NMR DONEPEZILDonepezil 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.
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.
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.
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.
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.
| 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 | |||||||
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.
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.
Patent Citations
| Cited Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| US7332606 * | Oct 12, 2006 | Feb 19, 2008 | Eisai R&D Management Co., Ltd. | senile dementias; subjecting 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methyl-piperidine or a solvate thereof to catalytic hydrogenation in the presence of a palladium-alumina catalyst |
| 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 |
| US20090253746 * | Nov 14, 2006 | Oct 8, 2009 | Nuria Soldevilla Madrid | Synthesis and Preparations of Intermediates and New Polymorphs Thereof Useful For The Preparation Of Donepezil Hydrochlcoride |
| US20100022615 * | Sep 14, 2007 | Jan 28, 2010 | Onconova Therapeutics, Inc | Activated cytotoxic compounds for attachment to targeting molecules for the treatment of mammalian disease conditions |
No comments:
Post a Comment