate the formation of impurity 5 in the case of KOtBu (Table
nomical at commercial scale because of the use of highly ex- 1, entries 5—9). Surprisingly, reaction performed using
pensive reagent like PtO2. Replacement of Adam’s catalyst nBuLi at Ϫ78 °C in THF reduced the impurity as low as 6%
with Pd/C proceeded with debenzylated impurities which
Table 1. Optimization of Reaction Parameters for the Darzen Condensa-
were very difficult to remove in final API. A strong demand
tion of 2-Bromo-5,6-dimethoxy Indanone 2 with Pyridine-4-carboxaldehyde
3
of donepezil hydrochloride led to the development of several
synthetic schemes which are either too long or led to forma-
tion of several process related impurities or use of an expen-
sive catalyst such as PtO2 and thus are not feasible for large
scale preparation.14—18) The other drawback associated with
most of the reported protocols is the limited solubility of the
above mentioned intermediates consuming higher volumes of
solvents for the reactions. We envisioned that an efficient
route to 1 without involving hazardous reagents should make
economic sense besides giving a new practical industrial
method within the acceptable environmental and toxicological
concerns. We further reasoned that the new method involving
intermediates from cheap commercially available conven-
tional starting material other than the usual alkylidene or
Entry
Base
Solvent
Temp. (°C)
Conversion (%)a)
1
2
3
4
5
6
7
8
9
NaH (60%)
NaH (60%)
NaH (60%)
NaH (60%)
KOtBu
Toluene
DMF
THF
THF
THF
THF
THF
DMSO
DMF
THF
20—25
20—25
20—25
0—5
20—25
0—5
Ϫ10—Ϫ15
15—20
0—5
— (—)
— (100)
— (100)
— (—)
20 (80)
30 (70)
50 (50)
— (100)
— (100)
60 (40)
94 (6)
KOtBu
KOtBu
KOtBu
KOtBu
10
11
nBuLi
Ϫ20
Ϫ78
nBuLi
THF
a) Yields in the paranthesis refer to percentage of impurity 5 formed during the
arylidene indanone would be more appealing that display im- reaction.
∗ To whom correspondence should be addressed. e-mail: dubeyshailendra11@gmail.com
© 2010 Pharmaceutical Society of Japan

1158
Vol. 58, No. 9
(a) nBuLi, Ϫ78 °C, THF, 6 h, 82%; (b) 5% Pd/C, H2 (0.5 kg/cm2), 1 : 1 MeOH–CH2Cl2, RT, 2 h, 85%; (c) Zn–AcOH, 55 °C, 3 h, 81%; (d) 5% Pd/C, H2 (6.5—
7.0 kg/cm2), CH3COOH, CH3COONa, 1 : 1 MeOH–CH2Cl2, 75 °C, 10 h, 70%; (e) 5% Pd/C, H2 (6.5—7.0 kg/cm2), perchloric acid (cat.), 1 : 1 MeOH–CH2Cl2, 75 °C, 10 h,
90%; (f) (i) BnCl, 9 : 1 EtOAc–H2O, K2CO3, PEG-200 (cat.), 55 °C, 14 h; (ii) Con. HCl, 80%.
Chart 1. Process for the Synthesis of Donepezil Hydrochloride 1
ous methanol in the presence of Pd/C at 20—25 °C and
0.5 kg/cm2 hydrogen pressure forming 7 in 85% yield.25) De-
oxygenation of the resulting secondary alcohol was achieved
with zinc-acetic acid at 50—55 °C affording 8 in 81%
yield.26) The final hydrogenation of 8 to compound 6 was
studied with different metal catalysts (platinum, rhodium,
palladium etc.) but due to economical barrier, Pd/C remained
the best choice of reagent for this particular transformation.
The optimized procedure for the aromatic hydrogenation
employs 5% Pd/C, an organic acid and its salts (acetic
acid and sodium acetate) in the presence of an alcoholic or
non alcoholic solvents (methanol, ethanol or chloroform,
dichloromethane) or in the mixture of dichloromethane and
methanol at 70—75 °C and at about 6.0—7.0 kg/cm2 of hy-
drogen pressure.17) The mixture of solvents was however pre-
Fig. 1. ORTEP Representation (30% Probability) of Single-Crystal X-Ray
Structure of Epoxide 4 (Hydrogen Atoms Are Omitted for Clarity)
ferred because of the enhanced solubility of intermediate 8
(1.5 times reduction of solvent volume was achieved with the
binary solvent system).
affording the best condition for the transformation (Table 1,
The other route is a one shot conversion of 4 to 6 that
entry 11). The structure of epoxy intermediate 4 was con- involves deoxygenation and ring hydrogenation in one step.
firmed by spectral data and single crystal X-ray diffraction The process was complicated by formation of a major impu-
structure (Fig. 1).22) One of the most important features of rity 9 (Fig. 2) by competitive side reaction of carbonyl moi-
this reaction is that the product is obtained in high yield ety. Hence, to minimize side products formation, optimiza-
(85—90%) without any chromatographic purification as tion studies were carried out on the basis of previous results
compared to the known literature process.
adopted for the stepwise transformation of 4 to 6 (tempera-
The conversion of epoxide 4 to 6 was troublesome and ture, reaction time, hydrogen pressure and choice of solvents
required optimization. Two different approaches were etc.). A catalytic amount of perchloric acid (1% by weight)
adopted for the above transformation (Chart 1).23—25) The proved essential for the reaction and the best hydrogenation
first route is a three step transformation that involves epox- procedure was optimized by hydrogenating 4 with 5% Pd/C
ide-ring opening of 4 under catalytic hydrogenation in aque- in a 1 : 1 mixture of methanol–dichloromethane in the pres-

September 2010
1159
Fig. 2. Structures of Process Related Impurities
Table 2. Optimization of High Pressure Hydrogenation Reactions with Metal Catalysts
Entry
Substrate
Catalysta)
Solventb)
Time (h)
Conversion (%)c)
Yield of 6 (%)d)
1
2
3
4
5
6
7
8
9
8
8
8
8
8
4
4
4
4
4
4
5% Rh/C
5% Pt/C
5% Pt/C
10% Pd/C
MeOH
MeOH
MeOH
MeOH–DCM
MeOH–DCM
MeOH
4
9
12
8
10
12
7
10
10
24
5
86 (14)
98 (2)
92 (8)
72
90
75
86
91
70
63
90
81
68
73
97.5 (2.5)
98.5 (1.5)
80 (18)
75 (22)
94 (5)
87 (13)
73 (10)
82 (15)
5% Pd/C
5% Pd/CϩCat. HClO4
10% Pd/CϩCat. HClO4
5% Pd/CϩCat. HClO4
5% Pd/CϩCat. HCl
5% Pd/CϩCat. AcOH
10% Pd/CϩCat. HClO4
MeOH
MeOH–DCM
MeOH–DCM
MeOH–DCM
MeOH–DCM
10
11
a) All the reactions were performed at 70—75 °C and at 6.0—7.0 kg/cm2 pressure. b) MeOH (15 volumes); 1 : 1 MeOH–DCM (10 volume). c) Yields in the paranthesis
refer to impurity 9. d) Isolated yields.
Table 3. Effect of Phase Transfer Catalyst (PTC) on N-Benzylationa) of 6
dibenzylated product could not be eliminated. Careful
screening of various PTC revealed that 2% by weight of
Time
(h)
Conversion
(%)
Dibenzylated
Yield
Entry
PTCb)
PEG-200 added to the reaction mixture restricted 10 to 2—
4% (Table 3, entry 2). A 9 : 1 ethyl acetate–water system with
benzyl chloride, potassium carbonate in the presence of
PEG-200 gave the best acceptable result with satisfactory
yield (90%) of 1, as well as facilitated the precipitation of the
unwanted dibenzyl impurity 10 as a filterable solid from the
reaction mass. Purification of the crude 1 with methanol–di-
isopropylether afforded highly pure donepezil hydrochloride
impurity 10 (%) (%)c)
1
2
3
TBAI
PEG-200
18-crown-6
10
12
14
90
90
75
10
3
15
65
80
60
a) 1.1 eq K2CO3, 9 : 1 EtOAc–H2O, 55 °C. b) 2% by weight. c) Isolated
yields.
ence of perchloric acid at 70—75 °C and 6.0—7.0 kg/cm2 hy- in 60% overall yield.
drogen pressure for 8—10 h to accomplish 6 with 90% yield
In summary, we have developed a novel and efficient route
and more than 98.5% purity (HPLC purity). Other acids like for the synthesis of donepezil hydrochloride (E2020) with
HCl and AcOH used in the place of perchloric acid afforded the potential for the production at commercial scale. The im-
lower yield of products as a result of impurity formation in proved process for the preparation of donepezil hydrochlo-
the former case and a longer reaction time in the later.
ride 1 has an overall yield around 60% and involves only
The final N-benzylation of 6 was achieved using benzyl three isolation and drying steps. The enhanced solubility of
chloride (Chart 1). Though this chemical transformation the newly developed key intermediate 5,6-dimethoxy-3-pyri-
appears simple and straight, it afforded very unpredictable dine-4-ylspiro(indene-2,2-oxiran)-1(3H)-one 4 is the signifi-
results at the initial feasibility studies. The reported proce- cant feature of the method. The process offers distinctive ad-
dures for benzylation (benzyl chloride, 60—65 °C, triethyl- vantages over earlier reported procedures in terms of mini-
amine)14) resulted in a very poor yield (19.5%) with forma- mal effluent generation, avoiding the use of hazardous
tion of dibenzylated quaternary salt 10 (Fig. 2) (around 15%) reagents as well as significant cost reduction on commercial
as impurity. The reaction conditions were therefore modified scale.
suitably that precludes the contamination of the final product
by 10. Preliminary experiments on the N-alkylation disclosed
that the nature of solvent and quantity of benzyl chloride
plays critical role in controlling competitive dibenzyl product
10. Various single organic solvents (acetone, dichloromethane,
acetonitrile, isopropyl ether etc.) employed for the reaction
resulted in poor yields of 1. Therefore N-benzylation was spectra were recorded using a JASCO FT/IR 410 spectrometer.
examined in biphasic medium (toluene–Water, ethyl acetate–
water etc.) in the presence of phase transfer catalyst (PTC)
and inorganic base (K2CO3, KHCO3, NaHCO3, Na2CO3, etc.).
Experimental
All reactions were carried out in anhydrous solvents. THF was distilled
from sodium-benzophenone under argon and CH2Cl2 was distilled from
CaH2. 1H-NMR spectra were obtained at 400 MHz, and 13C-NMR spectra
were obtained at 100.6 MHz using a Bruker NMR spectrometer. Chemical
shifts (d) are reported in ppm relative to CDCl3 (7.26, 77.0 ppm). Infrared
5,6-Dimethoxy-3-(pyridine-4-yl)spiro[indene-2,2؅-oxiran]-1(3H)-one
(4) THF (250 ml) was taken in a 500 ml three-neck flask equipped with a
stirrer, nitrogen inlet, gas bubbler and thermometer and cooled to Ϫ78 °C.
To this cold solution was added n-butyllithium (11.77 g, 1.6 M in hexane,
0.184 mol) followed by the addition of 2-bromo-5,6-dimethoxyindanone 2
(50 g, 0.184 mol). After 10 min, pyridine-4-carboxaldehyde 3 (19.74 g,
Considerable improvement in the yield of 1 was observed
with biphasic solvent medium though the formation of

1160
Vol. 58, No. 9
2-[{4-(N-Benzylpiperidinyl)}methyl]-5,6-dimethoxyindanone hydrochlo-
ride (1) Benzyl chloride (1.92 g, 0.0156 mol), potassium carbonate (2.28 g,
0.0165 mol) and PEG-200 (80 mg, 2% by weight) were added to a clear
biphasic solution of 2-[(4-piperidyl)methyl]-5,6-dimethoxyindan-1-one 6 (4 g,
0.0138 mol) in 9 : 1 EtOAc–H2O (40 ml). The reaction mixture was heated to
50—55 °C and monitored on TLC. After completion of reaction (14 h), the
solid was filtered and the filtrate was washed with water (4 ml). The EtOAc
layer was separated, added water (8 ml) and acidified with conc. HCl till a
pH 2. EtOAc layer was discarded and the acidic aqueous layer was extracted
with CH2Cl2 (2ϫ16 ml). The CH2Cl2 layer was separated, dried over anhy-
drous Na2SO4, filtered and evaporated under vacuum to yield the crude salt
as a residue. The residue was dissolved in methanol (20 ml) followed by the
addition of isopropyl ether (40 ml) and stirred for a further 1 h. The precipi-
tated solid was filtered and dried under vacuum to yield pure donepezil hy-
drochloride 1. Yield 5.14 g (89%); HPLC: 99.963%; IR (KBr, cmϪ1) 3588,
3372, 2923, 2535, 1683, 1591, 1501, 1455, 1315, 1266, 1217, 1119, 1038,
700; 1H-NMR (400 MHz, CDCl3) d: 7.44—7.63 (m, 3H), 7.12 (s, 1H), 6.85
(s, 1H), 4.12—4.19 (m, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 3.38—3.45 (m, 2H),
3.28 (dd, Jϭ8, 17.6 Hz, 1H), 2.63—2.67 (m, 4H), 1.82—2.08 (m, 6H),
1.49—1.51 (m, 1H); 13C-NMR (100 MHz, CDCl3) d: 206.9, 155.7, 149.5,
148.7, 131.5, 130.1, 129.2, 128.8, 128.1, 107.3, 104.3, 60.9, 56.2, 56.0,
52.4, 52.3, 44.1, 38.1, 34.0, 32.1, 29.4, 28.4; MS (ESI) m/z 380 [Mϩϩ1].
0.184 mol) was added to the reaction mass at Ϫ78 °C and stirred at the same
temperature till the completion of the reaction. After completion of reaction
(5 h) water (750 ml) was added to the reaction mass to precipitate the prod-
uct. The solid was filtered, washed with methanol and dried under vacuum to
yield the product 4 as a 2 : 1 mixture of diastereomers. Yield: 45 g (82%);
Yellow solid; HPLC 98.5%; FT-IR (KBr, cmϪ1): 3545, 3419, 2959, 1688,
1634, 1595, 1545, 1500, 1306, 1258, 1125; Major diastereomer: 1H-NMR
(400 MHz, CDCl3) d: 8.55 (d, Jϭ5.2 Hz, 2H), 7.45 (d, Jϭ6.0 Hz, 2H), 7.01
(s, 1H), 6.89 (s, 1H), 4.41 (s, 1H), 3.96 (s, 3H), 3.81 (s, 3H), 3.38 (dd, Jϭ
17.2, 34.4 Hz, 2H); 13C-NMR (400 MHz, CDCl3) d: 195.2, 156.2, 149.8,
148.9, 144.8, 141.8, 129.2, 122.1, 107.4, 104.3, 66.8, 63.9, 56.3, 55.9, 32.8;
Minor diastereomer: 1H-NMR (400 MHz, CDCl3) d: 8.61 (dd, Jϭ1.6,
4.4 Hz, 2H), 7.22—7.25 (m, 2H), 6.81 (s, 1H), 4.42 (s, 1H), 3.92 (s, 3H),
3.89 (s, 3H), 3.13 (d, Jϭ18 Hz, 1H), 2.76 (d, Jϭ18 Hz, 1H); 13C-NMR (400
MHz, CDCl3) d: 196.4, 159.4, 149.8, 146.4, 144.0, 128.3, 121.1, 107.5,
104.4, 67.3, 60.7, 56.2, 56.1, 28.6; MS electrospray ionization (ESI) m/z
298.6 [Mϩϩ1].
2-[(4-Piperidinyl)methyl]-5,6-dimethoxyindanone (6) To a stirred so-
lution of 5,6-dimethoxy-3-pyridine-4-yl-spiro(indene-2,2-oxiran)-1(3H)-one
4 (50 g, 0.168 mol) in 1 : 1 MeOH–CH2Cl2 (500 ml) was added 5% Pd/C
(5 g, 10% by wt) and a catalytic amount of perchloric acid (0.5 g, 1% by
weight). The solution was hydrogenated at 6.5 kg/cm2 hydrogen pressure at
60—65 °C, till the reaction was completed by TLC (10 h). After the comple-
tion of the reaction, the catalyst was filtered through a pad of celite and
washed with 1 : 1 MeOH–CH2Cl2 (10 ml). The combined filtrate was evapo-
rated under vacuum and the residue was taken in ethyl acetate (500 ml) and
washed with water (50 ml). The EtOAc layer was separated, dried over anhy-
drous sodium sulphate, filtered and evaporated under reduced pressure to
yield the product 6. Yield 43.7 g (90%); HPLC 98.5%; IR (KBr, cmϪ1) 2938,
2797, 2717, 2630, 2511, 2460, 1678, 1589, 1500, 1473, 1365, 1315, 1265,
1118, 1039; 1H-NMR (400 MHz, CDCl3) d: 9.65 (s, 1H), 9.39 (s, 1H), 7.15
(s, 1H), 6.87 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.51 (t, Jϭ12 Hz, 2H), 3.29
(dd, Jϭ8, 17.6 Hz, 1H), 2.86—2.93 (m, 2H), 2.66—2.71 (m, 2H), 1.93—
2.05 (m, 4H), 1.72—1.84 (m, 2H), 1.41—1.52 (m, 1H); 13C-NMR (100
MHz, CDCl3) d: 206.7, 155.7, 149.6, 148.5, 129.0, 107.4, 104.4, 56.3, 56.1,
44.5, 44.0, 38.1, 33.6, 32.5, 29.7, 28.9, 28.7. MS (ESI) m/z 290 [Mϩϩ1].
2-Hydroxy-5,6-dimethoxy-2-(pyridine-4-yl-methyl)indan-1-one (7)
To a stirred solution of 5,6-dimethoxy-3-pyridine-4-yl-spiro(indene-2,2-oxi-
ran)-1(3H)-one 4 (50 g, 0.168 mol) in 1 : 1 MeOH–CH2Cl2 (500 ml) was
added 5% Pd/C (5.0 g, 10% by weight). The solution was hydrogenated at
0.5 kg/cm2 hydrogen pressure at room temperature till the reaction was com-
pleted. The reaction mixture was worked-up as described above to afford 7
which was taken for next step without any further purification. Yield: 42.6 g
(85%); HPLC 98.2%; 1H-NMR (400 MHz, CDCl3) d: 8.41 (dd, Jϭ1.36, 4.6
Hz, 2H), 7.09—7.11 (m, 3H), 6.72 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.13
(d, Jϭ17 Hz, 1H), 2.94 (dd, Jϭ13.6, 17 Hz, 2H), 2.82 (d, Jϭ13.6 Hz, 1H).
13C-NMR (100 MHz, CDCl3) d: 204.8, 156.8, 150.0, 149.3, 146.9, 145.3,
126.1, 125.6, 107.4, 104.9, 79.5, 56.3, 56.2, 43.5, 39.3; MS (ESI) m/z 300
[Mϩϩ1].
Acknowledgements The authors wish to thank the management of
Jubilant Organosys Ltd., for supporting this work. Cooperation from col-
league’s analytical research department is appreciated.
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2-[(4-Pyridyl)methyl]-5,6-dimethoxyindanone (8) Zinc powder (10 g,
0.153 mol) was added to a stirred solution of 2-hydroxy-5,6-dimethoxy-2-
(pyridine-4-yl-methyl)indan-1-one 7 (50 g, 0.167 mol) in acetic acid (200
ml) at ambient temperature. The reaction mixture was heated to 50—55 °C
and stirred for 2 h at the same temperature. After completion of the reaction
(3 h, TLC), the reaction was cooled to room temperature, filtered and the fil-
trate was concentrated under reduced pressure to yield a residue. The residue
was taken in ethyl acetate (100 ml) and water (100 ml) and the solution was
basified (pH 7—7.5) with 50% NaOH solution. The organic layer was sepa-
rated, washed with water and the solvent was evaporated under vacuum to
yield 8. Yield: 38.3 g (81%).
2-[(4-Piperidinyl)methyl]-5,6-dimethoxyindanone (6) To a solution of
2-[(4-pyridyl)methyl]-5,6-dimethoxyindan-1-one 8 (10 g, 35.30 mmol) in 1 :
1 methanol–CH2Cl2 (200 ml) was added sodium acetate (2.83 g, 34.51
mmol) and acetic acid (2.04 ml, 35.66 mmol). 5% Pd/C (1.0 g, 10% by
weight) was then added and the reaction mixture was hydrogenated at 70—
75 °C and 6—7 kg/cm2 hydrogen pressure for 10 h. After completion of the
reaction, the reaction mixture was filtered through a pad of celite, washed
with 1 : 1 MeOH–CH2Cl2 (20 ml) and evaporated under reduced pressure.
The residue was taken in ethyl acetate (30 ml) and water (25 ml) and the so-
lution was basified (pH 9—9.5) with 50% NaOH solution. The organic layer
was separated, washed with water, brine and dried over anhydrous sodium
sulfate. The solution was filtered and evaporated under vacuum to yield 6.
Yield 7.14 g (70%). HPLC: 99.03%.
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