WO2011037244A1

WO2011037244A1 - Novel benzonitrile compounds and method for preparing the same

Info

Publication number: WO2011037244A1
Application number: PCT/JP2010/066750
Authority: WO
Inventors: Seiji Yoshikawa; Akio Kayano
Original assignee: Eisai R&D Management Co., Ltd.
Priority date: 2009-09-25
Filing date: 2010-09-21
Publication date: 2011-03-31
Also published as: JP2012176901A

Abstract

By subjecting a compound represented by the following formula (II):wherein R represents a fluorine atom or a methoxy group and a compound represented by the following formula (III):to a coupling reaction, there can be prepared a compound represented by the following formula (I):wherein R is as defined above, which is a novel intermediate useful for producing a compound which is useful for the treatment of neurodegenerative diseases.

Description

DESCRIPTION

NOVEL BENZONITR1LE COMPOUNDS AND METHOD

FOR PREPARING THE SAME

TECHNICAL FIELD

[0001]

The present invention relates to a novel benzonitrile compound, which is an intermediate of a compound useful as an amyloid beta (hereinafter, referred to as Αβ) production inhibitor effective in treating neurodegenerative diseases caused by Αβ, such as Alzheimer disease and Down syndrome and a method for preparing the same.

A bicyclic cinnamide compound represented by the following formula:

wherein:

represents a single bond or a double bond; An represents a phenyl group or pyridinyl group which is optionally substituted with 1 to 3 substituents; each of R¹ and R² represents a CI -6 alkyl group, a hydroxyl group, or the like; Zi represents an optionally substituted methylene group or vinylene group, an oxygen atom, or an imino group which is optionally substituted with a CI -6 alkyl group or a C 1-6 acyl group; and each of p, q, and r represents an integer of 0 to 2, (PATENT DOCUMENT 1) and a cinnamide compound represented by the following formula:

wherein Αΐι represents an optionally substituted imidazolyl group; Ar₂ represents an optionally substituted phenyl group or the like; and Xi represents an optionally substituted double bond or the like (PATENT DOCUMENT 2) have been known as Αβ production inhibitors. These patent documents disclose, as an intermediate in production of the compound in their working examples, a compound represented by the following formula:

which is a representative example of a 4-imidazolylbenzaldehyde compounds.

PRIOR ART DOCUMENT PATENT DOCUMENT

[0003]

PATENT DOCUMENT 1 : International Publication No. WO 07/060821 pamphlet

PATENT DOCUMENT 2: International Publication No. WO 05/115990 pamphlet

DISCLOSURE OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0004]

However, the methods for preparing the above compounds use expensive reagents; do not have a high yield, due to necessity of column purification and a large number of steps; and impose not a small burden on the environment. Therefore, the method has not been satisfactory as a commercial method.

MEANS FOR SOLVING THE PROBLEMS

[0005]

The present inventor has conducted extensive and intensive studies with a view toward solving the above-mentioned problems, and, as a result, the present invention has been completed. Specifically, the present invention is directed to:

<1> a method for preparing a compound represented by the following formula (I):

wherein R represents a fluorine atom or a methoxy group

or a salt thereof,

wherein the method comprises subjecting a compound represented by the following formula (Π):

wherein R is as defined above

or a salt thereof and a compound represented by the following formula (III): ΝΗ (Ml) or a salt thereof to a coupling reaction;

<2> a method for preparing a compound represented by the following formula (I b):

or a salt thereof,

wherein the method comprises subjecting a compound represented by the following formula (I-a):

or a salt thereof to a methoxylation reaction;

<3> the method for preparing a compound and a salt thereof according to item <2> above, the method comprising subjecting a compound represented by the following formula (Il-a):

r a salt thereof and a compound represented by the following formula (III):

or a salt thereof to a coupling reaction to obtain the compound represented by formula (I-a):

, and further subjecting the compound of formula (I-a) or a salt thereof to a methoxylation reaction after isolation or without isolating the compound of formula (I-a) or a salt thereof;

<4> a method for preparing a compound represented by the following formula

(IV):

or a salt thereof,

wherein the method comprises subjecting a compound represented by the following formula (I-b):

or a salt thereof to a reduction reaction; and

<5> a compound represented by the following formula (I-b):

or a salt thereof.

ADVANTAGE OF THE INVENTION

[0006]

By the present invention, a bicyclic cinnamide compound, which is an Αβ production inhibitor, and a 4-imidazolylbenzaldehyde useful as an intermediate in production of the cinnamide compound can be commercially advantageously prepared through a novel 4- imidazolylbenzonitrile.

MODE FOR CARRYING OUT THE INVENTION

[0007]

Hereinbelow, the preparation method of the present invention will be described in detail.

Preparation method A

wherein R represents a fluorine atom or a methoxy group.

[0008]

Step-A in preparation method A of the present invention can be performed in a flow or atmosphere of inert gas, such as nitrogen gas or argon gas.

The reaction in this method can be conducted in a solvent or without a solvent. The solvent used in the above-described reaction is not particularly limited as long as the starting compounds are dissolved in the solvent to some extent and the solvent does not adversely affect the reaction. Specifically, examples of the solvent include amides, such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, N-methylpyrrolidone, and dimethylimidazolidinone; aromatic hydrocarbons, such as toluene, benzene, xylene, and mesitylene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,

dimethoxyethane, and diethylene glycol dimethyl ether; alcohols, such as methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol, and methyl cellosolve; nitriles, such as acetonitrile and isobutyronitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; esters, such as methyl acetate, ethyl acetate, propyl acetate, and diethyl carbonate; water; and mixed solvents of these solvents. Preferred are amides and sulfoxides, and more preferred are dimethylformamide, N- methylpyrrolidone, and dimethyl sulfoxide.

The reaction temperature is not particularly limited, and is preferably -30°C to the reflux temperature of the solvent, more preferably 0 to 100°C.

The reaction time is not particularly limited, and is preferably 10 minutes to 96 hours, more preferably 30 minutes to 24 hours.

[0009]

The reaction may be conducted either in the absence of a base or in the presence of a base. The base is not particularly limited as long as, for example, a desired compound can be obtained and the base does not form a by-product which cannot be separated from the desired compound. Specifically, examples of the bases include inorganic bases, such as tripotassium phosphate, trisodium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, cesium hydrogencarbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, sodium acetate, barium hydroxide, potassium hydroxide, sodium hydroxide, potassium fluoride, and cesium fluoride; metal alkoxides, such as sodium ethoxide, sodium t-butoxide, and potassium t- butoxide; alkali metal acetates, such as sodium acetate and potassium acetate; and organic bases, such as triethylamine and diazabicycloundecene. Preferred are metal alkoxides and organic bases, and more preferred are potassium t-butoxide and diazabicycloundecene.

The base can be used in an amount of 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of the compound of formula (II) (hereinafter, referred to as compound (II), and a similar abbreviation applies to other compounds).

Compound (ΙΠ) can be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to 1 mol of compound (Π).

In preparation method A of the present invention, compound (II), compound (III), and compound (I) may be in the form of their respective salts. Specific examples of the salt include inorganic acid salts, such as sulfates, nitrates, phosphates, hydrochlorides, and hydrobromates; organic carboxylic acid salts, such as acetates, maleates, tartrates, fiimarates, and citrates; and organic sulfonic acid salts, such as methanesulfonates, toluenesulfonates, and camphorsulfonates. [0010]

[0011]

Step B-l in preparation method B of the present invention can be performed in the same manner as in the above-mentioned step A.

In preparation method B of the present invention, step B-2 can be performed in a flow or atmosphere of inert gas, such as nitrogen gas or argon gas. Prior to this step, compound (I-a) may be or may not be isolated in the previous step.

When the isolation is conducted, methanol is solely used or a mixture of the solvent used in the above-mentioned step A and methanol is used as a solvent for the isolation. When no isolation is conducted, methanol is added to the reaction mixture obtained in the above- mentioned step A and the reaction in this step is conducted.

In this step, the reaction is generally conducted in the presence of a base. The base is not particularly limited as long as, for example, a desired compound can be obtained and the base does not form a by-product which cannot be separated from the desired compound. Specifically, examples of the base can include inorganic bases, such as tripotassium phosphate, trisodium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, cesium hydrogencarbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, sodium acetate, barium hydroxide, potassium hydroxide, sodium hydroxide, potassium fluoride, and cesium fluoride; metal alkoxides, such as sodium ethoxide, sodium t-butoxide, and potassium t- butoxide; alkali metal acetates, such as sodium acetate and potassium acetate; and organic bases, such as triethylamine and diazabicycloundecene. Preferred are inorganic bases, and more preferred are potassium carbonate and cesium carbonate.

The base can be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to 1 mol of compound (Il-a).

The reaction temperature is not particularly limited, and is preferably 30°C to the reflux temperature of the solvent, more preferably 50 to 100°C.

The reaction time is not particularly limited, and is preferably 1 to 48 hours. Also in preparation method B of the present invention, compound (H-a), compound (ΠΙ), compound (I-a), and compound (I-b) may be in the form of their respective salts. Examples of the salt can include those mentioned above as examples of the salt.

[0012]

Preparation method C

[0013]

Step C in preparation method C of the present invention can be performed in a flow or atmosphere of inert gas, such as nitrogen gas or argon gas.

The reaction in this method can be conducted by reacting compound (I-b) with a reducing agent. Examples of the reducing agent can include sodium bis(2- methoxyethoxy)aluminum hydride (Vitride (TM); manufactured by Sigma-Aldrich Corporation) and diisobutylaluminum hydride.

The reducing agent can be used in an amount of 1 to 2 equivalents, preferably 1 to 1.5 equivalents, in terms of a hydrogen anion (hydride), relative to 1 mol of compound (I-b).

The reaction in this method can generally be conducted in a solvent. The solvent used in the reaction is not particularly limited as long as the starting substance is dissolved in the solvent to some extent and the solvent does not adversely affect the reaction. Specifically, examples of the solvent can include aromatic hydrocarbons, such as toluene, benzene, xylene, and mesitylene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; and mixed solvents of these solvents. Preferred are tetrahydrofuran, toluene, and mixed solvents thereof.

The reaction temperature is not particularly limited, and is preferably -70 to 30°C, more preferably -30 to 0°C.

The reaction time is not particularly limited, and is preferably 10 minutes to 10 hours, more preferably 30 minutes to 2 hours.

[0014]

Also in preparation method C of the present invention, compound (I-b) and compound (IV) may be in the form of their respective salts. Examples of the salt can include those mentioned above as examples of the salt.

Compound (Π-a), compound (II), and compound (III) are known compounds and easily available.

[0015]

Hereinbelow, the present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the scope of the present invention. In the present specification, the term room temperature means a temperature in the range of from 20 to 30°C, preferably about 25°C.

HPLC conditions are as follows.

HPLC conditions 1 : Examples 1, 2, and 5

• Detector: UV 254 nm

· Column: Inertsil ODS-3V (4.6 x 250 mm), manufactured by GL Sciences, Inc.

• Mobile layers:

Eluent A: 20 mM Aqueous ammonium acetate solution/methanol (50:50, v/v) mixture

Eluent B: Methanol

Gradient conditions

Time/B cone (%) = 0/40→ 30/90→ 40/90→ 40.01/40→ 50/Stop

• Column temperature: 40°C

• Flow rate: Constant flow rate around 1.0 mL/min

• Sample temperature: Room temperature

· Injection volume: 10 uL

• Run time: 40 Minutes

HPLC conditions 2: Examples 3 and 4 and Preparation Examples 1 and 2

• Detector: UV 210 and 245 nm

• Column: XBridge Shield RP18 (4.6 x 150 mm), manufactured by Waters Corporation

· Mobile layers:

Eluent A: Acetonitrile:water:phosphoric acid: sodium perchlorate monohydrate (10:990:1:8.5, v/v/v/w)

Eluent B: Acetonitrile:water:phosphoric acid:sodium perchlorate monohydrate (800:200:1:8.5, v/v/v/w)

Gradient conditions

Time/B cone (%) = 0/0→ 10/15→ 35/40→ 37/100→ 45/Stop

• Column temperature: 35°C

• Flow rate: Constant flow rate around 0.7 mL/min • Sample temperature: 10°C

• Injection volume: 10 uL

• Run time: 45 Minutes

[Example 1]

[0016]

Synthesis of 3-fluoro-4-(4-methyl-lH-imidazol-l-yl)benzonitrile (Synthesis of compound (I-a) by step B-l of preparation method B)

4-Methylimidazole (2.71 g, 33 mmol) was dissolved in N,N-dimethylformamide (15 mL) in a nitrogen gas flow, and the resultant solution was cooled to 7°C. To the solution was added potassium tert-butoxide (3.7 g, 33 mmol) at an internal temperature of 5 to 10°C while stirring, and N,N-dimethylformamide (6 mL) was further added to ensure complete mixing. The resultant suspension was stirred at an external temperature of 10°C for 30 minutes and then, to the suspension was added dropwise a solution of 3,4-difluorobenzonitrile (4.17 g, 30 mmol) in N,N-dimethylformamide (4.1 mL) at an internal temperature of 10 to 15°C, and N,N- dimethylformamide (2 mL) was further added to ensure complete mixing. The resultant reaction mixture was stirred at an external temperature of 10°C for one hour, and the progress of the reaction was confirmed by HPLC. The reaction mixture was diluted with ethyl acetate (27 mL), and then a 5% aqueous ammonium chloride solution (21 mL) was added to the diluted mixture while stirring. The aqueous layer was separated, and then the organic layer was washed with a 5% aqueous sodium chloride solution (12 mL) twice and then with water (12 mL). The solvent was distilled off under a reduced pressure, and then ethyl acetate was added to the residue and distilled off, and further dried under a reduced pressure to obtain 4.54 g of a solid material. The ¹ H-NMR spectrum showed that the amount of the title compound contained in the solid material was 3.1 g. Yield: 50%.

1H-NMR (400 MHz, CD₃OD/ppm); 8.03-8.02 (lH, m), 7.85 (lH, dd, J=10.8, 2.0 Hz), 7.79-7.70 (2H, m), 7.29-7.28 (1H, m), 2.26 (3H, d, J=1.2 Hz).

[Example 2]

[0017]

Synthesis of 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzonitrile (Synthesis of compound (I- b) by steps B-l and B-2 of preparation method B)

N-Methylpyrrolidone (11 mL) containing potassium tert-butoxide (3.53 g, 31.5 mmol) was cooled to 7°C in a nitrogen gas flow while stirring. To the resultant solution was added a solution, which had been prepared by dissolving 4-methylimidazole (2.71 g, 33 mmol) in N-methylpyrrolidone (11 mL), at an internal temperature of 7 to 13 °C while stirring, and N- methylpyrrolidone (1.4 mL) was further added to ensure complete mixing, and the resultant mixture was stirred at 10°C for one hour. To the mixture was added dropwise a solution of 3,4- difluorobenzonitrile (4.17 g, 30 mmol) in N-methylpyrrolidone (8.4 mL) at an internal temperature of 10 to 13°C, the resultant reaction mixture was stirred at 10°C for one hour, and the progress of the reaction was confirmed by HPLC. To the reaction mixture were added methanol (29 mL) and potassium carbonate (6.2 g), followed by heating at 70°C for 19 hours while stirring. After cooling to room temperature, water (45 mL) and ethyl acetate (40 mL) were added to the reaction mixture to perform an extraction, and the aqueous layer was separated and then, the organic layer was washed with a 10% aqueous sodium chloride solution (40 mL). The washing solution was extracted twice with ethyl acetate (60 mL, 40 mL), and then above organic layers were combined and washed twice with a 10% aqueous sodium chloride solution (40 mL x 2) and then once with water (40 mL). The organic layer was concentrated under reduced pressure, and ethyl acetate was added to the concentrate and further distilled off to obtain a crude product (7.05 g). Ethyl acetate (33 mL) was added to the crude product, the mixture was heated to 65 to 70°C to dissolve the crude product in ethyl acetate, and tert-butyl methyl ether (33 mL) was slowly added dropwise to the resultant solution so that the internal temperature was not lower than 60°C. Then, the solution was cooled to 50°C while stirring. Deposition of solids was confirmed at about 50°C, and then the slurry was gradually cooled to 23 °C over 1.5 hours. The slurry was further cooled to 10°C, and, after 19 hours, the solids were collected by filtration, washed with an ethyl acetate/tert-butyl methyl ether (1:1) mixture (2 mL) which was cooled to 10°C in advance, and dried under reduced pressure at 45°C for 1.5 hours to obtain 2.49 g of a title compound. Yield: 39%.

1H-NMR (600 MHz, CD₃OD/ppm); 7.91 (IH, d, J=1.2 Hz), 7.59 (IH, d, J=1.8 Hz), 7.54 (IH, d, J=7.8 Hz), 7.44 (IH, dd, J=7.8, 1.8 Hz), 7.158-7.156 (IH, m), 3.94 (3H, s), 2.23 (3H, d, J=1.2 Hz).

[Example 3]

[0018]

Synthesis of 3-methoxy-4-(4-methyl-lH-imidazol-l-vnbenzonitrile (Synthesis of compound (I- b) by steps B-1 and B-2 of preparation method B. which is different from the method in Example B

A mixture of 4-methylimidazole (25.0 g, 305 mmol), 3,4-difluorobenzonitrile (12.1 g, 87.0 mmol), and dimethyl sulfoxide (36.3 mL) was heated to 90°C in an argon gas atmosphere while stirring. The mixture was stirred at 90°C for 24 hours, and then cooled to room temperature, and then the progress of the reaction was confirmed by HPLC. To the resultant reaction mixture were added methanol (50 mL) and potassium carbonate (30.1 g, 218 mmol), followed by heating at 70°C for 76 hours while stirring. The reaction mixture was cooled to room temperature, then ethyl acetate (120 mL) and water (230 mL) were added to the reaction mixture to perform an extraction, the aqueous layer was separated and then the organic layer was washed with a 10% aqueous sodium chloride solution (50 mL) four times and then with water (50 mL). The organic layer was concentrated under reduced pressure to obtain 19.0 g of a crude product. The obtained crude product was dissolved in ethyl acetate (60.5 mL) at 70°C, tert-butyl methyl ether (120 mL) was added thereto over 5 minutes, and the resultant solution was stirred for 14.5 hours so that the solution was naturally cooled to room temperature, and further cooled at 6°C for 7 hours while stirring. The solids collected by filtration were washed twice with an ethyl acetate/tert-butyl methyl ether (1:9) mixture (12 mL) which was cooled with ice in advance, and dried in a nitrogen gas flow to obtain 5.88 g of a title compound. Yield: 32%.

[Example 4]

[0019]

Synthesis of 3-methoxy-4-(4-methyl-lH-imidazol-l-ynbenzonitrile (Synthesis of compound (I) wherein R is a methoxy group by step A of preparation method A)

4-Methylimidazole (249 mg, 3.03 mmol), 4-fluoro-3-methoxybenzonitrile (417 mg, 2.76 mmol), and cesium carbonate (1.89 g, 5.80 mmol) were placed in a reaction vessel in a nitrogen gas atmosphere, N,N-dimethylformamide (5.0 mL) was added to the vessel and the resultant mixture was stirred at room temperature for 96 hours. To the reaction mixture were successively added water (2 mL) and ethyl acetate (6 mL) to perform an extraction, and the aqueous layer was separated and then, the organic layer was washed with water (5 mL). To the organic layer were added ethyl acetate (5 mL) and water (5 mL) to perform an extraction, and the aqueous layer was separated and then, the organic layer was washed with water (5 mL) and concentrated under a reduced pressure to obtain 499 mg of a crude product. To the crude product was added tert-butyl methyl ether (2.5 mL) to obtain a suspension, and the solids collected by filtration of the suspension were washed with tert-butyl methyl ether/heptane (2.5 ml; 1 :3) three times to obtain 431 mg of a crude product. To the obtained crude product was added tert-butyl methyl ether (4.3 mL) in a nitrogen gas atmosphere, and the resultant mixture was stirred at 50°C for 30 minutes and then naturally cooled to room temperature, and the solids collected by filtration were washed with tert-butyl methyl ether/heptane (2.1 mL; 1 :3) twice and dried under a reduced pressure to obtain 310 mg of a title compound. Yield: 53%.

[Example 5]

[0020]

Synthesis of 3-methoxy-4-(4-methyl-lH-imidazol-l-yDbenzaldehyde (Synthesis of compound (IV) by step C of preparation method C)

3-Methoxy-4-(4-methyl-lH-imidazol-l-yl)benzonitrile (3.50 g, 16.4 mmol) was suspended in tetrahydrofuran (31.6 ml) in a nitrogen gas atmosphere at -10°C and then, to the resultant suspension were added dropwise a Vitride (TM, manufactured by Sigma- Aldrich Corporation) toluene solution (65 wt%, 3.47 g, 11.2 mmol) using a syringe. After completion of the dropwise addition, the solution was stirred at -10°C for one hour, and disappearance of the raw material was confirmed by TLC (silica gel; developing solvent: ethyl acetate; UV detector). Acetone (0.26 mL, 3.58 mmol) was added to the reaction mixture and stirred for 10 minutes, and then the resultant mixture was added dropwise to 5 M hydrochloric acid (18 mL) cooled at 7°C while stirring, followed by temperature elevation to room temperature. The resultant solution was added dropwise to a mixture of a 5 M aqueous sodium hydroxide solution (20.4 mL) and toluene (32 mL), which was cooled to 7°C in advance, while stirring, and the temperature of the resultant mixture was elevated to room temperature. The lower layer (aqueous layer) was separated from the organic layer, the aqueous layer was further extracted with toluene (18 mL) and the toluene layer and the above organic layer were combined. The combined organic layer was washed with a 10% aqueous sodium chloride solution (18 mL x 4) and then filtered through a Celite (1 g) pad, and the resultant filtrate was concentrated under a reduced pressure at a water bath temperature of 50°C. The residue was further subjected to azeotropic distillation with toluene under a reduced pressure to obtain 3.70 g of a crude product containing a title compound.

The obtained crude product was dissolved in a mixture of toluene (3.5 mL) and acetone (7 mL) at 60°C, and n-heptane (15.8 mL) was slowly added dropwise to the resultant solution while stirring so that the internal temperature was maintained at 50°C or higher. After completion of the dropwise addition, the solution was subjected to crystallization (seed crystal: lot# A6103102) at 53°C, the water bath was removed and the slurry was gradually cooled to room temperature and stirred overnight. The resultant slurry was further cooled to 7°C and stirred for 9 hours and 30 minutes, and then the solids were collected by filtration and washed with an acetone/n-heptane (1/3) mixture which was cooled to 7°C in advance, and dried under a reduced pressure at 45 to 50°C for 1.5 hours to obtain 2.64 g of a title compound (yield: 74.4%). The quantitative determination by HPLC showed that the loss of the compound into the mother liquor was 0.435 g (12.3%).

The above-obtained title compound (2.64 g) and the mother liquor (containing 0.435 g of the compound) were mixed together, the mixture was concentrated, the concentrate was dissolved in a mixture of toluene (3 mL), acetone (6 mL), and tert-butyl methyl ether (18 mL), which was warmed at 48°C, and then the resultant solution was cooled to 42°C to perform a crystallization. The resultant slurry was gradually cooled to room temperature and stirred overnight. To the slurry was further added dropwise tert-butyl methyl ether (9 mL), and then the resultant mixture was stirred for one hour, cooled to 8°C and stirred for one hour, followed by stirring at 4°C overnight (17 hours). The solids were collected by filtration and dried under a reduced pressure to obtain 1.97 g of a title compound (yield: 64.6%). The quantitative determination by HPLC showed that the loss of the compound into the mother liquor was 0.674 g (22%).

Preparation Example 1

[0021]

Synthesis of 3-methoxy-4-(4-methyl-lH-imidazol-l-ynbenzoic acid hydrochloride

3-Methoxy-4-(4-methyl-lH-imidazol-l-yl)benzonitrile (100 mg, 0.469 mmol) was placed in a reaction vessel, and a 5 M aqueous sodium hydroxide solution (1 mL) and methanol (2 mL) were successively added to the vessel. The resultant mixture was stirred at room temperature for 2 hours, and then further stirred at 65°C for 5 hours. The resultant reaction mixture was concentrated under a reduced pressure, and a 2 M aqueous hydrochloric acid solution (4 mL) and water (4 mL) were successively added to the concentrate. The solids collected by filtration were dried under a reduced pressure to obtain 98 mg of a title compound. Yield: 78%.

Preparation Example 2

[0022]

Synthesis of methyl 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzoate To a mixture of 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzoic acid hydrochloride (50 mg, 0.186 mmol) and methanol (1 mL) was added thionyl chloride (28.3 uL) in a nitrogen gas atmosphere while cooling with ice. The reaction mixture was stirred at room temperature for 2.3 hours, and then further stirred at 65°C for 1.7 hours. The resultant reaction mixture was concentrated under a reduced pressure, and ethyl acetate (8 mL) and a 1 M aqueous sodium hydroxide solution (4 mL) were added to the concentrate and the aqueous layer was separated and then, the organic layer was successively washed with a 1 M aqueous sodium hydroxide solution (1 mL) and water (1 mL). The organic layer was concentrated under a reduced pressure to obtain 47 mg of a title compound. Yield: >99%.

INDUSTRIAL APPLICABILITY

[0023]

In the present invention, there are provided a novel benzonitrile compound useful as an intermediate for producing a compound which is useful for the treatment of

neurodegenerative diseases, such as Alzheimer disease and Down syndrome and a method for preparing the same.

Claims

A method for reparing a compound represented by the following formula (I):

wherein R represents a fluorine atom or a methoxy group

or a salt thereof,

the method comprising subjecting a compound represented by the following formula (II):

wherein R is as defined above

or a salt thereof and a compound represented by the following formula (III): ΝΗ (Ml) or a salt thereof to a coupling reaction.

2. A method for preparing a compound represented by the following formula (I-b):

or a salt thereof,

the method comprising subjecting a compound represented by the following formula (I-a):

or a salt thereof to a methoxylation reaction.

3. The method for preparing a compound and a salt thereof according to claim 2, the method comprising subjecting a compound represented by the following formula (Il-a):

or a s lt thereof and a compound represented by the following formula (ΠΙ):

, and further subjecting the compound of formula (I-a) or a salt thereof to a methoxylation reaction after isolation or without isolating the compound of formula (I-a) or a salt thereof.

4. A method for preparing a compound represented by the following formula (IV):

or a salt thereof,

the method comprising subjecting a compound represented by the following formula (I-b):

or a salt thereof to a reduction reaction.

5. A compound represented by the following formula (I-b):

or a salt thereof.