KR20080099007A - Method of preparing donepezil and its intermediate - Google Patents

Abstract

A donepezil and a manufacturing method of an intermediate of the donepezil is provided to produce the donepezil from 5,6-dimethoxy-1-indanone only a process of 2 steps and to improve a yield and a purity by using a safe reagent easy to be searched. A 1-benzyl-4-[(5,6- dimethoxy-1-indanone)-2-ylidenyl] methyl piperidine indicated as a chemical formula (II) is manufactured by dissolving a 5,6-dimethoxy-1-indanone indicated as a chemical formula (III) and a 1-benzyl-4-piperidine-carbo aldehyde indicated as a chemical formula (IV) successively or at the same time in an alcoholic solvent and adding an amine of the catalyst quantity and reacting it with the 5,6-dimethoxy-1-indanone and the 1-benzyl-4-piperidine-carbo aldehyde.

Description

Method of Preparing Donepezil and its Intermediates {Method of Preparing Donepezil and Its Intermediate}

The present invention exhibits an excellent effect in the treatment of mild or moderate dementia in the form of Alzheimer's disease and in the improvement of vascular dementia. Thus, 1-benzyl-4-[(5,6-) represented by the following formula (I) which can be used as a therapeutic agent for dementia: Dimethoxy-1-indanon) -2-yl] methylpiperidine (hereinafter referred to as 'donepezil') and a novel process for the preparation thereof. More specifically, the present invention is an acid or a base of 5,6-dimethoxy-1-indanon represented by the following formula (III) and 1-benzyl-4-piperidine-carboaldehyde represented by the following formula (IV) By reacting with a catalyst, 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by the following formula (II) is easily prepared, which The present invention relates to a method for producing donepezil represented by the following formula (I) by reducing with hydrogen under a palladium hydroxide-carbon catalyst.

Donepezil manufacturing method is Korean Patent Registration No. 46400, US Patent Registration No. 5,606,064, US Patent Registration No. 6,252,081, US Patent Registration No. 6,492,522, International Patent Publication No. 2005/076749, International Patent Publication No. 2005/044805 US Patent Publication No. 2004 / 0143121A, International Patent Publication No. 97/22584, International Patent Publication No. 2005/105742, US Patent Registration No. 6,649,765, and International Patent Publication No. 2005/003092.

Korea Patent Registration No. 46400, the first patent application describing a method for producing donepezil, introduces the synthesis process of donepezil hydrochloride as shown in Scheme 1.

Scheme 1

Synthesis method shown in Scheme 1 is the first method used for the synthesis of donepezil consists of a simple two-step process. That is, as shown in Scheme 1, the patent discloses 5,6-dimethoxy-1-indanon represented by formula (III) and 1-benzyl-4-piperidine-carboaldehyde represented by formula (IV). Reaction with lithium diisopropylamide at low temperature to prepare 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by formula (II) Then, it was reduced with hydrogen under a palladium-carbon catalyst to prepare donepezil hydrochloride represented by the formula (I).

In this method, 1 represented by formula (II) from 5,6-dimethoxy-1-indanon represented by formula (III) and 1-benzyl-4-piperidine-carboaldehyde represented by formula (IV) Lithium diisopropylamide used in the preparation of -benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine is very expensive and dangerous to use. In addition, the reaction must be carried out at a very low temperature of -78 ℃, there is a serious problem that it is difficult to use in the mass production process because many kinds of reagents are used together. Reduction of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by formula (II) with hydrogen using a palladium-carbon catalyst In the process of preparing donepezil hydrochloride represented by the general formula (I), there is a problem that a by-product from which the benzyl group is removed is represented by the following formula (V). Due to these problems, each reaction process requires purification using a silica gel column. Nevertheless, the overall reaction yield was only 50.8%.

U.S. Patent No. 5,606,064 also introduces a process for synthesizing donepezil as shown in Scheme 2.

The U.S. Patent specifically presents a synthesis process of Scheme 2 in the Examples, in which 5,6-dimethoxy-1-indanon represented by the formula (III) is reacted with pyridine-4-aldehyde. 2- (pyridin-4-yl) -methylene-indan-1-one is prepared and reacted with benzyl bromide to yield 1-benzyl-4- (5,6-dimethoxyindan-1-one-2-ylidene ) -Methyl-pyridinium bromide is prepared, and donepezil represented by the formula (I) is prepared by reacting platinum oxide with hydrogen.

Scheme 2

In the synthesis method shown in Scheme 2, a total reaction yield of 58.5% was obtained using a three-step reaction process. This reaction process slightly increased the yield compared to the process according to Scheme 1, and by using a platinum oxide instead of palladium-carbon in the final step it can be more prevented to produce the by-product represented by the formula (V). However, low yields, increased reaction processes, and the use of expensive platinum oxides remain serious problems.

On the other hand, US Patent No. 6,252,081 introduces a method for synthesizing donepezil through a four-step reaction process as shown in Scheme 3. According to the method introduced in Scheme 3, 5,6-dimethoxy-1-indanon represented by the formula (III) is reacted with diethyl carbonate to give 5,6- (dimethoxy) -2- (ethoxy Prepare carbonyl) -indan-1-one and react with 4-pyridylmethyl chloride to produce 5,6-dimethoxy-2- (4-pyridyl) methyl-1-indanone, benzylbromide To 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl] methylpyridinium bromide, which is reacted with hydrogen under a platinum oxide catalyst to hydrochloride salt of donepezil To prepare.

Scheme 3

In Scheme 3, the overall reaction yield could be improved to 75.8% by using a more complex four-step reaction process than the prior arts introduced above. The yield of the reaction has been greatly improved, but the increased reaction process, the use of many kinds of reagents, and the use of expensive platinum oxides remain a problem.

US Pat. No. 6,492,522 introduces methods for producing donepezil through a series of synthetic processes, including intramolecular cyclization. The reaction process shown in Scheme 4 is one of the processes introduced in US Pat. No. 6,492,522 to prepare donepezil represented by the formula (I) through a number of reaction processes as follows. This patent describes that donepezil represented by the formula (I) can be obtained at a high purity of 99.9% in the final stage, but the overall reaction yield is only 59.35%, which is used in too many reaction processes and final stages. Silica gel column purification still remains a serious problem.

Scheme 4

In addition, 5,6-dimethoxy-1-indanon represented by the general formula (III) in International Patent Nos. 2005/076749, International Patent Nos. 2005/044805 and US Patent Application No. 2004/0143121 is used as starting materials. To introduce new methods of producing donepezil. International Patent No. 97/22584 introduces the synthesis of donepezil using an intramolecular cyclization reaction. In addition, International Patent No. 2005/105742, US Patent No. 6,649,765, and International Patent No. 2005/003092 introduce processes for synthesizing donepezil, starting from the intermediates of donepezil in the prior arts. However, these processes still suffer from the problems described above, such as many reaction processes or using expensive reagents.

Scheme 1 described in Korean Patent Registration No. 46400, the first patent application related to the donepezil manufacturing method, is not only a dangerous reagent that is expensive in the first process and difficult to use in production, but also a very low temperature of -78 ° C. The reaction temperature is required. In addition, it contains unwanted impurities in the final step, and these impurities require silica gel purification, and the reaction yield also has a serious problem of low. The publicly known technologies filed after Korean Patent Registration No. 46400 have tried to solve these problems, but the process steps have been greatly increased, and there are still many problems such as the need for expensive reagents or a low yield.

Accordingly, the present inventors have attempted to develop a method for preparing donepezil represented by the formula (I) and intermediates thereof in a higher yield in a simpler manner than known methods.

In particular 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl represented by the formula (II) which is the most useful intermediate for the synthesis of donepezil represented by the formula (I) Since the process of preparing or purifying denyl] methyl piperidine is very complicated or difficult to use for mass production, the present inventors have simplified the preparation and purification process of this reaction step and the desired compound with high purity. The research focused on finding reaction conditions that can be prepared.

As a result, the present inventors reacted 5,6-dimethoxy-1-indanon represented by the formula (III) with 1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV) with an acid or a base catalyst. To easily prepare 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by the formula (II), and palladium hydroxide It has been found that donepezil represented by formula (I) can be easily produced in high yield by reduction with hydrogen under a carbon catalyst. In addition, the newly developed aldol condensation reaction allows 1-benzyl-4-[(5,6) to be represented by the formula (II) in the simplest way without the use of difficult or expensive reagents used in the prior art. It can be found that -dimethoxy-1-indanon) -2-ylideneyl] methyl piperidine can be easily produced in high purity and from which donepezil represented by the formula (I) can be easily produced. there was.

According to the present invention, the chemical formula can be formulated in a higher yield than a known method by using a dangerous reagent such as lithium diisopropylamine or a single step without requiring a separate separation process without reacting at a very low temperature of -78 ° C. 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine, which is an intermediate of donepezil represented by (II), can be prepared. Further, according to the present invention, the intermediate compound represented by the formula (II) is reduced to atmospheric hydrogen under a palladium hydroxide-carbon catalyst to prepare donepezil represented by the formula (I) in high yield. It is possible to perform a simple and economical reduction process in which little by-products represented by V) are produced.

The present invention is to provide a new method for producing donepezil that can be used as a treatment for dementia by showing an excellent effect on the treatment of mild, moderate dementia of the Alzheimer's type and improvement of vascular dementia.

Another object of the present invention is a key intermediate of donepezil in a one-step reaction without separate separation process, without using reagents or conditions that are difficult to use in mass production processes or complex multiple processes, unlike the known art. It is to provide a method for preparing benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine.

Another object of the present invention is to provide a method for producing donepezil, unlike known techniques, which produces little by-products without using expensive catalysts such as platinum oxides.

Another object of the present invention is to provide a method for producing donepezil in high purity and high yield more simply and economically.

Another object of the present invention is to provide a method suitable for the preparation of donepezil and its intermediate compounds in large quantities.

The above and other objects of the present invention can be achieved by the present invention described below.

The present invention relates to 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylideneyl represented by donepezil represented by formula (I) and intermediates thereof (II). It relates to a process for preparing methyl piperidine.

The process for preparing 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine as an intermediate of donepezil according to the present invention is shown in Scheme 5 and Scheme 6 and the process for preparing the final product donepezil can be plotted as in Scheme 7 below.

Scheme 5

Scheme 6

Scheme 7

As shown in Schemes 5 and 6, 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylidenyl] methyl represented by formula (II), which is a key intermediate of donepezil Piperidine simultaneously or sequentially with 5,6-dimethoxy-1-indanon represented by the formula (III) and 1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV) in an alcoholic solvent It can be prepared by dissolving and reacting by adding a catalytic amount of amine or by dissolving simultaneously or sequentially in xylene and by adding arylsulfonic acid.

On the other hand, donepezil represented by formula (I) is 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl represented by formula (II) as shown in Scheme 7. Denyl] methyl piperidine can be prepared by reacting hydrogen at atmospheric pressure in the presence of a palladium hydroxide-carbon catalyst in the reaction solvent.

In the following, the present invention is described in more detail.

1-benzyl-4-[(5,6- Dimethoxy -One- Indanon )-2- Ilidenyl ] methyl  Piperidine ( II ) Manufacturing process 1

In one embodiment of the present invention, as shown in Scheme 5, 5,6-dimethoxy-1-indanon represented by the formula (III) under an alcoholic solvent and 1-benzyl-4-pi represented by the formula (IV) Ferridine-carboaldehyde is dissolved simultaneously or sequentially and reacted with the addition of a catalytic amount of amine to react with 1-benzyl-4-[(5,6-dimethoxy-1-) represented by formula (II) which is a key intermediate of donepezil. Indanone) -2-yridenyl] methyl piperidine is prepared.

Alcoholic solvents used in the reaction are methanol, ethanol, isopropanol, and the higher the polarity of the solvent, the higher the reaction yield. Hence the most polar methanol is most preferred.

1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV) is preferably used in an amount of 0.9 to 1.1 equivalents, preferably 5,6-dimethoxy-1-indanon represented by the formula (III). Preferably used in equivalence.

The reaction temperature is the boiling point of the solvent, and the reaction time is between 12 hours and 24 hours.

Amines are pyrrolidine, piperidine, 1-methylpyrrolidine, 1-methylpiperidine, triethylamine, N, N-diisopropylethylamine, pyridine and the like, preferably pyrrolidine or pyridine Secondaryalkylamines such as ferridine, more preferably pyrrolidine. The amount of the amine used is 0.05 equivalents to 0.2 equivalents, more preferably 0.1 equivalents to 5,6-dimethoxy-1-indanon represented by the formula (III).

1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by the formula (II) obtained through the reaction as described above was used as the reaction solution. After cooling to crystallization it may be recovered by filtration.

According to the present invention, 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by formula (II) is represented by formula (III) It can be prepared in high yield and high purity from 5,6-dimethoxy-1-indanon and 1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV). In particular, the present invention not only does not use reagents such as lithium diisopropylamide, which are difficult to use in mass production processes, but also 1-benzyl-4-[(5,6-) represented by formula (II) in only one step process. Dimethoxy-1-indanon) -2-ylideneyl] methyl piperidine can be prepared in a relatively high yield, it can be obtained in high purity without a separate purification process.

Although the aldol condensation reaction using an amine and an alcoholic solvent is generally well known, the prior art represented by Scheme 1 used lithium diisopropylamide, which was expected to have a better result at the level of ordinary skill in the art. There was a downside to this being difficult to use. However, the inventors have found that by using an amine and an alcoholic solvent, 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylidenyl] methyl piperidine represented by the formula (II) It can be produced with significantly improved yield and purity compared to the prior art.

1-benzyl-4-[(5,6- Dimethoxy -One- Indanon )-2- Ilidenyl ] methyl  Piperidine ( II ) Manufacturing process 2

In another embodiment of the present invention, as shown in Scheme 6, 5,6-dimethoxy-1-indanon represented by formula (III) in xylene solvent and 1-benzyl-4- represented by formula (IV) Piperidine-carboaldehyde was dissolved simultaneously or sequentially and refluxed by addition of arylsulfonic acid to yield 1-benzyl-4-[(5,6-dimethoxy-1-) represented by formula (II) which is an intermediate of donepezil. Indanone) -2-yridenyl] methyl piperidine is prepared.

1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV) is preferably used in an amount of 0.9 to 1.1 equivalents, preferably 5,6-dimethoxy-1-indanon represented by the formula (III). Preferably used in equivalence.

The reaction temperature is the boiling point of the solvent, and the reaction time is between 10 hours and 30 hours.

Aryl sulfonic acid is p-toluenesulfonic acid, benzenesulfonic acid, etc., Most preferably, it is p-toluenesulfonic acid. The use amount of arylsulfonic acid is used in the amount of 1 to 2 equivalents based on 5,6-dimethoxy-1-indanone represented by the general formula (III), more preferably 1.2 to 1.5 equivalents.

The product obtained by the above method was cooled to room temperature, and then added with a solvent such as dichloromethane and an aqueous sodium bicarbonate solution to extract the organic layer, and then concentrated and added by a conventional recrystallization method using isopropanol and n-hexane. Can be purified.

According to the present invention, 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by formula (II) is represented by formula (III) From 5,6-dimethoxy-1-indanon and 1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV) in a relatively high yield of up to 60%. In particular, the present invention not only does not use lithium diisopropylamide, which is difficult to use in mass production processes, but also 1-benzyl-4-[(5,6-dimethy) represented by formula (II) in only one step process. Methoxy-1-indanon) -2-ylydenyl] methyl piperidine can be prepared in a relatively high yield. In addition, in the case of the aldol condensation reaction using an acid catalyst, toluene is generally used as a reaction solvent. However, when preparing the donepezil intermediate, when toluene is used as the solvent, the compound is hardly produced. As a result of changing the reaction solvent to xylene, the reaction yield was found to increase dramatically and the present invention was completed.

Of Donepezil (I)  Manufacture process

In the present invention, as shown in Scheme 7, 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by the formula (II) is reacted. Donepezil, represented by Formula (I), is prepared by dissolving in a solvent and reacting under normal pressure hydrogen gas in the presence of palladium hydroxide-carbon.

The reaction solvent is a solvent that does not react with hydrogen, and may include ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane; Alcohols such as methanol, ethanol, propanol, isopropanol; Halogenated hydrocarbons such as dichloromethane, trichloromethane, dichloroethane; Acetone, acetonitrile or dimethylformamide, of which tetrahydrofuran is most preferred.

The amount of palladium hydroxide-carbon used as a catalyst is 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylidenyl] methyl piperi, represented by the formula (II). It is used in the range of 1% to 20% by weight of the Dean.

Reaction temperature is 0-50 degreeC, Preferably it is 15-30 degreeC. The reaction time is 1 hour to 5 hours, preferably 2 hours to 3 hours.

The reaction solution obtained by the above method was filtered through celite, concentrated, ethyl acetate and water were added to extract the organic layer, and then concentrated to obtain the desired donepezil represented by the formula (I).

In addition, hydrochloric acid gas or 10% hydrochloric acid solution was added to ethyl acetate solution of donepezil according to a known method to obtain crystals by vacuum concentration, and the crystals were recrystallized from ethanol / isopropyl ether to obtain high purity and high yield of donepezil hydrochloride. (The yield of donepezil hydrochloride is 92%) easily.

According to the present invention, donepezil represented by formula (I) is 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylidenyl] methyl represented by formula (II). It can be easily prepared from piperidine in a very high yield of 97%. In particular, it has the advantage of preventing the production of by-products represented by the formula (V) without the benzyl group often obtained in the prior art donepezil manufacturing process without using expensive platinum oxide which is difficult to use in mass production process. have.

The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection defined by the appended claims.

Example

Example 1: 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine ( II)  Produce

After dissolving 38.44 g (0.20 mol) of 5,6-dimethoxy-1-indanone in 300 ml of methanol, 40.65 g (39.63 ml, 0.20 mol) of 1-benzyl-4-piperidine-carboaldehyde and pyrroli 2.84 g (3.34 mL, 0.04 mol) of Dean was added to reflux for 20 hours. After the reaction was completed, the reaction solution heated by the reflux process was cooled to 0 ℃ and stirred for 1 hour. The resulting crystals were filtered, washed with 200 ml of methanol and dried to give 62.02 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine. . The yield obtained was 82.15%.

1 H NMR (CDCl ₃ ) δ = 1.60 to 1.72 (4H, m) 2.02-2.09 (2H, dt), 2.33 (1H, m), 2.91 to 2.94 (2H, bd), 3.48 (2H, s), 3.59 ( 2H, s), 3.92 (3H, s), 3.97 (3H, s), 6.64-6.68 (1H, td), 6.89 (1H, s), 7.22-7.33 (6H, m)

Example 2: 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine ( II)  Produce

After dissolving 38.44 g (0.20 mol) of 5,6-dimethoxy-1-indanone in 300 ml of ethanol, 40.65 g (39.63 ml, 0.20 mol) of 1-benzyl-4-piperidine-carboaldehyde and pyrroli 2.84 g (3.34 mL, 0.04 mol) of Dean was added to reflux for 20 hours. After the reaction was completed, one third of the reaction solvent was distilled off, and the reaction solution heated by reflux was cooled to room temperature. The resulting crystals were filtered, washed with 200 ml of ethanol and dried to give 48.70 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylidenyl] methyl piperidine. . The yield obtained was 64.51%.

1 H NMR (CDCl ₃ ) δ = 1.60 to 1.72 (4H, m) 2.02-2.09 (2H, dt), 2.33 (1H, m), 2.91 to 2.94 (2H, bd), 3.48 (2H, s), 3.59 ( 2H, s), 3.92 (3H, s), 3.97 (3H, s), 6.64-6.68 (1H, td), 6.89 (1H, s), 7.22-7.33 (6H, m)

Example 3: 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine ( II)  Produce

After dissolving 38.44 g (0.20 mol) of 5,6-dimethoxy-1-indanone in 500 ml of xylene, 40.65 g (39.63 ml, 0.20 mol) of 1-benzyl-4-piperidine-carboaldehyde and p 53.26 g (0.28 mol) of toluenesulfonic acid monohydrate was added and refluxed for 24 hours. After the reaction was completed, the reaction solution heated by the reflux process was cooled to room temperature, and 300 ml of 10% aqueous sodium carbonate solution was slowly added. The reaction solution was extracted twice with 500 ml of dichloromethane, and the separated organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The solvent was removed, and the remaining oily solution was dissolved in 200 ml of isopropanol, and then 700 ml of hexane was slowly added. The resulting crystals were filtered off, washed with 100 ml of a 2: 7 mixed solution of isopropanol and hexane and dried to yield 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylideneyl. ] 42.32 g of methyl piperidine was obtained. The yield obtained was 56.05%.

1 H NMR (CDCl ₃ ) δ = 1.60 to 1.72 (4H, m) 2.02-2.09 (2H, dt), 2.33 (1H, m), 2.91 to 2.94 (2H, bd), 3.48 (2H, s), 3.59 ( 2H, s), 3.92 (3H, s), 3.97 (3H, s), 6.64-6.68 (1H, td), 6.89 (1H, s), 7.22-7.33 (6H, m)

Example  4: 1-benzyl-4-[(5,6- Dimethoxy -One- Indanon )-2 days] Methylpiperidine  Preparation of (I)

After dissolving 75.49 g (0.20 mol) of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine in 500 ml of tetrahydrofuran, palladium hydroxide 7.54 g of side-carbon and hydrogen gas at atmospheric pressure were added thereto, followed by stirring for 3 hours. After the reaction was completed, insoluble materials were removed by filtration through celite, and the filtrate was distilled under reduced pressure to give a white solid of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl] 73.64 g of methylpiperidine was obtained. The yield of solids was 97.02%.

1 H NMR (CDCl ₃ ) δ = 1.27 to 1.42 (3H, m) 1.42 to 1.55 (1H, m), 1.63 to 1.77 (2H, m), 1.87 to 2.03 (3H, m), 2.66 to 2.74 (2H, m) ), 2.86-2.94 (2H, m,), 3.23 (1H, dd, J = 8 Hz, J = 17.6 Hz), 3.50 (2H, s), 3.90 (3H, s), 3.96 (3H, s), 6.85 (1H, s), 7.17 (1H, s), 7.22-7.73 (5H, m)

Reference Example  1: 1-benzyl-4-[(5,6- Dimethoxy -One- Indanon )-2 days] Methylpiperidine  Preparation of Hydrochloride

Dissolve 73.64 g (0.19 mol) of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylideneyl] methyl piperidine in 500 ml of ethyl acetate, and then add hydrochloric acid gas. Stir for 1 hour. After the reaction was completed, the resulting crystals were filtered and washed with 200 ml of ethyl acetate to obtain the crystals. The obtained crystals were recrystallized from 800 ml of ethanol and 350 ml of isopropanol to give 74.25 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yl] methylpiperidine hydrochloride as white crystals. Got. The yield of the crystal was 91.01%.

1 H NMR (CDCl ₃ ) δ = 1.49 to 1.57 (1H, m) 1.76 to 1.89 (2H, m), 1.89 to 2.06 (1H, m), 2.06 to 2.18 (3H, m), 2.58 to 2.63 (4H, m) ), 3.28 (1H, dd, J = 7.6 Hz, J = 17.2 Hz), 3.42-3.51 (2H, m), 3.89 (3H, s), 3.95 (3H, s), 4.17-4.19 (2H, m) , 6.84 (1H, s), 7.11 (1H, s), 7.45 (3H, m), 7.63 (2H, br-s), 12.4 (1H, m)

The present invention simultaneously or sequentially dissolves 5,6-dimethoxy-1-indanon represented by the formula (III) and 1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV) in an alcoholic solvent. 1-benzyl-4-[(5) represented by formula (II) which is a key intermediate of donepezil, and reacted by adding a catalytic amount of amine, or by simultaneously or sequentially dissolving in xylene, and reacting with arylsulfonic acid. , 6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine was prepared, and the intermediate compound 1-benzyl-4-[(5,6-dimethoxy-1-indanonone It is effective to provide a method for producing donepezil by reacting a) -2-yldenyl] methyl piperidine with hydrogen at atmospheric pressure in the presence of a palladium hydroxide-carbon catalyst in a reaction solvent.

Prior art related to the preparation of donepezil involves the use of hazardous reagents such as lithium diisopropylamide at very low temperatures of -78 ° C, or use of very expensive platinum oxide and many reaction processes. It has a variety of problems, such as providing low yield products and producing unwanted byproducts. However, the present invention not only can produce donepezil from the 5,6-dimethoxy-1-indanon represented by the formula (III) in a two-step process but also uses a safe and easy-to-use reagent that is easy for mass production. This has the advantage of greatly improving the yield and purity of donepezil. In particular, the present invention shows the highest reaction yield despite being composed of a simpler reaction process than any prior art, thereby providing a drastically improved process for producing donepezil. The total synthetic yield of donepezil according to the present invention is 75 to 81%, the total synthetic yield of donepezil hydrochloride reaches 73 to 77%.

Simple modifications and variations of the present invention can be readily understood by those skilled in the art, and all such variations or modifications can be considered to be included within the scope of the present invention.

Claims (10)

5,6-dimethoxy-1-indanon represented by the formula (III) and 1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV) are dissolved simultaneously or sequentially in an alcoholic solvent, and the catalytic amount To react with the addition of an amine to produce 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by the formula (II).

5,6-dimethoxy-1-indanon represented by the formula (III) and 1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV) are simultaneously or sequentially dissolved in xylene, and aryl A method of producing 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by the formula (II) by reacting with sulfonic acid.

5,6-dimethoxy-1-indanon represented by the formula (III) and 1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV) are dissolved simultaneously or sequentially in an alcoholic solvent, and the catalytic amount React with addition of an amine to prepare 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by formula (II), and 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by the formula (II) in the reaction solvent is palladium hydroxide-carbon catalyst A process for producing donepezil represented by the formula (I) by reacting with hydrogen at ordinary pressure in the presence of.

5,6-dimethoxy-1-indanon represented by the formula (III) and 1-benzyl-4-piperidine-carboaldehyde represented by the formula (IV) are simultaneously or sequentially dissolved in xylene, and aryl React with addition of sulfonic acid to prepare 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by formula (II), and 1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine represented by the formula (II) in the reaction solvent is palladium hydroxide-carbon catalyst A process for producing donepezil represented by the formula (I) by reacting with hydrogen at ordinary pressure in the presence of.

1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-yridenyl] methyl piperidine, represented by the formula (II), was reacted with a palladium hydroxide-carbon catalyst in a reaction solvent. A process for producing donepezil represented by the formula (I) by reacting with hydrogen at atmospheric pressure in the presence.

The solvent according to any one of claims 3 to 5, wherein the reaction solvent is a solvent which does not react with hydrogen, an ether selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane; Alcohols selected from methanol, ethanol, propanol, isopropanol; Halogenated hydrocarbons selected from dichloromethane, trichloromethane, dichloroethane; A process selected from acetone, acetonitrile, or dimethylformamide. The method according to any one of claims 3 to 5, wherein the amount of the palladium hydroxide-carbon catalyst is represented by formula (II) 1-benzyl-4-[(5,6-dimethoxy-1 -Indannon) -2-ylideneyl] methyl piperidine in the range of 1% to 20% by weight. The method of claim 1 or 3, wherein the alcoholic solvent is methanol, ethanol, or isopropanol. The method of claim 1 or 3, wherein the amine is pyrrolidine, piperidine, 1-methylpyrrolidine, 1-methylpiperidine, triethylamine, N, N-diisopropylethylamine, or It is selected from pyridine, and the amount of amine used is 0.05 equivalent to 0.2 equivalent based on 5,6-dimethoxy-1-indanone represented by general formula (III). The method of claim 2 or 4, wherein the arylsulfonic acid is p-toluenesulfonic acid or benzenesulfonic acid, and the amount of the arylsulfonic acid is 1 to 5,6-dimethoxy-1-indanone represented by the formula (III). The preparation method used for 2 equivalent.