MXPA01008494A - Method crystallising n-(4-trifluoromethylphenyl)-5-methyl-isoxazole-4-carboxamide - Google Patents

Abstract

The invention relates to a method for obtaining N-(4-trifluoromethylphenyl)-5-methyl-isoxazole-4-carboxamide in crystalline form which is essentially free of by-products. To this end, N-(4-trifluoromethylphenyl)-5-methyl-isoxazole-4-carboxamide is converted into an organic solvent or to mixtures of organic solvents and water, the quantity of by-product in the solution is determined by quantitative analysis and an equimolar quantity of a base is added. N-(4-trifluormethylphenyl)-5-methyl-isoxazole-4-carboxamide is separated from the resulting solution by crystallisation.

Description

PROCESS TO CRYSTALLIZE N- (4-TRIFLUORQMETI FENIL) -5- METILISOXAZOL-4-CARBQXAMIDA The invention relates to a process for obtaining N- (4-trifluoromethylphenyl-5-methylisoxazole-4-carboxamide in crystalline form, which is essentially free of by-products.) The compound of the formula I it is known per se and is also referred to as N- (4-trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide or lefluonomide (H A 486). The compound of the formula I can be obtained by the method described in the European Patent EP 0 013 376 Bl or the equivalent North American Patent 4,284,786. In the patents, processes for crystallization from toluene are also described. The disadvantage of the known processes for obtaining compounds of the formula I is that the by-products such as N- (4-trifluoromethylphenyl-2-cyano-3-hydroxy-thromonamide (compound 2 below) can not be separated essentially by crystallization from solutions containing the compound of the formula I and the compound 2. The compound 2 is described, for example, in the European Patent EP 0 217 206 Bl and the equivalent North American Patent 4,965,276 The object of the invention is to provide, by modifying the conditions of the process , a compound of formula I in high yields which is essentially free of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromamide The object is achieved by transferring the compound of formula I, which contains compound 2 as byproduct, within an organic solvent or within mixtures of organic solvent and water, determining the amount of compound 2 in the solution by an appropriate method of analysis and adding a approximately equimolar antity of a base, for example NaHCO 3 or KHCO 3, and by separating the compound of the formula I by crystallization from the obtained solution. The invention therefore relates to a process for obtaining the compound of the formula I from a solution containing water, at least one organic solvent, the compound of formula I and N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromamide, which is isopropanol, have also proved useful. The dissolution process is preferably carried out at elevated temperature up to the boiling point of the respective solvent. In the obtained solution, the amount of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide is determined. Suitable methods of determination are customary quantitative methods of measurement, such as high pressure liquid chromatography (HPLC) or alkalimetric titration. A sample of the solution is taken, and the amount of the compound 2 is determined in a standard apparatus. The base is then added to the solution. With the addition of 70 mol% to 130 mol%, good results are obtained by HPLC based on the determined amount of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromamide (compound 2). If the amount of compound 2 is determined by alkalimetric titration, the amounts of 95 mol% to 105 mol% are advantageous. The quantitatively determined amount of compound 2 is in each case taken as 100%, and the corresponding molar amount of the base added in each case is determined. It is preferable to add 85 mol% to 120 mol%, preferably particularly 100 mol% to 115 mol%, very particularly preferred 108 mol% to 112 mol%. The base can be added in dissolved or solid form; the addition in dissolved form is preferred. The order in which the components water, solvent, compound of formula I and base are dissolved also differs from the order mentioned above. For example, the base can also be added before the addition of the solvent, the water before the addition of the solvent, or the base is not added until the solution has warmed up. Suitable bases are, for example, organic bases such as mono-, di- or trialkylamine, for example, trimethylamine, triethylamine, tripropylamine, tributylamine, triisobutylamine, tripentylamine, trihexylamine, dibutylmethylamine, dimethylamine or diethylamine, the unsubstituted or monosubstituted alkylamines being up to trisubstituted by phenyl or benzyl, aromatic amines, such as aniline and substituted anilines, unsubstituted and substituted heterocyclic amines, such as pyridine, piperidine, pyrrole, indole, pyrazine, pyrimidine, morpholine, pyrazole or imidazole, for example alkylpyridine (C1-C4). Suitable additional bases are inorganic bases such as sodium bicarbonate (NaHCO3), sodium carbonate (Na2C03), potassium bicarbonate (KHC03), potassium carbonate (K2C03), sodium acid phosphate (Na2HP04), sodium diacid phosphate (NaH2P04), phosphatothrixic acid (Na3P04), potassium hydrogen phosphate (K2HP04), diacid phosphate potassium (KH2P04) or tripotassium phosphate (K3P04) -, preferably NaHCO3. The solution or suspension obtained is heated and maintained at the boiling point for a time to ensure the complete solution of the compound of formula I. Then, the optionally filtered solution is cooled so slowly that crystals of the compound of the formula I are formed. . The cooling occurs preferably at the final temperatures of 20 ° C to -10 ° C, in particular at temperatures of 10 ° C to -5 ° C, very particularly preferred at temperatures of 10 ° C to 5 ° C. The crystals are isolated and washed optionally with isopropanol and then with water. The substance is dried at an elevated temperature, preferably at 60 ° C, under reduced pressure or at atmospheric pressure. Other crystallization methods are also possible, such as evaporative crystallization or displacement crystallization. A preferred process comprises dissolving the compound of the formula I in isopropanol at 80% strength at the boiling point of isopropanol under atmospheric pressure or reduced pressure, carrying out the determination of the amount of N- (4-trifluoromethylphenyl) -2 -cyano-3-hydroxy-chrononamide by HPLC, adding the equimolar amount of base and then cooling the hot solution slowly so that crystallization occurs at temperatures of more than 40 ° C, preferably 40 ° C to 85 ° C, particularly preferably from 45 ° C to 80 ° C, in particular from 50 ° C to 70 ° C. The crystals that have been separated are washed several times with isopropanol and dried under reduced pressure. The crystallization can be carried out without seeding with crystals of the compound of the formula I or preferably in the presence of crystals of the compound of the formula I, which are introduced into the solution when seeding. Planting can also be done several times at different temperatures. The amount of seed material depends on the amount of solution and can be easily determined by a person skilled in the art. A particularly preferred process for obtaining the compound of the formula I from a solution containing water, at least one organic solvent, the compound of the formula I and N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-chrononamide comprises a) determining the amount of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide in the solution by alkalimetric titration, b) adding the approximately equimolar amount of a base; c) heating the obtained solution at a temperature of 41 ° C to the boiling point of the organic solvent, d) diluting the resulting solution with water or distilling the organic solvent so that the organic solvent and water are preferably present in a ratio of 4: 1 to 0.3: 1 and e) carry out the crystallization at temperatures above 40 ° C. Preferably, the obtained solution is filtered after the process of step b). The aforementioned bases are suitable; Sodium bicarbonate, sodium carbonate and potassium bicarbonate are particularly preferred. Good results are obtained with the addition of 90 mol% to 110 mol% of the base, based on the determined amount of compound 2, determined by alkalimetric titration. The quantitatively determined amount of compound 2 is in each case taken as 100%, and the corresponding molar amount of the base added in each case is then determined. It is preferable to add from 95 mol% to 105 mol%, preferably particularly from 98 mol% to 102 mol%. Advantageous mixtures contain organic solvent and water in the ratio of 1: 1 to 8: 1, preferably 2: 1 to 6: 1, in particular 3: 1 to 5: 1. The preparation of the solution is preferably carried out at elevated temperature, in particular at temperatures of 41 ° C to the boiling point of the respective solvent. The heated solution is, for example, maintained at the boiling point for a time to ensure complete dissolution of the compound of formula I. The dissolution process can also be carried out at superatmospheric pressure. The solution is filtered afterwards. The filter used has a pore diameter of about 0.lμm to 200μm. Then water, which advantageously has the same temperature as the filtered solution, is added to the filtered solution, or the organic solvent is distilled. Advantageously obtained solutions contain the organic solvent and water in the ratio of 4: 1 to 0.3: 1, preferably 2: 1 to 0.6: 1, preferably particularly of 1.6: 1 to 0.8: 1. The cooling is then carried out slowly to a minimum temperature of 40 ° C. The crystals are isolated and washed with isopropanol and then with water. The drying of the substances is advantageously carried out at elevated temperature, preferably at 60 ° C, under reduced pressure or atmospheric pressure. A particularly preferred process comprises dissolving the compound of the formula I in a mixture of isopropanol and water in the ratio of 4: 1 to 5: 1 and in the boiling point of isopropanol under atmospheric pressure or reduced pressure and filtering the solution. Water at the same temperature as the hot solution is then added to the solution in an amount such that a ratio of isopropanol to water of 2: 1 to 0.8: 1 is present. The crystallization is then carried out at temperatures of more than 40 ° C, preferably from 40 ° C to 85 ° C, preferably particularly from 45 ° C to 80 ° C, in particular from 50 ° C to 70 ° C. The crystals that have separated are then washed several times with isopropanol and dried under reduced pressure. The purity of more than 99.9% and the residual content of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide of less than 0.05%, determined by high-pressure liquid chromatography (HPLC), are advantageous in recovery , according to the invention, of the compound of the formula I.

EXAMPLE 1 Stability of leflunomide to sodium bicarbonate In experiment a), 40 g of the compound of formula I were dissolved in 80 ml of isopropanol and 63 ml of water (ratio of isopropanol to water 1.27: 1) and stirred for 1 hour. hour (h) at 84 ° C. Then, a sample was taken and analyzed quantitatively by HPLC. Then 0.62 g, 5 mol% was added based on the compound of the formula I of NaHCO 3 and the stirring was continued for 5 h at 84 ° C. In experiment b), a ratio of isopropanol to water of 4: 1 was used and the experiment was carried out analogously to a), except that the temperature was 80 ° C. The formation of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide (compound 2) was observed by measuring HPLC as a function of time. The results of the HPLC measurement and pH of the individual measurements are summarized in Tables 1 and 2. Table 1 shows the formation of compound 2 in the absence of sodium bicarbonate, while Table 2 shows the formation of compound 2 in the presence of sodium bicarbonate.

Table 1 In experiment a) (Table 1), a pH of 4.0 was measured in the initial solution, and the value did not change even after 1 h. The amount of compound 2 increased in this time from 0.026 percent in area (% in area) to 0.082% in area. In experiment b) (as Table I), the determination of the pH or the amount of compound 2 was not carried out.

Table 2: Isopropanol to water 1.27: 1 Isopropanol to water (Experiment a)) 4: 1 (Experiment b)) n.d. means not determined In experiment a) (Table 2), a pH of 8.5 was measured in the solution directly after the addition of sodium bicarbonate, and the pH decreased to 4.3 over the course of 5 hours. The formation of compound 2 after the addition of sodium bicarbonate happened very quickly. Immediately after the addition of sodium bicarbonate, 3.4% was detected in the area of compound 2, and as much as 6.6% in area after 30 minutes (min). After 5 h, an amount of 7.2% was reached in area. In experiment b), the formation of the compound was comparably rapid. An amount of 5.6% was reached in area of compound 2 after 5 h. The results clearly show that an excess of sodium bicarbonate essentially leads to the formation of compound 2. Because, depending on the batch for the preparation of compound I, the content of compound 2 may vary, it is important to determine in advance the amount required of sodium bicarbonate by quantitative analysis of the amount of compound 2. This is carried out, for example, by HPLC or alkalimetric titration.

Quantitative HPLC Determination Apparatus: Liquid Chromatograph (Waters 2690 with PDA 996 detector Column Material: stainless steel Length: 125 mm Internal diameter: 4 mm Stationary phase; Lichrospher © 100 RP 18 plugged at the end, particle size 5 μm Mobile phase acetonitrile 350 parts by volume water 650 parts by volume triethylamine 5 parts by volume the pH was adjusted to 4.0 with 85% phosphoric acid volume injected: 10 μl Flow rate: 1.0 mlJmin Detection: UV / Vis, 210 nm Run Time: 40 min Test solution: Approximately 20.0 mg of the substance to be investigated were dissolved in 4 ml of acetonitrile and taken to 20.0 ml with mobile phase Calculation: The content of compound 2 was calculated by calculating the arithmetic mean of all the injections. 100 = content of compound 2 in% BA = peak area of compound 2 in the chromatogram of test solution B = sum of the peak areas in the chroma tograma of the test solution. Test system: System test solution: 20 mg of 4-trifluoromethylaniline (4-TFMA) is diluted to 10.0 ml with mobile phase (SS1). 30 mg of compound 2 and 10 mg of 3-TFMP isomer were weighed, 1.0 ml of the SS1 solution and 5 ml of acetonitrile were added. The obtained mixture was brought to 100.0 ml with mobile phase (SS2) and stirred until the solution was clear. 100 mg of the compound of formula I (reference standard leflunomide) were dissolved in 2 ml of acetonitrile, 1.0 ml of SS2 was added and the solution was raised to 100.0 ml with mobile phase (SS3). SS3 had the following concentration:. 1 mg / ml leflunomide; 0.003 mg / ml of compound 2; 0.0001 mg / ml of the 3- TFMP isomer; 0.0002 mg / ml of 4-TFMA. Selectivity: The chromatogram of the standard SS3 solution had to satisfy the following requirements: Relative retention time of compound 2: approximately 0.13 to 0.23 Relative retention time of 4-TFNA: approximately 0.36 to 0.44 Absolute retention time of leflunomide: approximately 22 to 35 Abbreviations: 4-TFMA: 4-Trifluoromethylaniline 3-TFMP: N- (3'-trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide Alkalimetric Titration Apparatus: Crusher with automatic point-end detection (for example Metrohm Titroprocessor 716) Electrode: combined glass electrode (for example Mettier Toledo DG 112-SC) Factor of the standard solution: 0.05 g of succinic acid was dissolved in 50 ml of water and titrated with 0.1 N sodium hydroxide solution Procedure: 1.0 g of the substance to be tested was dissolved in 50 ml of methanol and immediately titrated with 0.1 N sodium hydroxide solution. sodium hydroxide solution 0.1 N): • 1000 = Sodium hydroxide solution factor 0.1 N C-59.05 C = Consumption of 0.1 N sodium hydroxide solution (1 ml of sodium hydroxide solution 0.1 is equivalent to 59.05 mg of succinic acid) W = Weight of succinic acid taken in g Calculation: CF-27.02 = Compound 2 (in%) WC = Consumption of 0.1 N sodium hydroxide solution in ml F = Hydrochloric acid factor 1 N W = Weight of the substance to be tested in g Example 2 Crystallization in the presence of NaHCO 3 16 kg of the compound of formula I (lefluonomide) were dissolved in 28 liters (I) of isopropanol and water so that the total amount of water was 9 1. The amount of compound 2 of the The solution obtained was then determined by alkalimetric titration. The equimolar amount of sodium bicarbonate was calculated and added in solid form to the solution (see Table 3). Then, the heating was carried out from 78 ° C to 82 ° C, the stirring was carried out for 25 minutes at this temperature and the filtration was then carried out through a suction filter inside a container already similarly heated thereto. temperature. The suction filter was then washed with the amount of isopropanol which, together with the isopropanol used, gave an isopropanol / water ratio of 4: 1 (in this case about 4 1). Then 32 1 of water, also preheated from 78 ° C to 82 ° C, were added (gave an isopropanol / water ratio of 0.8: 1). The solution became turbid and then cooled to about 65 ° C in 20 minutes was maintained at this temperature for about 40 minutes, then cooled to about 40 ° C in 70 minutes and stirred for an additional 20 minutes. The crystalline compound of the formula I was isolated by centrifugation. Table 3 summarizes the results of three different crystallizations.

Table 3 An average yield of 7.4% of the theoretical was achieved with only very small deviations within the individual blocks (± 0.6%), obtaining a purity of an average of 99.93% (HPLC,% in area). The amount of compound 2 in the individual blocks according to the HPLC determination of 0.02% in area at 0.04% in area.

Example 3 Crystallization in the presence of NaHCO 3 50 g of the compound of the formula I, containing 0.46% of the compound 2 - the determination of the amount of the compound 2 was carried out by HPLC measurement - to 25 ml of isopropanol and ml of water; then 28.65 mg of NaHCO 3 was added and the obtained suspension was stirred at room temperature of about 21 ° C for 15 to 30 minutes. Then, 76 ml of isopropanol and 1 g of activated carbon were added, the heating was also carried out at 80 ° C and the filtration was carried out through a suction filter. The obtained filtrate was cooled to 60 ° C, seeded with a few crystals of the compound of the formula I and then cooled from 0 ° C to 5 ° C. The obtained crystals were filtered with suction and washed with 37.5 ml of isopropanol and 3 times with 125 ml of water. The yield was 77% of the compound in formula I and the purity was more than 99.9% according to the HPLC measurement. The content of compound 2 according to the HPLC measurement was less than 0.01%, based on the compound of formula I as 100% EXAMPLE 4 Comparative example for crystallization without sodium bicarbonate 50 g of the compound of formula I, containing 1.7% of compound 2 - was suspended - the determination of the amount of compound 2 was carried out by HPLC measurement - in 93.75 ml of isopropanol and 25 ml of water. After the addition of 1 g of activated carbon, the suspension obtained was heated to 84 ° C and filtered through a suction filter. The filtered solution was washed with 6.25 ml of isopropanol. The solution was cooled to room temperature of about 21 ° C in the course of 2 hours. Then, the solution was cooled to 0 ° C over the course of 30 minutes and this temperature was maintained for 2 hours until the solution was filtered through a suction filter. The filter cake obtained was washed with two 6.25 ml portions of water. The crystals of the compound of the formula I were dried at 50 ° C under reduced pressure. Yield: 41.8 g of the compound of the formula I, purity 99.1% according to the HPLC measurement. The content of compound 2 was determined by HPLC measurement as 0.86% based on the compound of formula I as 100%

Claims (11)

CLAIMS 1. A process to obtain the compound of the formula I from a solution containing water, at least one organic solvent, the compound of the formula I and N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-chrononamide, comprising a) quantitatively determining the amount of N- ( -trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide in the solution, b) add the amount of a corresponding base of 50 mol% to 150 mol% of the amount of N- (4-trifluoromethylphenyl) -2-cyano-3 - hydroxyrotonamide determined in a), c) crystallize the compound of the formula I and d) separate the resulting crystals of the compound of the formula I from the solution. 2. The process as claimed in claim 1, wherein the inorganic base used is sodium bicarbonate. 3. The process as claimed in claim 1 or 2, wherein the water-miscible solvent used is isopropanol. 4. The process as claimed in one or more of claims 1 to 3, wherein the crystallization occurs at temperatures of more than 40 ° C, preferably from 41 ° C to 80 ° C, in particular from 50 ° C to 70 ° C ° C. 5. The process as claimed in one or more of claims 1 to 4, wherein the amount of aggregate base corresponds from 100 mol% to 115 mol%, preferably very particularly from 108 mol% to 112 mol%, of the amount of N- (-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide determined by high pressure liquid chromatography in the process of step a) in claim 1. 6. The process as claimed in one or more of the claims 1 to 5, wherein the amount of added base corresponds to 90 mol% to 110 mol%, preferably 95 mol% to 105 mol%, preferably particularly 98 mol% to 102 mol%, of the amount of N- (4-trifluoromethylphenyl) -2-cyano-3-hydroxy-thromonamide determined by alkalimetric titration in the process of step a) in claim 1. 7. The process as claimed in one or more of claims 1 to 6, wherein the crystallization is carried out in the presence of aggregated crystals of the compound of to formula I. The process as claimed in one or more of claims 1 to 7, wherein the obtained solution is filtered after the process of step b) according to claim 1. 9. The process as claimed in one or further from claims 1 to 8, wherein the mixture of the organic solvent and water according to the process of step b) is heated to a temperature of 40 ° C to 85 ° C. The process as claimed in one or more of claims 1 to 9, wherein the ratio of organic solvent to water in the process of step a) is 1: 1 to 8: 1, preferably 2: 1 to 6: 1, in particular 3: 1 to 5: 1. The process as claimed in one or more of claims 1 to 10, wherein the ratio of organic solvent to water in the process of step c) is from 4: 1 to 0.3: 1, in particular of 2: 1 to 0.6: 1, preferably from 1.6: 1 to 0.8:

1.