KR20030022763A - Production of polymorphic forms i and ii of finasteride by complexation with group i or ii metal salts - Google Patents

Abstract

The polymorphic Type I finasteride of the present invention is formed of an almost insoluble complex of finasteride and a Group I or Group II metal salt such as lithium bromide first, and then dissociates the complex by dissolving the salt component with water, thereby almost pure type I polymorphic crystal finasteride. It can be manufactured by obtaining.

Description

Process for preparing polymorphic Form I and Form II of finasteride by complexation with Group I or Group II metal salts {PRODUCTION OF POLYMORPHIC FORMS I AND II OF FINASTERIDE BY COMPLEXATION WITH GROUP I OR II METAL SALTS}

Finasteride is chemically (5α, 17β) -N- (1,1-dimethylethyl) -3-oxo-4-aza-androst-1-ene-17-carboxamide of the formula:

It has been reported to be active in inhibiting the activity of the testosterone-5α-reductase, which leads to the expansion of the prostate and consequently a malignant condition, namely the dihydrotestosterone of the testosterone in the body suggesting the growth of prostate cancer, the reduction to DHT. Thus, finasteride is a prescription for alleviation of prostate cancer.

Finasteride may exist in two different polymorphic Forms I and II, which differ from each other in terms of their crystal structure. Different polymorphs can be prepared by controlling the crystallization conditions. Finasteride Polymorph Form I is a conventional form and is a commercially available form as the active ingredient of the finasteride drug formulation PROSCAR®. According to Canadian Patent Application No. 2,103,107 (Dolling et al.) (Corresponding to European Patent Application No. 0599376), Finasteride polymorph Form I has a d-spacing of 6.44, 5.69, 5.36, 4.89, 4.55, 4.31, 3.85, 3.59 and 3.14. Is characterized by an X-ray powder diffraction pattern. According to the same Canadian patent application, finasteride polymorph II forms an X-ray powder diffraction pattern with d-spacings 14.09, 10.36, 7.92, 7.18, 6.40, 5.93, 5.66, 5.31, 4.68, 3.90, 3.60 and 3.25. .

The preparation of finasteride is described and claimed in US Pat. No. 4,377,584 and also in US Pat. No. 4,760,071. Other patents pertaining to the manufacture of finasterides include Canadian Patent Application No. 2,029,859; U.S. Patents 5,084,574 and 5,116,983; And Canadian Patent Applications 2,049,882 and 2,049,881. All of them teach how to convert the final intermediate to finasteride to purify and isolate as a crystalline solid. Although finasteride polymorphs are not specifically mentioned in this prior art, panasterides obtained using them as crystalline solids must be one or the other of the known polymorphs, or a mixture of both.

Canadian Patent Application No. 2,103,107 (Dolling et al.), Published May 20, 1994, describes a process for preparing finasteride and its specific polymorphic Forms I and II. In particular, this patent application is intended to ensure that the amount of organic solvent and water in the mixture exceeds the solubility of the unsolvated form of finasteride (form I) and that the unsolvated form of finasteride is less soluble than any other form of finasteride in the mixture. It is taught that polymorph I can be prepared by crystallizing from a mixture of an organic solvent and optionally a panisteride in water to a sufficient degree. The document also teaches that the polymorphic Form I of finasteride can be prepared by heating the polymorphic Form II of finasteride to at least 25 ° C. for a time sufficient to effect the conversion in water or organic solvent. This document discloses that the amount of organic solvent and water in the mixture exceeds the solubility of the solvated form of finasteride and that the solvated form of finasteride is less soluble than any other form of finasteride in the mixture and optionally water After crystallization from the panisteride mixture in the solid, the polymorph form II can be prepared by recovering the solid, removing the solvent therefrom, or heating the polymorph I type finasteride to at least about 150 ° C. for a time sufficient to complete the conversion. It teaches that it can.

Purification of crude organic compounds by precipitation with metal salt complexes by treatment with Group I and II metal salts in nonhydroxyl solvents is described in GB 2094795, US Pat. No. 4,452,994 and US Pat. No. 4,529,811. The crystal lattice energy between the very small ionic radius of the Group I or Group II metal cations and the very large ionic radius of the selected anion tends to promote the incorporation of such organic materials into the lattice if the organic material can assist in the solvation of small cations. It is hypothesized that this is the case, but the actual formation of such complexes cannot be reliably predicted for complex molecules and should be explained by experiment.

The present invention relates to a finasteride, ie a 4-aza-steroid compound, which exhibits pharmacological activity as an inhibitor of the enzyme testosterone 5-α-reductase and is useful for the treatment of prostate cancer. More specifically, the present invention relates to a process for preparing finasteride in a specific polymorph.

It is an object of the present invention to provide a novel process for preparing finasteride to its pharmaceutically preferred polymorph I form.

Another object of the present invention is to provide novel intermediates useful for the preparation of polymorph I type finasteride and for other aspects of finasteride production.

According to one aspect of the invention, there is provided a process for the preparation of polymorph I type finasteride, which method comprises preparing a finasteride group I or group II metal salt complex in the presence of a non-hydroxyl solvent, adding the acidified water to the complex Dissociating and recovering the crystal I-form finasteride thus formed.

According to a second aspect of the present invention, there is provided a chemical complex of finasteride with a salt of group I or group II, the complex being dissociable upon addition of acidified water to obtain a water insoluble polymorph I type finasteride.

According to another aspect of the present invention, there is provided a process for preparing a chemical complex of finasteride with a Group I or Group II metal salt, the method comprising dissolving crude finasteride in a chemically inert organic solvent of a nonhydroxyl and Adding a salt of a Group I or Group II metal to the solution thus formed.

Finasteride-metal salt complexes formed in the process of the present invention were found to be near amorphous solids by X-ray powder diffraction. Spectral lines of Form I or Form II of finasteride do not exist as such amorphous solids. When such complexes are dissociated by addition of acidified water according to the invention, the metal salts are dissolved and the solid obtained by filtration has surprisingly and unexpectedly proved to be finasteride type I. The precursor complex and any finasteride solvate initially present as impurities do not exhibit a polymorphic crystalline form as well.

Another aspect of the invention is a method of isolating a finasteroid from a solution in an organic non-hydroxyl solvent to a nearly pure polymorph form I, which is poorly soluble with finasteride by adding a salt of a Group I or Group II metal to the solution. Forming a complex, filtration off the finasteride complex and adding acidification water to decompose the complex and to form a nearly pure separable polymorph I type finasteride.

When acidified water, for example water containing about 10% v / v acetic acid, is added to an amorphous solid complex, the metal salt is dissolved and removed in an aqueous solution, and the polymorph I type finasteride in an almost pure state of the finasteride component, which is not dissolved at all. It catalyzes the conversion to which can be filtered, washed and dried.

Group I or II metal salts preferably used in the present invention are lithium salts and calcium salts having relatively large anions such as bromide, iodide, tetrafluoroborate, perchlorate, hexafluorophosphate, and the like, and lithium Salts are most preferred. Lithium bromide is particularly preferred.

In the preparation of the finasteride-metal complex according to the invention, in any polymorphic form, as a mixture of polymorphic forms, or as a solvate with an organic solvent, or in the form of impurities, as a solution in a nonhydroxyl, non-reactive organic solvent. Finasteride is dissolved in a nonhydroxyl organic solvent that does not contain complexable functional groups that will interact with finasteride. In a particularly preferred embodiment, the finasteride solution is (5α, 17β) -N- (1,1-dimethylethyl) -3-oxo-4-aza-androstan- in a solution of a nonhydroxyl inert organic solvent, for example. It is formed by producing a reaction mixture from the chemical synthesis of finasteride by the process of reacting 17-carboxamide with dichlorodicyanoquinone and bistrimethylsilyltrifluoroacetamide. When a metal salt is added to this solution, a poorly soluble finasteride-metal salt complex precipitates. This finasteride-metal salt complex can be dried optionally without heat or without heat. Suitable solvents include hexane and other aliphatic hydrocarbons, cycloaliphatic hydrocarbons, aromatic hydrocarbons such as benzene, toluene, xylene, halogenated aliphatic hydrocarbons such as methylene chloride and other chlorinated hydrocarbons, ethers such as diethyl ether, diisopropyl ether and t- Butylmethyl ether, and ketones such as methyl isobutyl ketone, and mixtures of two or more such compatible solvents. The amount of solvent is not important.

Finasteride-metal salt complexes may be prepared at any suitable temperature at which the selected solvent remains in a liquid state. The temperature chosen is not critical. Room temperature is appropriate and easy. Likewise, the stoichiometry of finasteride and metal salts is not critical, but it is economical to operate close to the stoichiometric ratio and avoid waste of reagents.

Complex formation is advantageous due to the presence of water or a small catalytic amount of organic solvent solution of lower (C ₁ -C ₆ ) alkanols. This has the effect of increasing the formation speed of the complex. The catalytic amount is suitable to exhibit its catalytic acceleration effect, but should be chosen so as to be quite competitive with the metal salt or not sufficient to significantly increase the low solubility of the complex. An amount of water or lower alkanol of about 1% or less is suitable.

The invention is illustrated by the following specific examples.

Example 1 Preparation of Finasteride-Lithium Bromide Complex

3.71 g of finasteride was weighed into a 100 ml round bottom flask equipped with a magnetic stirrer and equipped with a nitrogen inert atmosphere. Methylene chloride (20 mL) was added and the slurry was stirred to dissolve the substrate. 0.87 g of anhydrous lithium bromide was added to the clear light yellow solution. The solid was washed and reacted with 5 ml of methylene chloride. The slurry was stirred. Within one minute, one drop of n-propanol was added with a disposable pipette. The slurry was stirred overnight while removing water under an inert nitrogen atmosphere. The slurry was filtered on a Buchner funnel and the flask and solid were washed with 10 ml of methylene chloride. After vacuum drying the solid at 50 ° C., the weight of the solid complex was 4.17 g. The methylene chloride solution contained 0.35 g of nonvolatile residue.

Example 2-Finasteride Form I

In a 25 ml round bottom flask equipped with a magnetic stirrer and a static nitrogen purge was placed 0.53 g of finasteride-lithium bromide complex. To this was added 10 ml of 9: 1 v / v water / acetic acid and the slurry was stirred at 50 ° C. for 2 hours. The slurry was cooled to 20-25 ° C. and filtered. The solid on the filter was washed with water and dried in vacuo at 40-45 ° C. Solid weight was 0.37 g.

Three different samples of finasteride prepared in three separate experiments according to Example 2 were analyzed by x-ray powder diffraction and the accompanying figures show these three x-ray powder diffraction patterns. They are identical to each other and the product is found to be finasteride type I. Further confirmation of the identification of whether the product was finasteride type I was made with a differential scanning calorimeter.

Claims (17)

Of a polymorph I type finasteride, comprising preparing a finasteride-I or group II metal salt complex in the presence of a non-hydroxyl solvent, dissociating the complex by adding an acidified water, and recovering the formed crystalline type I finasteride Manufacturing method. The method of claim 1 wherein the metal salt of the complex is a lithium salt having a relatively large anion. The method of claim 2, wherein the lithium salt is lithium bromide. The process of claim 1, wherein the acidified water is a water-acetic acid mixture. The method of claim 1, wherein the nonhydroxyl solvent is an aliphatic hydrocarbon, an alicyclic hydrocarbon, a halogenated aliphatic hydrocarbon, an aromatic hydrocarbon, an ether, a ketone, or a mixture of two or more such compatible solvents. The method of claim 5, wherein the solvent is methylene chloride. A chemical complex of finasteride with a Group I or Group II metal salt, which dissociates upon addition of acidification to give a water insoluble polymorph I type finasteride. The complex according to claim 7, wherein the metal salt is a lithium salt having a relatively large anion. The complex according to claim 8, wherein the metal salt is lithium bromide. Dissolving the crude finasteride in a chemically inert organic solvent of nonhydroxyl and adding a salt of Group I or Group II metal to the solution thus formed, the chemical complex of finasteride with Group I or Group II metal salt Manufacturing method. The method of claim 10, wherein the salt is a lithium salt with a relatively large anion. The method of claim 11, wherein the salt is lithium bromide. The process according to claim 10, which is catalyzed by a catalytic amount of water or lower (C ₁ -C ₆ ) alkanols in the reaction medium. Adding a salt of a Group I or II metal to a finasteride solution in an organic nonhydroxyl solvent to form a poorly soluble complex with finasteride, filtration-separating the finasteride complex, and adding acidified water to decompose the complex, A method for isolating finasteride to a nearly pure polymorph I type from a solution of finasteride in an organic nonhydroxyl solvent, comprising forming a pure isolable polymorph type I finasteride. The method of claim 14, wherein the salt is a lithium salt with a relatively large anion. The method of claim 15, wherein the salt is lithium bromide. The process according to claim 14, wherein the insoluble complex is formed in the presence of a catalytic amount of water or lower (C ₁ -C ₆ ) alkanols.