JP7452810B2 - Method for producing donepezil by flow reaction using immobilized catalyst - Google Patents

Description

Application of Article 30, Paragraph 2 of the Patent Act March 1, 2019 Chemical Society of Japan 99th Spring Annual Meeting (2019) Lecture Proceedings DVD “Development of Atom-economical C-C and C-N Bond Forming Reactions for Flow Fin e Published as a lecture paper on ``Synthesis.'' March 1, 2019 Published as a lecture paper in the 99th Spring Annual Meeting of the Chemical Society of Japan (2019) Lecture Proceedings DVD ``Development of continuous flow synthesis method for donepezil by aldol condensation and aromatic ring hydrogenation''. Published on March 16, 2019 at the 99th Spring Annual Meeting of the Chemical Society of Japan (2019), lecture number 1F4-25. Published on March 16, 2019 at the 99th Spring Annual Meeting of the Chemical Society of Japan (2019), lecture number 1F4-27. March 26, 2019 American Chemical Society Organic Process Research & Development website “https://pubs.acs.org/doi/10.1021/acs.oprd.9b00 It was released through ``048''.

The present invention relates to a method for producing donepezil, which comprises an aldol condensation step and a hydrogenation step, and in which at least one of the aldol condensation step and the hydrogenation step is performed continuously by a flow method using a reactor in which a catalyst is immobilized. .

Donepezil hydrochloride is an acetylcholinesterase inhibitor used to treat Alzheimer's disease, and is sold in Japan under the product name "Aricept."

Donepezil hydrochloride is represented by the chemical name (2RS)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydro-1H-inden-1H-one hydrochloride. The structural formula is represented by the following formula (I).

A typical production scheme of donepezil hydrochloride described in patent documents is shown below.

A typical method for producing donepezil hydrochloride that has been reported so far is as shown in the above production scheme. First, 5,6-dimethoxy-1-indanone represented by formula (III) and formula (IV ) 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2- Donepezil represented by formula (II) is obtained by obtaining [ylidene]methylpiperidine and performing a hydrogenation reaction. By adding hydrochloric acid to donepezil, donepezil hydrochloride represented by formula (I) can be obtained.

In US Pat. No. 4,895,841 (Patent Document 1) and Patent No. 5,001,151 (Patent Document 2), an aldol condensation reaction using 5,6-dimethoxy-1-indanone and 1-benzyl-4-formylpiperidine, It is carried out in a homogeneous reaction using an organometallic base such as lithium diisopropylamide (LDA) and sodium methoxide/methanol solution to produce 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]. A method of making methylpiperidine is disclosed. Also, Navanath Niphade et al., "An Improved and Efficient Process for the Production of Donepezil Hydrochloride: Substitution of Sodium Hydroxide for n-Butyl Lithium via Phase Transfer Catalysis", Org. Process Res. Dev., 2008, 12 (4) , pp 731-735 (Non-Patent Document 1), sodium hydroxide was reacted in a mixed solvent system of water and toluene or dichloromethane in the presence of a phase transfer catalyst (PTC) such as tetrabutylammonium bromide (TBAB). It has been proposed to carry out the aldol condensation reaction using Furthermore, in these production methods, the intermediate is isolated after each reaction is completed, and the next step is performed.

In International Publication No. 2007/108011 (Patent Document 3) and International Publication No. 2007/043440 (Patent Document 4), 1-benzyl-4-[(5,6-dimethoxy- A method for producing donepezil by hydrogenating 1-indanone)-2-ylidene]methylpiperidine is disclosed.

U.S. No. 4,895,841 Patent No. 5001151 International Publication No. 2007/108011 International Publication No. 2007/043440

Navanath Niphade et al., "An Improved and Efficient Process for the Production of Donepezil Hydrochloride: Substitution of Sodium Hydroxide for n-Butyl Lithium via Phase Transfer Catalysis", Org. Process Res. Dev., 2008, 12 (4), pp 731-735

Up until now, donepezil has been manufactured by performing an aldol condensation reaction and a hydrogenation reaction, but the aldol condensation reaction requires complicated operations such as neutralization of bases, liquid separation, crystallization, and extraction of crystals. Since the hydrogenation reaction uses a metal catalyst such as palladium or platinum, a separation operation is required. Furthermore, since the hydrogenation reaction is generally carried out under pressurized conditions, it is difficult to control the reaction, and there is a problem in that debenzylated products, which are overreaction products, are produced.

The production of donepezil disclosed so far has been carried out by a batch method, and since the batch size affects the production amount, it is difficult to adjust the production amount. In addition, the batch method has a problem in that the larger the production scale, the more difficult it becomes to control the temperature.

Therefore, there is currently a need for a method for producing donepezil that is simpler, allows the reaction to be easily controlled, and allows the production amount to be easily adjusted.

The present invention solves these problems, and allows production in the required amount at the required time while precisely controlling the reaction time and temperature. The purpose of the present invention is to provide a method for producing donepezil that can significantly reduce labor and working time because separation and purification steps can be omitted.

As a result of intensive research to solve this problem, the present inventor has found that the following formula (II)

A method for producing donepezil represented by the following formula (III)

5,6-dimethoxy-1-indanone represented by and the following formula (IV)

The following formula (V) is obtained by carrying out an aldol condensation reaction with 1-benzyl-4-formylpiperidine represented by

an aldol condensation step to obtain 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine, and 1-benzyl-4-[(5,6-dimethoxy- a hydrogenation step of hydrogenating 1-indanone)-2-ylidene]methylpiperidine to obtain donepezil represented by the above formula (II), and at least one of the aldol condensation step and the hydrogenation step. discovered a method for producing donepezil continuously using a flow method using a reactor with an immobilized catalyst.

In the method for producing donepezil of the present invention, the catalyst used in the aldol condensation step is preferably a basic resin, and the basic resin is more preferably a resin crosslinked with a crosslinking agent. Furthermore, the catalyst used in the aldol condensation step is preferably a resin into which a tertiary amino group or a quaternary ammonium group is introduced, and a dialkylamino group, a trialkylammonium group, or a dialkyl alcohol ammonium group is introduced. It is more preferably a resin, and even more preferably a resin into which a dimethylamino group, a trimethylammonium group, or a dimethylethanolammonium group has been introduced, and a resin into which a dimethylamino group, a trimethylammonium group, or a dimethylethanolammonium group has been introduced, and divinylbenzene. A polystyrene resin or a polyacrylic acid ester resin crosslinked with divinylbenzene is even more preferred, and a polystyrene resin crosslinked with divinylbenzene is particularly preferred. .

In the method for producing donepezil of the present invention, the catalyst used in the hydrogenation step is preferably at least one selected from the group consisting of palladium-based catalysts, platinum-based catalysts, and nickel-based catalysts, and dimethylpolysilyl-palladium alumina , dimethylpolysilyl-palladium silica gel, platinum carbon, platinum alumina, and dimethylpolysilyl-platinum carbon.

In the method for producing donepezil of the present invention, a first reactor for performing the aldol condensation reaction and a second reactor for performing the hydrogenation reaction are connected, and the aldol condensation step is performed in the first reactor. 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine obtained by continuously carrying out the above by a flow method is provided to the second reactor, and the second reaction Preferably, the hydrogenation step is carried out continuously in the reactor by a flow method.

According to the present invention, the required amount can be produced when required while precisely controlling the reaction time and temperature, and post-reaction neutralization, separation operations, isolation of intermediates, and purification steps can be omitted. Therefore, it is possible to provide a method for producing donepezil that can significantly reduce labor force and working time.

FIG. 1 is a flowchart showing the case of producing donepezil hydrochloride using an example of the method for producing donepezil of the present invention. FIG. 2 is a flowchart showing the case of producing donepezil hydrochloride by a conventional batch method, and FIG. 2(a) shows the process up to obtaining donepezil intermediate according to Example 1 of Patent No. 5001151 (Patent Document 2). and FIG. 2(b) shows the process up to obtaining donepezil hydrochloride using a donepezil intermediate according to Example 1 of International Publication No. 2007/043440 (Patent Document 4).

Hereinafter, embodiments according to the present invention will be described, but the present invention is not limited thereto.

As shown in the reaction scheme below, the present invention provides a method for producing donepezil represented by the following formula (II), comprising: 5,6-dimethoxy-1-indanone represented by the following formula (III); 1-Benzyl-4-[(5,6-dimethoxy-1-indanone) represented by the following formula (V) is obtained by subjecting 1-benzyl-4-formylpiperidine represented by the formula (IV) to an aldol condensation reaction. -2-ylidene]methylpiperidine (step A in the reaction scheme below) and 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine with hydrogen. a hydrogenation step (step B in the reaction scheme below) to obtain donepezil represented by the above formula (II) through a reaction, and at least one of the aldol condensation step and the hydrogenation step (i.e., the following reaction In the scheme, only step A, only step B, or both steps A and B) are performed continuously by a flow method using a reactor with an immobilized catalyst (by flow reaction using an immobilized catalyst). This is a method for producing donepezil. Here, the "flow method" refers to a method in which a substance continuously flows into a reactor and a product continuously flows out from the reactor. Furthermore, "immobilizing the catalyst" means that the catalyst itself is not dissolved in the liquid phase, but a solid catalyst is supported (preferably packed) in the internal space of the reactor so that the reaction is catalyzed on the surface of the solid phase. refers to something. In the present invention, the target product is donepezil, which is a base, and by adding hydrochloric acid to it, donepezil hydrochloride, which is sold in Japan under the product name "Aricept", can be produced.

Here, FIG. 1 is a flowchart showing a case where donepezil hydrochloride is manufactured using an example of the donepezil manufacturing method of the present invention. FIG. 1 shows Example 1, which will be described later, and exemplifies a case where both step A and step B are performed continuously by a flow method. In the example shown in FIG. 1, the step of starting the flow reaction to the step of collecting the reaction liquid corresponds to the method for producing donepezil of the present invention, and donepezil is produced through these two steps. In the example shown in FIG. 1, donepezil hydrochloride is finally produced using the obtained donepezil.

On the other hand, FIG. 2 is a flowchart showing the case of producing donepezil hydrochloride by a conventional batch method, and FIG. The process up to obtaining (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine represented by formula (V)) is shown. As shown in Figure 2(a), in the batch method, (1 ) Preparation, (2) Stirring, (3) Elevating temperature, (4) Dripping, (5) Reaction, (6) Cooling, (7) Collection by filtration, (8) Washing of crystals with water, (9) Washing with methanol. It is necessary to go through the steps of crystal washing and (10) drying.

FIG. 2(b) shows donepezil intermediate (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene] according to Example 1 of WO 2007/043440 (Patent Document 4)). methylpiperidine) to obtain donepezil hydrochloride. As shown in Figure 2(b), in the batch method, donepezil is obtained from 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine by hydrogenation reaction. It is necessary to go through the steps of (11) charging, (12) hydrogen substitution, (13) reaction, and (14) filtration.

As is clear from comparing Figures 1 and 2, according to the method for producing donepezil of the present invention, post-reaction neutralization, separation operations, intermediate isolation, and purification steps that are required in the batch method can be omitted. Compared to the batch method, donepezil can be produced with a significantly fewer number of steps, and the labor force and working time can be significantly reduced. Furthermore, the method for producing donepezil of the present invention has the advantage that it can be produced in the required amount at the required time while precisely controlling the reaction time and temperature.

[1] Aldol condensation step (Step A)
In the method for producing donepezil of the present invention, when the aldol condensation step (Step A) is performed continuously by a flow method using a reactor in which a catalyst is immobilized, 5,6-dimethoxy-1-indanone and 5,6-dimethoxy-1-indanone are used as the raw material solution. It is preferable to use 1-benzyl-4-formylpiperidine completely dissolved in a solvent and to send the liquid at a constant flow rate, but it is more preferable to use a liquid sending pump to send the liquid.

The concentration of the raw material solution should be below the concentration at which the raw material dissolves, but 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine may precipitate in the system. Because of its properties, it is preferably 0.5M or less, more preferably 0.01 to 0.2M, and particularly preferably 0.1M.

The equivalent of 1-benzyl-4-formylpiperidine relative to 5,6-dimethoxy-1-indanone is preferably within the range of 0.8 to 2 equivalents, and preferably within the range of 1.0 to 1.2 equivalents. is more preferable, and particularly preferably within the range of 1.05 to 1.1 equivalents. If the equivalent of 1-benzyl-4-formylpiperidine to 5,6-dimethoxy-1-indanone is less than 0.8 equivalent, unreacted 5,6-dimethoxy-1-indanone remains and impurities occur. In addition, if the equivalent of 1-benzyl-4-formylpiperidine to 5,6-dimethoxy-1-indanone exceeds 2 equivalents, unreacted 1-benzyl-4-formylpiperidine There is a risk that impurities may increase.

The solvent used for the raw material solution is not particularly limited, as long as it is an organic solvent used in general organic synthesis reactions, but examples include 1-benzyl-4-[(5,6-dimethoxy-1- Indanone)-2-ylidene]methylpiperidine has high solubility in toluene and tetrahydrofuran, and as described below, when a basic resin is used as a catalyst in the aldol condensation step, the basic resin swells with the alcohol solvent. It is preferable to use toluene, tetrahydrofuran, and alcoholic solvents alone or as a mixed solvent because they are activated. Furthermore, as will be described later, when a basic resin is used as a catalyst in the aldol condensation step, the degree of swelling of the resin can be controlled, and the effect of water improves the activity and life of the resin catalyst. , the solvent may contain water. When the solvent contains water, the amount is preferably 0.1 to 20% (v/v), more preferably 1 to 10% (v/v), and more preferably 2 to 5% (v/v). v), particularly preferably 2% (v/v).

When the aldol condensation step (Step A) is performed continuously by a flow method using a reactor in which a catalyst is immobilized, the amount of raw material solution to be fed depends on the amount of catalyst used for the aldol condensation reaction, the volume of the reactor, etc. Depending on the situation, an arbitrary amount of liquid may be sent, and there is no particular restriction.

The reactor used to carry out the aldol condensation reaction must have an inlet and an outlet that communicate the inner space and the outer space of the reactor so that the reaction can be carried out continuously by the flow method. Although its shape is not particularly limited, it is preferable to use a cylindrical reactor, and commercially available columns such as those exemplified in the Examples described later can be suitably used. The material of the reactor is not particularly limited as long as it has resistance to the solvent used, but stainless steel or glass is preferred.

When the aldol condensation step (Step A) is performed continuously by a flow method using a reactor in which a catalyst is immobilized, the reactor may have an inlet and an outlet in either direction to feed the liquid. . A tube for feeding the liquid (liquid feeding tube) is attached to the inlet and outlet of the reactor, and the material of the liquid feeding tube is not particularly limited as long as it is resistant to the solvent used. , polytetrafluoroethylene (PTFE) or stainless steel are preferred.

The reaction temperature of the aldol condensation reaction can be controlled by heating or cooling the reactor and liquid delivery tube, and for this purpose, a water bath, oil bath, ice bath, constant temperature bath, column oven, etc. can be used. When the aldol condensation step (Step A) is carried out continuously by a flow method using a reactor in which a catalyst is immobilized, the reaction temperature may be from 0°C to below the boiling point of the solvent, but within the range of 20 to 80°C. It is preferable that

When the aldol condensation step (step A) is performed continuously by a flow method using a reactor in which a catalyst is immobilized, it is preferable to use a basic resin as the catalyst for the aldol condensation reaction. When performing an aldol condensation reaction continuously by a flow method using a reactor with an immobilized catalyst as in the present invention, a basic resin that is not normally used as a catalyst for an aldol condensation reaction in a conventional batch method is used. It is preferable to use as a catalyst.

The basic resin used as a catalyst when performing the aldol condensation step (Step A) continuously by a flow method using a reactor with an immobilized catalyst may be either strongly basic or weakly basic. However, since strong basicity had higher reactivity than weak basicity, strong basicity is preferable. Moreover, it is preferable that this basic resin is a resin crosslinked with a crosslinking agent.

Moreover, the basic resin is preferably a resin into which a tertiary amino group or a quaternary ammonium group is introduced because it is commercially available. Here, the tertiary amino group is

(In the above formula, R ₁ and R ₂ may be any substituent other than hydrogen.)
A quaternary ammonium group refers to a group in the state of

(In the above formula, R _A , R _B , and R _C may be any substituent other than hydrogen.)
It refers to the basis of the state. Among these, a resin into which a dialkylamino group, a trialkylammonium group, or a dialkyl alcohol ammonium group is introduced is more preferable, and a resin into which a dimethylamino group, a trimethylammonium group, or a dimethylethanolammonium group is introduced is even more preferable. . Furthermore, resins introduced with quaternary ammonium groups having hydroxide ions as counteranions become strongly basic resins, and resins into which tertiary amino groups are introduced become weakly basic resins. Since strong basicity had higher reactivity than weak basicity, quaternary ammonium groups are preferable to tertiary amino groups.

In addition, basic resins have dimethylamino groups, trimethylammonium groups, or dimethylethanolammonium groups introduced for reasons such as ease of production and availability, suitable particle size and shape, and strength that can withstand the reaction conditions. It is preferable to use polystyrene resin crosslinked with divinylbenzene or polyacrylic acid ester resin.Since polystyrene resin has higher reactivity than polyacrylic acid ester resin, dimethylamino group , a polystyrene resin into which a trimethylammonium group or a dimethylethanolammonium group is introduced and crosslinked with divinylbenzene is more preferable.

Such basic resins include, for example, anion exchange resin Amberlyst ^(trademark) A26 (Sigma-Aldrich, 542571-1KG), anion exchange resin IRA900 (Organo, Amberlyst ^(trademark) IRA900J), anion exchange resin IRA958. (Organo, Amberlite ^(trademark) IRA958), anion exchange resin WA30 (Mitsubishi Chemical, Diaion ^(trademark) ), ORLITE DS-5 (Organo), anion exchange resin IRA910 (Organo, Amberlite ^(trademark) IRA910CT) Commercially available products such as anion exchange resin IRA904 (Organo, Amberlite ^(trademark) IRA904) can be suitably used.

Catalysts used when the aldol condensation step (Step A) is continuously carried out by a flow method using a reactor in which a catalyst is immobilized include those commercially available in granules, spheres, and cartridges. The shape is not particularly limited, and any size can be used, but if it is a granular material, it has the strength to withstand the reaction conditions without the catalyst flowing out from the column used. For this reason, the particle size is preferably between 30 μm and 3 mm.

[2] Hydrogenation step (Step B)
In the method for producing donepezil of the present invention, when the hydrogenation step (Step B) is continuously performed by a flow method using a reactor in which a catalyst is immobilized, 1-benzyl-4-[(5,6-dimethoxy- As the solvent for 1-indanone)-2-ylidene]methylpiperidine, the same solvents as mentioned above for the aldol condensation step can preferably be used.

When the hydrogenation step (Step B) is carried out continuously by a flow method using a reactor with an immobilized catalyst, 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene] The amount of methylpiperidine to be fed is not particularly limited, and may be any amount depending on the amount of catalyst used in the hydrogenation reaction, the volume of the reactor, etc. Further, as described above regarding the aldol condensation step, it is preferable to feed the liquid at a constant flow rate, but it is more preferable to feed the liquid using a liquid feeding pump.

As the reactor used for carrying out the hydrogenation reaction and the liquid feeding tube attached thereto, the same reactor and liquid feeding tube as those described above for the aldol condensation step can be preferably used.

Even when the hydrogenation step (Step B) is performed continuously by a flow method using a reactor with an immobilized catalyst, the reactor can be installed with the inlet and outlet in either direction and the liquid can be fed. However, since the specific gravity of hydrogen is smaller than that of air, if it flows from bottom to top it will be discharged out of the system regardless of the flow rate. It is preferable to install the device vertically and send the liquid.

The reaction temperature of the hydrogenation reaction can also be controlled by heating or cooling the reactor and liquid delivery tube in the same way as described above for the aldol condensation reaction, and for this purpose water baths, oil baths, ice baths, thermostatic baths, etc. , column oven, etc. can be used. When the hydrogenation step (Step B) is carried out continuously by a flow method using a reactor with an immobilized catalyst, the reaction temperature may range from 0°C to below the boiling point of the solvent, but the reaction temperature may be between 0°C and below the boiling point of the solvent. The temperature is preferably within the range of 15 to 55°C, and more preferably within the range of 25 to 55°C, for the purpose of suppressing the formation of debenzylated products, which are impurities.

When the hydrogenation step (Step B) is carried out continuously by a flow method using a reactor in which a catalyst is immobilized, the hydrogenation reaction catalyst is selected from the group consisting of palladium-based catalysts, platinum-based catalysts, and nickel-based catalysts. It is preferable that at least one of the following is selected. These catalysts are preferably supported on a solid phase using any one or a combination of carbon, polyalkylsilane, and metal oxide as a solid phase support. Preferred examples of such catalysts include dimethylpolysilyl-palladium alumina, dimethylpolysilyl-palladium silica gel, platinum carbon, platinum alumina, dimethylpolysilyl-platinum carbon, and the like. As a catalyst for such a hydrogenation reaction, commercially available products can be suitably used, as exemplified in the Examples described later.

The catalyst used when the hydrogenation step (Step B) is continuously carried out by a flow method using a reactor in which a catalyst is immobilized is commercially available in granules, spheres, pellets, or cartridges. There is no particular restriction on the shape of the catalyst, and it can be of any size. However, if it is a granular material, it is necessary to prevent the catalyst from flowing out of the column used. The particle size is preferably between 30 μm and 3 mm.

Furthermore, when the hydrogenation step (step B) is performed continuously by a flow method using a reactor in which a catalyst is immobilized, a co-filling agent may be added to the above-mentioned catalyst. When a co-filling agent is added, there are advantages over the case where no co-filling agent is added in that the hydrogen pressure can be controlled and the outflow of the catalyst from the column can be prevented. As such a co-filler, one can be used as long as it does not react with or dissolve in 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine, a solvent, or a catalyst. Alumina, glass beads, cellulose, celite, etc. are preferred because they have a wide range of particle size and shape options and are commercially available.

When the hydrogenation step (Step B) is performed continuously by a flow method using a reactor with an immobilized catalyst, the hydrogenation reaction is performed by flowing hydrogen at an arbitrary hydrogen linear velocity depending on the volume of the reactor and the amount of liquid fed. However, since the reaction efficiency decreases if the linear velocity is high, the linear velocity within the reactor is preferably within the range of 0.02 to 0.95 cm/sec.

When the hydrogenation step (Step B) is performed continuously by a flow method using a reactor with an immobilized catalyst, the pressure inside the reactor can be set arbitrarily depending on the size of the reactor, but the pressure is set as follows. If the conditions are below this value, unreacted 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine will tend to remain, and if the pressure is higher than the set value below. The condition is preferably within the range of 18 to 120 kPa because the amount of debenzylated products increases.

In the method for producing donepezil of the present invention, only the aldol condensation step (step A) may be performed continuously by a flow method using a reactor with an immobilized catalyst, or the aldol condensation step (step A) may be performed continuously using a reactor with an immobilized catalyst. Only the hydrogenation step (step B) may be performed continuously by a flow method. If the reaction is carried out continuously using a flow method using a reactor with an immobilized catalyst, the hydrogenation reaction may be carried out after the product obtained in the aldol condensation step is isolated and purified, or the hydrogenation reaction may be carried out without isolation and purification. It may also be used in the hydrogenation step.

In the method for producing donepezil of the present invention, preferably, a first reactor for performing the aldol condensation reaction and a second reactor for performing the hydrogenation reaction are connected, and in the first reactor, the 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine obtained by continuously performing the aldol condensation step by a flow method is provided to the second reactor, The hydrogenation step is carried out continuously in the second reactor by a flow process. In this way, by performing both the aldol condensation step (Step A) and the hydrogenation step (Step B) continuously using the flow method, the necessary Donepezil can be produced in the required amount at any time, and post-reaction neutralization, separation operations, isolation of intermediates, and purification steps can be omitted, resulting in a significant reduction in labor and work time. .

Donepezil produced by the method of the present invention is converted into a hydrochloride for use as a pharmaceutical, and in the hydrochlorination step, donepezil is purified to a purity suitable for use as a pharmaceutical. The hydrochlorination step can be carried out by a known method (methods described in Patent Documents 3 and 4) or a similar method, but a method using acetonitrile or acetonitrile containing water as a solvent and concentrated hydrochloric acid as a hydrochloric acid source has the best purification effect. is high and desirable.

The present invention will be explained in more detail with reference to Examples. However, the present invention is not limited to these Examples.

<Example 1>
100 g of strongly basic styrenic anion exchange resin Amberlyst ^(trademark) A26 (Sigma-Aldrich, 542571-1KG) (hereinafter referred to as "anion exchange resin A26") was mixed with 170 mL of water x 3, ethanol 170 mL x 3, and tetrahydrofuran: 2 - Washed with 170 mL of a mixed solvent of propanol: distilled water = 88:10:2 x 3 in this order. As a first reactor for carrying out the aldol condensation step continuously by a flow method, a stainless steel column (Tokyo Rika Kikai) with a diameter of 23 mm and a length of 300 mm was filled with 100 g of the anion exchange resin A26, and the lid was closed. , and installed in a column oven (Tokyo Rika Kikai). This is used as the first column, and a polytetrafluoroethylene (PTFE) tube connected to liquid pump 1 (UI-22-410D, manufactured by Fromm) is connected to the lower part of the first column. A tube was attached to the tube for guiding the solution after the reaction to a column for carrying out the hydrogenation reaction, which is a second reactor for carrying out the next hydrogenation step continuously by a flow method.

12.47 g of 5% platinum alumina (NE Chem Cat, AA1501) and 90.52 g of activated alumina (Fuji Film Wako Pure Chemical, for column chromatography, 019-08295, approximately 75 μm) were weighed out and mixed uniformly. Thereafter, a stainless steel column (Tokyo Rika Kikai) with a diameter of 23 mm and a length of 300 mm was filled, the lid was closed, and the mixture was placed in a column oven (Tokyo Rika Kikai). This was used as the second column. The upper part of the second column has a shape that allows connection of two channels, one of which is connected to the outlet side of the tube connected to the upper part of the first column, and the other channel is connected to a liquid pump. 2 (manufactured by Fromm, U1-22-110D) was connected to a tube with a hydrogen flow path merged in advance. A tube was connected to the bottom of the second column, and the tip of the tube was introduced into a container for storing the reaction solution. Thereafter, the column oven for the first column was set at 55°C, and the column oven for the second column was set at 45°C, and heated.

A mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2 was fed from the liquid pump 1 at a flow rate of 2.4 mL per minute, and tetrahydrofuran was fed from the liquid feed pump 2 at a flow rate of 1.4 mL per minute for 1 hour. did.

After the liquid was fed for 1 hour, hydrogen was fed at a rate of 0.95 cm/sec (240 mL per minute) for 1 hour while continuing the liquid feeding. Hydrogen was supplied from a hydrogen cylinder, and the supply amount was controlled by a regulator and mass flow controller (Brooks, Model SLA5850S/H2) connected to the hydrogen cylinder.

19.22 g of 5,6-dimethoxy-1-indanone (100 mmol) and 21.98 g of 1-benzyl-4-formylpiperidine (108 mmol) were mixed in 1000 mL of a mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2. A solution was prepared by completely dissolving the solution to a concentration of 0.1M, and the solution was delivered from the liquid delivery pump 1 at a flow rate of 2.4 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 5 minutes, drawing out 500 μL from there, and making the volume up to 25 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1). The purity of donepezil 7 hours after the start of the reaction was 93.9%. The total amount of the resulting reaction solution was quantified by HPLC to obtain 33.6 g of donepezil (yield: 88%).

A reaction solution equivalent to 22.7 g of donepezil was divided from the obtained reaction solution and concentrated under reduced pressure. The residue was dissolved in 180 mL of 3% aqueous acetonitrile, heated to 70° C., 6.3 mL of concentrated hydrochloric acid was added, and the mixture was stirred for 3 hours. Donepezil hydrochloride was added as a seed and cooled to 0°C. The obtained crystals were filtered and dried to obtain 18.3 g of donepezil hydrochloride (yield: 74%). The purity of the obtained donepezil hydrochloride was 99.6%.

<Example 2>
10 g of anion exchange resin A26 was washed in the following order: 17 mL x 3 of water, 17 mL x 3 of ethanol, and 17 mL x 3 of a mixed solvent of tetrahydrofuran:2-propanol:distilled water = 90:10:2. As a first reactor for carrying out the aldol condensation step continuously by a flow method, 6.8 g of the above anion exchange resin A26 was placed in a stainless steel column (Tokyo Rika Kikai, CLM-1010) with a diameter of 10 mm and a length of 100 mm. It was filled, the lid was closed, and it was placed in a column oven (Tokyo Rika Kikai, XCR-1000). This is used as the first column, and a PTFE tube connected to liquid pump 1 (Fromm, UI-22-110) is connected to the bottom of the first column, and the solution after the aldol condensation reaction is placed in the top of the first column. A tube was attached to the tube for guiding the hydrogenation reaction column, which was a second reactor for continuously performing the next hydrogenation step by a flow method.

Weigh out 0.46 g of 5% platinum carbon (NE Chemcat, 5% Pt carbon powder (water-containing product)) and 6.0 g of activated alumina (same as Example 1), mix them uniformly, and then prepare a powder with a diameter of 10 mm. A stainless steel column (Tokyo Rika Kikai, CLM-1010) with a length of 100 mm was filled, the lid was closed, and the column was placed in a column oven (Tokyo Rika Kikai, XCR-1000). This was used as the second column. The upper part of the second column has a shape that allows connection of two channels, one of which is connected to the outlet side of the tube connected to the upper part of the first column, and the other channel is connected to a liquid pump. 2 (manufactured by Fromm, KP-22-01) was connected to a tube with a hydrogen flow path merged in advance. A tube was connected to the bottom of the second column, and the tip of the tube was introduced into a container for storing the reaction solution. Thereafter, the column oven for the first column was set at 55°C, and the column oven for the second column was set at 25°C, and heated. A mixed solvent of tetrahydrofuran:2-propanol:distilled water=88:10:2 was fed from the liquid feed pump 1 at a flow rate of 1.0 mL per minute for 25 minutes.

While feeding a mixed solvent of tetrahydrofuran: 2-propanol: distilled water = 88:10:2 from the liquid feeding pump 1 at a flow rate of 0.15 mL per minute, and feeding tetrahydrofuran from the liquid feeding pump 2 at a flow rate of 0.09 mL per minute. , hydrogen was supplied at a rate of 0.32 cm/sec (15 mL per minute) for 1 hour. Hydrogen was supplied from a hydrogen cylinder, and the supply amount was controlled by a regulator and mass flow controller (KOFLOC, D8500MC) connected to the hydrogen cylinder.

9.6 g of 5,6-dimethoxy-1-indanone (50 mmol) and 10.7 g of 1-benzyl-4-formylpiperidine (52.5 mmol) were mixed in a ratio of tetrahydrofuran: 2-propanol: distilled water = 88:10:2. A 0.1M solution was prepared by completely dissolving the solution in 500 mL of the solvent, and the solution was delivered from the liquid delivery pump 1 at a flow rate of 0.15 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1).

The purity of donepezil 6 hours after the start of the reaction was 95.3%, and the purity of donepezil 21 hours after the start of the reaction was 94.3%.

224 mL of the collected flow solution was concentrated under reduced pressure, and the residue was dissolved in 45 mL of toluene and washed once with 25 mL of water. The organic layer was concentrated under reduced pressure to obtain 6.8 g of crude donepezil. 0.91 g of the obtained crude donepezil was dissolved in 7.6 mL of acetonitrile, and 0.26 mL of water was added. When this solution was quantified by HPLC, it was found to contain 0.77 g of donepezil. This solution was stirred at 70°C for 30 minutes, then 0.20 mL of concentrated hydrochloric acid was added, stirred for 3 hours, seed crystals were added, and the mixture was cooled to 0°C. The obtained crystals were filtered and dried to obtain 0.59 g of donepezil hydrochloride (yield: 70%). The purity of the obtained donepezil hydrochloride was 99.7%.

<Example 3>
110.7 g of anion exchange resin A26 was washed in the following order: 185 mL x 3 of water, 185 mL x 3 of ethanol, and 185 mL x 3 of a mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2. As a first reactor for continuously performing the aldol condensation step by a flow method, a stainless steel column (same as Example 1) with a diameter of 23 mm and a length of 300 mm was packed with 103.0 g of the anion exchange resin A26. , the lid was closed and placed in a column oven (same as in Example 1). This was used as the first column, and a PTFE tube connected to liquid pump 1 (same as in Example 1) was connected to the bottom of the first column. A tube for guiding the hydrogenation reaction to a column, which is a second reactor for performing the hydrogenation step continuously by a flow method, was attached.

Weigh out 4.3 g of dimethylpolysilyl-palladium alumina (PPD-100, manufactured by JGC Catalysts Kasei) and 101.5 g of activated alumina (same as in Example 1), mix them uniformly, and prepare a 23 mm diameter, 300 mm long A stainless steel column (same as Example 1) was filled, the lid was closed, and the mixture was placed in a column oven (same as Example 1). This was used as the second column. The upper part of the second column has a shape that allows connection of two channels, one of which is connected to the outlet side of the tube connected to the upper part of the first column, and the other channel is connected to a liquid pump. 2 (same as in Example 1) was connected to a tube in which the hydrogen flow path had been merged in advance. A tube was connected to the bottom of the second column, and the tip of the tube was introduced into a container for storing the reaction solution. Thereafter, the column oven for the first column was set at 55°C, and the column oven for the second column was set at 25°C, and heated.

A mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2 was fed from the liquid pump 1 at a flow rate of 2.4 mL per minute, and tetrahydrofuran was fed from the liquid feed pump 2 at a flow rate of 1.4 mL per minute for 1 hour. did.

After liquid feeding for 1 hour, hydrogen was fed at a rate of 0.36 cm/sec (90 mL per minute) for 1 hour while continuing liquid feeding. Hydrogen was supplied from a hydrogen cylinder, and the supply amount was controlled by a regulator and a mass flow controller (same as in Example 1) connected to the hydrogen cylinder.

57.7 g of 5,6-dimethoxy-1-indanone (300 mmol) and 64.0 g of 1-benzyl-4-formylpiperidine (315 mol) were mixed in 3000 mL of a mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2. A solution was prepared by completely dissolving the solution to a concentration of 0.1M, and the solution was delivered from the liquid delivery pump 1 at a flow rate of 2.4 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1). The purity of donepezil 7 hours after the start of the reaction was 92.8%.

2000 mL of the collected flow solution was concentrated under reduced pressure, and the residue was dissolved in 180 mL of toluene and washed twice with 150 mL of water. The organic layer was concentrated under reduced pressure to obtain 42.8 g of crude donepezil.

1.0 g of the obtained crude donepezil was dissolved in 9.7 mL of acetonitrile, and 0.3 mL of water was added. This solution was stirred at 70°C for 30 minutes, then 0.26 mL of concentrated hydrochloric acid was added, stirred for 3 hours, seed crystals were added, and cooled to 0°C. The obtained crystals were filtered and dried to obtain 0.79 g of donepezil hydrochloride (yield: 72%). The purity of the obtained donepezil hydrochloride was 99.6%.

<Example 4>
10 g of anion exchange resin A26 was washed in the following order: 17 mL x 3 of water, 17 mL x 3 of ethanol, and 17 mL x 3 of a mixed solvent of tetrahydrofuran:ethanol = 90:10. A stainless steel column (same as in Example 2) with a diameter of 10 mm and a length of 100 mm was filled with 7.4 g of the anion exchange resin A26, the lid was closed, and the column was placed in a column oven (same as in Example 2). A PTFE tube connected to liquid pump 1 (same as in Example 2) was connected to the bottom of the column, a tube was attached to the top of the column, and the solution was introduced into a container for collecting the solution after the aldol condensation reaction. Thereafter, the column oven was set at 20°C and heated. A mixed solvent of tetrahydrofuran:ethanol=90:10 was fed from the liquid feed pump 1 at a flow rate of 0.3 mL per minute for 1 hour.

Completely dissolve 1.92 g of 5,6-dimethoxy-1-indanone (10 mmol) and 2.19 g of 1-benzyl-4-formylpiperidine (10.8 mmol) in 100 mL of a mixed solvent of tetrahydrofuran:ethanol = 90:10. A 0.1M solution was prepared, and the solution was delivered from the liquid delivery pump 1 at a flow rate of 0.3 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1).

The purity of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine 6 hours after the start of the reaction was 85.5%.

<Example 5>
30 g of strongly basic styrenic anion exchange resin IRA900 (Organo, Amberlite ^(trademark) IRA900J) (hereinafter referred to as "anion exchange resin IRA900") was mixed with 17 mL x 3 of water, 17 mL x 3 of ethanol, 17 mL x 3 of tetrahydrofuran, and toluene. It was washed in the order of 17 mL x 3. A stainless steel column (Tokyo Rika Kikai, CLM-1030) with a diameter of 10 mm and a length of 300 mm was filled with 22.0 g of the anion exchange resin IRA900, the lid was closed, and the column oven (Tokyo Rika Kikai, XCR-1000 300L) was placed. It was installed in A PTFE tube connected to liquid pump 1 (same as in Example 2) was connected to the bottom of the column, a tube was attached to the top of the column, and the solution was introduced into a container for collecting the solution after the aldol condensation reaction. Thereafter, the column oven was set at 80°C and heated. Toluene was fed from the liquid feeding pump 1 at a flow rate of 0.3 mL per minute for 1 hour.

Completely dissolve 1.92 g of 5,6-dimethoxy-1-indanone (10 mmol) and 2.19 g of 1-benzyl-4-formylpiperidine (10.8 mmol) in toluene to make 0.05M solution, and prepare 200 mL of the solution. The solution was prepared, and the solution was delivered from the delivery pump 1 at a flow rate of 0.3 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was carried out for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by NMR. As for the sample, a flow solution was collected in a container for 10 minutes, and 4 mL was drawn out accurately from there. After concentration and drying, it was dissolved in deuterated chloroform, and NMR was measured to determine the purity.

Seven hours after the start of the reaction, the purity of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine was 87.0%.

<Example 6>
10 g of anion exchange resin A26 was washed in the following order: 17 mL x 3 of water, 17 mL x 3 of ethanol, and 17 mL x 3 of a mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2. A stainless steel column (same as in Example 2) with a diameter of 10 mm and a length of 100 mm was filled with 6.3 g of the anion exchange resin A26, the lid was closed, and the column was placed in a column oven (same as in Example 2). A PTFE tube connected to liquid pump 1 (same as in Example 2) was connected to the bottom of the column, a tube was attached to the top of the column, and the solution was introduced into a container for collecting the solution after the aldol condensation reaction. Thereafter, the column oven was set at 60°C and heated. A mixed solvent of tetrahydrofuran:2-propanol:distilled water=88:10:2 was fed from the liquid feed pump 1 at a flow rate of 0.15 mL/min for 1 hour.

1.92 g of 5,6-dimethoxy-1-indanone (10 mmol) and 2.19 g of 1-benzyl-4-formylpiperidine (10.8 mmol) were mixed in a mixture of tetrahydrofuran:2-propanol:distilled water = 88:10:2. A 0.1M solution was prepared by completely dissolving the mixture in 100 mL of the mixed solvent, and the solution was delivered from the liquid delivery pump 1 at a flow rate of 0.15 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1).

Seven hours after the start of the reaction, the purity of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine was 88.3%.

<Example 7>
10 g of anion exchange resin A26 was washed in the following order: 17 mL x 3 of water, 17 mL x 3 of ethanol, and 17 mL x 3 of a mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2. A stainless steel column (same as in Example 2) with a diameter of 10 mm and a length of 100 mm was filled with 6.4 g of the anion exchange resin A26, the lid was closed, and the column was placed in a column oven (same as in Example 2). A PTFE tube connected to liquid pump 1 (same as in Example 2) was connected to the bottom of the column, a tube was attached to the top of the column, and the solution was introduced into a container for collecting the solution after the aldol condensation reaction. Thereafter, the column oven was set at 55°C and heated. A mixed solvent of tetrahydrofuran:2-propanol:distilled water=88:10:2 was fed from the liquid feed pump 1 at a flow rate of 0.15 ml per minute for 35 minutes.

11.54 g of 5,6-dimethoxy-1-indanone (60 mmol) and 13.19 g of 1-benzyl-4-formylpiperidine (64.8 mmol) were mixed in a mixture of tetrahydrofuran:2-propanol:distilled water = 88:10:2. A 0.1M solution was prepared by completely dissolving the mixture in 600 mL of the mixed solvent, and the solution was delivered from the liquid delivery pump 1 at a flow rate of 0.15 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1).

The purity of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine 74 hours after the start of the reaction was 91.8%.

4.0 g of 5% platinum carbon was added to 516.3 g of the collected reaction solution (20.4 g as a quantitative value of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine). was added, and the hydrogenation reaction was carried out in a batchwise manner under stirring at room temperature for 14 hours. After the hydrogenation reaction, the catalyst was removed by filtration through Celite to obtain donepezil with a purity of 95.4% as determined by HPLC of 21.2 g.

<Example 8>
Weigh out 0.28 g of dimethylpolysilyl-palladium alumina PPD-100 (same as Example 3) and 6.4 g of activated alumina (same as Example 1), mix them uniformly, and then form a powder with a diameter of 10 mm and a length of 100 mm. The mixture was packed into a stainless steel column (same as Example 2), the lid was closed, and the mixture was placed in a column oven (same as Example 2). The upper part of the column has a shape that allows two channels to be connected; one channel is connected to a PTFE tube connected to liquid feed pump 1 (same as in Example 2), and the other channel is connected to a A tube connected to the liquid pump 2 (same as in Example 2) was connected to a tube in which a hydrogen flow path had been merged in advance. A tube was connected to the bottom of the column, and the tip of the tube was introduced into a container for storing the reaction solution. The column oven was then set at 25°C. A mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2 was fed from the liquid pump 1 at a flow rate of 0.15 mL per minute, and tetrahydrofuran was fed from the liquid feed pump 2 at a flow rate of 0.09 mL per minute for 1 hour. did.

After liquid feeding for 1 hour, hydrogen was fed at a rate of 0.13 cm/sec (6 mL per minute) for 1 hour while continuing liquid feeding. Hydrogen was supplied from a hydrogen cylinder, and the supply amount was controlled by a regulator and a mass flow controller (same as in Example 2) connected to the hydrogen cylinder.

Weigh out 3.77 g (10 mmol) of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine, and mix it with tetrahydrofuran:2-propanol:distilled water = 88:10:2. A solution of 0.1M was prepared by completely dissolving it in 100 mL of the solvent, and the solution was fed from the liquid feed pump 1 at a flow rate of 0.15 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1). The purity of donepezil 6 hours after the start of the reaction was 93.3%.

<Example 9>
Weigh out 0.46 g of dimethylpolysilyl-palladium alumina PPD-60 (JGC Catalysts Kasei) and 6.4 g of activated alumina (same as Example 1), mix them uniformly, and then add a stainless steel plate with a diameter of 10 mm and a length of 100 mm. A manufactured column (same as in Example 2) was filled with the solution, the lid was closed, and the column was placed in a column oven (same as in Example 2). The upper part of the column has a shape that allows two channels to be connected; one channel is connected to a PTFE tube connected to liquid feed pump 1 (same as in Example 2), and the other channel is connected to a A tube connected to the liquid pump 2 (same as in Example 2) was connected to a tube in which a hydrogen flow path had been merged in advance. A tube was connected to the bottom of the column, and the tip of the tube was introduced into a container for storing the reaction solution. The column oven was then set at 25°C. A mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2 was fed from the liquid pump 1 at a flow rate of 0.15 mL per minute, and tetrahydrofuran was fed from the liquid feed pump 2 at a flow rate of 0.09 mL per minute for 1 hour. did.

After liquid feeding for 1 hour, hydrogen was fed at a rate of 0.13 cm/sec (6 mL per minute) for 1 hour while continuing liquid feeding. Hydrogen was supplied from a hydrogen cylinder, and the supply amount was controlled by a regulator and a mass flow controller (same as in Example 2) connected to the hydrogen cylinder.

Weigh out 3.77 g (10 mmol) of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine and mix it with tetrahydrofuran:2-propanol:distilled water = 88:10:2. A solution of 0.1M was prepared by completely dissolving the solution in 100 mL of the solvent, and the solution was fed from the liquid feed pump 1 at a flow rate of 0.15 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1). The purity of donepezil 7 hours after the start of the reaction was 94.7%.

<Examples 10 to 12>
10 g of anion exchange resin A26 was washed in the following order: 17 mL x 3 of water, 17 mL x 3 of ethanol, and 17 mL x 3 of a mixed solvent having the solvent composition shown in Table 1 below. A stainless steel column (same as in Example 2) with a diameter of 10 mm and a length of 100 mm was filled with 6.4 g of the anion exchange resin A26, the lid was closed, and the column was placed in a column oven (same as in Example 2). A PTFE tube connected to liquid pump 1 (same as in Example 2) was connected to the bottom of the column, a tube was attached to the top of the column, and the solution was introduced into a container for collecting the solution after the aldol condensation reaction. Thereafter, the column oven was set at 55°C and heated. A mixed solvent having the solvent composition shown in Table 1 below was pumped from the liquid pump 1 at a flow rate of 0.15 mL per minute for 1 hour.

Completely dissolve 3.84 g of 5,6-dimethoxy-1-indanone (20 mmol) and 4.27 g of 1-benzyl-4-formylpiperidine (21 mmol) in a mixed solvent with the solvent composition listed in Table 1 below. A 0.1M solution was prepared, and the solution was delivered from the liquid delivery pump 1 at a flow rate of 0.15 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1).

The purity of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine 5 hours after the start of the reaction in each example is as shown in Table 1 below.

<Example 13>
Weigh out 0.28 g of dimethylpolysilyl-palladium alumina PPD-100 (same as Example 3) and 5.0 g of activated alumina (same as Example 1), mix them uniformly, and then form a material with a diameter of 10 mm and a length of 100 mm. The mixture was filled into a glass column (same as in Example 2) and the lid was closed. The lower part of the column has a shape that allows two channels to be connected; one channel is connected to a PTFE tube connected to liquid feed pump 1 (same as in Example 2), and the other channel is connected to a A tube connected to the liquid pump 2 (same as in Example 2) was connected to a tube in which a hydrogen flow path had been merged in advance. A tube was connected to the top of the column, and the tip of the tube was introduced into a container for storing the reaction solution. A mixed solvent of tetrahydrofuran:2-propanol=90:10 was fed from the liquid feed pump 1 at a flow rate of 0.3 mL per minute, and tetrahydrofuran was fed from the liquid feed pump 2 at a flow rate of 0.06 mL per minute for 1 hour.

After the liquid was fed for 1 hour at room temperature, hydrogen was fed at a rate of 0.13 cm/sec (6 mL per minute) for 1 hour while continuing the liquid feeding. Hydrogen was supplied from a hydrogen cylinder, and the supply amount was controlled by a regulator and a mass flow controller (same as in Example 2) connected to the hydrogen cylinder.

Weigh out 11.3 g (30 mmol) of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine and completely dissolve it in a mixed solvent of tetrahydrofuran:2-propanol=90:10. 300 mL of a 0.1M solution was prepared, and the solution was delivered from the liquid delivery pump 1 at a flow rate of 0.3 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1). The purity of donepezil 6 hours after the start of the reaction was 98.1%.

<Examples 14 to 16>
The same operation as in Example 13 was performed except that the hydrogen flow rate and the amount of liquid fed by the liquid feed pump 2 were changed, and the hydrogen flow rate in the hydrogenation step was examined. Table 2 shows the purity of donepezil 6 hours after the start of the reaction in each Example.

<Example 17>
10 g of anion exchange resin A26 was washed in the following order: 17 mL x 3 of water, 17 mL x 3 of ethanol, and 17 mL x 3 of a mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2. As the first reactor for carrying out the aldol condensation step continuously by flow method, 6.5 g was packed into a stainless steel column (same as in Example 2) with a diameter of 10 mm and a length of 100 mm, the lid was closed, and the column oven was opened. (same as in Example 2). This will be used as the first column, and a PTFE tube connected to liquid pump 1 (same as in Example 2) will be connected to the bottom of the first column. A tube for guiding the hydrogenation reaction to a column, which is a second reactor for performing the hydrogenation step continuously by a flow method, was attached.

Weigh out 1.7 g of 5% platinum carbon (same as Example 2) and 5.4 g of activated alumina (same as Example 1), mix them uniformly, and place them in a stainless steel column with a diameter of 10 mm and a length of 100 mm ( The mixture was filled into a column oven (same as in Example 2), closed with a lid, and placed in a column oven (same as in Example 2). This was used as the second column. The upper part of the second column has a shape that allows connection of two channels, one of which is connected to the outlet side of the tube connected to the upper part of the first column, and the other channel is connected to a liquid pump. 2 (same as in Example 2) was connected to a tube in which the hydrogen flow path had been merged in advance. A tube was connected to the bottom of the second column, and the tip of the tube was introduced into a container for storing the reaction solution. Thereafter, the column oven for the first column was set at 55°C, and the column oven for the second column was set at 25°C. A mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2 was fed from the liquid pump 1 at a flow rate of 0.15 mL per minute, and tetrahydrofuran was fed from the liquid feed pump 2 at a flow rate of 0.09 mL per minute for 1 hour. did.

After liquid feeding for 1 hour, hydrogen was fed at a rate of 0.32 cm/sec (15 mL per minute) for 1 hour while continuing liquid feeding. Hydrogen was supplied from a hydrogen cylinder, and the supply amount was controlled by a regulator and a mass flow controller (same as in Example 2) connected to the hydrogen cylinder.

1.92 g of 5,6-dimethoxy-1-indanone (10 mmol) and 2.19 g of 1-benzyl-4-formylpiperidine (10.8 mmol) were mixed in a ratio of tetrahydrofuran:2-propanol:distilled water = 88:10:2. A solution of 0.1M was prepared by completely dissolving the solution in 100 mL of the solvent, and the solution was fed from the liquid feed pump 1 at a flow rate of 0.15 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1). The purity of donepezil 5 hours after the start of the reaction was 95.6%.

<Examples 18-20>
The same operation as in Example 17 was performed except that the catalyst co-filling agent in the hydrogenation step and its filling amount were changed, and the co-filling agent in the hydrogenation step was examined. Table 3 shows the purity of donepezil 5 hours after the start of the reaction in each Example.

<Example 21>
Weigh 20.2 g of weakly basic styrene-based anion exchange resin WA30 (Mitsubishi Chemical, Diaion ^(trademark) ) (hereinafter referred to as "anion exchange resin WA30") into a 200 mL wide-necked eggplant flask, and add 100 mL of water and sodium hydroxide. 3.97 g was added, and the mixture was stirred at room temperature and pressure for 15 hours using an evaporator. The anion exchange resin WA30 after stirring was collected by filtration and washed in the following order: 17 mL x 3 of water, 17 mL x 3 of ethanol, and 17 mL x 3 of a mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2. A stainless steel column (same as Example 2) with a diameter of 10 mm and a length of 100 mm was filled with 5.9 g of the washed anion exchange resin WA30, the lid was closed, and the column was placed in a column oven (same as Example 2). A PTFE tube connected to liquid pump 1 (same as in Example 2) was connected to the bottom of the column, a tube was attached to the top of the column, and the solution was introduced into a container for collecting the solution after the aldol condensation reaction. Thereafter, the column oven was set at 55°C and heated. A mixed solvent of tetrahydrofuran:2-propanol:distilled water=88:10:2 was fed from the liquid feed pump 1 at a flow rate of 0.15 mL/min for 1 hour.

0.961 g of 5,6-dimethoxy-1-indanone (5.0 mmol) and 1.097 g of 1-benzyl-4-formylpiperidine (5.4 mmol) were mixed in tetrahydrofuran:2-propanol:distilled water = 88:10: 2 was completely dissolved in 50 mL of a mixed solvent to prepare a 0.1M solution, and the solution was delivered from the liquid delivery pump 1 at a flow rate of 0.15 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1).

Five hours after the start of the reaction, the purity of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine was 86.2%.

<Example 22>
Weigh 12.2 g of strongly basic acrylic anion exchange resin IRA958 (Organo, Amberlite ^(trademark) IRA958) (hereinafter referred to as "anion exchange resin IRA958") into a 200 mL wide-necked eggplant flask, and add 100 mL of water and sodium hydroxide. 2.6 g was added and stirred for 15 hours at normal temperature and normal pressure using an evaporator. The anion exchange resin IRA958 after stirring was collected by filtration and washed in the following order: 17 mL x 3 of water, 17 mL x 3 of ethanol, and 17 mL x 3 of a mixed solvent of tetrahydrofuran:2-propanol:distilled water = 88:10:2. A stainless steel column (same as in Example 2) with a diameter of 10 mm and a length of 100 mm was filled with 6.0 g of the washed anion exchange resin IRA958, the lid was closed, and the column was placed in a column oven (same as in Example 2). A PTFE tube connected to liquid pump 1 (same as in Example 2) was connected to the bottom of the column, a tube was attached to the top of the column, and the solution was introduced into a container for collecting the solution after the aldol condensation reaction. Thereafter, the column oven was set at 55°C and heated. A mixed solvent of tetrahydrofuran:2-propanol:distilled water=88:10:2 was fed from the liquid feed pump 1 at a flow rate of 0.15 mL/min for 1 hour.

1.345 g of 5,6-dimethoxy-1-indanone (7.0 mmol) and 1.536 g of 1-benzyl-4-formylpiperidine (7.6 mmol) were mixed in tetrahydrofuran:2-propanol:distilled water = 88:10: 2 was completely dissolved in 70 mL of a mixed solvent to prepare a 0.1M solution, and the solution was delivered from the liquid delivery pump 1 at a flow rate of 0.15 mL per minute. This liquid feeding start time was defined as the reaction start time.

Sampling was performed for a certain period of time from 2 hours after the start of the reaction, and the purity was measured by HPLC. A sample for HPLC measurement was prepared by collecting the flow solution in a container for 10 minutes, drawing out 200 μL from there, and making the volume up to 10 mL with a diluted solution (0.1% trifluoroacetic acid aqueous solution: acetonitrile = 1:1).

Five hours after the start of the reaction, the purity of 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine was 67.1%.

The embodiments, examples, and experimental examples disclosed this time are illustrative in all respects, and should not be considered restrictive. The scope of the present invention is indicated not by the above description but by the claims, and it is intended that all changes within the meaning and range of equivalency to the claims are included.

Claims (10)

The following formula (II)

A method for producing donepezil represented by
The following formula (III)

5,6-dimethoxy-1-indanone represented by and the following formula (IV)

The following formula (V) is obtained by carrying out an aldol condensation reaction with 1-benzyl-4-formylpiperidine represented by

an aldol condensation step to obtain 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine,
a hydrogenation step of hydrogenating 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine to obtain donepezil represented by the above formula (II),
At least one of the aldol condensation step and the hydrogenation step is performed continuously by a flow method using a reactor in which a catalyst is immobilized,
A method for producing donepezil , wherein the catalyst used in the aldol condensation step is a basic resin . The method for producing donepezil according to claim 1 , wherein the basic resin is a resin crosslinked with a crosslinking agent. The method for producing donepezil according to claim 1 or 2 , wherein the catalyst used in the aldol condensation step is a resin into which a tertiary amino group or a quaternary ammonium group is introduced. The method for producing donepezil according to claim 3 , wherein the catalyst used in the aldol condensation step is a resin into which a dialkylamino group, a trialkylammonium group, or a dialkylalcohol ammonium group is introduced. The method for producing donepezil according to claim 4 , wherein the catalyst used in the aldol condensation step is a resin into which a dimethylamino group, a trimethylammonium group, or a dimethylethanolammonium group is introduced. The method for producing donepezil according to claim 5 , wherein the resin is a polystyrene resin or polyacrylic acid ester resin into which a dimethylamino group, a trimethylammonium group, or a dimethylethanolammonium group is introduced and crosslinked with divinylbenzene. The method for producing donepezil according to claim 6 , wherein the resin is a polystyrene resin into which a dimethylamino group, a trimethylammonium group, or a dimethylethanolammonium group is introduced and crosslinked with divinylbenzene. The method for producing donepezil according to claim 1, wherein the catalyst used in the hydrogenation step is at least one selected from the group consisting of a palladium-based catalyst, a platinum-based catalyst, and a nickel-based catalyst. 9. The catalyst used in the hydrogenation step is at least one selected from dimethylpolysilyl-palladium alumina, dimethylpolysilyl-palladium silica gel, platinum carbon, platinum alumina, and dimethylpolysilyl-platinum carbon. Method for producing donepezil. A first reactor for performing the aldol condensation reaction and a second reactor for performing the hydrogenation reaction are connected, and the aldol condensation step is continuously performed in the first reactor by a flow method. The obtained 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpiperidine is provided to the second reactor, and the hydrogenation step is performed in the second reactor by a flow method. The method for producing donepezil according to any one of claims 1 to 9 , which is carried out continuously by:

Images