NMR DONEPEZIL
Donepezil is one of the most important drugs for
treating Alzheimer's disease and has been approved by FDA in 1996 under
the brand Aricept®.
The conventional method for making donepezil starts
with a reduction reaction by using
(E)-2-((1-benzylpiperidine-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one
(hereinafter denoted as “E2M”) as a precursor, whose structure is as
shown in formula 1.
Donepezil, 2-((1-benzylpiperidine-4-yl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one, has a structure as shown in Formula 2.
With reference to U.S. patent publications
2007/0088055 and 2009/0253746, in these methods the “carbon=carbon”
double bond of E2M is reduced to the “carbon-carbon” single bond of
donepezil with catalyst. The catalysts used in the references are
hydrogen gas (H
2) and palladium (Pd)/aluminum(III) oxide (Al
2O
3),
and hydrogen gas and platinum (Pt)/carbon (C) respectively, both of
which allow hydrogen on the surface of a noble metal, palladium or
platinum reducing the “carbon=carbon” double bond of E2M to the
“carbon-carbon” single bond, resulting in donepezil.
Utilizing the conventional methods not only acutely
raises safety concerns by employing hydrogen for reduction, but also
raises the cost by using the noble metal such as palladium or platinum.
In addition, the reaction times of the inefficient catalyzed reactions
as disclosed in the aforementioned references are respectively 3 hours
and 7 hours.
http://www.google.com/patents/US8552195
Example 1
In
this example a method for preparing E2M, the precursor for making
donepezil, is demonstrated. The method for preparing E2M comprises the
following steps:
1. Obtaining a potassium hydroxide aqueous solution by dissolving sodium hydroxide in water;
2. Adding 1) tetrabutylammonium bromide, 2)
5,6-Dimethoxy-1-indanone, 3) dichloromethane, and 4)
N-benzylpiperidine-4-carboxyaldehyde into the aforementioned potassium
hydroxide aqueous solution to obtain a potassium hydroxide mixture
solution;
3. Heating the potassium hydroxide mixture solution
while stirring to allow reaction for obtaining a heated potassium
hydroxide mixture solution that has an organic layer; and
4. Extracting the organic layer of the heated
potassium hydroxide mixture solution with methylbenzene (toluene) to
obtain a product and crystallizing and filtering the product to obtain
E2M.
In the instant example, the foregoing steps were specifically performed as follows.
1. 11.11 grams or 0.0535 mol of
N-benzylpiperidine-4-carboxyaldehyde having a structure as shown in
Formula 3, and 10 grams or 0.051 mol of 5,6-Dimethoxy-1-indanone having a
structure as shown in Formula 4 were prepared.
13.46 grams or 0.2039 mol of potassium hydroxide
(KOH), 100 ml of water, 8.39 grams or 0.0255 mol of tetrabutylammonium
bromide, and 80 ml of dichloromethane were prepared, wherein the mole
ratio of aforementioned compounds was:
N-benzylpiperidine-4-carboxyaldehyde:5,6-Dimethoxy-1-indanone:potassium hydroxide:tetrabutylammonium bromide=1.05:1:4:0.5.
In a container potassium hydroxide was dissolved in
water, added with tetrabutylammonium bromide, dichloromethane,
N-benzylpiperidine-4-carboxyaldehyde and 5,6-Dimethoxy-1-indanone to
form a mixture, and then the mixture was stirred and heated to allow
reacting at 38 degrees Celsius for 1.5 hours to obtain a heated
potassium hydroxide mixture solution, wherein the tetrabutylammonium
bromide was employed as a phase transfer catalyst.
2. An organic layer was separated from an aqueous
layer of the heated potassium hydroxide mixture solution, washed with 80
ml of water, dehydrated with anhydrous magnesium sulfate, and condensed
and dried.
3. 100 ml of methylbenzene was added to the organic
layer to obtain a mixture. The mixture was stirred and heated to 78
degrees Celsius to allow dissolution and clearance. Gradually the
temperature was lowered to 68 degrees Celsius to allow generation of
crystals. Stirring of the mixture was continued for 30 minutes and the
temperature was further lowered to room temperature. The mixture was
ice-bathed for 2 hours and filtered and a powder was obtained.
With reference to FIG. 1,
by hydrogen-1 NMR analysis the powder is identified as E2M. With the
method as demonstrated in the instant example, the molecular weight of
E2M is 377.5 and the yield of E2M is more than 90% while the purity
thereof reaches 98.551%.
The reaction performed in the instant example is shown in Reaction 1.
Example 2 In this example a
method for making donepezil with E2M is demonstrated. The method for
making donepezil comprises the following steps:
1. Mixing methylbenzene, E2M, sodium hydrogen
carbonate, sodium dithionite and tetrabutylammonium bromide to obtain an
E2M mixture solution;
2. Heating the E2M mixture solution and adding water
to allow reaction for obtaining a heated E2M aqueous solution having a
methylbenzene layer; and
3. Extracting the methylbenzene layer from the
heated E2M aqueous solution, and condensing and drying the methylbenzene
layer to obtain donepezil.
In the instant example, the foregoing steps were specifically performed as follows.
1. At room temperature 1 gram or 0.0026 mol of E2M
powder and 10 ml of methylbenzene were placed into a container, and
further added with 4.01 grams or 0.0472 mol of sodium hydrogen
carbonate, 4.83 grams or 0.0236 mol of sodium dithionite and 0.43 grams
or 0.0013 mol of tetrabutylammonium bromide, wherein the molar ratio of
E2M:sodium hydrogen carbonate:sodium dithionite:tetrabutylammonium
bromide was 1:18:9:0.5.
Methylbenzene, E2M, sodium hydrogen carbonate,
sodium dithionite and tetrabutylammonium bromide were added in the
container, the temperature was raised to 70 degrees Celsius and 20 ml of
water was added at a rate of 5 ml/min, allowing reacting for 60
minutes, and then heating was ceased to stop the reaction to obtain a
heated E2M aqueous solution.
2. A methylbenzene layer was taken out from the
heated E2M aqueous solution, washed with 10 ml of water, and condensed
and dried.
3. A powder was obtained from the condensed and dried methylbenzene layer.
With reference to FIG. 2,
by hydrogen-1 NMR analysis the powder is identified as donepezil. With
the method as demonstrated in the instant example, the molecular weight
of donepezil is 379.5 and the yield of donepezil is more than 85% while
the purity of the donepezil produced reaches 99.756%.
The reaction performed in the instant example is shown in Reaction 2.
The instant example shows that sodium dithionite is a safer reducing
agent than hydrogen gas. Furthermore, sodium dithionite is more stable
in a weak basic environment, which may be provided in the heated E2M
aqueous solution with the addition of sodium hydrogen carbonate in order
to facilitate the reaction. The synthesis reaction is a two-phase
reaction wherein sodium dithionite is dissolved only in an aqueous phase
instead of the organic phase (methylbenzene). E2M is, however, an
organic compound and dissolved only in the organic phase, thus
tetrabutylammonium bromide, the phase transfer catalyst, is added to
allow the reaction. In summary, as shown in the instant example, the
reducing agent, sodium dithionite, employed in the present invention is
low-cost and safe, and the synthesis performed therewith requires only a
short reaction time of 60 minutes.
Example 3 The instant example demonstrates another method for making donepezil with E2M. The method comprises the following steps:
1. Mixing ethyl acetate, E2M, sodium hydrogen
carbonate, sodium dithionite, tetrabutylammonium bromide and water to
obtain an E2M mixture solution;
2. Heating the E2M mixture solution to obtain a heated E2M aqueous solution having an organic layer; and
3. Extracting the organic layer from the heated E2M
aqueous solution, and condensing and drying the organic layer to obtain
donepezil.
In the instant example, the foregoing steps were specifically performed as follows:
1. At room temperature 1 gram or 0.0026 mol of E2M
powder and 15 ml of ethyl acetate were placed into a container, and
further added with 1.35 grams or 0.0159 mol of sodium hydrogen
carbonate, 1.09 grams or 0.0053 mol of sodium dithionite and 0.44 grams
or 0.0013 mol of tetrabutylammonium bromide, wherein the mole ratio of
E2M:sodium hydrogen carbonate:sodium dithionite:tetrabutylammonium
bromide was 1:6:2:0.5.
Ethyl acetate, E2M, sodium hydrogen carbonate and
tetrabutylammonium bromide were added in the container, further added
with 15 ml of water, the temperature was raised to 65 degrees Celsius,
sodium dithionite was added, allowing reacting for 30 minutes and then
heating was ceased to stop the reaction to obtain a heated E2M aqueous
solution.
2. An organic layer was taken out from the heated
E2M aqueous solution, washed with water, dehydrated with anhydrous
magnesium sulfate and then condensed and dried to obtain a powder from
the condensed and dried organic layer.
With the method as demonstrated in the instant
example, the molecular weight of donepezil is 379.5 and the yield of
donepezil is 88% while the purity of the donepezil produced reaches
99.802%.
The reaction performed in the instant example is shown in Reaction 3.
Example 4 The instant example demonstrates another method for making donepezil with E2M. The method comprises the following steps:
1. Mixing isobutanol (isobutyl alcohol or
2-Methylpropan-1-ol), E2M, sodium hydrogen carbonate, sodium dithionite,
tetrabutylammonium bromide and water to obtain an E2M mixture solution;
2. Heating the E2M mixture solution to obtain a heated E2M aqueous solution having an organic layer; and
3. Extracting the organic layer from the heated E2M
aqueous solution, and crystallizing and filtering the organic layer to
obtain donepezil.
In the instant example, the foregoing steps were specifically performed as follows:
1. At room temperature 1 gram or 0.0026 mol of E2M
powder and 15 ml of isobutanol were placed into a container, and further
added with 2.7 grams or 0.0318 mol of sodium hydrogen carbonate, 1.09
grams or 0.0053 mol of sodium dithionite and 0.44 grams or 0.0013 mol of
tetrabutylammonium bromide, wherein the mole ratio of E2M:sodium
hydrogen carbonate:sodium dithionite:tetrabutylammonium bromide was
1:12:2:0.5.
Isobutanol, E2M, sodium hydrogen carbonate and
tetrabutylammonium bromide were added in the container, further added
with 15 ml of water, the temperature was raised to 65 degrees Celsius,
sodium dithionite was added, allowing reacting for 30 minutes and then
heating was ceased to stop the reaction to obtain a heated E2M aqueous
solution.
2. An organic layer was taken out from the heated
E2M aqueous solution, washed with water, dehydrated with anhydrous
magnesium sulfate and then condensed and dried to obtain a powder from
the condensed and dried organic layer.
With the method as demonstrated in the instant
example, the molecular weight of donepezil is 379.5 and the yield of
donepezil is 84.93% while the purity of the donepezil produced reaches
91.178%.
The reaction performed in the instant example is shown in Reaction 4.
The following table 1 demonstrates the advantages of
the present invention in comparison with conventional methods disclosed
in a plurality of prior documents.
|
TABLE 1 |
|
|
|
Method |
|
|
|
3 |
|
5 |
|
|
1 |
2 |
Reaction |
4 |
Price of |
6 |
|
Reagents |
Solvent |
time |
Yield |
reagents |
Purity |
|
|
| Present |
sodium hydrogen |
Methyl |
1 |
hour |
More |
Inexpensive |
99.756% |
| invention |
carbonate, sodium |
benzene/ |
|
|
than |
|
dithionite, |
water |
|
|
85.2% |
|
tetrabutylammonium |
|
bromide |
|
sodium hydrogen |
Ethyl |
0.5 |
hour |
More |
Inexpensive |
99.802% |
|
carbonate, sodium |
acetate/ |
|
|
than |
|
dithionite, |
water |
|
|
88.8% |
|
tetrabutylammonium |
|
bromide |
| EP0296560, |
Hydrogen gas, |
Tetrahydro- |
6 |
hours |
More |
Expensive |
Not |
| U.S. Pat. No. 5,100,901, |
palladium/carbon |
furan |
|
|
than |
|
available |
| U.S. Pat. No. 4,895,841 |
|
|
|
|
82% |
| EP1939178, |
Hydrogen gas, |
Tetrahydro- |
3 |
hours |
More |
Expensive |
99.9% |
| US2007088055, |
palladium/aluminum |
furan |
|
|
than |
| WO2007043440 |
oxide |
|
|
|
90% |
| US2010113793, |
Hydrogen gas, |
Ethyl |
2 |
hours |
More |
Expensive |
99.93% |
| WO2007108011 |
platinum/carbon |
acetate |
|
|
than |
|
|
|
|
|
67% |
| EP1960357, |
Hydrogen gas, |
Ethyl |
7 |
hours |
More |
Expensive |
99.85% |
| WO2007119118, |
platinum/carbon |
acetate |
|
|
than |
| JP2009515945, |
|
|
|
|
47.6% |
| US2009253746 |
|
Example 5 The instant example
demonstrates a method for making a derivate with donepezil made by the
method in accordance with the present invention, e.g., donepezil
hydrochloride. The method for making donepezil hydrochloride comprises
the following steps:
1. Preparing donepezil by any of the methods described in examples 2 to 4;
2. Adding the donepezil into methanol to obtain a donepezil methanol solution;
3. Heating the donepezil methanol solution and
adding concentrated hydrochloric acid to obtain a donepezil
hydrochloride methanol solution; and
4. Adding diisopropyl ether to the donepezil
hydrochloride methanol solution and lowering the temperature of the
solution to facilitate formation of crystals therein, ice-bathing the
solution and then filtering and vacuum-drying the solution to obtain
donepezil hydrochloride.
In the instant example, the foregoing steps were specifically performed as follows:
1. 1.67 grams or 0.0044 mol of donepezil was added
into 1.98 ml of methanol to obtain a mixture and the mixture was heated
to 40 degrees Celsius to dissolve the donepezil in order to obtain a
donepezil methanol solution.
2. 0.6 ml or 0.0053 mol of concentrated hydrochloric
acid was added at the rate of 0.5 mL/min to the donepezil methanol
solution to obtain a mixture. Filtration of the mixture was performed to
obtain a filtered mixture.
3. 32.89 ml of diisopropyl ether was added to the
filtered mixture to obtain a second mixture, the temperature was lowered
at the rate of 3 degrees Celsius per 15 minutes so as to allow
generation of crystals in the second mixture, and stirring of the second
mixture was continued for 30 minutes until the temperature was lowered
to room temperature.
4. The second mixture was ice-bathed at 5 to 10
degrees Celsius for 2 hours, filtration was performed to obtain a filter
cake, the filter cake was washed with an icy solution having
volumetrically equal amount of methanol and diisopropyl ether, and
vacuum-drying was performed to obtain a white powder of donepezil
hydrochloride, whose molecular weight was 416.
With the method as demonstrated in the instant
example, the yield of donepezil hydrochloride is more than 90% while the
purity thereof is 99.637%.
The reaction performed in the instant example is shown in Reaction 5.
Employing sodium dithionite as a reducing agent
improves safety over hydrogen gas used in conventional methods and
lowers the cost in contrast to the conventional noble metal catalysts
that are extremely expensive. Furthermore, the method of the present
invention requires only 60 minutes of reaction time to synthesize
donepezil with a promising yield more than 85%, which greatly raises the
efficiency and economic value of the manufacture of donepezil.
As described above, the method for making donepezil
in accordance with the present invention is capable of overcoming the
shortcomings and mitigating or obviating the problems of the prior art.
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| US7511148 * | Oct 27, 2004 | Mar 31, 2009 | Sandoz Ag | Process for preparing thiazolidinediones |
| US8124783 * | Dec 30, 2004 | Feb 28, 2012 | Jubilant Organosys Limited | Process for producing 1-benzyl-4-[5,6-dimethoxy-1-indanon-2-yl)methyl] piperidine or its salt thereof via novel intermediate |
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