KR960007080B1 - Preparation of polymorphically pure terfenadine - Google Patents

Abstract

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Description

Process for the preparation of pure terpenadine isoforms

-하이드록시디페닐메틸)-1'-피페리디닐]부탄올은 비-진정성 항히스타민제이다. 테르펜에 대한 이전의 결정화 방법들은 분석적으로는 순수하지만 매우 다양한 융점을 지닌 생성물을 생선한다. 최근에, 각각의 형태가 상이한 융점을 갖는, 두개의 뚜렷한 결정 또는 동질 이형체로 존재하는 고체 테르펜아딘을 발견하였다. 또한, 선행 기술 방법에 의해 결정화된 테르펜아딘은 다양한 동질이형체 조성물로 존재할 수 있고, 이 동질이형체의 존재로 인해 테르펜아딘의 융점이 다양하게 관찰된다. 출원인은 순수한 테르펜아딘 동질이형체를 제조하는 방법을 발견하였다. 이 방법은 대규모의 테르펜아딘의 제조와 관련하여 질 조절기능을 용이하게 하는 물리적 성질에 대한 조절 세트를 갖는 물질을 제공한다.Terpenadine, 1- (p-tert-butylphenyl) -4- [4 '-(

-Hydroxydiphenylmethyl) -1'-piperidinyl] butanol is a non-true antihistamine. Previous crystallization methods for terpenes produce products that are analytically pure but with a wide variety of melting points. Recently, solid terpenadines have been found that exist as two distinct crystals or isoforms, each form having a different melting point. In addition, terpenadine crystallized by the prior art methods can exist in various isoisomeric compositions, and the melting point of terpenadine is observed due to the presence of this isoform. Applicants have discovered a method for preparing pure terpenadine isoforms. This method provides a material with a controlled set of physical properties that facilitates vaginal control in connection with the production of terpenadine on a large scale.

The high melting point isomers of terpenadine dissolve terpenadine in water-miscible lower alkanols, heat the solution at approximately reflux temperature, and provide sufficient water under stirring to produce almost all of the dissolved terpenadine as crystals. Is added slowly, cooled to about 25 ° C., and the crystalline product is collected and prepared. Low melting isomers of terpenadine are prepared by dissolving terpenadine in a suitable solvent at about 0 ° C. to about 35 ° C., evaporating the solvent slowly and collecting the resulting crystal product.

High melting point isomers of terpenadine are crystalline forms of near pure terpenadine with melting points of about 149-151 ° C. The low melting isoform of terpenadine is a crystalline form of terpenadine, which is almost pure with a melting point of 146 ° C.

"Lower alkanol solvent" means a water-miscible, lower alkanol in which terpenadine can be dissolved and includes primary, secondary and tertiary alcohols having 1 to 6 carbon atoms. Suitable lower alkanol solvents include methanol, ethanol, primary-propanol, isopropanol, isobutanol, amyl alcohol, tert-butanol and cyclohexanol. The lower alkanol solvents used in the preparation of the high melting point isomers of terpenadine are preferably methanol, ethanol or propanol. Ethanol is the most preferred solvent. Also mixtures of two or more lower alkanols are suitable as a solution of water and lower alkanols, where water will be about 10-20% by weight or less of the solution.

Typically a solution of terpenadine in a lower alkanol solvent is prepared. Typically, a solution of the material to be recrystallized is highly concentrated to the saturation point of the solute in the solvent. For example, when ethanol is the solvent, the ratio of weight to volume of terpenadine to ethanol may be 0.1 g / ml to 0.3 g / ml, preferably 0.15 g / ml to 0.2 g / ml. Typically, the solution to be recrystallized is heated to approximately the reflux temperature of the solution. If ethanol is the solvent, the temperature is about 78 ° C. It is desirable to filter the hot, concentrated solution to remove insoluble particulate matter. Filtration is particularly important when the high melting point isoform of terpenadine is prepared directly from impure terpenadine.

Water is added to the heated concentrated solution to crystallize terpenadine. Preferably enough water is added to crystallize almost all of the terpenadine. When ethanol is a solvent, when ethanol is a solvent of water, the volume ratio of ethanol to water is 0.75 to 1.5 ml / ml, preferably about 1 ml / ml. Preferably up to 10% dissolved terpenadine remains in solution after complete addition of water. The amount of water required depends on several factors, including solvent, heating temperature, concentrated solution and the concentration of the solution. The amount of water needed to recover almost all of the terpenadine as crystals of high melting point isomers can be readily determined by one skilled in the art.

The water added to the heated concentrated terpenadine solution is also preferably heated to a temperature of 60 ° C to 100 ° C. The preheating of the water keeps the temperature of the heated, concentrated solution of terpenadine more constant.

It is desirable to add water to the heated concentrated terpenadine solution so that the temperature of the solution can be maintained at approximately its reflux temperature. For example, it is preferable to add gradually dropwise, stirring and shaking. Typically, water is added for 10 minutes to 2 hours. After all the water has been added to the lower alkanol solution, it is preferred to digest the crystals before filtration to recover the product. Warming of the crystals can be carried out by continuing the heating of the lower alkanol solution of terpenadine after the addition of water. The temperature at the time of warming will preferably be the reflux temperature of the solution, but may in particular be approximately ambient temperature. The warm needle may proceed for about 1 day or less, preferably about 0 to 6 hours.

Water is added completely to the concentrated solution of heated terpenadine in lower alkanols and the crystals are decomposed and optionally the resulting mixture is allowed to cool to ambient temperature, about 25 ° C. The cooling reaction is preferably carried out by simply removing the heat source and is not accelerated by any cooling means. Once cooled to ambient temperature, the mixture is cooled to about 0-5 ° C. using a simple ice-water bath. In some cases, salts such as sodium chloride or calcium chloride may be used to lower the temperature of the ice bath to a much lower temperature. The cold mixture is filtered from the slurry to recover the solid product. The solid product can be washed with additional water, preferably cooling water or with a small amount of a mixture of water and alkanol (eg 5-% aqueous ethanol). The product is dried in a conventional manner under vacuum and is preferably heated to about 50-75 ° C., most preferably about 60 ° C. to promote the loss of residual water and lower alkanols.

"Compliant solvent" as used in connection with the preparation of the low melting point isoform of terpenadine means any solvent which terpenadine can dissolve, such as a hydrocarbon solvent, which is complex such as pentane, hexane, benzene, toluene and xylene It is a solvent containing carbon and hydrogen, and also ketones or aldehydes having 1 to 10 carbon atoms may be used, such as methyl ethyl ketone, 2-butanone, cyclopentanone, isopropylmethylketone and acetophenone. Mixtures of two or more lower ketones are also suitable. Ketone solvents are preferred as well as toluene. Acetone is the most preferred solvent.

The solution of terpenadine is prepared by simply adding the solvent to the homoisomeric mixture of terpenadine or the high melting point isoform of terpenadine under stirring. Nearly pure terpenadine, that is, terpene with little contaminants other than isoforms of terpenadine, is used in preparing a solution for producing a pure, low melting isoform of terpenadine.

Heating to increase the dissolution rate is undesirable, and other solutions to be used to recrystallize the solutes, solutions of terpenadine in the lower ketone solvents used above, need not be saturated or are almost saturated. For example, a solution of 50 ml of terpenadine in about 12 ml of acetone is preferred. It is desirable to filter the solution to remove undissolved terpenadine or other impurities.

The low-ketone solvent is evaporated. At this time, it is preferable to allow the solution to stand in the ring-opening vessel for several hours to several days at room temperature and to gradually evaporate it. For example, a solution of 50 mg of terpenadine in 12 ml of acetone is evaporated over two days. Heating to increase the evaporation rate is undesirable. Room temperature evaporation is preferred. The use of a vacuum system is also undesirable but the use of good air circulation is recommended to prevent excessive evaporation of the solvent. The resulting crystal product is almost pure and has a low melting point isomer of terpenadine.

Example 1

Preparation of low-melting isomers of terpenadine from acetone solution

Approximately 50 ml of terpenadine (19% high melting point isomer, 81% low melting point isomer) is dissolved in 12 ml of acetone at room temperature. Acetone is slowly evaporated over two days. Anhydrous product, terpenadine, is a 100% low melting point isomer.

Example 2

Preparation of high-melting isomers of terpenadine

In a 500 ml magnetic flask equipped with a magnetic rod, 72.6 g of damp, impure terpenadine (about 51% water) is contained. 250 ml of absolute ethanol was added to the flask and the slurry was heated to reflux to produce a cloudy solution. The solution is filtered in a 1 ι three necked flask equipped with a reflux condenser fixed with a magnetic stirrer, a nitrogen bubbler, and a pressure-equilibrium addition funnel. The ethanol solution is maintained at reflux temperature and 200 ml of deionized water is slowly added over 30 minutes to crystallize terpenadine. The resulting slurry is heated at reflux for 5 hours to crystallize the product. The slurry is cooled slowly to room temperature. The slurry is cooled for 30 minutes in an ice bath. The solid was filtered from the slurry, washed with 50 ml of 50/50 (V / V) ethanol / water, washed twice with 50 ml of water, air dried and vacuum dried at 60 ° C. to give a pure solid having a melting point of 149.5 to 151 ° C. -37.0 g of terpenadine are obtained as the melting point isomer.

Elemental Analysis: C ₃₃ H ₄₁ NO ₂

Calculated: C; 81.48, H; 8.76, N; 2.97

Found: C; 81.5, H; 8.70, N; 2.94

Ignition residue: 0.02%

Example 3

Preparation of Terpenadine

A 1 L three-necked flask equipped with a mechanical stirrer, pressure-equilibrium addition funnel and a reflux condenser fixed with nitrogen bubbler contains 72.8 g (0.149 mole) of terpenadon monohydrate and 320 ml of anhydrous ethanol. The mixture is heated to reflux, resulting in a clear solution and 12.0 g (0.317 mol) of sodium borohydride and 25.6 ml of water in 83.2 g of 50% sodium hydroxide are added dropwise over 1 hour with stirring. After complete addition, the reaction mixture is stirred at reflux for 2 hours. Terpenadine crystallizes. The slurry is diluted with 320 ml of water by adding water so that the reaction remains at reflux. The slurry is cooled slowly. The solid was filtered from the slurry and washed with 100 ml of 50/50 (V / V) ethanol / water, washed twice with 250 ml of deionized water, air dried and vacuum dried at 60 ° C. to homogeneous isomers having a melting point of 149.5 to 150 ° C. 68.2 g (yield 97%) of terpenadine are obtained as a mixture of.

Example 4

Preparation of high-melting isomers of terpenadine

The terpenadine obtained from Example 3 is placed in a 1ι conical flask and mixed with 250 ml of absolute ethanol. The mixture is heated to reflux and a cloudy colorless solution is obtained. The solution is filtered in a 1? Three neck flask equipped with a reflux condenser equipped with a mechanical stirrer, pressure-equilibrium addition funnel, and a nitrogen bubbler. The flask and filter are washed with 70 ml of reflux ethanol. The filtrate is kept at reflux and 320 ml of deionized water is added so that the mixture remains under reflux. After the addition reaction is complete, the fished slurry is kept under reflux for 10 minutes and then slowly cooled to room temperature. The solid was filtered from the slurry, washed with 100 ml of 50/50 (V / V) ethanol / water, washed twice with 250 ml of deionized water each time, air dried and vacuum dried at 60 ° C. for terpenadine having a melting point of 148.5 to 150 ° C. 66.2 g (97% recovery) are obtained. This indicates that terpenadine was obtained in 94% yield from terpenadon through reduction, crystallization and recrystallization.

Elemental Analysis: C ₃₂ H ₄₁ NO ₂

Calculated: C; 81.48, H; 8.76, N; 2.97

Found: C; 81.7, H; 8.89, N; 2.87

Residue on ignition: not detected at 0.04% limit

Example 5

Preparation of low-melting isomers of terpenadine from toluene solution

Approximately 50 mg of terpenadine (19% high melting point isomer, 81% low melting point isomer) is dissolved in 12 ml of toluene at room temperature. Toluene is slowly evaporated over two days. Anhydrous product is a low-melting isomer of 100% pure terpenadine.

Claims (11)

Dissolve terpenadine in water-miscible lower alkanols, heat the solution at approximately reflux, add sufficient water with gentle stirring to substantially crystallize terpenadine, cool and collect crystalline product Thereby producing a high-melting homomorph of terpenadine. The method of claim 1 wherein the water-miscible lower alkanol is methanol, ethanol or isopropanol. The method of claim 1 wherein the water-miscible lower alkanol is ethanol. The method of claim 1 wherein the weight to volume ratio of terpenadine to ethanol in solution is between 0.1 g / ml and 0.3 g / ml. The method of claim 3 wherein the volume ratio of ethanol to water is about 0.75 ml / ml to 1.5 ml / ml. The process of claim 3 wherein the volume ratio of ethanol to water is about 1.0 mmol / ml. 4. The method of claim 3 wherein the solution temperature of terpenadine in ethanol is about 78 ° C. The amount of water of claim 1 wherein the solution of terpenadine in ethanol with a weight to volume ratio of terpenadine to ethanol of about 0.15 to 0.25 is heated to 78 ° C. and the volume ratio of ethanol to water is about 1 ml / ml. Is added over about 30 minutes and the resulting slurry is heated at its reflux temperature for 0 to 5 hours, slowly cooled to room temperature, then cooled to 0 ° C to 5 ° C, filtered and the recovered terpenadine is dried . At about 0 ° C. to about 35 ° C., wherein the terpenadine is dissolved in a suitable solvent, the solvent is evaporated slowly and the crystalline product is collected, thereby producing a low-melting isomer of terpenadine. The method of claim 9 wherein the solvent is acetone. The method of claim 9 wherein the solvent is toluene.