KR101153713B1 - Preparation method of itopride and intermediate compound - Google Patents

Abstract

The present invention relates to a novel process for preparing itopride which can produce it in high yield and high purity without the generation of harmful gases and the like and intermediate compounds used therein.
The method for preparing the itopride includes reacting a compound of Formula 4 with a predetermined peracid-based compound in the presence of Lewis acid to form an itopride:
[Chemical Formula 4]

Description

Preparation method of intermediates and intermediate compounds {PREPARATION METHOD OF ITOPRIDE AND INTERMEDIATE COMPOUND}

The present invention relates to a novel process for preparing itopride which can produce it in high yield and high purity without the generation of harmful gases and the like and intermediate compounds used therein.

The compound of formula 1 is N- [4- [2- (dimethoxyamino) ethoxy] benzyl] -3,4-dimethoxybenzamide, a substance commonly known by the generic name itofride. This isopride is widely used as a useful drug to improve the gastrointestinal anhydrous symptoms represented by gastrointestinal discomfort or bloating.

[Formula 1]

The preparation method of the itopride is specified in European Patent Publication No. 0306827, Korean Patent Publication No. 1994-0000058 or Korean Patent Publication No. 2005-0101614.

The preparation method of the itopride disclosed in these prior documents is as summarized in Scheme 1 below.

Scheme 1

Referring to Reaction Scheme 1, in the previous production method by reacting a benzoic acid derivative of Formula 7 with thionyl chloride or dialkyl phosphate, etc. to form an intermediate compound of Formula 8 or 9, and then reacting the intermediate compound with the compound of Formula 3 It was prepared to prepare the etopriide of formula 6 or the etopriide hydrochloride of formula (1).

However, in such a manufacturing method, since a large amount of harmful gases such as sulfurous acid gas (SO ₂ ) and hydrochloric acid gas is generated in the process of forming an intermediate compound such as the formula (8), a separate device or process was required for its removal. . In addition, through such a manufacturing method, there was a limit in obtaining the itopride in high yield and high purity, as well as a sudden temperature increase in the reaction process with the compound of Formula 3, and thus the risk of explosion or temperature control was not easy. Was in.

In particular, the above conventional manufacturing method has a long reaction time and low yield, which requires a process improvement for the industrial mass production of itopride.

Accordingly, the present invention is to provide a novel method for producing an itopride can be produced in high yield, high purity without the generation of harmful gases.

The present invention also aims to provide novel polymeric compounds that can be used for the preparation of itoprides.

The present invention is a method for producing an itopride comprising the step of reacting a compound of formula (4) with a peracid compound of R ₁ C (= O) OOH in the presence of a Lewis acid to form an itopride of formula (1) Provides:

[Formula 4]

[Formula 1]

The invention also provides a compound of formula

[Formula 4]

Hereinafter will be described a method for preparing an itopride and an intermediate compound used therein according to a specific embodiment of the present invention.

According to an embodiment of the present invention, in the presence of Lewis acid, reacting a compound of Formula 4 with a peracid-based compound of R ₁ C (= 0) OOH to form an itopride of Formula 1 Processes for the preparation of itopride are provided:

[Formula 4]

[Formula 1]

In addition, according to another embodiment of the invention, as a novel polymer compound used in such a production method, the compound of formula (4) is provided.

As supported by the examples described below, the results of the inventors of the present invention, using the compound of Formula 4 as an intermediate compound, when reacted with a peracid-based compound of R ₁ C (= O) OOH in the presence of Lewis acid, It has been found that it can be produced in high yield and high purity without fear of generation of harmful gases.

More specifically, when the compound of Formula 4 is reacted with a peracid-based compound in the presence of Lewis acid, rearrangement of molecules occurs as shown in Formula 5 of Scheme 2, thereby converting the imine group of Formula 4 to an amide group, It has been found that the itopride of Formula 1 can be prepared:

Scheme 2

In the above formula, R ₁ is hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group or a halogen substituted phenyl group, and R ₄ is a Lewis acid.

Through this reaction, it is possible to obtain etopriide in high yield and high purity without generating harmful gases such as sulfurous acid gas or hydrochloric acid gas. In addition, this reaction can be carried out in a single step at room temperature, which not only simplifies and proceeds safely, but also significantly lowers production costs. In particular, in the case of the conventional manufacturing method, the reaction time is long, and a large amount of impurities are likely to occur due to acid gas or a high reaction temperature. It is relatively short and can proceed at room temperature and does not generate acid gases, etc., making it possible to prepare the itopride with higher purity and yield.

Therefore, the manufacturing method according to one embodiment of the present invention can be very preferably applied for the industrial mass production of itopride.

The preparation method of this itopride is described in more detail in each step as follows.

In the preparation method, the compound of formula 1 is prepared by reacting a compound of formula 4 with a predetermined peracid-based compound through molecular rearrangement of the equilibrated hexacyclic ring as shown in Formula 5.

At this time, as the peracid-based compound, a peracid-based compound having hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group or a halogen substituted phenyl group, preferably an alkyl group having 1 to 6 carbon atoms, a phenyl group or a halogen substituted phenyl group may be used. . By reacting with such a peracid-based compound, the above-described molecular rearrangement can be appropriately produced to produce an itopride in high yield. Such peracid compounds may be used in a proportion of 0.5 to 4 equivalents, preferably 1 to 2 equivalents, and more preferably 1 to 1.5 equivalents, relative to 1 equivalent of the compound of formula 4. That is, even when the equivalent acid peroxide compound is reacted with the compound of Formula 4, it is preferable to complete the molecular rearrangement to prepare the itopride in high yield, thereby reducing the occurrence of residual reactants or by-products. .

In addition, in preparing the itopride through the reaction process, by reacting the compound of Formula 4 with a silyl compound, to protect the amine group (-N (CH ₃ ) ₂ ) with a silyl group, as shown in the following formula 4-a, Such a compound can also be reacted with the above-mentioned peracid-based compound. As such, by protecting the amine group with the silyl group, the reaction with the peracid-based compound and the molecular rearrangement through it are made more smoothly and the generation of by-products is reduced, so that the itopride of Formula 1 may be prepared in higher yield and purity. Can be.

[Formula 4-a]

In this case, any of the silyl compounds may be used without any limitation as long as the silyl group to which a hydrogen atom or an alkyl group (for example, an alkyl group having 1 to 6 carbon atoms) is introduced can be introduced as an amine protecting group. Examples of such silyl compounds include trimethylsilane, hexamethyldisilazane, hexamethyldisilane, N, 0 -bistrimethylsilylacetamide , bissilylurea, and the like. Appropriate protecting groups can be introduced into the group. Such silyl compounds may be used in a proportion of 0.5 to 4 equivalents, preferably 1 to 2 equivalents, and more preferably 1 to 1.5 equivalents, relative to 1 equivalent of the compound of formula 4.

In addition, the reaction process with the peracid-based compound proceeds in the presence of Lewis acid, which is used as a kind of catalyst that promotes the formation of itopride through molecular rearrangement, as confirmed by Scheme 2. The Lewis acid may be ZnCl ₂ , SnCl ₂ , BF ₃ ether or BF ₃ etherate, and the like, and various other Lewis acids may be used without particular limitation. This Lewis acid may be used in an amount of 0.1 to 1 equivalents, preferably 0.2 to 0.3 equivalents, relative to 1 equivalent of the compound of formula (4). In such an equivalence ratio, it is possible to appropriately promote the rearrangement of molecules using the Lewis acid to obtain the itopride in high yield, while improving the convenience and economical efficiency of the process.

In addition, the reaction process with the peracid-based compound may proceed in the presence of a dehydrating agent, whereby the reaction for the formation of the itopride may proceed faster and the yield may also be higher. Typical examples of such dehydrating agents include anhydrous magnesium sulfate or anhydrous sodium sulfate, and various dehydrating agents capable of removing water molecules during other reactions may be used. Such a dehydrating agent may be used in an amount of 0.2 to 2 equivalents, preferably 0.2 to 1 equivalents, and more preferably 0.4 to 0.6 equivalents, based on 1 equivalent of the compound of Formula 4.

Meanwhile, the reaction process of the compound of Formula 4 and the peracid-based compound may be performed at 10 to 40 ° C., preferably at 20 to 25 ° C. In this way, it is possible to prepare the itopride through a single reaction process at room temperature, so that the reaction process of the itopride can be more economical and simplified, and can reduce the generation of by-products caused by the high reaction temperature, resulting in high yield and high purity. Itopride can be obtained.

This reaction process can also proceed using any organic solvent as the reaction solvent, preferably in an inert solvent that does not leave the silyl group introduced into the protecting group of the amine group. Specific examples of such a reaction solvent include ether solvents such as tetrahydrofuran, diethyl ether, ethylene glycol diethyl ether, dimethyl sulfoxide or tert -butyl ether; Amide solvents such as dimethylformamide, diethylacetamide or 1-methyl-2-pyrrolidinone; Nitrile solvents such as acetonitrile; Or halogenated hydrocarbon solvents such as chloroform, dichloroethane or dichloromethane, and two or more kinds of mixed solvents selected from them may be used. Among these, a halogenated hydrocarbon solvent can be used preferably.

Such a reaction solvent may be used at a volume ratio of 1 to 20 times, preferably 2 to 10 times, and more preferably 4 to 6 times with respect to the total reactant, in consideration of proper progress of the reaction process and economical efficiency. have.

In addition, even when the silyl group is introduced into the protecting group of the amine group in the above-described reaction step, such silyl group can be removed by adding water and the like after the above reaction step is proceeded without any additional step, and thus, the amine group is deprotected. Itopride can be prepared.

On the other hand, in the method for producing an itopride according to an embodiment of the present invention, the intermediate compound of Formula 4 may be formed by reacting the benzaldehyde-based compound of Formula 2 and the benzylamine-based compound of Formula 3:

[Formula 2]

(3)

Hereinafter, the reaction process for forming the compound of Formula 4 will be described in detail.

The reaction process of the compounds of Formulas 2 and 3 may be carried out by a dehydration reaction between them, for this purpose it may be carried out in the presence of a dehydrating agent. Anhydrous magnesium sulfate or anhydrous sodium sulfate may be used as such a dehydrating agent, and various dehydrating agents capable of removing water molecules during other reactions may be used. In addition, the reaction process may be carried out at 10 to 25 ℃, according to the reaction temperature to determine the amount of the dehydrating agent that can establish the effective equilibration conditions by HPLC, an appropriate amount of dehydrating agent can be used for each reaction time. Through this, the reaction process can also be carried out at room temperature, it is possible to proceed to the subsequent step of forming the itopride without separate by-products, it is possible to obtain a high yield and purity of the final product isopride. More specifically, the dehydrating agent may be used in an amount of 0.2 to 2 equivalents, preferably 0.2 to 1 equivalents, and more preferably 0.4 to 0.6 equivalents, based on 1 equivalent of the compound of Formula 2.

In addition, the reaction process of the compounds of Formulas 2 and 3 may be carried out in any inert organic solvent which is commonly used in imine formation reactions and improves the stability of the compounds of Formula 4. Specific examples of such reaction solvents include halogenated hydrocarbon solvents such as chloroform, dichloroethane or dichloromethane, and two or more kinds of mixed solvents selected from them may be used. In addition, such a reaction solvent has a volume ratio of 1 to 20 times, preferably 2 to 10 times, and more preferably 4 to 6 times the volume ratio with respect to the total reactants in consideration of appropriate progress and economical efficiency of the reaction process. Can be used.

The process of forming the compound of Formula 4 and the subsequent process of forming the itopride may be performed in the same reaction solvent, for example, a halogenated hydrocarbon solvent. That is, the two step process may be performed separately, but when the same reaction solvent is used in these two step processes, the two step process may be continuously performed without separate separation and purification process of the compound of formula (4). have. In this case, the same dehydrating agent may be used in a two-step continuous process, thereby improving stability of the compound of Formula 4 and achieving a faster reaction rate and higher yield.

On the other hand, after forming the itopride through the two-step reaction process described above, it can be reacted with an acid to prepare an acid addition salt of the itopride. For example, it may be reacted with hydrochloric acid to form the itopride hydrochloride.

As described above, according to the present invention, pharmaceutically useful itopride can be produced in higher yield and purity without fear of generation of harmful gases.

In addition, the room temperature reaction is possible and the reaction time is also shortened, which not only contributes greatly to the efficiency, simplification and economic efficiency of the overall itopride manufacturing process, but also greatly reduces the risk in this manufacturing process.

Thus, according to the present invention, a method for mass production of industrially useful itopride and an intermediate compound therefor can be provided.

The invention is explained in more detail in the following examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited by the following examples.

Example 1: Synthesis of 2- (4-((3,4-dimethoxybenzylideneamino) methyl) phenoxy) -N, N-dimethylethanamine (when the concentration of dichloromethane was tested under 0.03 molar concentration)

2- (4- (aminomethyl) phenoxy) -N, N in a solution in which 1.66 g (10 mmol) of 3,4-dimethoxybenzaldehyde (1.661 g, 10 mmol, 1 eq) was dissolved in 330 mL of dichloromethane. 1.94 g (10 mmol) of -dimethylethanamine was added and stirred at room temperature for 3 hours. During the reaction, 12 g of anhydrous magnesium sulfate was added and stirred for 30 minutes. The reaction solution was filtered and dried under reduced pressure to obtain 3.4 g of the target compound 2- (4-((3,4-dimethoxybenzylideneamino) methyl) phenoxy) -N, N-dimethylethanamine as a yellow oil (yield 99). %).

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 2.3 (6H), 2.72 (2H), 3.91 (6H), 4.11 (2H), 4.73 (2H), .6.88 (2H), 7.21 (4H), 7.46 (1H), 8.26 (1H)

Example 2: Synthesis of 2- (4-((3,4-dimethoxybenzylideneamino) methyl) phenoxy) -N, N-dimethylethanamine (experimental in general concentration under chloroform solvent)

5.83 g (30 mmol) of 2- (4- (aminomethyl) phenoxy) -N, N-dimethylethanamine in a solution in which 4.98 g (30 mmol) of 3,4-dimethoxybenzaldehyde was dissolved in 300 mL of chloroform. ) Was added and 12 g of anhydrous magnesium sulfate was added at room temperature, followed by stirring for 5 hours. The reaction solution was filtered and dried under reduced pressure to yield 10.2 g of a yellow oil of the desired compound 2- (4-((3,4-dimethoxybenzylideneamino) methyl) phenoxy) -N, N-dimethylethanamine (yield 99). %).

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 2.3 (6H), 2.72 (2H), 3.91 (6H), 4.11 (2H), 4.73 (2H), .6.88 (2H), 7.21 (4H), 7.46 (1H), 8.26 (1H)

Example 3: Synthesis of N- (4- (2-dimethylaminoethoxy) phenyl) methyl-3,4-dimethoxybenzamide (common name: Itopride)

342 mg (1 mmole) of 2- (4-((3,4-dimethoxybenzylideneamino) methyl) phenoxy) -N, N-dimethylethanamine obtained in Example 1 was dissolved in 10 mL of dichloromethane. To the solution was added 283 mg of anhydrous sodium sulfate and stirred for 20 minutes. 130 mg of trimethylsilane was added to the solution, which was stirred for 30 minutes at room temperature. 42.58 mg of triroroboran ether was added and stirred for 10 minutes. Subsequently, 189 mg of perchlorobenzoic acid was added thereto, followed by reaction at room temperature for 4 hours, followed by removal of impurities with a solvent of ethyl acetate: water = 1: 1 in a short path column (3 cm * 5 cm), and ethyl acetate: methanol. It developed by the solvent of = 2: 1 and isolate | separated and refined. The solution was filtered and dried under reduced pressure to obtain 297 mg (yield 83%) of the title compound N- (4- (2-dimethylaminoethoxy) phenyl) methyl-3,4-dimethoxybenzamide as a white solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 2.3 (6H), 2.68 (2H), 3.86 (6H), 4.01 (2H), 4.51 (2H), 6.69 to 7.43 (8H)

Example 4: Synthesis of N- (4- (2-dimethylaminoethoxy) phenyl) methyl-3,4-dimethoxybenzamide (common name: Itopride)

5.83 g (30 mmol) of 2- (4- (aminomethyl) phenoxy) -N, N-dimethylethanamine in a solution in which 4.98 g (30 mmol) of 3,4-dimethoxybenzaldehyde was dissolved in 300 mL of chloroform. ) Was added and 12 g of anhydrous magnesium sulfate was added at room temperature, followed by stirring for 5 hours. 3.9 g of trimethylsilane was added to the reaction solution, and the mixture was stirred at room temperature for 50 minutes. Then 1.27 g of tribroroborane ether was added and stirred for 20 minutes. Subsequently, 5.67 g of perchlorobenzoic acid was added and reacted at room temperature for 5 hours, followed by removing impurities with a solvent of ethyl acetate: water = 1: 1 in a short path column (3 cm * 5 cm), and ethyl acetate: methanol. It developed by the solvent of = 2: 1 and isolate | separated and refined. The solution was filtered and dried under reduced pressure to obtain 8.01 g (yield 74.7%) of the title compound N- (4- (2-dimethylaminoethoxy) phenyl) methyl-3,4-dimethoxybenzamide as a white solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 2.3 (6H), 2.68 (2H), 3.86 (6H), 4.01 (2H), 4.51 (2H), .6.69 to 7.43 (8H)

Example 5 Synthesis of N- (4- (2-dimethylaminoethoxy) phenyl) methyl-3,4-dimethoxybenzamide

5.83 g (30) of 2- (4- (aminomethyl) phenoxy) -N, N-dimethylethanamine in a solution in which 4.98 g (30 mmol) of 3,4-dimethoxybenzaldehyde was dissolved in 300 mL of dichloroethane. mmol) was added and 8 g of anhydrous sodium sulfate was added at room temperature, followed by stirring for 7 hours. 1.27 g of tribroroborane ether was added and stirred for 20 minutes. Subsequently, 5.67 g of perchlorobenzoic acid was added and reacted at room temperature for 5 hours, followed by removing impurities with a solvent of ethyl acetate: water = 1: 1 in a short path column (3 cm * 5 cm), and ethyl acetate: methanol. It developed by the solvent of = 2: 1 and isolate | separated and refined. The solution was filtered and dried under reduced pressure to obtain 6.98 g (yield 65%) of the title compound N- (4- (2-dimethylaminoethoxy) phenyl) methyl-3,4-dimethoxybenzamide as a white solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ (ppm) 2.3 (6H), 2.68 (2H), 3.86 (6H), 4.01 (2H), 4.51 (2H), .6.69 to 7.43 (8H)

Example 6.Synthesis of N- (4- (2-dimethylaminoethoxy) phenyl) methyl-3,4-dimethoxybenzamide hydrochloride (common name: Itopride hydrochloride)

To a solution of 3.58 g (10 mmol) of N- (4- (2-dimethylaminoethoxy) phenyl) methyl-3,4-dimethoxybenzamide dissolved in 100 mL of isopropanol, 0.83 ml of concentrated hydrochloric acid was added and distilled under reduced pressure. Crystallized in hydrochloride form. To the resulting product, 20 ml of anhydrous ethanol was added and slurried, followed by filtration of the crystals to obtain pure white solid target compound N- (4- (2-dimethylaminoethoxy) phenyl) methyl-3,4-dimethoxybenzamide hydrochloride 3.70 g (yield 94%) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ (ppm) 2.2 (6H), 2.6 (2H), 3.79 (3H), 3.8 (3H), 4.01 (2H), 4.2 (2H), 6.84 to 7.56 (7H ), 8.82 (1 H)

Claims (14)

Reacting a compound of Formula 4 with a peracid-based compound of R ₁ C (═O) OOH in the presence of Lewis acid to form an itopride of Formula 1:
[Chemical Formula 4]

[Formula 1]

In the above formula, R ₁ is hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group or a halogen substituted phenyl group.
The method of claim 1, wherein the compound of formula 4 is reacted with the silyl compound to protect the amine group (-N (CH ₃ ) ₂ ), and the reaction of the topride to react the compound protected with the amine group with a peracid-based compound Manufacturing method.
The method of claim 1, wherein the compound of Formula 4 is formed by reacting a benzaldehyde compound of Formula 2 with a benzylamine compound of Formula 3 below:
(2)

(3)

The method of claim 3, wherein the reaction of the benzaldehyde-based compound of Formula 2 with the benzylamine-based compound of Formula 3 proceeds in the presence of a dehydrating agent comprising anhydrous magnesium sulfate or anhydrous sodium sulfate.
The method according to claim 1, further comprising the step of reacting the itopride with hydrochloric acid to form the itopride hydrochloride.
The method of claim 1, wherein the Lewis acid comprises at least one selected from the group consisting of ZnCl ₂ , SnCl ₂ , BF ₃ ether, and BF ₃ etherate.
The method of claim 1, wherein the Lewis acid is used in an amount of 0.1 to 1 equivalent based on 1 equivalent of the compound of Formula 4.
The method of claim 2, wherein the silyl compound is an isopride containing at least one selected from the group consisting of trimethylsilane, hexamethyldisilazane, hexamethyldisilane, N, 0 -bistrimethylsilylacetamide and bissilylurea Method of preparation.
The method of claim 2, wherein the silyl compound is used in an amount of 0.5 to 4 equivalents relative to 1 equivalent of the compound of formula 4.
The method of claim 1, wherein the peracid compound is used in an amount of 0.5 to 4 equivalents based on 1 equivalent of the compound of Formula 4.
The method of claim 1, wherein the reaction of the compound of Formula 4 and the peracid-based compound proceeds at 10 to 40 ° C.
The method of claim 1, wherein the reaction of the compound of Formula 4 and the peracid-based compound proceeds in the presence of a dehydrating agent.
The method of claim 1, wherein the reaction of the compound of Formula 4 and the peracid-based compound is carried out in at least one solvent selected from the group consisting of an ether solvent, an amide solvent, a nitrile solvent, and a halogenated hydrocarbon solvent. Manufacturing method.
A compound of formula
[Chemical Formula 4]