The present invention relates to an improved, efficient and industrially advantageous
process for preparation of 5,6-dimethoxy-1-indanone of formula I,
Formula I
which is a key intermediate of donepezil hydrochloride.
5 BACKGROUND OF THE INVENTION
Donepezil hydrochloride formula II, is an acetylcholinesterase inhibitor, and is
chemically known as (±)-2, 3-dihydro-5, 6-dimethoxy-2-[[1-(phenylmethyl)-4-
piperidinyl]methyl]-1H-inden-1-one hydrochloride,
Formula II
Donepezil hydrochloride is marketed as under the trade name ARICEPT®
10 and has
been used for the treatment of dementia of the Alzheimer’s type.
Donepezil hydrochloride and its process of preparation were first disclosed in US
patent 4,895,841. The process to prepare donepezil hydrochloride comprise the step
of condensation of 5,6-dimethoxy-1-indanone with 1-benzyl-4-piperidine-1-
15 carboxaldehyde in presence of n-butyllithium and diisopropylamine to obtain 1-
benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]-methylpiperidine, which on further
reduction with palladium on carbon followed by use of hydrochloric acid results
donepezil hydrochloride which is depicted as below:
3
This patent does not discloses the preparation of starting material i.e. 5,6-dimethoxy1-indanone.
Several methods have been reported in literature to prepare 5,6-dimethoxy-1-
5 indanone; some of which have been incorporated here for reference.
A Japanese patent publication JPH 11302216 A discloses preparation of 5,6-
dimethoxy-1-indanone starting from 3-chloro-3',4'-dimethoxypropiophenone. The
process comprises dissolving 3-chloro-3',4'-dimethoxypropiophenone in
concentrated sulfuric acid followed by stirring at 70°C for 2 hours to 5 hours. The
10 resulting reaction mixture was cooled to room temperature and poured into ice cold
water and extracted with dichloromethane. The resulting organic layer was then
washed with 10% aqueous sodium hydroxide and organic layer was dried and
distilled under reduced pressure to obtain crude product. The resulting crude product
was recrystallized from acetone/ n-hexane to obtain 5,6-dimethoxy-1-indanone
15 which is depicted as below:
The process disclosed in above patent application results in 63% -68% yields. This
patent is silent about formation of impurities and cause of low yield. In our hands we
have observed formation of about 20% to 30% of 6-hydroxy-5-methoxy-1-indanone
4
as a major impurity during the reaction of 3-chloro-3',4'-dimethoxypropiophenone
with concentrated sulfuric acid. This patent is also silent about formation of 6-
hydroxy-5-methoxy-1-indanone impurity.
A PCT publication WO2000/043342 discloses preparation of 5,6-dimethoxy-1-
5 indanone using 3-chloro-3',4'-dimethoxypropiophenone and sulfuric acid.
This patent application does not discloses the procedure for isolation of 5,6-
dimethoxy-1-indanone and is also silent about formation of 6-hydroxy-5-methoxy-1-
indanone as impurity during the reaction and its conversion to desired 5,6-
dimethoxy-1-indanone.
10 US patent 4,273,773 discloses a process for the preparation of 5,6-dimethoxy-1-
indanone comprises reaction of 3-(3,4-dimethoxyphenyl)propionic acid with
phosphorus pentoxide and benzene to obtain 5,6-dimethoxyindan-1-one which is
depicted as below:
15 Above process requires phosphorus pentoxide which is hazardous and not advisable
for large scale process.
Chinese patent application CN 101798284 A discloses a process for the preparation
of 5,6-dimethoxy-1-indanone comprises reaction of 3,4-dimethoxy benzene
propionic acid with oxalyl chloride followed by in situ conversion of 3,4-dimethoxy
20 benzene propionyl chloride using dichloromethane, aluminium chloride followed by
column chromatography using ethyl acetate and petroleum ether to obtain 5,6-
dimethoxy-1-indanone which is depicted as below:
5
Above process requires use of aluminium chloride which is hazardous. Further
process required application of column chromatography for the purification of 5,6-
dimethoxy-1-indanone making the process industrially un-viable. Further, for
5 column chromatography, petroleum ether is used which is also not advisable for
large scale process.
As most of the prior art references are silent about the formation and removal of 6-
hydroxy-5-methoxy-1-indanone impurity during the conversion of 3-chloro-3',4'-
dimethoxypropiophenone into 5,6-dimethoxy-1-indanone in the presence of
10 concentrated sulfuric acid. Therefore, there is an urgent need to develop a process for
the preparation of 5,6-dimethoxy-1-indanone wherein either the formation of 6-
hydroxy-5-methoxy-1-indanone impurity has been minimized or improve the yield
of 5,6-dimethoxy-1-indanone. Thus, the present invention provides an improved
process for the preparation of 5,6-dimethoxy-1-indanone of formula I with improved
15 yield.
OBJECT OF THE INVENTION
The main objective of the present invention is to provide an efficient and industrially
advantageous process for the preparation of 5,6-dimethoxy-1-indanone of formula I,
Formula I
20 which is a key intermediate of donepezil hydrochloride.
6
The another objective of the present invention is to provide an efficient and
industrially advantageous process for the preparation of 5,6-dimethoxy-1-indanone
of formula I,
Formula I
5 with improved yield.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of 5,6-
dimethoxy-1-indanone of formula I,
Formula I
comprising the steps of:
10 a) reacting 3-chloro-3',4'-dimethoxypropiophenone of formula III;
Formula III
with an acid;
b) treating the resulting reaction product containing 5,6-dimethoxy-1-
indanone of formula I with 6-hydroxy-5-methoxy-1-indanone of formula IV
15 as mixture;
Formula I Formula IV
7
with a suitable methylating agent in the presence of a base and solvent to
obtain 5,6-dimethoxy-1-indanone of formula I ; and
c) isolating pure 5,6-dimethoxy-1-indanone of formula I.
5 DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved, efficient and industrially advantageous
process for the preparation of 5,6-dimethoxy-1-indanone of formula I, which is an
important intermediate for the preparation of donepezil hydrochloride.
According to one aspect, the present invention provides an improved, efficient and
10 industrially advantageous process for the preparation of 5,6-dimethoxy-1-indanone
of formula I, by converting the process related impurity of formula IV to the
desired product to increase its yield.
Generally, 5,6-dimethoxy-1-indanone of formula I of can be prepared starting from
3-chloro-3',4'-dimethoxypropiophenone of formula III. 3-Chloro-3',4'-dimethoxy
15 propiophenone of formula III can be procured from market or can be prepared by the
processes known in the art.
5,6-Dimethoxy-1-indanone of formula I can be prepared by reaction of 3-chloro3',4'-dimethoxypropiophenone of formula III with an acid.
Generally, reaction of 3-chloro-3',4'-dimethoxypropiophenone of formula III with
20 acid can be carried out at 50°C to 65°C, preferably at 55°C to 60°C. The acid can be
selected from methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic
acid, sulfuric acid and the like; preferably concentrated sulfuric acid is used for the
reaction. The reaction can be carried out for few minutes to few hours, preferably for
5 hours to 9 hours; more preferably for 6 to 8 hours.
8
The progress of the reaction can be monitored by suitable chromatographic
techniques such as high pressure liquid chromatography (HPLC), gas
chromatography (GC), ultra pressure liquid chromatography (UPLC), thin layer
chromatography (TLC) and the like.
5 During process development, it has been found that when 3-chloro-3',4'-dimethoxy
propiophenone of formula III is reacted with sulphuric acid, the desired compound
5, 6-dimethoxy-1-indanone of formula I is formed in 55% to 75% ratio along with
20% to 40% of an impurity of formula IV and some other impurities too as depicted
below:
10
It is also observed that formation of 6-hydroxy-5-methoxy-1-indanone impurity
depends on amount of acid used, reaction temperature and time duration of reaction.
Higher the quantity of sulphuric acid used or higher the reaction temperature as
well as longer the reaction time, higher is the proportion of formation of 6-hydroxy15 5-methoxy-1-indanone impurity of formula IV.
In most of the prior art references, after reaction of 3-chloro-3',4'-
dimethoxypropiophenone with acid is over, the mass is treated with sodium
hydroxide wherein the in-situ formed 6-hydroxy-5-methoxy-1-indanone (6-
HMI) impurity of formula IV converts into its sodium salt, which being water
20 soluble gets eliminated during aqueous workup eventually reducing the yield of the
product making the process commercially unviable. Therefore, it is necessary to
develop conditions in which either the formation of 6-hydroxy-5-methoxy-1-
indanone impurity of formula IV is minimalized or if formed can be converted into
desired 5,6-dimethoxy-1-indanone of formula I to increase the yield and make the
25 overall process commercially competitive.
9
Generally, in the present invention, after completion of reaction of 3-chloro-3',4'-
dimethoxy propiophenone of formula III with sulphuric acid, the reaction mass can
be cooled to 20°C to 30°C and then poured into cold water at temperature of 5-
15°C. The temperature can be further raised to 20°C to 30°C and resulting reaction
5 mixture can be extracted with an appropriate solvent. The solvent can be selected
from halogenated solvent such as chloroform or dichloromethane and preferably
dichloromethane can be used. Thereafter, the resulting organic layer can be washed
with 10% aqueous sodium bicarbonate followed by water. Thereafter, the solvent
can be distilled to obtain crude residue or the layer can be used as such for next step.
10 In one of the aspect of present invention, the solvent can be distilled to obtain crude
residue and to this a suitable solvent such as cyclohexane can be added. The
resulting reaction mixture can be stirred for 20 to 30 minutes at 25°C to
30°C followed by filtration of the resulting suspension, followed by washing with
cyclohexane and drying at 50°C to 60°C for 2 hours to 12 hours to obtain 5, 6-
15 dimethoxy-1-indanone of formula I as a crystalline solid. Generally, the resulting
compound has HPLC purity of 67-72%, and contains 6-hydroxy-5-methoxy-1-
indanone of formula IV in the ratio of 20-28 % as impurity.
The resulting solid material containing a mixture of 5,6-dimethoxy-1-indanone of
formula I and 6-hydroxy-5-methoxy-1-indanone impurity of formula IV can be
20 further reacted with a methylating agent in presence of a base and a solvent. The
solvent can be selected from dichloromethane, 1,2- dichloroethane, tetrahydrofuran,
Dimethoxy ethane, 1,2-diethoxyethane, N,N-dimethylformamide, dimethyl
sulphoxide, 1,4-dioxane, toluene, 1,2 xylene, preferably the solvent used is
dichloromethane. The base can be added initially to adjust pH 7 to 10, preferably 7
25 to 9. The base can be selected from sodium hydroxide, potassium hydroxide, sodium
carbonate, potassium carbonate. Preferably the base is sodium hydroxide. The
methylating agent can then be added slowly to the resulting reaction mixture at 20°C
10
to 30°C. The methylating agent can be selected from methyl iodide, methyl
bromide, dimethyl sulfate, methyl triflate, dimethyl carbonate. Preferably the
methylating agent is dimethyl sulfate. The resulting reaction mixture can be heated to
30°C to 45°C, preferably at 35°C to 45°C and can be stirred for 5 to 12 hours,
5 preferably for 6 to 10 hours. After completion of reaction, the mixture can be cooled
to 20°C to 30°C and water can be added and stirred for 30 minutes. The organic
layer can be washed with aqueous sodium hydroxide followed by water and aqueous
sodium chloride solutions. The organic layer can then be treated with activated
carbon at 25°C to 40°C, preferably at 30°C to 35°C after which the reaction mixture
10 can be filtered through hyflo bed to remove the suspended particles. Thereafter,
the solvent from the resulting filtrate can be distilled out completely at 40°C to 45°C
to obtain the residue. Optionally to the residue, a suitable solvent such as n-hexane,
heptane, petroleum ether, cyclohexane or a mixture of these solvents with
dichloromethane or chloroform can be added. In a preferred embodiment,
15 cyclohexane can be added. Cyclohexane can be added at 20°C to 35°C, preferably
at 25°C to 30°C. Resulting solid can be filtered, washed with cyclohexane followed
by drying at 40°C to 60°C, preferably at 50°C to 60°C for 10 to 15 hours, preferably
12 hours to obtain 5,6-dimethoxy-1-indanone of formula I free from 6-hydroxy-5-
methoxy-1-indanone of formula IV.
20 In another aspect of present invention, the organic layer obtained after the reaction of
3-chloro-3',4'-dimethoxy propiophenone III with sulphuric acid can be used directly
for methylation step. Generally, methylation can be carried out in the presence of a
suitable methylating agent and a base. The base can be added initially to adjust pH at
7 to 10, and preferably at 7 to 9. The base can be selected from sodium hydroxide,
25 potassium hydroxide, sodium carbonate, potassium carbonate. Preferably the base
used can be sodium hydroxide. The methylating agent can then be added slowly to
the resulting reaction mixture at 20°C to 30°C. The methylating agent can be
selected from methyl iodide, methyl bromide, dimethyl sulfate, methyl triflate,
11
dimethyl carbonate. Preferably the methylating agent can be dimethyl sulfate. The
resulting reaction mixture can be heated to 30°C to 45°C, preferably at 35°C to 45°C
and can be stirred for 5 to 12 hours, preferably for 6 to 10 hours. After completion of
reaction, the mixture can be cooled to 20°C to 30°C and water can be added and
5 stirred for 30 minutes. The organic layer can be washed with aqueous sodium
hydroxide followed by water and aqueous sodium chloride solutions. The organic
layer can then be treated with activated carbon at 25°C to 40°C, preferably at 30°C to
35°C after which the reaction mixture can be filtered through hyflo bed to remove
the suspended particles. Thereafter, the solvent from the resulting filtrate can be
10 distilled out completely at 40°C to 45°C to obtain the residue. Optionally to the
residue, a suitable solvent such as n-hexane, heptane, petroleum ether,
cyclohexane or a mixture of these solvents with dichloromethane or chloroform can
be added. In a preferred embodiment, cyclohexane can be added. Cyclohexane can
be added at 20°C to 35°C, preferably at 25°C to 30°C. Resulting solid can be filtered,
15 washed with cyclohexane followed by drying at 40°C to 60°C, preferably at 50°C to
60°C for 10 to 15 hours, preferably 12 hours to obtain 5,6-dimethoxy-1-indanone of
formula I free from 6-hydroxy-5-methoxy-1-indanone of formula IV.
The resulting 5,6-dimethoxy-1-indanone of formula I has purity of above 98.0% by
HPLC and has yield of greater than 80%. The resulting 6-dimethoxy-1-indanone of
20 formula I free from 6-hydroxy-5-methoxy-1-indanone of formula IV can
be converted into donepezil hydrochloride by the processes known in the art.
We have not found any reference in literature, wherein 3-chloro-3',4'-
dimethoxypropiophenone of formula III is cyclized in the presence of an acid and
reported preparation of a mixture of 5,6-dimethoxy-1-indanone of formula I and 6-
25 hydroxy-5-methoxy-1-indanone impurity of formula IV; which on further reaction
with a methylating agent, in the presence of a base and solvent affords the desired
5,6-dimethoxy-1-indanone of formula I with high yield. Therefore, these steps,
12
involving the reaction of a mixture of 5,6-dimethoxy-1-indanone of formula I and 6-
hydroxy-5-methoxy-1-indanone impurity of formula IV with methylating agent to
convert 6-hydroxy-5-methoxy-1-indanone impurity of formula IV to 5,6-dimethoxy1-indanone of formula I form the inventive part of the invention.
5 Major advantages realized in the present invention is to provide a process for
preparation of 5,6-dimethoxy-1-indanone of formula I from 3-chloro-3',4'-
dimethoxypropiophenone of formula III, having HPLC purity of greater than
98.0%, and including the in-between step of methylation of 6-hydroxy-5-methoxy1-indanone impurity of formula IV and hence the yield has been enhanced to greater
10 than 80%.
Although, the following examples illustrate the present invention in more detail, but
should not be construed as limiting the scope of the invention.
While the present invention has been described in terms of its specific aspects and
15 embodiments, certain modifications and equivalents will be apparent to those skilled
in the art and are intended to be included within the scope of the present invention.
Examples:
Reference example
20 A solution of 3-chloro-3,4-dimethoxypropiophenone (200.0g) in concentrated
sulphuric acid (400 mL) was stirred under nitrogen atmosphere at 55°C to 59°C for 6
hours. After completion of reaction (monitored by HPLC), resulting solution cooled
to 20-30°C and poured into ice water (1200 mL) at 5-15°C. The temperature of the
reaction mixture was then raised to 20-30°C and dichloromethane (1600 ml) was
25 added to the reaction mixture. The layers were separated and aqueous layer was
extracted two times consecutively with dichloromethane [600 mL and 400 mL]. The
13
resulting combined organic layer’s HPLC graph shows 5,6-dimethoxy-1-indanone
(70.08%) and another major impurity 6-hydroxy-5-methoxy-1-indanone (26.50%).
Resulting organic layer was divided into two equal parts. One part 1300 ml of
organic layer was kept aside.
5 Another part (1300 ml) of organic layer was washed successively with 2.5% aqueous
sodium hydroxide solution (5x400 ml), water (2x300 ml) and 20% aqueous sodium
chloride solution (300 ml). The resulting organic layer was treated with activated
carbon (5 g) at 30-35°C and filtered through hyflo bed and the hyflo bed was washed
with dichloromethane (100 mL). The solvent of resulting filtrate was distilled
10 completely under vacuum at 40-45°C to obtain crude 5,6-dimethoxy-1-indanone
(56.0 g). Cyclohexane (300 mL) was then added to crude and stirred at 25-30 °C for
20-30 min. The suspension was then filtered and washed with cyclohexane (100
mL). The resulting wet material was dried under vacuum at 50-60 °C for 12 hours to
obtain 52.0 g of 5,6-dimethoxy-1-indanone (61.9%).
15 Example 1: Preparation of 5,6-dimethoxy-1-indanone
A solution of 3-chloro-3',4'-dimethoxypropiophenone (200.0 g) in concentrated
sulfuric acid (400 mL) was stirred at 55°C to 59°C for 9 hours under inert
atmosphere. After completion of reaction (monitored by HPLC), resulting solution
was cooled to 20°C to 30°C and poured into ice water (1200 mL) at 5°C to 15°C.
20 The temperature of reaction mixture was then raised to 20°C to 30°C and
dichloromethane (1600 mL) was added and stirred for 20-30minutes. The layers
were separated and aqueous layer was extracted two times consecutively with
dichloromethane 600 mL and 400 mL.) HPLC analysis of the combined organic
layer indicated that 5,6-dimethoxy-1-indanone has purity 70.07% and another
25 major impurity is 6-hydroxy-5-methoxy-1-indanone and is present at a levels of
20.29% . The resulting organic layer was divided into two equal parts:
14
Part-1 (as per known method):
One part of organic layer was washed successively washed with 2.5% of aqueous
sodium hydroxide solution (5x400 mL), water (2x300 mL) and 20% aqueous sodium
chloride solution (300 mL). The organic layer was separated, treated with activated
5 carbon (5.0 g) at 30°C to 35°C, filtered through hyflo bed and the bed was washed
with dichloromethane (100 mL). The solvent was then distilled at 40°C to 45°C to
obtain crude 5,6-dimethoxy-1-indanone 55g [65.47%] which displayed HPLC purity
of 92.89% and 6-hydroxy-5-methoxy-1-indanone impurity was not detected.
Part-2 (as per the present invention process using methylation step):
10 To the second part of organic layer, 10% aqueous sodium bicarbonate (260 mL) was
added to adjust pH at 6 to 7 and stirred for 15-20 min. The layers were then
separated and organic layer was washed with water (200 mL) and after separation of
layers, the solvent was distilled off to yield a solid residue 73 g. Cyclohexane (300
mL) was added and the resulting suspension stirred for 30 minutes at 25°C to 30°C.
15 The suspension was then filtered, on a Buchner funnel, washed with cyclohexane
(100 mL) and dried under vacuum at 50°C to 60°C for 12 hours to obtain 5,6-
dimethoxy-1-indanone (71.0 g) which displayed HPLC purity of 71.99% along with
20.71% of 6-hydroxy-5-methoxy-1-indanone impurity. The above material was then
dissolved in dichloromethane (650 mL) and to the resulting solution; powdered
20 sodium hydroxide (22.10 g) and dimethyl sulfate (21.2 g) were then successively
added at 20 to 30°C. The temperature was then slowly raised to 35°C to 45°C and
stirred at this temperature for 6 hours till HPLC indicated the completion of the
reaction. The reaction mixture was then cooled to 20°C to 30°C and water (600 mL)
was added and stirred for 30 minutes. The layers were then separated and the organic
25 layer was successively washed with 2.5% aqueous sodium hydroxide (400
mL), water (2x300 mL) and 20% aqueous sodium chloride (300 mL). The resulting
organic layer was then treated with activated carbon (5.0 g) at 30°C to 35°C and
15
filtered through hyflo bed and washed with dichloromethane (100 mL). Solvent was
then distilled off at 45°C to 50°C to obtain crude 5,6-dimethoxy-1-indanone 76g
having purity 92.67% by HPLC and 6-hydroxy-5-methoxy-1-indanone impurity was
0.01%
5 Example 2: Preparation of 5,6-dimethoxy-1-indanone
A solution of 3-chloro-3',4'-dimethoxypropiophenone (100.0 g) in concentrated
sulfuric acid (200 mL) was stirred at 55°C to 59°C for 8 hours under inert
atmosphere. After completion of reaction (monitored by HPLC), resulting solution
was cooled to 20°C to 30°C and poured into ice water (600 mL) at 5°C-15°C. The
10 temperature of reaction mixture was then raised to 20°C to 30°C and
dichloromethane (800 mL) was added and stirred for 20-25 min. The layers were
separated, the aqueous layer was extracted two times consecutively with
dichloromethane 300 mL and 200 mL and aqueous sodium bicarbonate (10 % w/w,
200 mL) solution was added to the resulting organic layer to adjust pH 6 to 7. The
15 layers were then separated and organic layer was washed with water (400 mL).
Solvent was distilled off under vacuum having bath temperature at 45°C to
50°C. Cyclohexane (300 mL) was added to resulting residue and stirred for 30
minutes at 25°C to 30°C. The resulting suspension was then filtered on a Buchner
funnel, washed with cyclohexane (100 mL) and the wet material was dried under
20 vacuum at 50°C to 60°C for 12 hours to obtain 5,6-dimethoxy-1-indanone (70.0 g)
having purity of 69.24% by HPLC and 6-hydroxy-5-methoxy-1-indanone impurity:
was 27.91%.
Above crude 5,6-dimethoxy-1-indanone (70.0 g) was dissolved in dichloromethane
(650 mL) and sodium hydroxide (24.88 g) was added and stirred for 10 minutes at
25 25-35 °C. Dimethyl sulfate (28.76 g) was then slowly added to the reaction mixture
at 25-35 °C, temperature was slowly raised to around 35°C-45°C and stirred for 10
hours till the TLC indicated the completion of reaction. The reaction mixture was
16
then cooled to 20°C to 30°C and water (600 mL) was added and stirred for 30
minutes. The layers were then separated and organic layer was successively washed
with 2.5% aqueous sodium hydroxide (400 mL), water (2x300 mL) and 20%
aqueous sodium chloride (300 mL). The organic layer was then treated with
5 activated carbon (5.0 g) at 30°C to 35°C and filtered through hyflo bed and the bed
was washed with dichloromethane (100 mL). Solvent was then distilled under
vacuum at 40°C to 45°C to obtain 5,6-dimethoxy-1-indanone (73 g) having purity
97.80% by HPLC and 6-hydroxy-5-methoxy-1-indanone impurity was not detected.
Cyclohexane (300 mL) was added to above residue, stirred for 30 minutes at 25°C
10 to 30°C and the resulting suspension was filtered, washed with cyclohexane (100
mL) and dried under vacuum at 50°C to 60°C for 12 hours to afford 5,6-dimethoxy1-indanone (70.0 g) having purity of 98.59% by HPLC.
Example 3: Preparation of 5,6-dimethoxy-1-indanone
A solution of 3-chloro-3',4'-dimethoxypropiophenone (250.0 g) in concentrated
15 sulfuric acid (500 mL) was stirred at 55-59°C for 8 hours under inert atmosphere.
After completion of reaction (monitored by HPLC), resulting solution was cooled to
20-30°C and poured into ice water (1500 mL) at 5-15°C. The temperature of reaction
mixture was then raised to 20-30°C, added dichloromethane (2000 mL) and stirred
for 20-25 minutes. The layers were separated. The aqueous layer was extracted two
20 times consecutively with dichloromethane 750 mL and 500 mL, and aqueous sodium
bicarbonate (10 % w/w, 400 mL) solution was added to the resulting organic layer to
adjust pH 6 to 7. The layers were then separated, and organic layer was washed with
water (750 mL). Solvent was distilled off under vacuum having bath temperature at
45-50°C. Cyclohexane (500 mL) was added to resulting residue and stirred for 30
25 minutes at 25°C to 30°C. The resulting slurry was then filtered, washed with
cyclohexane (125 mL) and the wet material was dried under vacuum at 50-60°C for
17
2 hours to obtain 5,6-dimethoxy-1-indanone having purity of 74.56% by HPLC and
22.15% of 6-hydroxy-5-methoxy-1-indanone impurity.
Above crude 5,6-dimethoxy-1-indanone was dissolved in dichloromethane (1625
mL), added sodium hydroxide (24.91 g) and stirred for 10 minutes at 25-35 °C.
5 Dimethyl sulfate (52.34 g) was added slowly to the reaction mixture at 25-35 °C.
Thereafter, temperature was slowly raised to around 35-45°C and stirred for 10 hours
till the TLC indicated the completion of reaction. The reaction mixture was then
cooled to 20-30°C; added dichloromethane (1625 ml) and water (1500 mL), and
stirring continued for 30 minutes. The layers were then separated, and organic layer
10 was successively washed with 2.5% aqueous sodium hydroxide (1000 mL), water
(3x750 mL) and 20% aqueous sodium chloride (750 mL). The organic layer was
then treated with activated carbon (12.5 g) at 30-35°C, filtered through hyflo bed and
the bed was washed with dichloromethane (125 mL). Solvent was then distilled
under vacuum at 40-45°C.
15 To the above residue, cyclohexane (500 mL) was added and stirred for 30 minutes at
35-45°C. Thereafter, resulting slurry was cooled to 20-30°C, filtered, washed with
cyclohexane (250 mL) and dried under vacuum at 30-40°C for 6 hours to afford 5,6-
dimethoxy-1-indanone (165.4 g; yield 78.72%) having purity of 98.57% by HPLC.
It will be apparent to those skilled in the art that various modifications and variations
20 can be made in the present invention and specific examples provided herein without
departing from the spirit and scope of the invention. Thus, it is intended that the
present invention covers the modifications and variations of this invention that come
within the scope of any claims and their equivalents.

WE CLAIM:

1. A process for the preparation of 5,6-dimethoxy-1-indanone of formula I,
Formula I
comprising the steps of:
a) reacting 3-chloro-3',4'-dimethoxypropiophenone of formula III;
Formula III
5 with an acid;
b) treating the resulting reaction product containing mixture of 5,6-dimethoxy1-indanone of formula I and 6-hydroxy-5-methoxy-1-indanone of formula
IV;
Formula I Formula IV
with a methylating agent in the presence of a base and solvent to obtain 5,6-
10 dimethoxy-1-indanone of formula I ; and
c) isolating pure 5,6-dimethoxy-1-indanone of formula I.
2. The process as claimed in claim 1, wherein in step a), the acid is selected from
sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic
acid, or mixture thereof.
15 3. The process as claimed in claim 1, wherein in step a), the reaction is carried out at
50°C to 65°C for 5 hours to 9 hours.
19
4. The process as claimed in claim 1, wherein in step b), the methylating agent is
selected from the group comprising: methyl iodide, methyl bromide, dimethyl
sulfate, methyl triflate, and dimethyl carbonate.
5. The process as claimed in claim 1, wherein in step b), the base is selected from the
5 group comprising: sodium hydroxide, potassium hydroxide, sodium carbonate,
and potassium carbonate.
6. The process as claimed in claim 1, wherein in step b), the solvent is selected from
the group comprising: dichloromethane, 1,2- dichloroethane, tetrahydrofuran,
dimethoxy ethane, 1,2-diethoxyethane, N,N-dimethylformamide, dimethyl
10 sulphoxide, 1,4-dioxane, toluene, 1,2 xylene, or mixture thereof.
7. The process as claimed in claim 1, wherein the reaction in step b) is carried out at
30°C to 45°C for 5 to 12 hours