JPH11263774A - Production of donepezil derivative and intermediate therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain in an industrially and economically excellent way the subject compound useful as a preventive/therapeutic agent for senile dementia, in particular Alzheimer's disease, by reducing a specific quaternary ammonium salt. SOLUTION: This new compound of formula II e.g. 1-benzyl-4-[(5,6- dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride} is obtained by reducing a quaternary ammonium salt of formula I (R<1> is H or a lower alkoxy; (n) is 1-4; X is a halogen) e.g. 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2- yl]methylpyridinium bromide} normally at normal temperatures and pressures for several hours through hydrogenation in a solvent such as methanol pref. in the presence of a catalyst such as platinum (IV) oxide. By the way, the quaternary ammonium salt of formula I is prepared, preferably, by reaction between a 2-(4-pyridyl)methyl-1-indanone derivative of formula III and a benzyl halide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a medicament disclosed in JP-A-64-79,151 (EP-296,560-A1, US-4,895,841).
Specifically, a donepezil derivative or a pharmacologically acceptable salt thereof having an excellent action as a prophylactic / therapeutic agent for senile dementia, in particular, a prophylactic / therapeutic agent for Alzheimer's disease, and more specifically, Example 4 of the publication Donepezil Hydrochloride (Chemical name: 1-benzyl-4-)
Donepezil (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-), which is a precursor for the production of [(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine hydrochloride A novel industrial production method of 2-yl] methylpiperidine, a free form) or a hydrohalide thereof, and an intermediate thereof.

[0002]

2. Description of the Related Art Conventional indanone derivatives are disclosed in
As described in Examples 3 and 4 of No. 1 Publication, for example,
5,6-Dimethoxy-1-indanone and 1-benzyl-4-formylpiperidine are reacted in the presence of a strong base such as lithium diisopropylamide (Example 3), and then reduced (Example 3).
4) Manufactured. The yield of donepezil through Examples 3 and 4 by this method was 50.8% (62% × 82%).

[0003]

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Further, Japanese Patent Application Laid-Open No. 8-225,527 (EP-711,756-A
Examples 2,4,6 of (1, US-5,606,064) include 5,6-dimethoxy-
Reaction of 1-indanone and pyridine-4-aldehyde to give 5,6
-Dimethoxy-2- (pyridin-4-yl) methyleneindan-1-
After turning on (Example 2), it was reacted with benzyl bromide to give 1-
Benzyl-4- (5,6-dimethoxyindan-1-one-2-ylidene) methylpyridinium bromide (Example 4), and further reduced in the presence of a platinum oxide catalyst to give donepezil
(Example 6) A method is described. The yield of donepezil through Examples 2, 4, and 6 in this method was 58.5% (87% × 83
% X 81%).

[0005]

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Further, in Production Examples 1-3 and Examples 1-6 of WO 97/22584, 3- (pyridin-4-yl)-is obtained by reacting (pyridin-4-yl) carboxaldehyde with malonic acid. 2-
Prepare propenoic acid (Preparation 1), then reduce to 3
-(Piperidin-4-yl) -2-propionic acid
n 2) and then reacted with methyl chlorocarbonate to give 3- [N- (methoxycarbonyl) piperidin-4-yl] propionic acid.
(Preparation 3), followed by reaction with oxalyl chloride 4
-(2-Chlorocarbonylethyl) piperidine-1-carboxylate (Example 1) and then reacted with 1,2-dimethoxybenzene in the presence of aluminum chloride to give 4- [3- (3,4-dimethoxyphenyl) Methyl 3- [3-oxopropyl] piperidine-1-carboxylate (Example 2) and then reacted with tetramethyldiaminomethane to give methyl 4- [2- (3,4-dimethoxybenzoyl) allyl] piperidine-1-carboxylate (Ex
ample 3) and then treated with sulfuric acid to give 4- (5,6-dimethoxy-1-
Oxoindan-2-ylmethyl) piperidine-1-carboxylate (Example 4), and then treated with a base to give 5,6-
Dimethoxy-2- (piperidin-4-ylmethyl) indan-1-
On (Example 5) and further reacted with benzyl bromide to give donepezil (Example 6). Although the yield of Example 1 is not described in this publication example, even if it is assumed to be 100%, the yield of donepezil through all the steps is 19.3% (70% × 84% × 100 % × 68% × 79%
× 61%).

[0007]

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[0008]

[Problems to be Solved by the Invention] However, the overall process yield of donepezil from general-purpose raw materials is at most 58.5% according to the method disclosed in JP-A-8-225,527, and then to JP-A-64-79,
According to the method of JP-A No. 151, it was 50.8%, and the lowest was 19.3% according to the method of WO 97/22584, which was not sufficient as an industrial production method. Although the method disclosed in JP-A-8-225,527 has the highest yield among these methods, it is difficult to reproduce the yield of the last reduction step when actually performing additional tests. It seems to be much worse than the method of 64-79,151 (see Reference Example below). Even if the yield described in the publication is correct, the overall process yield is 58.5%,
No superior effect was recognized as compared with the prior art (total process yield of 50.8% in JP-A-64-79,151). Therefore, in recent years, the number of patients has rapidly increased, and a prophylactic / therapeutic agent for senile dementia of high public interest, particularly a donepezil derivative having an excellent action as an Alzheimer's disease preventive / therapeutic agent, is an industrially and economically excellent method. There was not yet.

[0009]

Means for Solving the Problems The present inventors have intensively studied to improve the above problems. as a result,
It has been surprisingly found that a donepezil derivative can be obtained from a general-purpose raw material in a total process yield of as much as 82.5% by passing through a novel quaternary ammonium salt (I), thereby completing the present invention. That is, the present invention provides a novel industrially excellent method for producing a donepezil derivative and an intermediate thereof.

[0010] More specifically, the present invention is any one of the following production methods for producing a donepezil derivative. (1) The quaternary ammonium salt (I) is reduced. (2) quaternary ammonium salt by reacting 2- (4-pyridyl) methyl-1-indanone derivative (III) with benzyl halide
(I), and then reduced. (3) 2-alkoxycarbonyl-1-indanone derivative (IV)
With (4-pyridyl) methyl (V) or a salt thereof, followed by decarboxylation to give a 2- (4-pyridyl) methyl-1-indanone derivative (III), followed by reaction with benzyl halide. It is converted to a quaternary ammonium salt (I) and further reduced. (4) reacting a 1-indanone derivative (VI) with a carbonate (VII) to form a 2-alkoxycarbonyl-1-indanone derivative
(IV), and then reacted with (4-pyridyl) methyl halide (V) or a salt thereof, followed by decarboxylation to give a 2- (4-pyridyl) methyl-1-indanone derivative (III), and then halogenation The benzyl is reacted to form a quaternary ammonium salt (I), which is further reduced. These are represented by the following chemical reaction formulas.

[0011]

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(In the formula, R ¹ , R ² , n and X have the same meanings as described above.) Here, the quaternary ammonium salt (I) according to the present invention is represented by the following general formula.

[0013]

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In the formula, R ¹ is the same or different and represents a hydrogen atom or a lower alkoxy group, n represents an integer of 1 to 4, and X represents a halogen atom. The lower alkoxy group means a group in which an oxygen atom is bonded to a linear or branched lower alkyl group having 1 to 6 carbon atoms, specifically, for example, a methoxy group, an ethoxy group, an n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, t-butoxy group,
Examples include a pentyloxy group and a hexyloxy group. Among these, a methoxy group is more preferable from the viewpoint of the efficacy or safety of the donepezil derivative as the final compound. Further, a halogen atom specifically means a bromine atom, a chlorine atom, an iodine atom or a fluorine atom, and a bromine atom, a chlorine atom or an iodine atom gives more preferable results.

More specifically, examples of the quaternary ammonium salt (I) include the following compounds.
The present invention is not limited to these. (1) 1-benzyl-4- (1-indanone-2-yl) methylpyridinium chloride (2) 1-benzyl-4-[(4-methoxy-1-indanone) -2-chloride
Yl] methylpyridinium (3) 1-benzyl-4-[(5-methoxy-1-indanone) -2-chloride
Yl] methylpyridinium (4) 1-benzyl-4-[(6-methoxy-1-indanone) -2-chloride
Yl] methylpyridinium chloride (5) 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpyridinium chloride (6) 1-benzyl-4-[(5,7-dimethoxychloride 1-Indanone) -2-yl] methylpyridinium (7) 1-benzyl-4-[(4,7-dimethoxy-1-indanone) -2-yl] methylpyridinium (8) 1-benzyl-4 chloride -[(4,5-dimethoxy-1-indanone) -2-yl] methylpyridinium (9) 1-benzyl-4-[(6,7-dimethoxy-1-indanone) -2-yl] methylpyridinium ( 10) 1-benzyl-4-[(5,6,7-trimethoxy-1-indanone) -2-yl] methylpyridinium chloride (11) 1-benzyl-4-[(5,6-diethoxy-1-chloride (Indanone) -2-yl] methylpyridinium (12) 1-benzyl-4- (1-indanone-2-yl) methylpyridinium (13) 1-benzyl-4-[(4-methoxy-1-bromide (Indanone) -2
-Yl] methylpyridinium (14) 1-benzyl-4-[(5-methoxy-1-indanone) -2 bromide
-Yl] methylpyridinium (15) 1-benzyl-4-[(6-methoxy-1-indanone) -2 bromide
-Yl] methylpyridinium (16) 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpyridinium (17) 1-benzyl-4-[(5, 7-dimethoxy-1-indanone) -2-yl] methylpyridinium (18) 1-benzyl-4-[(4,7-dimethoxy-1-indanone) -2-yl] methylpyridinium (19) bromide 1-benzyl-4-[(4,5-dimethoxy-1-indanone) -2-yl] methylpyridinium (20) 1-benzyl-4-[(6,7-dimethoxy-1-indanone) -2 bromide -Yl] methylpyridinium (21) 1-benzyl-4-[(5,6,7-trimethoxy-1-indanone) -2-yl] methylpyridinium (22) 1-benzyl-4-[( 5,6-Diethoxy-1-indanone) -2-yl] methylpyridinium The quaternary ammonium salt (I) according to the present invention is a novel compound and is used for obtaining the desired donepezil derivative (II) in high yield. Useful as a key intermediate.

Next, the donepezil derivative hydrohalide (II) according to the present invention is represented by the following general formula.

[0017]

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In the formula, R ¹ , n and X have the same meaning as described above. More specifically, the donepezil derivative hydrohalide (II) includes, for example, hydrohalides of the following compounds, but the present invention is not limited thereto. (1) 1-benzyl-4- (1-indanone-2-yl) methylpiperidine (2) 1-benzyl-4-[(4-methoxy-1-indanone) -2-yl] methylpiperidine (3) 1 -Benzyl-4-[(5-methoxy-1-indanone) -2-yl] methylpiperidine (4) 1-benzyl-4-[(6-methoxy-1-indanone) -2-yl] methylpiperidine (5 ) 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-
Yl] methylpiperidine (6) 1-benzyl-4-[(5,7-dimethoxy-1-indanone) -2-
Yl] methylpiperidine (7) 1-benzyl-4-[(4,7-dimethoxy-1-indanone) -2-
Yl] methylpiperidine (8) 1-benzyl-4-[(4,5-dimethoxy-1-indanone) -2-
Yl] methylpiperidine (9) 1-benzyl-4-[(6,7-dimethoxy-1-indanone) -2-
Yl] methylpiperidine (10) 1-benzyl-4-[(5,6,7-trimethoxy-1-indanone) -2-yl] methylpiperidine (11) 1-benzyl-4-[(5,6-diethoxy (-1-Indanone) -2
-Yl] methylpiperidine If necessary, the donepezil derivative hydrohalide (II) according to the present invention may be subjected to a conventional method such as neutralization with a base followed by acid treatment, or treatment with a large amount of acid. ,
It can also be converted (salt exchange) into any pharmacologically acceptable salt. At this time, the kind of the salt is not limited, but preferably a hydrochloride can be used.

Next, the 2- (4-pyridyl) methyl-1-indanone derivative (III) according to the present invention is represented by the following general formula.

[0020]

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In the formula, R ¹ and n have the same meaning as described above. 2- (4-pyridyl) methyl-1-indanone derivative (III)
More specifically, for example, the following compounds can be mentioned, but the present invention is not limited thereto. (1) 2- (4-pyridyl) methyl-1-indanone (2) 2- (4-pyridyl) methyl-4-methoxy-1-indanone (3) 2- (4-pyridyl) methyl-5-methoxy- 1-Indanone (4) 2- (4-pyridyl) methyl-6-methoxy-1-indanone (5) 2- (4-pyridyl) methyl-5,6-dimethoxy-1-indanone (6) 2- (4 -(Pyridyl) methyl-5,7-dimethoxy-1-indanone (7) 2- (4-pyridyl) methyl-4,7-dimethoxy-1-indanone (8) 2- (4-pyridyl) methyl-4,5 -Dimethoxy-1-indanone (9) 2- (4-pyridyl) methyl-6,7-dimethoxy-1-indanone (10) 2- (4-pyridyl) methyl-5,6,7-trimethoxy-1-indanone (11) 2- (4-pyridyl) methyl-5,6-diethoxy-1-indanone These compounds are known compounds, for example, J. Heteroc
yclic Chem., 2 (4), 366-70 (1965). It can be produced according to the method described, [total process yield = 48.4% (55% × 88%)],
According to the method of the present invention, [total process yield = 82.5% (98% × 85% × 100% ×
99%)], and can be obtained in much higher yields.

Next, the 2-alkoxycarbonyl-1-indanone derivative (IV) according to the present invention is represented by the following general formula.

[0023]

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In the formula, R ² represents a lower alkyl group. R ¹
And n have the same meaning as described above. The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group. , I-butyl group, t-
Examples thereof include a butyl group, a pentyl group and a hexyl group, and a methyl group, an ethyl group or a propyl group is preferred.
More specifically, examples of the 2-alkoxycarbonyl-1-indanone derivative (IV) include the following compounds, but the present invention is not limited thereto. (1) 2-methoxycarbonyl-1-indanone (2) 2-methoxycarbonyl-4-methoxy-1-indanone (3) 2-methoxycarbonyl-5-methoxy-1-indanone (4) 2-methoxycarbonyl-6 -Methoxy-1-indanone (5) 2-methoxycarbonyl-5,6-dimethoxy-1-indanone (6) 2-methoxycarbonyl-5,7-dimethoxy-1-indanone (7) 2-methoxycarbonyl-4, 7-dimethoxy-1-indanone (8) 2-methoxycarbonyl-4,5-dimethoxy-1-indanone (9) 2-methoxycarbonyl-6,7-dimethoxy-1-indanone (10) 2-methoxycarbonyl-5 , 6,7-Trimethoxy-1-indanone (11) 2-methoxycarbonyl-5,6-diethoxy-1-indanone (12) 2-ethoxycarbonyl-1-indanone (13) 2-ethoxycarbonyl-4-methoxy- 1-indanone (14) 2-ethoxycarbonyl-5-methoxy-1-indanone (15) 2-ethoxycarbonyl-6-methoxy 1-indanone (16) 2-ethoxycarbonyl-5,6-dimethoxy-1-indanone (17) 2-ethoxycarbonyl-5,7-dimethoxy-1-indanone (18) 2-ethoxycarbonyl-4,7- Dimethoxy-1-indanone (19) 2-ethoxycarbonyl-4,5-dimethoxy-1-indanone (20) 2-ethoxycarbonyl-6,7-dimethoxy-1-indanone (21) 2-ethoxycarbonyl-5,6 , 7-Trimethoxy-1-indanone (22) 2-ethoxycarbonyl-5,6-diethoxy-1-indanone These compounds are also known compounds, for example, EP-534,859
It can be obtained almost quantitatively by the method described in Example 9-A1 (Yield = 98%).

Next, the (4-pyridyl) methyl halide (V) according to the present invention is represented by the following general formula. (In the formula, X means a halogen atom.)

[0026]

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As the (4-pyridyl) methyl halide (V), more specifically, for example, the following compounds may be mentioned, and these may be salts. (1) (4-pyridyl) methyl chloride (2) (4-pyridyl) methyl bromide (3) (4-pyridyl) methyl iodide These compounds are known compounds, and are generally used as reagents and industrial raw materials. Available.

Next, the 1-indanone derivative according to the present invention
(VI) is represented by the following general formula. (In the formula, R ¹ and n have the same meaning as described above.)

[0029]

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More specific examples of the 1-indanone derivative (VI) include the following compounds. (1) 1-indanone (2) 4-methoxy-1-indanone (3) 5-methoxy-1-indanone (4) 6-methoxy-1-indanone (5) 5,6-dimethoxy-1-indanone (6 ) 5,7-dimethoxy-1-indanone (7) 4,7-dimethoxy-1-indanone (8) 4,5-dimethoxy-1-indanone (9) 6,7-dimethoxy-1-indanone (10) 5 , 6,7-Trimethoxy-1-indanone (11) 5,6-diethoxy-1-indanone These compounds are also known compounds and are generally available as reagents and industrial raw materials.

Finally, the carbonate (VI) according to the present invention
I) is represented by the general formula (R ² O) ₂ CO. (In the formula, R ² has the same meaning as described above.) More specific examples of the carbonate (VII) include the following compounds. (1) Dimethyl carbonate (2) Diethyl carbonate (3) Dipropyl carbonate (4) Methyl ethyl carbonate These compounds are also known compounds, and are generally available as reagents and industrial raw materials.

Next, the production method according to the present invention will be described in detail.
(See the chemical reaction formula [Chem. 11]).(1) Process 1 In this step, the 1-indanone derivative (VI) and the carbonate (VI
I) to give 2-alkoxycarbonyl-1-indanone
The step of obtaining the derivative (IV), for example, EP-534,859
The method described in Example 9-A1, Chem. Pharm.Bull.42
(3), 541-550 (1994); Tetrahedron,Three
0, 507-512, 1974.
You. Among them described in Example 9-A1 of EP-534,859
The method has the highest yield and can be produced almost quantitatively.
it can.

(2) Step 2 This step comprises reacting a 2-alkoxycarbonyl-1-indanone derivative (IV) with a (4-pyridyl) methyl halide (V) or a salt thereof to form a 2-alkoxycarbonyl-2 This is a step of obtaining a-(4-pyridyl) methyl-1-indanone derivative (VIII). This step can be performed according to a conventional method in the presence of a base. For example, in a non-aqueous system, the base is not limited, but specifically, for example, sodium hydride, sodium, sodium amide, lithium diisopropylamide (LDA),
It can be carried out using lithium hexamethyldisilazane (LHMDS), sodium methoxide, sodium ethoxide, potassium t-butoxide and the like. The solvent used at this time is not limited, but specifically, for example, DMF, T
Examples thereof include HF, DMSO, dioxane, HMPA, and HMTT, and may be a mixture.

This step can also be carried out in a water-containing system in the presence of a phase transfer catalyst and a base. Here, the type of the phase transfer catalyst is not limited, but is generally a quaternary ammonium salt, a quaternary phosphonium salt or a sulfonium salt. Specific examples of the quaternary ammonium salt include, for example, tetramethylammonium iodide, tetraethylammonium iodide, tetrapropylammonium iodide,
Tetrabutylammonium iodide, tetrapentylammonium iodide, tetrahexylammonium iodide,
Tetraheptyl ammonium iodide, tetraoctylammonium iodide, tetrahexadecyl ammonium iodide, tetraoctadecyl ammonium iodide, benzyltrimethylammonium bromide, benzyltriethylammonium bromide, benzyltributylammonium bromide, 1-methylpyridinium iodide, 1-hexadecylpyridinium iodide, 1,4-ditylpyridinium iodide, tetramethyl-2-butylammonium chloride, trimethylcyclopropylammonium chloride, tetrabutylammonium bromide, tetraoctylammonium bromide, t-butylethyl bromide Examples thereof include dimethylammonium, tetradecyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, and octadecyltrimethylammonium bromide. Specific examples of the quaternary phosphonium salt include, for example, tributylmethylphosphonium iodide, triethylmethylphosphonium iodide, methyltriphenoxyphosphonium iodide, butyltriphenylphosphonium iodide, tetrabutylphosphonium bromide, and benzyltriphenylphosphonium bromide And hexadecyltrimethylphosphonium bromide, hexadecyltributylphosphonium bromide, hexadecyldimethylethylphosphonium bromide, tetraphenylphosphonium chloride and the like. Furthermore, specific examples of the sulfonium salt include dibutylmethylsulfonium iodide, trimethylsulfonium iodide, triethylsulfonium iodide and the like. These phase transfer catalysts
Generally available as reagents, industrial raw materials, etc.

The type of the base in the water-containing system is not limited. Specific examples include sodium hydroxide, potassium hydroxide, barium hydroxide and the like.

The type of solvent used at this time is not limited, but specific examples thereof include water, water-toluene, water-benzene, water-xylene, and water-chlorinated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, etc.). ), And may be a mixture.

(3) Step 3 In this step, 2-alkoxycarbonyl-2- (4-pyridyl) methyl-1-indanone derivative (VIII) is decarboxylated to give 2- (4-pyridyl) methyl-1-indanone This is a step of obtaining a derivative (III). This step is a decarboxylation reaction performed in the presence of a base, and can be performed according to a conventional method. The type of the base used here is not limited, but usually, potassium hydroxide, sodium hydroxide, barium hydroxide and the like can be mentioned.
Also, the type of the solvent is not limited, and lower alcohols such as ethanol, methanol, and propanol, THF, DMF, DM
Examples thereof include SO and dioxane, and may be a mixture. As another method of this process, Tetrahedron Let
Decarboxylation in water-DMSO, for example, in the presence of sodium chloride, can also be carried out according to the method described in T., 957, 1973.

(4) Step 4 This step comprises a 2- (4-pyridyl) methyl-1-indanone derivative
This is a step of producing a quaternary ammonium salt (I) by reacting (III) with a benzyl halide. This step can be performed according to a conventional method for producing a quaternary ammonium salt.Specifically, as a benzyl halide, for example, benzyl bromide, benzyl chloride or the like is used, and as a solvent, specifically, for example, acetonitrile, THF, DMF, DMSO, dioxane, 1,2-dimethoxyethane, ether, lower alcohol, acetone, MEK (2-butanone), MIBK (methyl isobutyl ketone), N-methylpyrrolidone, and the like. You may.

(5) Step 5 This step is a step of reducing the quaternary ammonium salt (I) to produce the desired donepezil derivative hydrohalide (II). Although the reduction method is not limited, the catalytic reduction is usually performed in the presence of a catalyst. Specifically, examples of the catalyst include a platinum compound such as platinum oxide, a palladium compound such as palladium / carbon, a nickel compound such as Raney nickel, and a ruthenium compound such as ruthenium oxide. As the solvent, for example, water, ethanol, lower alcohols such as methanol, THF, DMF, DMSO, dioxane,
Examples include N-methylpyrrolidone, chlorinated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, etc.), acetone, MEK, MIBK, acetonitrile, ethyl acetate, benzene, toluene, xylene, etc., and may be a mixture. Although the reaction conditions in this step are not limited, the reaction is usually completed within several hours at normal temperature and normal pressure. Further, the obtained donepezil derivative hydrohalide (II) can be converted into a free form or various pharmacologically acceptable salts according to a conventional method.

Next, the present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited to these examples.

EXAMPLES Example 1 5,6-Dimethoxy-2- (4-pyridyl)
Synthesis of methyl-1-indanone

[0041]

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5,6-Dimethoxy-2-ethoxycarbonyl-1-indanone obtained according to Example 9-A1 of EP-534,859
2.00 g (7.57 mmol) was dissolved in DMF (dimethylformamide) 40 ml, and under ice cooling, 60% -sodium hydride 0.73 g (18.3 mmo)
l) was added and the mixture was stirred at room temperature for 30 minutes. Thereafter, the mixture was ice-cooled again, and 1.49 g of 4-pyridylmethyl chloride (4-picolyl chloride) (18.
3 mmol) and stirred for 30 minutes. Thereafter, the mixture was further stirred at room temperature overnight. Under ice-cooling, add 200 ml of water, extract with 200 ml of ethyl acetate, and wash the organic layer with 200 ml of saturated saline.
Washing was performed with × 2. After drying (MgSO ₄ ), the solution was concentrated under reduced pressure to obtain 3.40 g of a brown oil. Dissolve this oil in 50 ml of ethanol, add 10 ml of water and 1.99 g of 85.5% potassium hydroxide (30.3 mmo
l) was added and the mixture was heated under reflux for 30 minutes. After allowing the reaction solution to cool to room temperature, it was concentrated under reduced pressure, and 50 ml of water was added. The precipitated crystals were separated by filtration and dried to obtain 1.82 g of the title compound as pale brown crystals.
(Yield: 85% in 2 steps)

Melting point: 192-193 ° C. [Literature: 190-191 ° C.
(J. Heterocyclic Chem., 2 (4), 366-70, 1965.)]. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm) 2.66-2.74 (2H, m), 2.96
3.04 (1H, m), 3.12 (1H, dd, J = 7.6Hz, J = 16.8Hz), 3.35 (1H, d
d, J = 4.4Hz, J = 14Hz), 3.92 (3H, s), 3.95 (3H, s), 6.82 (1H,
s), 7.18 (2H, d, J = 6Hz), 7.20 (1H, s), 8.51 (2H, d, J = 6Hz). ESI-MS: m / z = 284 (M + H) +.

Example 2 1-benzyl-4-[(5,6-dimethylbromide)
Toxi-1-indanone) -2-yl] methylpyridinium
Success

[0045]

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5,6-dimethoxy-2- (4-pyridyl) methyl-1-
30 ml of acetonitrile in 1.00 g (3.53 mmol) of indanone
Was added and dissolved by heating under reflux, followed by benzyl bromide 0.50m
l (4.21 mmol) was added. After heating and refluxing for another 2.5 hours,
It was allowed to cool to room temperature and concentrated under reduced pressure. N-hexane 50m to residue
l was added. The precipitated crystals were separated by filtration and dried to obtain 1.60 g of the title compound as pale yellow crystals. (Yield: quantitative)

Melting point: 173-177 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 2.70 (1 H, dd, J = 3.6 Hz,
J = 16.4Hz), 3.01 (1H, dd, J = 9.2Hz, J = 14Hz), 3.12 (1H, dd, J =
(7.6Hz, J = 16.4Hz), 3.16-3.24 (1H, m), 3.30-3.98 (1H, m), 3.
77 (3H, s), 3.83 (3H, s), 5.81 (2H, s), 7.06 (1H, s), 7.07 (1H,
s), 7.38-7.48 (3H, m), 7.50-7.56 (2H, m), 8.13 (2H, d, J = 6.4
Hz), 9.14 (2H, d, J = 6.4Hz). ESI-MS: m / z = 374 (M-Br) +.

Example 3 1-benzyl-4-[(5,6-dimethoxy
1-Indanone) -2-yl] methylpiperidine hydrochloride
Of Donepezil Hydrochloride

[0049]

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1.00 g (2.20 mmo) of 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpyridinium bromide
l) was dissolved in 15 ml of methanol, 0.1 g of platinum (IV) oxide was added, and hydrogenated at room temperature and normal pressure for 3 hours. After filtering off the catalyst,
The filtrate was concentrated under reduced pressure, a saturated aqueous solution of sodium carbonate (30 ml) was added to the residue, and the mixture was extracted with ethyl acetate (50 ml × 3). After drying (MgSO ₄ ), the solution is concentrated under reduced pressure to give donepezil free form.
0.83 g was obtained. (Yield: 99%)

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm) 1.27-1.42
(3H, m), 1.42-1.55 (1H, m), 1.63-1.77 (2H, m), 1.87-2.03 (3
H, m), 2.66-2.74 (2H, m), 2.86-2.94 (2H, m), 3.23 (1H, dd, J =
8Hz, J = 17.6Hz), 3.50 (2H, s), 3.90 (3H, s), 3.96 (3H, s), 6.8
5 (1H, s), 7.17 (1H, s), 7.22-7.33 (5H, m).

This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol / isopropyl ether to obtain 0.83 g of the title compound as white crystals. (Yield: 91% in 2 steps)

Melting point: 211-212 ° C. (decomposition) [Literature value: 211-2]
12 ° C. (decomposition), (Example 4 of JP-A-64-79151)]. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm) 1.48-1.58 (1 H, m), 1.76
1.90 (2H, m), 1.90-2.02 (1H, m), 2.02-2.20 (3H, m), 2.60-2.
76 (4H, m), 3.29 (1H, dd, J = 7.6Hz, J = 17.2Hz), 3.41-3.54 (2
H, m), 3.90 (3H, s), 3.96 (3H, s), 4.12-4.22 (2H, m), 6.85 (1
H, s), 7.12 (1H, s), 7.42-7.48 (3H, m), 7.64 (2H, br-s), 12.2
5-12.45 (1H, m). ESI-MS: m / z = 380 (M + H) +.

Reference Example 1 Synthesis of donepezil (free form):
(Repeated test result of Example 6 of JP-A-8-225,527) 10.0 g of 5,6-dimethoxy-2- (4-pyridyl) methyleneindan-1-one obtained according to Example 4 of JP-A-8-225,527 Two
2.1 mmol), 50 ml of methanol and 1 g of platinum (IV) oxide were added, and hydrogenated at room temperature and normal pressure for 24 hours. After filtering off the catalyst,
To the residue obtained by concentrating the filtrate under reduced pressure, 200 ml of 5% -sodium carbonate aqueous solution was added, and methylene chloride 150 ml × 1, 100 ml × 2
Extracted. After drying (MgSO ₄ ), the mixture was concentrated under reduced pressure to obtain 9.1 g of a black oil. This black oil is TLC (methanol /
Many by-product spots were observed on methylene chloride). This was purified by (NH) silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 3.2 g of the title compound as white crystals. (Yield: 38%, [Literature value: 81
%, (Example 6 of JP-A-8-225,527)])

Claims (10)

[Claims] 1. A quaternary ammonium salt (I) represented by the following general formula: Wherein R ¹ is the same or different and represents a hydrogen atom or a lower alkoxy group, n represents an integer of 1 to 4, and X represents a halogen atom, respectively. A method for producing a donepezil derivative hydrohalide (II) represented by the formula: Embedded image (In the formula, R ¹ , n and X have the same meanings as described above.) 2. A 2- (4-pyridyl) methyl-1-indanone derivative (III) represented by the following general formula: (Wherein R ¹ and n have the same meanings as described above) and a benzyl halide to react with a quaternary ammonium salt.
A method for producing a donepezil derivative hydrohalide (II), which comprises (I) and then reducing. 3. A 2-alkoxycarbonyl-1-indanone derivative (IV) represented by the following general formula: (Wherein R ² represents a lower alkyl group; R ¹ and n have the same meanings as described above) and (4-pyridyl) methyl halide (V) represented by the following general formula: ] (Wherein X represents a halogen atom) or a salt thereof, followed by decarboxylation to give a 2- (4-pyridyl) methyl-1-indanone derivative (III), followed by reaction with a benzyl halide. To produce a donepezil derivative hydrohalide (II), which is further reduced to a quaternary ammonium salt (I). 4. A 1-indanone derivative (VI) represented by the following general formula: (Wherein, R ¹ and n have the same meanings as described above) by converting a carbonate (VII) represented by the general formula (R ² O) ₂ CO (wherein R
² has the same meaning as described above. ) To give a 2-alkoxycarbonyl-1-indanone derivative (IV), and then react with (4-pyridyl) methyl halide (V) or a salt thereof, followed by decarboxylation to give 2- (4-pyridyl) Donepezil derivative hydrohalide, characterized by reacting with methyl-1-indanone derivative (III) and then benzyl halide to form a quaternary ammonium salt (I) and further reducing
Production method of (II). 5. The method according to claim 1, wherein the reduction is performed using platinum oxide, palladium / carbon,
5. The process for producing a donepezil derivative hydrohalide (II) according to claim 1, which is a catalytic reduction in the presence of Raney nickel or ruthenium oxide. 6. The process for producing a donepezil derivative hydrohalide (II) according to claim 1, wherein the halogen atom in the quaternary ammonium salt (I) is a bromine atom, a chlorine atom or an iodine atom. 7. The (4-pyridyl) methyl halide (V) is
7. The composition according to claim 1, which is (4-pyridyl) methyl chloride, (4-pyridyl) methyl bromide or (4-pyridyl) methyl iodide.
The method for producing the donepezil derivative hydrohalide (II) described above. 8. The process for producing a donepezil derivative hydrohalide (II) according to claim 1, wherein the carbonate (VI) is dimethyl carbonate, diethyl carbonate, dipropyl carbonate or methyl ethyl carbonate. 9. Donepezil derivative hydrohalide (I)
9. The process according to claim 1, wherein I) is donepezil hydrochloride, hydrobromide or hydroiodide. 10. A quaternary ammonium salt (I) represented by the following general formula. Embedded image (In the formula, R ¹ , n and X have the same meanings as described above.)