JP2657818B2 - Production of polymorphically pure terfenadine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION INDUSTRIAL APPLICATION Terfenadine, ie, 1- (p-tert-butylphenyl) -4- [4 '-(α-hydroxydiphenylmethyl) -1'-piperidinyl] butanol Is a non-sedating antihistamine.

[Conventional technology]

Previous crystallization procedures for terfenadine produce products that are analytically pure but still have very variable melting points. Recently, solid terfenadine has been found to exist in two distinct forms, crystalline or polymorphic, each having a different melting point. It has further been discovered that terfenadine crystallized by prior art methods varies widely in polymorph composition, and that this polymorphic diversity is the reason for the observed diversity in the melting point of terfenadine. Was.

[Problem solved by the invention]

Applicants have discovered a process for producing polymorphically pure terfenadine in the present invention. These methods facilitate the complete functionality associated with large-scale production of terfenadine. Provide a substance having a controlled set of physical properties.

[Means to solve the problem]

The high melting point polymorph of terfenadine is terfenadine,
Dissolve in a water-miscible lower alkanol, heat the solution to about its reflux temperature, slowly add sufficient water with stirring to effect crystal formation of substantially all of the dissolved terfenadine, Prepared by cooling to 25 ° C. and collecting the crystalline product. Low melting polymorphs of terfenadine are prepared by dissolving terfenadine in a suitable solvent at about 0 ° C. to about 35 ° C., slowly evaporating the solvent, and collecting the resulting crystalline product. .

The high melting point polymorph of terfenadine has a melting point of about 149-151 ° C.
Is a substantially pure crystalline form.
The low melting polymorph of terfenadine is a substantially pure crystalline form of terfenadine having a melting point of 146 ° C.

The term "lower alkanol solvent" refers to any water-miscible lower alkanol in which terfenadine is soluble and includes primary, secondary and alkanols of 1 to 6 carbon atoms. Contains tertiary and tertiary alcohols. Suitable lower alkanol solvents include methanol, ethanol, n-propanol, isopropanol, isobutanol, amyl alcohol, t-butanol and cyclohexanol. Preferably, the lower alkanol solvent used to prepare the high melting polymorph of terfenadine is methanol, ethanol or propanol.
Ethanol is the most preferred solvent. Also included are water and lower alkanol solutions, which are comprised of a mixture of two or more lower alkanols, and wherein water occupies up to about 10-20% of the solution by weight.

A solution of terfenadine in a lower alkanol solvent is
Manufactured by conventional methods. Typically, the solution of the material to be recrystallized will be highly concentrated near the solute saturation point in the solvent. For example, when ethanol is the solvent, the weight to volume ratio of terfenadine to ethanol is 0.
It can be 1 g / ml to 0.3 g / ml, preferably 0.15 g / ml to 0.25 g / ml. Typically, the solution to be recrystallized is heated,
The temperature of the solution to be recrystallized will be approximately the solution reflux temperature. This temperature is about 78 when using ethanol solvent.
° C. Preferably, the hot concentrated solution is filtered prior to crystal formation to remove any insoluble particulate matter. Filtration is particularly important when the terfenadine high melting polymorph is to be produced directly from impure terfenadine.

Water is added to the heated and concentrated solution to cause crystallization of terfenadine. Preferably, a sufficient amount of water will be added so that substantially all of the terfenadine crystallizes. When ethanol is the solvent,
The volume to volume ratio of ethanol to water is 0.75-1.5ml / m
l, preferably about 1 ml / ml. Preferably less than 10% of the dissolved terfenadine will remain in solution after complete addition of water. The amount of water required is
It depends on various factors, including the solvent, the temperature of the heated and concentrated solution, and the concentration of the solution. The amount of water required to recover substantially all of the terfenadine as crystals of the high melting polymorph can be readily determined by one skilled in the art.

The water to be added to the heated and concentrated terfenadine solution is preferably heated, preferably 60 ° C to 100 ° C
Heated to a temperature of Preheating the water facilitates maintaining a constant temperature of the heated and concentrated terfenadine solution.

Preferably, the water is added to the heated and concentrated terfenadine solution at a rate such that the temperature of the solution can be maintained at about its reflux temperature. For example, it is preferable to drop slowly while stirring by stirring. Typically, the addition of water takes 10 minutes to 2 hours. After all the water has been added to the lower alkanol solution of terfenadine, the crystals are preferably aged before filtration to collect the product. Crystal ripening can be achieved by continuing to heat the lower alkanol solution of terfenadine after the water addition is complete. Preferably the temperature during aging is the reflux temperature of the solution, but can be any temperature at about ambient temperature. Aging can proceed for any period of time, up to about 1 day, preferably about 0-6 hours.

After the addition of water to the heated concentrated terfenadine solution in the lower alkanol is complete, and after ripening of the crystals, the resulting mixture is allowed to cool to an ambient temperature of about 25 ° C, if desired. Preferably, this cooling is achieved by simply removing the heating source and is not facilitated by any cooling means. Once cooled to ambient temperature, the mixture is then cooled at about 0-5 ° C, for example by using a simple ice-water bath. Salts such as sodium chloride or calcium chloride can be used to reduce the temperature of the cooling bath, further reducing the temperature if desired. The cooled mixture is then filtered from the slurry to collect the solid product. The solid product can be washed with additional water, preferably a small amount of cold water or a mixture of water and alkanol, such as 50% aqueous ethanol. The product may then be dried by conventional means, for example under vacuum, and heated to preferably about 50-75 ° C, most preferably about 60 ° C, to facilitate the disappearance of residual water and lower alkanols. I can do it.

The term "suitable solvent" as used in the present invention for the preparation of low melting polymorphs of terfenadine refers to any solvent in which any terfenadine is soluble, e.g., only hydrocarbon solvents, i.e., only carbon and hydrogen elements. Containing solvents such as pentane, hexane, benzene, toluene and xylene, or ketones or aldehydes having 1 to 10 carbon atoms such as methyl ethyl ketone, 2-butanone, cyclobentanone, isopropyl methyl ketone and Acetophenone can be used. Also included are mixtures of two or more lower ketones. Ketone solvents and toluene are preferred. Acetone is the most preferred solvent.

Solutions of terfenadine are prepared in a conventional manner by simply adding the solvent to the polymorphic mixture of terfenadine or, for high melting polymorphs of terfenadine, with stirring. When preparing a solution for the purpose of producing a pure, low melting point polymorph of terfenadine, substantially pure terfenadine, i.e., a terfenadine polymorph that is substantially free of contaminants other than the polymorph of terfenadine Phenazine should be used.

Heating to increase the rate of dissolution is not preferred and, unlike the solution to be used to recrystallize the solute, the solution used here of terfenadine in a lower ketone solvent is saturated or substantially It need not be near saturation. For example, a solution of 50 mg of terfenadine in about 12 ml of acetone is satisfactory. Preferably, the solution is filtered to remove any undissolved terfenadine or other impurities.

Next, the lower ketone solvent is evaporated. It is preferred to evaporate slowly, for example by leaving the solution in an open container at room temperature for several hours to several days. For example, a solution of 50 mg of terfenadine in acetone in 12 ml is evaporated over 2 days. Heating to increase the rate of evaporation is not preferred. Evaporation at room temperature is preferred. The use of a vacuum system is also not preferred, but it is advisable to provide good air circulation to prevent accumulation of excessively evaporated solvent. The resulting crystalline product is a substantially pure low melting polymorph of terfenadine.

Example 1 Preparation of low melting polymorph of terfenadine from acetone solution Approximately 50 mg of terfenadine (19% high melting polymorph, 81%)
% Low melting polymorph) was dissolved in 12 ml of acetone at room temperature. The acetone was then slowly evaporated over 2 days. The dried product terfenadine was a 100% low melting polymorph.

Example 2 Preparation of a high melting polymorph of terfenadine 72.6 g of wet impure terfenadine (approximately 51% water) in a 500 ml Erlenmeyer flask equipped with a magnetic stirrer
Was charged. The flask was then charged with 250 ml of absolute ethanol and the slurry was heated to reflux to form a cloudy solution. The solution was filtered hot into a 1 l three-necked flask equipped with a mechanical stirrer, reflux condenser equipped with a nitrogen bubbler, and a pressure equalizing addition funnel. While maintaining the ethanol solution at reflux, 200 ml of deionized water was added slowly over 30 minutes, resulting in crystallization of terfenadine. The resulting slurry was then heated at reflux for 5 hours to effect crystal ripening of the product. The slurry was then slowly cooled to room temperature.
The slurry was then cooled in an ice bath for 30 minutes. The solid is filtered from the slurry, washed with 50 ml of 50/50 (v / v) ethanol / water, washed twice with 50 ml portions of water, air dried, and
Vacuum dried at 60 ° C. to give 37.0 g of terfenadine as pure high melting polymorph. 149.5-151 ° C.

Analysis: C ₃₂ H ₄₁ NO ₂ Calculated:. C, 81.48; H, 8.76; N, 2.97 Found:. C, 81.5; H, 8.70; N, 2.94 residue upon ignition: 0.02% EXAMPLE 3 Manufacture of terfenadine In a 1 l three-necked flask equipped with a mechanical stirrer, a pressure equalizing addition funnel, and a reflux condenser with a nitrogen bubbler
2.8 g (0.149 mol) of terfenadone monohydrate and 320 ml
Of absolute ethanol was charged. Heat the mixture to reflux,
A clear solution was formed and a solution of 83.2 g of 50% sodium hydroxide and 12.0 g (0.317 mol) of sodium borohydride in 25.6 ml of water was added dropwise with stirring over 1 hour.
After the addition was completed, the reaction mixture was stirred at reflux for 2 hours.
Terfenadine began to crystallize. The slurry is then 320m
One milliliter of water was diluted by adding at a rate such that the reaction remained at reflux. The slurry was then slowly cooled to room temperature. Filter the solids from the slurry and 100ml of 50/50 (v / v)
Wash with ethanol / water, wash twice with 250 ml portions of deionized water, air dry, vacuum dry at 60 ° C.,
% Yield) of terfenadine as a mixture of polymorphs. 149.5-150 ° C.

Example 4 Production of high melting point polymorph of terfenadine The terfenadine obtained in Example 3 was charged into one Enmeyer flask and mixed with 250 ml of absolute ethanol. The mixture was heated to reflux to give a cloudy colorless solution. The solution was filtered into a one-necked flask equipped with a mechanical stirrer, pressure equalizing addition funnel, and reflux condenser equipped with a nitrogen bubbler. The flask and filter were washed with 70 ml of refluxing ethanol. The filtrate was kept at reflux and 320 ml of deionized water was added at a rate such that the mixture remained at reflux. After the addition was complete, the resulting slurry was kept at reflux for 10 minutes and then cooled slowly to room temperature. The solid is filtered from the slurry, washed with 100 ml of 50/50 (v / v) ethanol / water,
Washed twice with ml of deionized water, air dried and vacuum dried at 60 ° C. to give 66.2 g (97% recovery) of terfenadine. 148.5-150 ° C. This is 94% of terfenadine from terfenadone through reduction, crystallization and recrystallization.
It represents the yield.

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 residual when the ignition: 0.04% of the limit Was not detected.

Example 5 Preparation of low melting polymorph of terfenadine from toluene solution Approximately 50 mg of terfenadine (19% high melting polymorph, 81
% Low melting polymorph) was dissolved in 12 ml of toluene at room temperature. The toluene was then slowly evaporated over 2 days. The dried product was a low melting polymorph of terfenadine with 100% purity.

 ──────────────────────────────────────────────────続 き Continuation of front page (72) Inventor David Double. Jetlaw United States 48640 Michigan Midland Duncourt 5

Claims (11)

(57) [Claims] 1. Dissolving terfenadine in a water-miscible lower alkanol, heating the solution to about its reflux temperature and adding a sufficient amount of water slowly with stirring to substantially crystallize the terfenadine. And producing a high melting polymorph of terfenadine comprising cooling and collecting the crystalline product. 2. The method according to claim 1, wherein the lower alkanol miscible with water is methanol, ethanol or isopropanol. 3. The method according to claim 1, wherein the lower alkanol miscible with water is ethanol. 4. The method of claim 1 wherein the weight to volume ratio of terfenadine to ethanol in the solution is from 0.1 g / ml to 0.3 g / ml. 5. The method according to claim 1, wherein the volume to volume ratio of ethanol to water is 0.
4. The method according to claim 3, wherein the amount is from 75 ml / ml to 1.5 ml / ml. 6. The method of claim 1, wherein the volume to volume ratio of ethanol to water is about
4. The method according to claim 3, wherein the amount is 1.0 ml / ml. 7. The method of claim 3, wherein the temperature of the solution of terfenadine in ethanol is about 78 ° C. 8. A solution of terfenadine in ethanol having a weight to volume ratio of terfenadine to ethanol of 0.15 to 0.25 is heated to 78 ° C. and sufficient to produce a volume to volume ratio of ethanol to water of 1 ml / ml. Water is added over 30 minutes and the resulting slurry is heated to reflux for 0-5 hours, slowly cooled to room temperature, then cooled to 0-5 ° C, filtered and the recovered terfenadine is dried The method of claim 1. 9. A process for preparing a low melting polymorph of terfenadine comprising dissolving terfenadine in a suitable solvent at 0 ° C. to 35 ° C. and slowly evaporating the solvent to collect the crystalline product. . 10. The method according to claim 9, wherein the solvent is acetone. 11. The method according to claim 9, wherein the solvent is toluene.