KR100368895B1 - A process for preparing 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one - Google Patents

Abstract

The present invention provides 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4 represented by the following Chemical Formula 1 The present invention relates to a method for preparing a temperature, and more particularly, to solve the problem of generating a large number of side reaction substances in the conventional manufacturing method and the trouble of carrying out a cumbersome process for separating and purifying intermediates. It relates to a method for producing a compound represented by.

Formula 1

Description

Method for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one {A process for preparing 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one}

The present invention provides 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4 represented by the following Chemical Formula 1 Regarding a method for preparing -one, more specifically, 4H-carbazol-4-one represented by the following Chemical Formula 2 and an amine compound represented by the following Chemical Formula 3 are reacted with a predetermined catalyst to synthesize an enamine intermediate, By reacting the synthesized enamine intermediate with dihalogenated methane and then continuously reacting with 2-methylimidazole to prepare a compound represented by the following formula (1), a number of side reaction substances as in the conventional production method via an imine intermediate And 1,2,3,9-tetrahydro-9-methyl- represented by the following Chemical Formula 1 by a one-pot reaction without performing a cumbersome process for intermediate separation and purification 3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one industrially It relates to a process for advantageously made of.

Wherein R ¹ and R ² are the same as or different from each other and are a hydrogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _2-6 alkenyl group, a phenyl group or a phenyl-C _1-3 alkyl group, or R ¹ and R ² may be bonded together with a nitrogen atom to form a heterocyclic ring of 5 to 6 elements including a pyrrolidine ring, a piperidine ring and a morpholine ring.

The compound represented by the formula (1) is known to have an antagonistic action on the 'neuronal' 5-HT receptor of the form located at the terminal of the primary afferent nerves, and also a variety of researches on the preparation method thereof.

Brief description of the conventional method for preparing the compound represented by Formula 1 or a derivative thereof is as follows.

U.S. Patent No. 4,695,578 discloses an intermediate compound synthesized via an imine derivative as an intermediate by reacting the compound represented by Formula 2 with the compound represented by Formula 3 in the presence of formaldehyde and acetic acid, as shown in Scheme 1 below. A method for producing the desired compound by reacting with methylimidazole is described.

In Scheme 1, R ^a represents a hydrogen atom, a C _1-10 alkyl group, a C _3-7 cycloalkyl group, a C _3-6 alkenyl group, a C _3-7 cycloalkyl- (C _1-4 ) alkyl group, C _3-6 An alkynyl group, a phenyl group or a phenyl-C _1-3 alkyl group; R ^b , R ^c and R ^d are the same as or different from each other and are a hydrogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _2-6 alkenyl group, a phenyl group or a phenyl-C _1-3 alkyl group.

In the case of the conventional production method according to Scheme 1, formaldehyde is used as a reactant in the presence of acetic acid, and a large number of side reactions are generated due to the possibility of the formation of di-substituted or dimers or polymers instead of mono-substitutes. In the manufacturing process, the intermediate separation and purification process must be performed prior to the reaction with the imidazole compound, and if the reaction with the imidazole compound is performed without performing this separation and purification process, the yield decrease and the difficulty of purification are performed. have.

As another preparation method, EP 191,562 describes a process for preparing the desired compound by reacting an ammonium salt intermediate with 2-methylimidazole, as shown in Scheme 2 below.

In Scheme 2: R ^a , R ^b , R ^c and R ^d are as defined in Scheme 1, respectively.

In the conventional preparation method according to Scheme 2, since the amine group of the starting material should be in the form of a free base, there is a problem that a reaction step of removing the salt in the entire reaction process should be added.

Accordingly, the present inventors use a number of conventional methods for preparing the compound represented by Chemical Formula 1 by using 4H-carbazol-4-one represented by Chemical Formula 2 and the amine compound represented by Chemical Formula 3 as starting materials. Efforts have been made to solve the problem of the formation of side reactions and the hassle of performing intermediate separation and purification. As a result, the 4H-carbazol-4-one represented by Chemical Formula 2 and the amine compound represented by Chemical Formula 3 are reacted under a specific catalyst to synthesize an enamine derivative as an intermediate first, and to dehalogenate the synthesized enamine intermediate. When reacted with methane and then with 2-methylimidazole, the present invention was completed by knowing that the reaction can be completed in a daily container without the cumbersome process for intermediate separation purification.

Accordingly, an object of the present invention is to provide a method for preparing the compound represented by Formula 1 as a more economical manufacturing method.

In the method for preparing a compound represented by the following formula 1 using 4H- carbazol-4-one represented by the following formula (2) and the amine compound represented by the following formula (3) as a starting material,

After reacting the dihalogenated methane represented by the following formula (5) to the enamine intermediate obtained by reacting the 4H-carbazol-4-one represented by the formula (2) with the amine compound represented by the formula (3) under a catalyst, 2- 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imide) represented by the following Chemical Formula 1 by a one-pot reaction by reacting methylimidazole It is characterized by a process for preparing dazol-1-yl) methyl] -4H-carbazol-4-one or pharmaceutically acceptable salts thereof or solvates thereof.

Formula 2

Formula 3

Formula 1

Wherein R ¹ and R ² are the same as or different from each other and are a hydrogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _2-6 alkenyl group, a phenyl group or a phenyl-C _1-3 alkyl group, or R ¹ and R ² may be bonded together with a nitrogen atom to form a heterocycle cyclized with 5 to 6 elements including a pyrrolidine ring, a piperidine ring and a morpholine ring; X, X ¹ and X ² are the same or different and are halogen elements including iodine, bromine, chloride.

Hereinafter, the process of preparing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention will be described in detail by each process.

First, 4H-carbazol-4-one represented by the following formula (2) is reacted with an amine compound represented by the following formula (3) to prepare an enamine derivative represented by the following formula (4) as an intermediate.

In carrying out the reaction as described above, as the amine compound represented by the formula (3), it is more preferable to use heterocyclic amine compounds such as pyrroline, piperidine and morpholine, heterocyclic amine compounds For the reaction used, there is a useful point to react quantitatively.

The reaction of 4H-carbazol-4-one represented by Chemical Formula 2 with the amine compound represented by Chemical Formula 3 may be performed by using a catalyst such as titanium chloride, p-toluenesulfonic acid, anhydrous potassium carbonate, or the like. It may be performed at 0 ° C. to 100 ° C. in an organic solvent such as toluene, acetonitrile or dioxane. The production method according to the present invention has the greatest feature in synthesizing the enamine derivative represented by Chemical Formula 4 as an intermediate. In the present invention, a specific catalyst is used as a reaction catalyst in reacting the compounds represented by Chemical Formulas 2 and 3. The enamine derivative was synthesized as an intermediate by the selective use, and thus the target compound of Chemical Formula 1 was synthesized through the transfer reaction and the substitution reaction in the reaction with dihalogenated methane and the reaction with dimethylimazole. It is. That is, the present invention is to set the reaction conditions as described above to design the reaction to produce the enamine derivative as an intermediate, the conventional manufacturing method should be carried out after the separation and purification of the intermediate produced during the reaction process with the imidazole compound It completely eliminates the hassle of the manufacturing process.

Then, after the substitution reaction of the synthesized enamine intermediate represented by the formula (4) with dihalogenated methane, the compound represented by the following formula (5) through a hydrolysis reaction, the compound represented by the following formula (6) by the mechanism as shown below To prepare.

The substitution reaction between the enamine intermediate represented by the formula (4) and the compound represented by the formula (5) in the reaction scheme is carried out at 0 ℃ to 100 ℃ in a solvent such as alcohols, chloroform, methylene chloride, benzene, toluene, acetonitrile, dioxane, etc. To perform. In addition, it is preferable to add the compound represented by the said Formula (5) in 1-10 equivalent ratio. Subsequently, the hydrolysis reaction carried out continuously is carried out at room temperature to 100 ° C using an excess of purified water.

Thereafter, the compound represented by Chemical Formula 6 is substituted with 2-methylimidazole to prepare a compound represented by Chemical Formula 1, which is an object of the present invention.

In the substitution reaction, 2-methylimidazole is added at a ratio of 1 to 10 equivalents, and the reaction is carried out at 0 ° C. to 100 ° C. under a solvent such as alcohol such as methanol to obtain a compound represented by the above formula (1).

In the preparation method according to the present invention described above it is characterized in that the reaction proceeds continuously without separation of the compound produced in each reaction step, and if necessary to separate and purify the intermediate produced in the reaction process to the next reaction It can also be done. In the process of carrying out the preparation method of the present invention, the method of separating and purifying a compound synthesized as an intermediate or a target compound is performed by conventional methods such as chromatography and recrystallization.

The compound represented by Chemical Formula 1 prepared by the above production method may be synthesized as a salt or a solvate by a conventional method as well as the compound itself. For example, the compound represented by Formula 1 may be an acid, for example an organic or inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, lactic acid, maleic acid, succinic acid and tartaric acid, or sodium, potassium It is also possible to form pharmaceutically acceptable salts thereof with alkali metal ions and ammonium ions such as these.

Meanwhile, the 4H-carbazol-4-one represented by Formula 2 and the amine compound represented by Formula 3, which are used as starting materials in the present invention, are known compounds and are commercially available or known synthetically. Method [ J. Med. Chem. 1993, 36, 3693 ].

The present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1 Synthesis of 9-methyl-3- (N-pyrrolidinyl) methyl-2,3-dihydro-4H-carbazol-4-one iodide

Pyrrolidine (662 g) was dissolved in 4 L of methylene chloride and cooled to 0 ° C., followed by dropwise addition of a solution of titanium chloride (302 g) diluted in 1.4 L of methylene chloride. After stirring for 5 minutes, 9-methyl-2,3-dihydro-4H-carbazol-4-one (239 g) was added in one portion, heated to reflux for 4 hours, filtered and concentrated to form a slightly impure enamine intermediate. Got.

The synthesized enamine intermediate was dissolved in 3.1 L of dioxane and 1.1 L of methylene chloride, and then diiodomethane (351 g) was added and refluxed at 80 ° C. for 18 hours. 0.5 L of water was added, the mixture was further refluxed for 1 hour, and then concentrated. The residue was purified by column chromatography [eluent: methylene chloride / methanol = 10/1 (v / v)] to obtain 340 g of the title compound ( Yield 69%).

Melting Point: 220 ~ 222 ℃

TLC (silica phase; chloroform / methanol / ammonia water = 4/2 / 0.1 (v / v / v)): r.f. 0.44

¹ H-NMR (DMSO-d ₆ ): δ 1.82 to 2.12 (m, 5H, pyrrolidine, C ₂ -H), 2.28 to 2.39 (m, 1H, C ₂ -H), 3.02 to 3.34 (m, 6H, pyrrolidine, C ₁ -H), 3.56 to 3.74 (m, 3H, C ₃ -H, N-CH ₂ ), 3.78 (s, 3H, N-CH ₃ ), 7.18 to 8.02 (m, 4H , Ar-H), 9.24 (brd. S, 1H, HI).

Example 2: Synthesis of 9-methyl-3- (N-pyrrolidinyl) methyl-2,3-dihydro-4H-carbazol-4-one bromate

Pyrrolidine (662 g) was dissolved in 4 L of methylene chloride and cooled to 0 ° C., followed by dropwise addition of a solution of titanium chloride (302 g) diluted in 1.4 L of methylene chloride. After stirring for 5 minutes, 9-methyl-2,3-dihydro-4H-carbazol-4-one (239 g) was added all at once, heated to reflux for 4 hours, filtered and concentrated to give somewhat impure enamine An intermediate was obtained.

The synthesized enamine intermediate was dissolved in 3.1 L of dioxane and 1.1 L of methylene chloride, and then bromochloromethane (233 g) was added and refluxed at 80 ° C. for 18 hours. 0.5 L of water was added thereto, the mixture was further refluxed for 1 hour, and then concentrated. The residue was purified by column chromatography [eluent: methylene chloride / methanol = 10/1 (v / v)] to give 170 g of the titled compound. Yield 39%).

Melting Point: 201 ~ 203 ℃

TLC (silica phase; chloroform / methanol / ammonia water = 4/2 / 0.1 (v / v / v)): r.f. 0.43

¹ H-NMR (DMSO-d ₆ ): δ 1.84 to 2.13 (m, 5H, pyrrolidine, C ₂ -H), 2.29 to 3.01 (m, 1H, C ₂ -H), 3.01 to 3.34 (m, 6H, pyrrolidine, C ₁ -H), 3.66 to 3.77 (m, 3H, C ₃ -H, N-CH ₂ ), 3.79 (s, 3H, N-CH ₃ ), 7.18 to 8.02 (m, 4H , Ar-H), 9.11 (brd. S, 1H, HI).

Example 3: Synthesis of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one

Method A

9-methyl-3- (N-pyrrolidinyl) methyl-2,3-dihydro-4H-carbazol-4-one iodide (49.1 g) and 2-methylimidazole (29.5 g) in purified water 0.5 Suspended in l and then heated to 100 ° C. for 20 hours with stirring and then cooled to room temperature. The resulting solid was filtered, dried and recrystallized with methanol to give 25 g (yield 71.2%) of the title compound.

Melting Point: 231 ~ 232 ℃

TLC (silica phase; chloroform / methanol / water = 4/2 / 0.1 (v / v / v)): r.f. 0.51

¹ H-NMR (DMSO-d ₆ ): δ 1.80 to 1.91 (m, 1H, C ₂ -H), 1.98 to 2.2 (m, 1H, C ₂ -H), 2.33 (s, 3H, CH ₃ ), 2.83 to 3.0 (m, 2H, C ₁ -H), 3.02 to 3.16 (m, 1H, C ₃ -H), 3.7 (s, 3H, N-CH ₃ ), 4.12 (dd, 1H, N-CH ₂ ), 4.4 (dd, 1H, N-CH ₂ ), 6.70 to 7.04 (d, 2H, imidazole), 7.13 to 8.03 (m, 4H, Ar-H).

Method B.

9-methyl-3- (N-pyrrolidinyl) methyl-2,3-dihydro-4H-carbazol-4-one bromate (43.5 g) and 2-methylimidazole (29.5 g) in 0.5 L purified water Suspended in and then heated to 100 ° C for 20 hours with stirring and then cooled to room temperature. The resulting solid was filtered, dried and recrystallized with methanol to give 24 g (68.4%) of the title compound.

Melting Point: 231 ~ 232 ℃

TLC (silica phase; chloroform / methanol / water = 4/2 / 0.1 (v / v / v)): r.f. 0.51

¹ H-NMR (DMSO-d ₆ ): δ 1.80 to 1.91 (m, 1H, C ₂ -H), 1.98 to 2.2 (m, 1H, C ₂ -H), 2.33 (s, 3H, CH ₃ ), 2.87 to 3.0 (m, 2H, C ₁ -H), 3.02 to 3.16 (m, 1H, C ₃ -H), 3.7 (s, 3H, N-CH ₃ ), 4.12 (dd, 1H, N-CH ₂ ), 4.42 (dd, 1H, N-CH ₂ ), 6.70 to 7.04 (d, 2H, imidazole), 7.11 to 8.03 (m, 4H, Ar-H).

Method C.

Pyrrolidine (66.2 g) was dissolved in 0.4 L of methylene chloride and cooled to 0 ° C., and then a solution of titanium chloride (30.2 g) diluted in 0.14 L of methylene chloride was added dropwise. After stirring for 5 minutes, 9-methyl-2,3-dihydro-4H-carbazol-4-one (23.9 g) was added in one portion, heated to reflux for 4 hours, filtered and concentrated to give somewhat impure enamine An intermediate was obtained.

The synthesized enamine intermediate was dissolved in 0.3 L of dioxane and 0.1 L of methylene chloride, and then diiodomethane (35.1 g) was added and refluxed at 80 ° C. for 18 hours. 50 ml of water were added and refluxed for another hour, followed by concentration to give a somewhat impure 9-methyl-3- (N-pyrrolidinyl) methyl-2,3-dihydro-4H-carbazol-4-one iodide. Got it. The residue and 2-methylimidazole (29.5 g) were suspended in 0.5 L of purified water, heated to 100 DEG C for 20 hours with stirring, and then cooled to room temperature. The resulting solid was filtered, dried and dissolved in 2.4 L of methanol, and then treated with activated carbon and filtered. The filtrate was concentrated and recrystallized with methanol to give 16.9 g (48% yield) of the title compound.

Melting Point: 231 ~ 232 ℃

TLC (silica phase; chloroform / methanol / water = 4/2 / 0.1 (v / v / v)): r.f. 0.51

¹ H-NMR (DMSO-d ₆ ): δ 1.81 to 1.91 (m, 1H, C ₂ -H), 1.98 to 2.2 (m, 1H, C ₂ -H), 2.33 (s, 3H, CH ₃ ), 2.82 to 3.0 (m, 2H, C ₁ -H), 3.01 to 3.16 (m, 1H, C ₃ -H), 3.7 (s, 3H, N-CH ₃ ), 4.12 (dd, 1H, N-CH ₂ ), 4.43 (dd, 1H, N-CH ₂ ), 6.70 to 7.04 (d, 2H, imidazole), 7.13 to 8.03 (m, 4H, Ar-H).

Method D.

Pyrrolidine (66.2 g) was dissolved in 0.4 L of methylene chloride and cooled to 0 ° C. A solution diluted with 0.14 L of titanium chloride (30.2 g) was added dropwise. After stirring for 5 minutes 9-methyl-2,3-dihydro-4H-carbazol-4-one (23.9 g) was added in one portion. Heated to reflux for 4 hours, filtered and concentrated to afford a somewhat impure enamine intermediate.

The intermediate was dissolved in 0.3 L of dioxane and 0.1 L of methylene chloride, bromochloromethane (23.3 g) was added, and the mixture was refluxed at 80 DEG C for 18 hours. 50 ml of water were added and further refluxed for 1 hour, followed by concentration to give a somewhat impure 9-methyl-3- (N-pyrrolidinyl) methyl-2,3-dihydro-4H-carbazol-4-one bromate . This residue and 29.5 g of 2-methylimidazole were suspended in 0.5 L of purified water, heated to 100 DEG C for 20 hours with stirring, and then cooled to room temperature to give a solid. The resulting solid was filtered, dried and dissolved in 2.4 L of methanol, and then treated with activated carbon and filtered. The filtrate was concentrated and recrystallized with methanol to give 12.3 g (35%) of the title compound.

Melting Point: 231 ~ 232 ℃

TLC (silica phase; chloroform / methanol / water = 4/2 / 0.1 (v / v / v)): r.f. 0.51

¹ H-NMR (DMSO-d ₆ ): δ 1.8 to 1.89 (m, 1H, C ₂ -H), 1.98 to 2.1 (m, 1H, C ₂ -H), 2.31 (s, 3H, CH ₃ ), 2.82 to 3.0 (m, 2H, C ₁ -H), 3.02 to 3.15 (m, 1H, C ₃ -H), 3.72 (s, 3H, N-CH ₃ ), 4.16 (dd, 1H, N-CH ₂ ), 4.43 (dd, 1H, N-CH ₂ ), 6.71 to 7.05 (d, 2H, imidazole), 7.15 to 8.04 (m, 4H, Ar-H).

Example 4 Synthesis of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate

1,2,3,9-tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one (118.3 g) with 118.6 mL of purified water It was suspended in 633.5 ml of isopropanol and then concentrated hydrochloric acid (42.8 ml) was added slowly. After addition, the mixture was dissolved by raising the temperature, and 2.3 L of isopropanol was added to the reaction mixture, and the mixture was left in a cold room. The resulting solid was filtered and dried and recrystallized with 51 mL of purified water and 428 mL of isopropanol to give 100 g (yield 67%) of the title compound.

Melting Point: 178.5 ~ 179.5 ℃

TLC (silica phase; chloroform / methanol / water = 4/2 / 0.1 (v / v / v)): r.f. 0.51

¹ H-NMR (DMSO-d ₆ ): δ 1.7 to 1.89 (m, 1H, C ₂ -H), 1.95 to 2.1 (m, 1H, C ₂ -H), 2.22 (s, 3H, CH ₃ ), 2.83 to 2.96 (m, 2H, C ₁ -H), 3.08 to 3.19 (m, 1H, C ₃ -H), 3.72 (s, 3H, N-CH ₃ ), 4.1 (dd, 1H, N-CH ₂ ), 4.45 (dd, 1H, N-CH ₂ ), 6.70 to 7.07 (d, 2H, imidazole), 7.20 to 8.05 (m, 4H, Ar-H)

As described above, the production method according to the present invention is economical and easy to operate because the reaction may proceed continuously without separating the intermediate compared to the conventional methods. In particular, the preparation method according to the invention is useful for introducing variously substituted amino alkyl groups at the α-position of a tetrahydrocarbazolone derivative.

Claims (5)

In the method for preparing a compound represented by the following formula 1 using 4H- carbazol-4-one represented by the following formula (2) and the amine compound represented by the following formula (3) as a starting material, Preparing an enamine intermediate obtained by reacting 4H-carbazol-4-one represented by Chemical Formula 2 with an amine compound represented by Chemical Formula 3 under a catalyst selected from titanium chloride, p-toluenesulfonic acid and calcium carbonate anhydride, Substituting the dihalogenated methane represented by the following formula (5) with the enamine intermediate and a hydrolysis reaction to prepare a compound represented by the following formula (6), 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H), which is prepared by a reaction with 2-methylimidazole to a compound represented by Chemical Formula 6. -Imidazol-1-yl) methyl] -4H-carbazol-4-one or a pharmaceutically acceptable salt thereof or a solvate thereof. Formula 2 Formula 3 Formula 5 Formula 1 Wherein R ¹ and R ² are the same as or different from each other and are a hydrogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _2-6 alkenyl group, a phenyl group or a phenyl-C _1-3 alkyl group, or R ¹ and R ² may be bonded together with a nitrogen atom to form a heterocycle cyclized with 5 to 6 elements including a pyrrolidine ring, a piperidine ring and a morpholine ring; X, X ¹ and X ² are the same or different and are halogen elements including iodine, bromine, chloride. According to claim 1, wherein the compound represented by Formula 2 and the compound represented by Formula 3 in chloroform, methylene chloride, benzene, toluene, acetonitrile and dioxane under a catalyst selected from titanium chloride, p-toluenesulfonic acid and calcium carbonate anhydride A process for producing an enamine intermediate by reacting at 0 to 100 ° C. using a selected solvent. The reaction of claim 1, wherein 1 to 10 equivalents of the dihalogenated methane represented by Formula 5 is reacted with the enamine intermediate at 0 to 100 ° C. using a solvent selected from chloroform, methylene chloride, benzene, toluene, acetonitrile and dioxane. And then performing a hydrolysis reaction at room temperature to 100 ° C. using purified water to produce a compound represented by Chemical Formula 6. According to claim 1, wherein the compound represented by the formula (6) and 2-methylimidazole using a solvent selected from purified water, aliphatic alcohols having 1 to 6 carbon atoms, chloroform, methylene chloride, benzene, toluene, acetonitrile and dioxane Reaction at 0 to 100 ℃ to produce a compound represented by the formula (1). The method according to claim 1, wherein the production process is performed by a one-pot reaction without separation of the enamine derivative produced during the preparation process and the compound represented by Chemical Formula 6.