KR101508565B1 - Novel method for preparing itopride and the intermediate obtained from the method - Google Patents

Abstract

The present invention relates to a novel intermediate of itopride, a process for preparing the same, and a process for producing itopride using the same. According to the production method of the present invention, the final itopride can be obtained in a high purity and a high yield through a stable benzamide derivative, and the production method of the present invention can be used for mass production of itopride It is possible.

Ito Pride, Indigestion, Digestion, Amide Compound, Manufacturing Method

Description

[0001] The present invention relates to a novel process for preparing ito pride and a novel intermediate compound obtained therefrom,

The present invention relates to a novel intermediate of itopride, a process for preparing the same, and a process for preparing itopride and hydrochloride isopride using the same.

The hydrochloride compound prepared by using ethanol and hydrochloric acid in itopride of formula (1) is used as a drug that activates gastric function in patients suffering from gastrointestinal symptoms caused by functional dyspepsia with general hydrochloric acid Itopride hydrochloride.

The preparation method of ito pride is described in European Patent No. 306827 and Korean Patent Application Publication No. 1989-0005036. As shown in the production method of the following Reaction Scheme 1, the intermediate compound 4- [2- (dimethylamino) Ethoxy] benzylamine (6).

≪ Formula 1 >

Since the method uses Raney-nickel and hydrogen at an ultra-high pressure (50 kg / cm 2), there is a risk of explosion, and ammonia gas saturated with methanol may be used, which may have a serious effect on the human body and the environment. There is a possibility that heavy metals may remain in the final compound by using nickel. Therefore, there is a problem of a high production cost such as a safety device. On the other hand, efforts have been made to develop a new manufacturing method of Ito Pride, but only a part of the synthesis route has been improved, and a synthesis method improving the entire synthesis route has not been proposed.

An object of the present invention is to provide a novel process for producing N - [[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide (hereinafter referred to as itopride) ≪ / RTI > That is, it is an object of the present invention to provide a production method and an intermediate product capable of mass-producing itopride at a low cost by obtaining a final itopride in a high purity and a high yield by a simple manufacturing process.

The present invention provides a novel process for preparing itopride and hydrochloride itopride, and provides novel intermediate compounds.

The preparation process of the present invention produces itopride and its hydrochloride isopride through a step of preparing a stable benzamide compound represented by the following formula (4), which is an intermediate material useful for preparing the itopride of the formula (1).

≪ Formula 4 >

R2: F, Cl, Br, I, OMs, OTs or OP = O (OR4)

R4: alkyl having 1 to 4 carbon atoms

At this time, the OMs are methane sulfonate

,

,

OTs is 4-methylbenzenesulfonate

OP = O (OR < 4 >) 2 is di-alkyl phosphate

to be.

The method for preparing the compound of formula (4) comprises the following steps:

Wherein R _{1 in the} formula (2) is a hydroxyl group, by amide condensation, and R ₁ is a group selected from the group consisting of F, Cl, Br, Or I, a compound of formula 4 is prepared by an amidation reaction, preferably using a reaction solvent selected from the group consisting of ethyl acetate, dichloromethane or tetrahydrofuran; And

Extraction with a solvent selected from the group consisting of chloroform, dichloromethane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and t-butyl acetate.

(2)

R ₁ : OH, F, Cl, Br, or I

(3)

R2: F, Cl, Br, I, OMs, OTs or OP = O (OR4)

R4: alkyl having 1 to 4 carbon atoms

≪ Formula 4 >

R2: F, Cl, Br, I, OMs, OTs or OP = O (OR4)

R4: alkyl having 1 to 4 carbon atoms

In one embodiment, R ₁ of the compound of Formula 2 is F, Cl, Br, or I, preferably, in the presence of 2.0 to 3.0 equivalents of triethylamine, with respect to 1.0 equivalent of the compound of Formula 2, 3 with 1.0 to 1.5 equivalents of the compound of Formula 4 at 20 to 50 < 0 > C.

In another embodiment, the step of preparing the compound of formula (4) is a process wherein R ₁ is a hydroxyl group and 1.0 to 1.2 equivalents of NHSu (N-HydroxySuccinimide) and 1.0 to 1.2 equivalents of DCC , N'-Dicyclohexylcarbodiimide) is stirred at 0 ° C or lower, and 1.0 to 1.5 equivalents of the compound of the formula 3 and 2.0 to 5.0 equivalents of the triethylamine group are added to 1.0 equivalent of the compound of the formula 2 by the amidation reaction Followed by stirring at 0 to 50 ° C.

At this time, the substitution reaction may be carried out as follows:

1.0 to 1.2 equivalents of HoBT (1-HydroxyBenzotriazole) and 1.0 to 1.2 equivalents of EDC (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride) are added to 1.0 equivalent of the compound of Formula 2 at 0 ° C or less;

1.0 to 1.2 equivalents of HATU (O- (7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate) is added to 1.0 equivalents of the compound of formula or

1.0 to 1.2 equivalents of DMAP (4- (Dimethylamino) pyridine) and 1.0 to 1.2 equivalents of DIC (N, N'-Diisopropylcarbodiimide) are stirred at 0 占 폚 or less with respect to 1.0 equivalent of the compound of Formula 2.

The present invention also provides a method for providing itopride using the compound of formula 4 thus prepared as an intermediate.

In one embodiment, there is provided a process for preparing itopride by coupling a compound of formula (4) and a compound of formula (5) via a substitution reaction wherein R ₂ of formula (4) is OMs, OTs or OP = O ₂, R ₃ in Chemical Formula 5 is a hydroxyl group or NaO, and R ₂ in Chemical Formula 4 is F, Cl, Br, or I, R ₃ in Chemical Formula 5 is a hydroxyl group.

≪ Formula 4 >

R2: F, Cl, Br, I, OMs, OTs or OP = O (OR4)

R4: alkyl having 1 to 4 carbon atoms

≪ Formula 5 >

R ₃ : OH or NaO

Preferably, 1.0 to 6.0 equivalents of the compound of the formula (5) is added to 1.0 equivalent of the compound of the formula (4) in the presence of 4.0 to 15.0 equivalents of a base selected from the compound of the formula (4), followed by stirring at room temperature , And examples of the solvent to be used include toluene, DMF, ethyl alcohol, methyl alcohol or isopropyl alcohol. When toluene or DMF is used as a solvent, the reaction may further include reflux cooling at 100 to 140 ° C after stirring, and when alcohol such as ethyl alcohol, methyl alcohol or isopropyl alcohol is used as a solvent, RTI ID = 0.0 > 85 C < / RTI >

One embodiment of the above process is shown in Scheme 2 below. The present invention relates to a process for preparing an intermediate of formula (4) by reacting a compound represented by formula (2) and (3). Then, the itopride is synthesized through a substitution reaction with the compound of the formula (5).

Specific examples of the preparation method are shown in the following Reaction Schemes 3 and 4.

(The same applies to the case where OTs is used instead of OMs in the above description)

(The same applies to the case where the F position is Br, Cl, I)

The present invention also provides a method for providing the above-prepared itopride with hydrochloric acid to give the hydrochlorofluorocarbons.

(6)

Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the present invention in more detail and are not intended to limit the scope of the present invention.

[Example 1]

Preparation of the starting material (compound of formula 3) I

11.91 g (0.10 mol) of 4-hydroxybenzonitrile was dissolved in 110.91 ml of dichloromethane, and 13.16 g (0.13 mol) of triethylamine was added thereto. Stirred for 30 minutes and added dropwise with 13.75 g (0.12 mol) of methanesulfonyl chloride. This mixture was stirred for 1 hour. After 1 hour, 200 ml of water was added and stirred for 30 minutes. The mixed solution was separated, and only dichloromethane layer was taken, and 1.2 g of anhydrous magnesium sulfate was added thereto, followed by filtration. The filtrate was distilled under reduced pressure and 119.1 ml of n-hexane was added. The precipitated compound was filtered and dried under reduced pressure to obtain 19.45 g (yield: 98.6%) of the desired compound.

[Example 2]

Preparation of the starting material (compound of formula 3) II

11.91 g (0.10 mol) of 4-hydroxybenzonitrile was dissolved in 110.91 ml of dichloromethane, and 13.16 g (0.13 mol) of triethylamine was added thereto. After stirring for 30 minutes, 22.88 g (0.12 mol) of 4-methylbenzene-1-sulfonyl chloride was added dropwise. This mixture was stirred for 1 hour. After 1 hour, 200 ml of water was added and stirred for 30 minutes. The mixed solution was separated, and only dichloromethane layer was taken, and 1.2 g of anhydrous magnesium sulfate was added thereto, followed by filtration. The filtrate was distilled under reduced pressure and 119.1 ml of n-hexane was added. The precipitated compound was filtered and dried under reduced pressure to obtain 26.62 g (yield 97.4%) of the desired compound.

[Example 3]

Preparation of the starting material (compound of formula 3) III

19.45 g (0.10 mol) of 4-cyanophenyl methanesulfonate was dissolved in 195 ml of ethanol at room temperature (20 to 25 ° C). To this mixture were added 12.83 g (0.10 mol) of nickel chloride (NiCl ₂ ) and 11.24 g (0.30 mol) of sodium borohydride and stirred for 30 minutes. The mixture was filtered using Celite and concentrated under reduced pressure to obtain 18.45 g (93.11%) of the title compound.

[Example 4]

Preparation of the starting material (compound of formula 3) IV

19.45 g (0.10 mol) of 4-cyanophenyl methanesulfonate was dissolved in methanol (195 ml) at room temperature (20 to 25 ° C). 1.95 g (10% w) of Pd / C (Palladium on Activated Carbon) was added to the mixture, and the mixture was stirred under a hydrogen gas pressure (4 Bar) for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain 17.86 g (90.0%) of the desired compound.

[Example 5]

Preparation of starting material (compound of formula 3) V

19.45 g (0.10 mol) of 4-cyanophenyl methanesulfonate was dissolved in THF (195 ml) at room temperature (20 to 25 ° C). It was added dropwise a BH ₃ and _{S (Me) 2 9.03ml (0.12} mol) to the mixture and stirred for 2 hours. This mixture was filtered and concentrated under reduced pressure to give the desired compound (17.40 g, 87.5%).

[Example 6]

Preparation of intermediate (compound of formula 4) I

19.45 g (0.09 mol) of 4- (aminomethyl) phenyl methanesulfonate was dissolved in methanol, and 17.65 g (0.04 mol) of 3,4-dimethoxybenzoyl chloride 0.09 mol) was added thereto and stirred for 10 minutes. 36.8 ml (0.26 mol) of triethylamine was added dropwise to the mixture, and the mixture was stirred for 2 hours. After stirring, the mixture was cooled to 0 占 폚 and then filtered to obtain the objective compound (30.51 g, 95.0%). ^{1 H-NMR (300MHz) C} 17 H 19 NO 6 S δ 3.134 (s, 3H) 3.914 (s, 6H) 4.623 (d, J = 6Hz, 2H) 6.547 (s, 1H) 6.853 (d, J = 8.4 (D, J = 1.8 Hz, 1H) 7.341

[Example 7]

Preparation of intermediate (compound of formula 4) II

16.03 g (0.09 mol) of 3,4-dimethoxybenzoic acid and 12.15 g (0.11 mol) of N-hydroxysuccinimide were dissolved in 80 ml of dichloromethane, And stirred at 10 ° C to 0 ° C for 10 minutes. To this mixture was added dropwise 21.78 g (0.11 mol) of dicyclohexylcarbodiimide dissolved in 40 ml of dichloromethane. This mixture was refluxed with stirring for 2 hours. After 2 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure. After concentrating under reduced pressure, 80 ml of methanol and 19.45 g (0.09 mol) of 4- (aminomethyl) phenyl methanesulfonate were added, and then 15.47 ml of triethylamine was added dropwise. This mixture was refluxed with stirring for 2 hours. After completion of the reflux stirring, the mixture was cooled to 0 캜, filtered, and dried under reduced pressure to obtain 27.39 g (85.3%) of the desired compound. ^{1 H-NMR (300MHz) C} 17 H 19 NO 6 S δ 3.134 (s, 3H) 3.914 (s, 6H) 4.623 (d, J = 6Hz, 2H) 6.547 (s, 1H) 6.853 (d, J = 8.4 (D, J = 1.8 Hz, 1H) 7.341

[Example 8]

Preparation of intermediate (compound of formula 4) III

16.03 g (0.09 mol) of 3,4-dimethoxybenzoic acid and 12.15 g (0.11 mol) of N-hydroxysuccinimide were dissolved in 80 ml of dichloromethane, The mixture was stirred at 10 to 0 ° C for 10 minutes. To this mixture was added dropwise 21.78 g (0.11 mol) of dicyclohexylcarbodiimide dissolved in 40 ml of dichloromethane. This mixture was refluxed with stirring for 2 hours. After 2 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure. To the compound under reduced pressure, 80 ml of methanol and 13.77 g (0.11 mol) of 4-fluorobenzylamine were added, and then 15.47 ml of triethylamine was added dropwise. This mixture was refluxed with stirring for 2 hours. After completion of the reflux stirring, the mixture was cooled to 0 캜 and filtered, and the filtrate was dried under reduced pressure to obtain 25.07 g (98.5%) of the target compound. ^{1 H-NMR (300MHz) C} 16 H 16 FNO 3 δ 3.814 (s, 3H) 3.856 (s, 3H) 4.507 (d, J = 3.6Hz, 2H) 6.777 (d, J = 5.1Hz, 1H) 6.945 ( J = 4.2 Hz, 2H), 7.346 (d, J = 4.8 Hz, 1H) 7.436 (s,

[Example 9]

Preparation of intermediate (compound of formula 4) IV

16.03 g (0.09 mol) of 3,4-dimethoxybenzoic acid and 12.15 g (0.11 mol) of N-hydroxysuccinimide were dissolved in 80 ml of dichloromethane, The mixture was stirred at 10 to 0 ° C for 10 minutes. To this mixture was added dropwise 21.78 g (0.11 mol) of dicyclohexylcarbodiimide dissolved in 40 ml of dichloromethane. This mixture was refluxed with stirring for 2 hours. After 2 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure. To the compound under reduced pressure, 80 ml of methanol and 15.30 g (0.11 mol) of 4-chlorobenzylamine were added, and then 15.47 ml of triethylamine was added dropwise. This mixture was refluxed with stirring for 2 hours. After completion of the reflux stirring, the mixture was cooled to 0 ° C and filtered, and the filtrate was dried under reduced pressure to obtain 26.77g (99.5%) of the target compound. ^{1 H-NMR (300MHz) C} 16 H 16 ClNO 3 δ 3.866 (s, 3H) 3.889 (s, 3H) 4.544 (d, J = 3.3Hz, 2H) 6.812 (d, J = 5.1Hz, 1H) 6.912 ( (s, 1 H) 7.227 - 7.274 (m, 4 H) 7.329 (d, J = 5.1 Hz,

[Example 10]

Ito pride  Manufacturing I

9.20 ml (0.09 mol) of 2- (dimethylamino) ethanol and 7.26 g (0.18 mol) of sodium hydroxide were dissolved in 300 ml of toluene and stirred under reflux for 30 minutes. To this mixture was added 30.51 g (0.08 mol) of 4 - ((3,4-dimethoxybenzamido) methyl) phenyl methanesulfonate and the mixture was refluxed for 1 hour and 30 minutes. The mixture was cooled to room temperature (20 to 25 ° C), filtered and concentrated under reduced pressure. To this mixture were added 600 ml of dichloromethane and 300 ml of purified water and the layers were separated. The dichloromethane layer was separated and 450 ml of 1 N HCl aqueous solution was added to separate the layers. The aqueous 1 N HCl solution was separated into layers by adding 600 ml of dichloromethane and 225 ml of 3N aqueous NaOH. The organic layer was concentrated under reduced pressure and crystallized using acetic acid ether and hexane to obtain 23.94 g (80.0%) of the target compound

[Example 11]

Ito pride  Produce II

30.0 g (0.08 mol) of sodium 2- (dimethylamino) ethanolate and 30.51 g (0.08 mol) of 4 - ((3,4-dimethoxybenzamido) methyl) phenyl methanesulfonate were dissolved in 300 ml of dimethylformamide And the mixture was refluxed for 1 hour and 30 minutes. The mixture was cooled to room temperature (20 to 25 DEG C), filtered and concentrated under reduced pressure. To this mixture were added 600 ml of dichloromethane and 300 ml of purified water and the layers were separated. The dichloromethane layer was separated and 450 ml of 1 N HCl aqueous solution was added to separate the layers. The aqueous 1 N HCl solution was separated into layers by adding 600 ml of dichloromethane and 225 ml of 3N aqueous NaOH. The organic layer was concentrated under reduced pressure and crystallized using acetic acid ether and hexane to obtain 23.94 g (80.0%) of the target compound.

[Example 12]

Manufacture of Ito Pride III

1.66 g (0.015 mol) of sodium 2- (dimethylamino) ethanolate and 0.14 g (0.001 mol) of CuBr were dissolved in 50 ml of N-methylpyrrolidone, 3.05 g (0.01 mol) of N- (4-chlorobenzyl) -3,4- Dissolved and refluxed for 2 hours. The mixture was cooled to room temperature (20 to 25 DEG C), filtered and concentrated under reduced pressure. 60 ml of dichloromethane and 30 ml of purified water were added to the mixture and the layers were separated. The dichloromethane layer was separated, and 45 ml of 1 N HCl aqueous solution was added to separate the layers. The 1N HCl aqueous layer was separated into layers by adding 60 ml of dichloromethane and 23 ml of 3N aqueous NaOH. The organic layer was concentrated under reduced pressure and crystallized using acetic acid ether and hexane to obtain 0.72 g (20.0%) of the target compound.

[Example 13]

Preparation of hydrochloric acid itopride

23.94 g of N - [[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide (itopride) obtained in Example 11 or 12 was dissolved in dichloromethane And 20 ml of HCl and 3.05 g of activated carbon were added thereto. The mixture was stirred for 30 minutes and filtered. The filtrate was concentrated under reduced pressure and crystallized with a mixed solvent of methanol and isopropyl alcohol to obtain 25.06 g (95%) of the desired compound.

The present invention provides a main intermediate for the preparation of itopride and a method for producing the final itopride, so that the itopride can be produced at a higher yield than the conventional methods, and at a higher cost without explosion risk and environmental pollution.

Claims (11)

A compound of the formula: < RTI ID = 0.0 > ≪ Formula 4 >

R2: F, Cl, Br, I, OMs (methanesulfonate), OTs (4-methylbenzenesulfonate) or OP = O (OR4) R4 is alkyl having 1 to 4 carbon atoms . A method for producing a compound according to claim 1, A process for preparing a compound represented by the following formula (4), which comprises using a compound represented by the following formula (2) and a compound represented by the following formula (3) as starting materials: (2)

R1: F, Cl, Br, or I (3)

R2: F, Cl, Br, I, OMs, OTs or OP = O (OR4) R4: alkyl having 1 to 4 carbon atoms ≪ Formula 4 >

R2: F, Cl, Br, I, OMs, OTs or OP = O (OR4) R4 is alkyl having 1 to 4 carbon atoms. A method for producing a compound according to claim 1, A process for preparing a compound represented by the following formula (4), which comprises using a compound represented by the following formula (2) and a compound represented by the following formula (3) as starting materials: (2)

R1: OH (3)

R2: F, Cl, Br, I, OMs, OTs or OP = O (OR4) R4: alkyl having 1 to 4 carbon atoms ≪ Formula 4 >

R2: F, Cl, Br, I, OMs, OTs or OP = O (OR4) R4 is alkyl having 1 to 4 carbon atoms. The method of claim 2, The step of preparing the compound of formula (4) Wherein 1.0 to 1.5 equivalents of the compound of the formula (3) are stirred at 20 to 50 占 폚 in the presence of 2.0 to 3.0 equivalents of triethylamine per 1.0 equivalent of the compound of the formula (2) Way. The method of claim 3, The step of preparing the compound of formula (4) 1.0 to 1.2 equivalents of NHSu (N-HydroxySuccinimide) and 1.0 to 1.2 equivalents of DCC (N, N'-Dicyclohexylcarbodiimide) are added to 1.0 equivalent of the compound of formula (2) 1.0 to 1.5 equivalents of the compound of the formula (3) and 2.0 to 5.0 equivalents of triethylamine are then added to 1.0 equivalent of the compound of the formula (2), followed by stirring at 0 to 50 占 폚. delete delete In the preparation of ito-pride, A process for preparing itopride by coupling through the substitution reaction of the compound of formula (4) and the compound of formula (5): ≪ Formula 4 >

R2: F, Cl, Br, I, OMs, OTs or OP = O (OR4) R4: alkyl having 1 to 4 carbon atoms ≪ Formula 5 >

R ₃ : OH or NaO. The method of claim 8, Adding 1.0 to 6.0 equivalents of the compound of Formula 5 to 1.0 equivalent of the compound of Formula 4 in the presence of 4.0 to 15.0 equivalents of a base selected from the compound of Formula 4 and stirring at room temperature, Thereafter, ≪ / RTI > The method of claim 9, In the presence of 4.0 to 15.0 equivalents of a base selected from the compound of Formula 4, 1.0 to 6.0 equivalents of the compound of Formula 5 are added to 1.0 equivalent of the compound of Formula 4, followed by stirring at room temperature. Lt; RTI ID = 0.0 > alcohol / isopropyl alcohol. ≪ / RTI > In the method for producing hydrochloric acid itopride, Preparing a compound of formula (1) by the process of claim 8 using the compound of formula (4) and the compound of formula (5); And obtaining a N - [[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide hydrochloride salt of the formula 6 by using hydrochloric acid in the compound of the formula 1, : ≪ ≪ Formula 4 >

R2: F, Cl, Br, I, OMs, OTs or OP = O (OR4) R4: alkyl having 1 to 4 carbon atoms ≪ Formula 5 >

R ₃ : OH or NaO ≪ Formula 1 >

(6)