KR20120133129A - New method for producing Loperamide oxide monohydrate - Google Patents

Abstract

PURPOSE: A method for preparing loperamide oxide monohydrate used as an antidiarrhoeal drug is provided to enable selective oxidation and to minimize side reactions without complex purification. CONSTITUTION: A method for preparing loperamide oxide monohydrate comprises: a step of reacting loperamide or loperamide HCl of chemical formula 2 in an organic solvent under the presence of a catalyst to prepare a loperamide oxide compound of chemical formula 3; and a step of reacting loperamide oxide under the presence of water and an organic solvent containing water. The catalyst is molybdic acid, selenium dioxide, sodium tungstate, benzene selenic acid, titanium silicone oxide, or a mixture thereof.

Description

Loperamide oxide monohydrate {New method for producing Loperamide oxide monohydrate}

The present invention relates to a method for preparing loperamide oxide monohydrate Formula 1, which is widely used as a branch office.

The present invention relates to a method for preparing loperamide oxide monohydrate Formula 1, which is widely used as a branch office. More particularly, the present invention relates to a method for preparing a compound of formula 1, which is a target compound, using an oxidizing agent such as hydrogen peroxide under a catalyst of loperamide or loperamide hydrochloride.

[Formula 1]

[Formula 2]

(3)

        Methods for preparing the compound represented by Formula 1 are reported in US Patent 3,714,159, Korean Patent 1994-00017772 (filed date 1986.09.03), European Patent 0219898, Japanese Patent 1987087569, US Patent 4,824,853, US Patent 4,898,873. According to the patent, 4- (4-chlorophenyl) -4-hydroxy-N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide (hereinafter, ' Loperamide ') is trans-4- (4-chlorophenyl) -4-hydroxy-N, N-dimethyl-α, which is a compound represented by Chemical Formula 3 using a hydrogen peroxide solution in the presence of methanol and toluene. α-diphenyl-1-piperidinebutanamide-N-oxide (hereinafter referred to as 'loperamide oxide') was prepared.

The by-product obtained in the process of introducing an oxide in the N position of the compound represented by the formula (2), that is, a mixture of methanol and toluene under a hydrogen peroxide solution at 60 ℃ condition to obtain the target compound represented by the formula (1) The mixture of trichloromethane, methanol, and methanol saturated with ammonia (volume ratio of 90: 9: 1) was used as an eluent, and purified by liquid chromatography, and then crystallized from a mixture of methanol and isopropyl ether, and again toluene. In addition, the process is complicated, and there is a problem of obtaining a very low yield of about 7%, and the loperamide oxide obtained under the reaction conditions has a problem of being obtained as an anhydride in an unstable crystal form that is impregnated in air.

An object of the present invention is 4- (4-chlorophenyl) -4-hydroxy-N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide hydrochloride (hereinafter referred to as loperamide hydrochloride). Or 4- (4-chlorophenyl) -4-hydroxy-N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide (hereinafter referred to as loperamide) Trans-4- (4-chlorophenyl) -4-hydroxy-N, N- which is a compound represented by Chemical Formula 3 by using an organic solvent such as methanol as a reaction solvent in the presence and oxidizing with an oxidizing agent such as hydrogen peroxide solution Trans-4- (4-chlorophenyl) -4-, a compound represented by the formula (1) in the preparation of dimethyl-α, α-diphenyl-1-piperidinebutanamide-N-oxide and in an organic solvent containing water Hydroxy-N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide-N-oxide monohydrate (hereinafter referred to as 'loperamide oxide monohydrate') is prepared.

In the reaction, when using loperamide hydrochloride as a starting material, a base such as triethylamine may be used. In addition, 4- (4-chlorophenyl) -4-hydroxy-N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide was purified using an organic solvent without any special purification process such as liquid chromatography. Crystallization to produce loperamide oxide solvate.

In order to achieve the above object, the present invention is to react the loperamide or hydrochloric acid loperamide with a hydrogen peroxide solution with a catalyst on a reaction solvent such as methanol to obtain a loperamide oxide solvate of the compound represented by the formula process; When using hydrochloric acid loperamide as a starting material, it can be reacted with a base as an acid scavenger, and water or water containing crude loperamide oxide or loperamide oxide solvate containing an organic solvent such as ethanol or the like To provide a process for making loperamide oxide monohydrate.

Here, the reaction solvent may be water, various ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, methyl formate, ethyl acetate, etc.), ethers (eg, dimethyl ether, tetrahydrofuran, etc.), halogenated hydrocarbons. (E.g., dichloromethane, chloroform, etc.), nitriles (e.g. acetonitrile, etc.), lower (C ₁ to C ₅ ) alcohols (e.g., methanol, ethanol, isopropanol, etc.) and the like, such solvents may be used alone or in mixtures. It can be used in the form, the amount of the reaction solvent may be used 100 to 3000 parts by weight based on 100 parts by weight of the reactants.

Particularly preferred solvents among the above-mentioned solvents are halogenated hydrocarbons and alcohols. When using loperamide hydrochloride as starting material, bases used as acid removers include hydrogen carbonates, carbonates, and hydroxides (e.g. sodium hydroxide, potassium hydroxide), lower alkyl (C ₁ to C ₄ ) groups of alkali metals ( For example secondary or tertiary amines substituted with methyl, ethyl, propyl, t-butyl, etc., in particular di- or tri- (C ₁ to C ₄ alkyl) amines and their corresponding quaternary ammonium salts,

In the case of using loperamide hydrochloride, the amount of the base used as the acid scavenger is preferably 0.5 to 50 moles per mole of loperamide hydrochloride, and more preferably 0.5 to 10 moles. If the amount of the base used is less than 0.5 mole, the solubility is lowered, and the yield is low. If the amount of the base is used more than 50 mole, the solution color may be colored brown, and the amount of by-products is increased, resulting in low purity.

As catalysts, molybdic acid, selenium dioxide, sodium tunstanate, benzeneseleninic acid, selenic acid, titanium silicon oxide And the like. The amount of the catalyst used is preferably 0.001 mol to 1 mol per mol of loperamide hydrochloride, and more preferably 0.005 to 0.1 mol. If the amount of the catalyst is less than 0.001 mole, the reactivity is low, yield and purity are low. If the amount of the catalyst is more than 1 mole, the amount of catalyst used is increased, resulting in poor economic efficiency.

Oxidizing agents include hydrogen peroxide, meta-chloroperoxybenzoic acid, perbenzoic acid, peracetic aicd, sodium percarbonate, calcium hypochlorite (calcium hypochlorite), sodium hypochlorite, and the like. The amount of the oxidizing agent used is preferably 0.5 to 10 moles per mole of loperamide hydrochloride, and more preferably 1 to 5 moles. If the amount of the base is less than 0.5 mole partially oxidized to lower the yield, if it exceeds 10 moles the amount of by-products is increased resulting in low purity and low yield.

Hereinafter, the present invention will be described in detail.

The present invention further comprises a process of crystallizing loperamide oxide or loperamide oxide, which is a compound represented by Formula 3, by reacting loperamide or loperamide hydrochloride with a peroxide solution on a reaction solvent such as methanol. May be included. Various solvates can be obtained depending on the solvent used in the crystallization process. Depending on the type of the raw material can be reacted by using a base, loperamide oxide represented by the formula (1) using only water or an aqueous solution containing an organic solvent such as ethanol, such as loperamide oxide or loperamide oxide solvate Provided are methods for making hydrates.

4- (4-Chlorophenyl) -4-hydroxy-N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide- which is a compound represented by the formula (1) used as a branching agent according to the present invention In order to prepare N-oxide monohydrate, loperamide hydrochloride, which is a starting material represented by Chemical Formula 2, is first added to an organic solvent such as methanol, and then a basic substance such as sodium hydroxide is added to dissolve loperamide. A catalyst such as selenic acid is added thereto, an oxidizing agent such as hydrogen peroxide is added dropwise, and the mixture is slowly heated to reflux. The reaction temperature is from 0 deg. C to reflux, more preferably from room temperature to 70 deg. When the reaction temperature is low, the reactivity is lowered and must be reacted for a long time. When the temperature is higher than 70 ° C., the reaction is increased but the reaction color is colored. Preferred reaction times are from 30 minutes to 6 hours.

After completion of the reaction, the reaction solvent was concentrated under reduced pressure and completely removed. Then, dichloromethane and water were added and the layers were separated. When the organic solvent obtained by layer separation is concentrated under reduced pressure, a crystallization solvent is added to the oil phase to prepare a loperamide oxide solvate represented by Chemical Formula 3. At this time, if necessary, the solution may be filtered to remove impurities before adding the crystallization solvent. Crystallization solvents used include ketones (e.g. acetone, methylethyl ketone, methyl isobutyl ketone, etc.), esters (e.g. methyl formate, ethyl acetate, etc.), ethers (e.g. dimethyl ether, tetrahydrofuran, etc.), nitrile (E.g., acetonitrile, etc.), lower alcohols (e.g., methanol, ethanol, isopropanol, etc.), and these solvents may be used alone or in mixtures, and the amount of crystallization solvent is 100 based on 100 parts by weight of the reactants. To 2000 parts by weight may be used. The content of loperamide oxide solvate differs depending on the crystallization solvent used. Acetone contains 0.5 mole per mole of loperamide oxide.

The loperamide oxide or loperamide oxide solvate prepared by the above method is reacted under an organic solvent including water or water to prepare a compound of formula 1 which is loperamide oxide monohydrate. In this case, the amount of water capable of converting loperamide oxide or loperamide oxide solvate to loperamide oxide monohydrate may be used including 1 to 2000 moles of water per mole of loperamide oxide.

As an organic solvent containing water, a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, methyl isobutyl ketone, tetrahydrofuran, and mixtures thereof is used. The amount of the solvent used may be 100 to 2000 parts by weight based on 100 parts by weight of the reactant.

The reaction temperature is from 0 deg. C to reflux, more preferably from room temperature to 100 deg. When the reaction temperature is low, the reactivity decreases, so the time for converting from loperamide oxide solvate to loperamide oxide monohydrate becomes longer and needs to be reacted for a long time. When temperature exceeds 100 ° C, the reaction is increased but the reaction color is colored. There is this. Preferred reaction times are from 30 minutes to 6 hours. After completion of the reaction, it is cooled and then filtered, washed, and dried in a conventional manner to obtain a final product.

As described above, the present invention relates to a method of formula (1) which is a loperamide oxide monohydrate widely used as a branch office. Preparation of the compound of Formula 2 obtained by the selective oxidation of loperamide hydrochloric acid or loperamide with a oxidizing agent such as hydrogen peroxide in the presence of a metal catalyst such as benzene selenic acid, ie NO oxidation do. Compound represented by the formula (2) provides a method for producing in the form of a polymorphic crystal obtained by a variety of solvates depending on the solvent. In addition, when the solvate of loperamide oxide according to the present invention is used as a starting material, hydrochloric acid is neutralized with a basic substance such as sodium hydroxide (NaOH), and then an oxidation reaction is selectively performed using an oxidizing agent such as hydrogen peroxide. Since side reactions can be minimized and solvates are formed by various solvents, complex purification processes such as column chromatography are not required, so the reaction process can be shortened innovatively, and high purity and high yield can be obtained. There is an advantage.

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited by the following examples.

Example 1

10 g of loperamide hydrochloride is added to 70 ml of methanol dissolved in 0.7 g of sodium hydroxide (NaOH) and stirred. Add 40 mg of selenic acid, add 3 ml of hydrogen peroxide, and heat to reflux. After completion of the reaction by TLC (thin layer chromatography), the mixture was cooled to room temperature, 80 ml of dichlorochloromethane was added, 80 ml of purified water was added, and the layers were separated. The organic layer obtained by layer separation is dehydrated with anhydrous magnesium sulfate. The reaction was filtered under reduced pressure to remove magnesium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The reaction product obtained above was crystallized with acetone, and the resulting crystals were filtered, washed with acetone and dried to obtain 9.16 g (yield: 92.06%) of white crystals of loperamide oxide acetone solvate.

[Example 2]

9.29 g of loperamide is added to 70 ml of methanol and stirred. Add 40 mg of selenic acid, add 3 ml of hydrogen peroxide, and heat to reflux. After completion of the reaction by TLC, after cooling to room temperature, 80 ml of dichlorochloromethane was added, 80 ml of purified water was added, and the layers were separated. The organic layer obtained by layer separation is dehydrated with anhydrous magnesium sulfate. The reaction was filtered under reduced pressure to remove magnesium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The reaction product obtained above was crystallized with isopropanol, and the resulting crystals were filtered, washed with isopropanol and dried to obtain 9.88 g (yield: 92.8%) of white crystals of loperamide oxide isopropanol solvate.

[Example 3]

10 g of loperamide hydrochloride is added to 70 ml of methanol dissolved in 0.7 g of sodium hydroxide (NaOH) and stirred. 40 mg of benzene selenic acid was added, 5 ml of peracetic acid was added, and the mixture was heated to reflux. After completion of the reaction by TLC, the mixture was cooled to room temperature, 80 ml of dichloromethane was added, 80 ml of purified water was added, and the layers were separated. The organic layer obtained by layer separation is dehydrated with anhydrous magnesium sulfate. The reaction was filtered under reduced pressure to remove magnesium sulfate, and the filtrate was concentrated under reduced pressure to remove the solvent. The reaction product obtained above was crystallized with acetone, and the resulting crystals were filtered, washed with ethanol and dried to obtain 9.16 g (yield: 92.06%) of white crystals of loperamide oxide ethanol solvate.

Example 4

10 g of crude loperamide oxide is added to 100 ml of water and stirred. Heat slowly to maintain 80 ~ 90 ℃ for 2 hours, then cool to room temperature. The resulting crystals were filtered, washed with water, and dried at 40 to 50 ° C. for 3 hours to obtain 9.3 g (yield: 93.1%, moisture: 3.9%) of white crystal loperamide oxide monohydrate.

[Example 5]

10 g of crude loperamide oxide is dissolved in 70 ml of water and 70 ml of ethanol. The mixture was slowly heated, concentrated under reduced pressure at 50 ° C, the organic solvent was concentrated, held at the same temperature for 2 hours, and then cooled to room temperature. The resulting crystals were filtered off, washed with water, and dried at 40 to 50 ° C. for 3 hours to obtain 9.2 g (yield: 92%, moisture: 3.8%) of white crystal loperamide oxide monohydrate.

[Example 6]

10 g of loperamide oxide acetonide was added to 70 ml of water and 140 ml of ethanol and stirred. The mixture was slowly heated, concentrated under reduced pressure at 50 ° C, the organic solvent was concentrated, held at the same temperature for 2 hours, and then cooled to room temperature. The resulting crystals were filtered, washed with water, and dried at 40 to 50 ° C. for 3 hours to obtain 9.1 g (yield: 91%, moisture: 3.7%) of white crystals of loperamide oxide monohydrate.

Claims (7)

Reacting the loperamide of formula 2 or loperamide hydrochloride with an oxidizing agent in the presence of a catalyst in an organic solvent to prepare a loperamide oxide compound of formula 3 (step 1); And
Preparing a loperamide oxide monohydrate of Formula 1 by reacting the loperamide oxide of Formula 3 with water or an organic solvent containing water (step 2);
Process for producing loperamide oxide monohydrate, characterized in that it comprises a.
[Formula 1]

(2)

(3)

Reacting the loperamide of formula 2 or loperamide hydrochloride with an oxidizing agent in the presence of a catalyst in an organic solvent to prepare a loperamide oxide compound of formula 3 (step 1);
Preparing a loperamide oxide solvate of the loperamide oxide of Formula 3 using an organic solvent (step 2); And
Preparing a loperamide oxide monohydrate of Chemical Formula 1 by reacting the loperamide oxide solvate under an organic solvent containing water or water (step 3);
Process for producing loperamide oxide monohydrate, characterized in that it comprises a.
[Formula 1]

(2)

(3)

3. The method according to claim 1 or 2,
The catalyst of step 1 is a loperamide oxide, characterized by using a catalyst selected from the group consisting of molybdic acid, selenium dioxide, sodium tungstate, benzene selenic acid, selenic acid, titanium silicon oxide and mixtures thereof. Method of producing monohydrate. 3. The method according to claim 1 or 2,
The oxidizing agent of step 1 includes an oxidizing agent selected from the group consisting of hydrogen peroxide, meta-perchlorobenzoic acid, perbenzoic acid, peracetic acid, sodium percarbonate, calcium hypochlorite, sodium hyperchlorite, and mixtures thereof. Process for producing loperamide oxide monohydrate, characterized in that. 3. The method according to claim 1 or 2,
The acid remover used in the case of loperamide hydrochloride in the first step is a secondary amine, tertiary amine substituted with hydrogen carbonate, carbonate, sodium hydroxide, potassium hydroxide, lower alkyl (C ₁ to C ₄ ) of alkali metal Or a quaternary ammonium salt is added to the method for producing loperamide oxide monohydrate. The method of claim 2,
Preparation of the loperamide oxide solvate of the second step is to wash the solution of the compound of formula 3 with water and then to methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, methyl isobutyl ketone, tetrahydrofuran and mixtures thereof A method for producing loperamide oxide monohydrate, characterized in that loperamide oxide solvate is prepared using a solvent selected from the group as a crystallization solvent. 3. The method according to claim 1 or 2,
The loperamide oxide or a solvate thereof is selected from the group consisting of water or water, methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, methyl isobutyl ketone, tetrahydrofuran and mixtures thereof. Process for producing loperamide oxide monohydrate, characterized in that used.