MXPA01001282A - Crystalline forms of osanetant - Google Patents

Abstract

The invention concerns a method for preparing crystalline forms I and II of (R)-(+)-N-[[3 -[1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl]prop- 1-yl]-4-phenyl piperidin -4-yl]-N-methylacetamide (osanetant), and said crystalline forms of osanetant. Preferably, the osanetant to be crystallised is prepared from its benzenesulphonate.

Description

CRYSTAL SHAPES OF OSANETANT The present invention relates to two different crystalline forms of (R) - (+) - N - [[3- [l-benzo] -1-3- (3,4-dichlorophenyl) p? Per? Dm-3? l] prop-l-? l] -4-phen? lp? pepdm-4-? l] -N-methylacetamide and a process for its preparation. The (R) - (+) - N - [[3- [l-benzo] l-3- (3,4-d? Chlorophenyl) p? Per? D? N -3? L] prop-l- ? l] -4-fen? lp? per? dm-4-? l] -N-met? lacetam? da, hereinafter referred to by its International Denomination "osanetant", is the first NK- receptor antagonist 3 described in the literature, whose preparation, especially garlic in the form of hydrochloride, is illustrated in European Patent PA-673 928. According to this document, the osanetant is prepared by reacting the N-methyl-N- (4-phenol. ? pendm-4-? l) acetam? da with l-benzo? l-3- (3, 4-d? chlorophen? l) -3- (methanesulfon? lox? prop-1-? l) -piperidy and transforming the osanetant thus obtained in its hydrochloride. It has been found that osanetant hydrochloride is isolated in the form of an amorphous solids that is difficult to cure. This product contains impurities that come from the previous synthesis stages. To obtain osanetant in pure form, preparative chromatography can be used from the base osanetant.

On the other hand, it has been found that by isolating the osanetant in the form of benzenesulfonate, for example, in the form of the solvate of its benzenesulfonate with 4-methyl-2-pentanone, an extremely pure product is obtained which easily gives the chemically pure osanetant . It has also been found that by crystallizing the osanetant in a convenient manner, two different crystalline forms are obtained. Preferably, the initial osanetant is chemically pure. By chemically pure, it is understood that the osanetant contains less than 20 percent impurities and preferably less than 10 percent. More particularly, a osanetant crystallization process has been found characterized in that: i) the osanetant is crystallized from a mixture of ethanol / water or isopropanol to give the crystalline Form I; ii) the osanetant is crystallized from a mixture of ethanol / isopropyl ether / water to give the crystalline Form II. Preferably, according to the present invention, the osanetant to be crystallized is prepared by neutralizing its benzenesulfonate. Thus, according to one of its aspects, the present invention relates to a process for the preparation of the osanetant characterized in that the osanetant benzenesulfonate is then neutralized with a base. The osanetant benzenesulfonate can be obtained from a osanetant salt. Thus, according to the process of the present invention: a) a osanetant salt is neutralized with a base and then the osanetant solution thus obtained is treated with benzenesulfonic acid; (b) the osanetant benzenesulfonate thus obtained is neutralized with a base. This process applies in particular to the preparation of pure osanetant from osanetant hydrochloride. Thus, according to a particular aspect of the process of the present invention: a) the osanetant hydrochloride is neutralized with a base and, next, the osanetant solution thus obtained is treated with the benzenesulfonic acid; and b) benzenesulfonate is neutralized with a base; then the pure osanetant thus obtained is isolated. In step (a), the osanetant hydrochloride is treated with a base such as soda, potash or ammonia in water in the presence of a solvent, preferably 4-methyl-2-pentanone, then the osanetant is advantageously isolated under the benzenesulfonate form by treating the osanetant solution thus obtained with benzenesulfonic acid, which allows the Obtaining an extremely pure product. Salification is generally carried out in 4-methyl-2-pentanone and this solvent tends to produce solvates, the osanetant benzenesulfonate may be in the form of solvate with 4-methyl-2-pentanone, preferably with 0.25 mol of these . The yields are practically quantitative, generally higher than 94 percent. In step (b) benzenesulfonate of osanetant, or in the case where in stage (a) is used as a solvent 4-methyl-2-pentanone, its solvate with 4-methyl-2-pentanone, is neutralized with a base such as sodium or potassium hydroxide or ammonia and osanetant is generally isolated from its solutions in an alcohol, preferably ethanol or isopropanol, or optionally in a mixture with other solvents, from which the osanetant is crystallized. The neutralization of step (b) is generally carried out in a halogenated solvent such as dichloromethane, 1,2-dichloroethane or 1,1,1-tr? Chloroethane, in admixture with water. The neutralization can also be carried out in a mixture of ethanol and water in order to directly obtain the osanetant under crystalline form I. According to another of its aspects, the present invention relates to a method for crystallizing the osanetant characterized in that: Water is added to a solution of osanetant in ethanol and heated to a temperature less than or equal to the reflux temperature of the solvent, preferably 60 to 75 ° C, then cooled to obtain the osanetant - crystalline Form I; - a solution of osanetant in isopropanol is heated to a temperature less than or equal to the reflux temperature of the solvent, preferably 60 to 75 ° C, and cooled to obtain the osanetant - crystalline Form I; - or isopropyl ether and water are added to a solution of osanetant in ethanol, heated, preferably under reflux of the solvent, and cooled to obtain osanetant - crystalline Form II. In the crystallization process of the invention, pure osanetant obtained can be used no matter which method. Advantageously, the osanetant obtained by the preparation process described hereinabove is used. Thus, for example, when the neutralization of the osanetant benzenesulfonate according to step (b) of the above procedure ends, the osanetant can be placed in solution in ethanol or isopropanol and can be isolated under its crystalline form I, or under the crystalline form II. According to a variant use of the crystallization process of the invention, it is possible, in order to isolate crystalline Form I, to add water to the ethanolic solution which it contains osanetant, for example, in a proportion of 40 percent water and 60 percent ethanol; then heat to 60-75 ° C and allow to cool under strong stirring to 20-25 ° C. The osanetant - Crystalline Form I crystallises and it is advantageously possible to accelerate the crystallization by seeding with crystals of osanetant - Crystalline Form I; the temperature is then increased to 45-50 ° C, cooled slowly to 0 ° C and maintained at this temperature until the crystallization is complete. The osanetant - Crystalline Form I is then isolated by filtration, washed and dried. According to an alternative, it is possible to isolate crystalline Form I, add water to the ethanol solution containing the osanetant, heat to 60-75 ° C, and allow to cool slowly under strong agitation at a temperature close to 40 ° C; Seed the medium with osanetant crystals - crystalline Form I, continue cooling slowly to 20-25 ° C, and keep at this temperature for a few hours; then slowly reheat the suspension of osanetant formed to 45-50 ° C, hold at this temperature for a few hours, then cool slowly to 20 ° C and finally filter the crystals formed. According to another embodiment of the crystallization process of the invention, it is also possible, in order to isolate crystalline Form I, to heat an isopropanol solution of osanetant at 60-80 ° C, preferably 60- 75 ° C, then cool it with stirring, preferably with a cooling ramp to 0 ° C. The osanetant - Form I is then isolated by filtration, washed and dried. Advantageously, the isopropanolic osanetant solution is cooled to a temperature between 0 ° C and 50 ° C, preferably from 35 to 50 ° C, then the crystallization is started by seeding and, if necessary, it is continued cooling to 0 ° C, then it is maintained at this temperature until the crystallization is complete. The concentration of osanetant in isopropanol preferably comprises between 200 grams and 350 grams / liter, more particularly between 250 grams and 300 grams / liter. When the crystallization is carried out in a reaction volume of 0.5 liter to 2 liters, stirring is preferably carried out at speeds between 200 and 600 revolutions / minute. It is possible, for example, to use speeds between 200 and 600 revolutions / minute. It is possible, for example, to use as agitator an agitation mobile with paddle, type "propeller". In order to effect controlled cooling, a linear cooling ramp of -10 to -30 ° C / hour, for example, of -20 ° C / hour, is preferably used. To isolate crystalline Form II, it is advantageous to add isopropyl ether to the solution Ethanol containing the osanetant, then heat to reflux, then add the isopropyl ether and 0.5 to 3 percent water. To cool to 40-50 ° C, crystalline Form II of the osanetant crystallizes; the suspension is preferably cooled to 25 ° C and crystalline Form II is isolated by filtration, washing and drying. When the two crystalline forms of the osanetant are obtained from ethanolic solutions of the product, it is possible to easily pass from one crystalline form to the other by heating to reflux in the mixtures of ethanol / water or ethanol / isopropyl ether / water under the indicated conditions previously in the present. More particularly, it is possible to pass the osanetant Crystal form I to osanetant - Crystalline form II by refluxing a mixture of crystalline Form I in a mixture of ethanol / isopropyl ether, approximately 1/1 (volume / volume), adding water and isopropyl ether and cooling as described hereinabove.

Also, it is possible to pass from osanetant - crystalline form II to osanetant - crystalline form I by refluxing the Crystal form II in an ethanol / water mixture, about 1/1 (volume / volume) and cooling as described hereinabove. In any case, it is preferable to filter the hot solutions, before cooling, to eliminate the parasite crystallization germs eventually present. Thus, according to an advantageous method of operation, the process for the preparation of the osanetant according to the present invention is characterized in that step (a) is conducted as illustrated hereinabove, then (b) the osanetant benzenesulfonate thus obtained is neutralized or a solvate thereof with 4-methyl-2-pentanone, with an alkaline hydroxide in a halogenated solvent chosen from dichloromethane, 1,2-dichloroethane or 1,1,1-trichloroethane, and ethanol is added, the halogenated solvent by azeotropic distillation and water is added to the ethanolic solution containing the osanetant at a temperature of 60 to 75 ° C and the osanetant is allowed to crystallize -Crystalline Form I; - or isopropanol is added, the halogenated solvent is distilled by azeotropic distillation, then, it is heated to a temperature of 60-80 ° C and the osanetant - Crystalline Form I is allowed to crystallize; - or ethanol is added, the halogenated solvent is distilled by azeotropic distillation and isopropyl ether and water are added to the ethanolic osanetant solution, then heated to reflux and the crystalline form osanetant II is allowed to crystallize. According to a particular aspect of this invention, the osanetant - Crystalline Form I is prepared by the process comprising the steps consisting of heating an ethanolic ethane solution to 60-75 ° C, adding water, cooling to 20-25 ° C then starting crystallization, or wait for the first crystals to appear and then increase the temperature to 45-50 ° C, cool to 0 ° C and maintain this temperature until the crystallization is complete. According to a preferred aspect of the present invention, osanetant-Form I can be obtained using the process comprising the steps consisting of: heating between 60 and 75 ° C a solution of osanetant in isopropanol at the concentration of 200-350 grams / liter, preferably 250-300 grams / liter; - cooling the solution to a temperature comprised between 0 ° and 50 ° C, for example, 35-50 ° C, preferably 40 ° C with a linear cooling ramp of -10 ° C to -30 ° C, preferably 20 ° C / hour, with stirring; sow the medium with 2 to 10 percent, preferably 5 percent of osanetant - Form I; cool the medium to 0 ° C with a linear cooling ramp of -10 ° C to -30 ° C / hour, preferably -20 ° C / hour, and keep at this temperature until the crystallization is complete; - isolate the crystals formed.

The application of the operating conditions according to the preferred process of the present invention makes it possible to obtain a crystallization yield of osanetant - Forma I, greater than 90 percent in a time less than 10 hours. According to another particular aspect of the present invention, the osanetant - Crystalline Form II is prepared by a process comprising the steps consisting of refluxing a osanetant solution in an ethanol / isopropyl ether mixture about 1/1 (volume / volume), add approximately isopropyl ether and water (proportions with respect to the final volume: isopropyl ether approximately 3.33 and water 0.02 to 0.05), let first cool to 40-50 ° C, for example, at approximately 45 ° C, then start crystallization, or wait for the first crystals to appear and then cool to 20-25 ° C until the crystallization is complete. According to another of its aspects, the present invention relates to osanetant - crystalline form I and osanetant - crystalline form II, capable of being obtained by the process illustrated hereinabove, especially by steps (a) and (b), as well as by the crystallization process from a osa * netant solution. More particularly, according to this aspect, the present invention relates to: - to osanetant - crystalline form I, obtainable: 1) by the process comprising the steps consisting in heating to 60-75 ° C an ethanolic solution of osanetant, adding water, cooling to 20-25 ° C then, initiate the crystallization, or wait for the first crystals to appear, and, then increase the temperature to 45-50 ° C, cool to 0 ° C and maintain at this temperature until crystallization is complete; 2) or by the process comprising the steps consisting of heating a solution of osanetant in isopropanol to 60-80 ° C, cooling to a temperature between 0 ° C and 50 ° C, preferably 35 to 50 ° C then, start crystallization, cool to 0 ° C and keep at 0 ° C until the crystallization is complete; - the osanetant - Crystalline form II, capable of being obtained by the process comprising the steps consisting in refluxing a mixture of osanetant and ethanol / isopropyl ether approximately 1/1 (volume / volume), add isopropyl ether and water in the proportions with respect to the final volume of: isopropyl ether approximately 3.33 and water 0.02 to 0.05 (volume / volume), let cool first to 40-50 ° C, then either start the crystallization, or wait for the crystals appear, cool immediately to room temperature (20-25 ° C) and keep at this temperature until the crystallization is complete. The essential characteristics of the new crystalline forms of osanetant were determined by differential calorimetric analysis (DSC) giving, by thermograms obtained with a PERKIN-ELMER calorimeter, the melting temperature of the enthalpy related to said fusion. The differential calorimetric analysis was carried out using a DSC 7 PERKIN-ELMER device whose contrast was made with respect to the indium and lead fusion or cyclohexane endotherms. For this analysis, 3 to 6 milligrams of product were used in flanged and perforated aluminum cup on the cover, in a temperature zone of 50 ° C to 180 ° C, at a heating rate of 10 ° C / minute, using nitrogen as a sweeping gas. In a general manner in the present invention, the physical constants were determined with the aid of samples of forms I and II whose purity is greater than or equal to 99.9 percent. The melting temperature of the enthalpy of fusion constitutes the essential characteristics to identify each crystalline form. These forms can be characterized by X-ray powder diffractometry. The powder X-ray diffraction profile (diffraction angles) was established with a SIEMENS D 500 TT diffractometer with a 40 kV generator, rear monochromator, Cu Kal source (? = 1.5406 A), port in silicon and in a sweep domain from 4o to 40 ° at Io per minute in 2 Bragg teat. The crystal form I of the osanetant, which has: - a melting temperature with a peak whose maximum is 143.6 ° C ± 0.5 ° C - a melting enthalpy of 68.5 ± 0.5 J / g, constitutes a preferred aspect of the present invention . The osanetant - crystalline form I was also analyzed by powder X-ray diffraction. The qualitative study of the diffractograms allowed to establish that this crystalline form presents characteristic stripes in 2 Bragg's teat at approximately 17.81 °; 11.04 ° and 16.84 °. Crystal Form II of the osanetant having: a melting temperature of 141.8 ± 0.5 ° C - a melting enthalpy of 65.0 ± 0.5 J / g, constitutes another preferred aspect of the present invention. The osanetant - crystalline form II was also analyzed by powder X-ray diffraction. The qualitative study of the diffractograms allowed to establish that this crystalline form presents characteristic stripes in 2 Bragg's teat at approximately 18.35 °; 18.58 ° and 18.97 °.

The fact of mastering the ability to reproduce the manufacturing process of each one of the crystalline forms of the osanetant allows to have very defined crystalline forms and therefore it is advantageous for the use of the osanetant as a medicine and for obtaining the necessary authorizations for the marketing of said medication. More particularly, obtaining a product having a very defined crystalline form makes it possible to prepare pharmaceutical formulations having a constant and reproducible composition, which is particularly advantageous when said formulations are intended for oral administration. Thus, according to another of its aspects, the subject of the present invention is a pharmaceutical composition containing, as an active principle, osanetant - crystalline form I or osanetant - crystalline form II. The administration of the crystalline forms of the invention can be conveniently carried out orally, parenterally, sublingually, transdermally or by inhalation. The amount of the active ingredient to be administered depends on the nature of the severity of the diseases to be treated as well as the weight of the patients. However, the active principle, administered in dosage unit, is present in said dosage unit in an amount of 0.5 to 500 milligrams, advantageously from 1 to 250 milligrams, preferably from 2 to 100 milligrams. This dose unit can be administered one to four times a day, preferably once or twice a day. In the unit forms of the pharmaceutical compositions of the present invention, the active ingredient is preferably mixed with pharmaceutical excipients and administered to animals and humans for the treatment of diseases in need of treatment based on the administration of an antagonist of NK-3 receivers, such as, for example, the indicators in European Publication EP-A-673928. Suitable unit administration forms preferably comprise oral forms such as tablets, optionally dryers, capsules, powders and granules (for which the dosage unit can be represented, for example, by a pouch) as well as forms of sublingual administration and buccal, transdermal administration forms can also be prepared using the new crystalline forms of the invention as active principles. When a solid composition is prepared in the form of tablets, the active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic. You can coating the tablets of sucrose or other suitable materials or they can also be treated in such a way that they have a prolonged or delayed activity and that a predetermined quantity of active principle is continuously released. A capsule preparation is obtained by mixing the active principle with a diluent and pouring the mixture thus prepared into the soft or hard capsules. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives. In aerosol forms, the active ingredient is administered by devices that allow the absorption by the respiratory route of a dose unit. In the pharmaceutical compositions according to the present invention, the active principle can also be formed of inclusion complex in the cyclodextrins, their ethers and their esters. Finally, the active principle can be associated with other active ingredients, for example, bronchodilators, antitussives or antihistamines. The following EXAMPLES illustrate the invention. EXAMPLE 1 (a) Osanetant benzenesulfonate solvate with 0.25 moles of 4-met? L-2-pentanone.

A suspension of 1,424 kilograms of osanetant hydrochloride obtained according to Patent Application EP-A-673 928 in 2.5 liters of water and 8.64 liters of 4-methyl-2-pentanone is prepared., 0.32 kilograms of NaOH solution is added to 30 percent. The mixture thus obtained is heated to 80-85 ° C under stirring for 15 minutes, then the aqueous phase is eliminated, the organic phase is washed until the pH becomes less than 8. It is dried by azeotropia and the solution at 25 ° C, then a solution of 0.36 kilograms of benzenesulfonic acid in 1.15 liters of 4-methyl-2-pentanone is added with stirring. After 15 hours of stirring, the osanetant benzenesulfonate is filtered, solvated with 0.25 mol of 4-m35yl-2-pentanone.; F = 176-177 ° C (DSC); Yield: 94.8 percent. (b) Osanetant To a mixture of 1.64 kilograms of the product obtained in step (a), 4.92 liters of dichloromethane and 3.28 liters of water, 0.3 kilograms of a 30 percent sodium hydroxide solution is added maintaining the temperature at about 20 ° C, then decanted and extracting the aqueous phase with dichloromethane. The combined organic phases are washed with water to a pH lower than 7.5, then dried and concentrated by distillation of the azeotrope dichloromethane / water. To the concentrated solution thus obtained, it is added 1. 4 liters of ethanol, then the azeotrope dichloromethane / ethanol is removed keeping the volume of the solution constant by adding ethanol. 1260 grams of osanetant are obtained in ethanol solution. EXAMPLE 2 Osanetant - Crystalline Form I. Operate as described in EXAMPLE 1, the ethanolic solution obtained, consisting of 3.3 kilograms of solution containing osanetant of ethanol is diluted with 1.76 kilograms of ethanol, then heated to 70 ° C. At this temperature, 3.2 liters of water are progressively added and the mixture cooled slowly to 20-25 ° C under strong agitation. Since the first crystals appear, stir for 15 hours, then heat to 45-50 ° C and leave the mixture for 3 hours at this temperature. The mixture is cooled to 0 ° C and left at this temperature for 15 hours. The precipitate is filtered, washed with a 60/40 (volume / volume) ethanol / water mixture preferably cooled to 0 ° C, and vacuum dried at 80 ° C. Under these conditions, osanetant - Crystalline Form I, of high performance liquid chromatography (HPLC) purity of 99.9 percent, is obtained in a yield of 90 percent in step (b). In differential calorimetric analysis (DSC), the osanetant crystalline Form I obtained in this preparation presented - a melting temperature of 143.6 ° C - a melting enthalpy of 68.5 J / g The powder X-ray diffraction analysis, with a SIEMENS D 500 TT diffractometer under the conditions given hereinabove, the osanetant - Form crystalline I obtained in this preparation presents the characteristic stripes of 2 Bragg teat of 17.81 °, 11.04 ° and 16.84 °. The relative diffractogram is recorded in the Figure 1. The powder X-ray diffraction profile (diffraction angles) of the osanetant Crystalline Form I of this preparation is given by the significant lines shown in TABLE 1, with the relative intensity, expressed as a percentage with respect to the most intense line.

TABLE 1 OSANETANT - CRYSTAL FORM I Diffraction bands Relative intensity (Bragg angles 2) 17.81 100 11.04 77.0 16.84 65.8 6.75 58.3 13.53 44.5 19.92 37.4 22.31 36.4 18.19 34.9 22.73 30.6 19.60 29.45 22.15 28.2 25.10 23.3 23.49 22.1 18.66 22.1 15.14 20.4 EXAMPLE 3 Osanetant - Crystal form II. The mixture of 100 grams of osanetant - crystalline Form I, of 92 milliliters of ethanol and 92 milliliters of isopropyl ether is heated under reflux under nitrogen, then 2.96 grams of water are added and 306 milliliters of isopropyl ether. The solution is filtered to eliminate all traces of parasitic germs, then it is cooled to 43-47 ° C under agitation and kept for 5-6 hours at this temperature. Under these conditions, the osanetant - crystalline form II crystallizes. It is then cooled to approximately 25 ° C and the mixture is kept under stirring for 3 hours. The separated crystals are filtered and washed with 100 milliliters of a mixture of ethanol / isopropyl ether 19/81 (volume / volume) and dried under vacuum at 65 ° C. In a preparation under these conditions, 73 grams of osanetant - Crystalline Form II of HPLC purity of 99.9 percent was obtained. To the differential calorimetric analysis (DSC), the osanetant - crystalline form II obtained in this preparation presented: - a melting temperature of 141.8 ° C - a enthalpy of fusion of 65.0 J / g. To the X-ray diffraction analysis of the powder, with a SIEMENS D 500 TT diffractometer under the conditions given hereinabove, the osanetant crystalline form II obtained in this preparation presents characteristic stripes of angles 2 Bragg's teat of 18.35 °, 18.58 ° and 18.97 °.

The relative diffractometer is reported in Figure 2. The X-ray diffraction profile of the powder (diffraction angles) of the osanetant - Crystalline Form II of this preparation is given by the significant dashes shown in TABLE 2, with the relative intensity expressed in a percentage with respect to the most intense line. TABLE 2 OSANETANT - CRYSTALLINE FORM II EXAMPLE 4 Osanetant - Crystalline Form II. The operation is carried out as described in EXAMPLE 1, but the ethanolic solution obtained at the end of stage (b, constituted by 3.3 kilograms of solution containing osanetant in ethanol, is concentrated in 2.2 kilograms, then diluted with 1175 liters of isopropyl ether, then it is refluxed with stirring and 37.9 milliliters of water and 3.9 liters of isopropyl ether are added to the mixture, the solution thus obtained is filtered, cooled to 45 ° C under stirring, crystallization is started and this temperature is maintained. for 5 hours and 30 minutes The mixture is cooled to 25 ° C and maintained under stirring for 3 hours at this temperature The product thus crystallized is filtered, washed with an ethanol / etherpropyl ether mixture. (volume / volume), and dried under vacuum at 65 ° C to a constant weight. The osanetant is thus obtained - crystalline Form II. EXAMPLE 5 Osanetant - Crystalline Form I To a solution of 100 grams of osanetant - Crystalline Form II (obtained as described in EXAMPLE 3) in 378 milliliters of ethanol, heated to 70 ° C, add 252 milliliters of water progressively, then cool slowly to 20-25 ° C or strong agitation, start the crystallization and the mixture is kept under stirring for 15 hours. Heat progressively to 45-50 ° C and leave the mixture at this temperature for 3 hours. Cool slowly to 0 ° C, keep at this temperature for 15 hours, then filter-the product thus precipitated, washed with a mixture of ethanol / water 60/40 (volume / volume) previously cooled to 0 ° C and it is dried under vacuum at 80 ° C. The osanetant is thus obtained - Crystalline Form I. EXAMPLE 6 Osanetant - Crystalline Form I It is operated as described in EXAMPLE 1, step a), and the first part of step b). After distillation of the azeotrope dichloromethane / water, isopropanol is added, then the azeotrope dichloromethane / isopropanol is removed keeping the volume constant by the addition of isopropanol. The thus obtained isopropanol solution is concentrated by distillation under reduced pressure to contain 225.4 grams of osanetant in 680 milliliters, or a concentration of 260 grams of osanetant / liter. This solution, whose temperature is close to 60 ° C, is stirred at 400 revolutions / minute with a mobile stirrer with a "propeller" blade of 7 centimeters of rotation diameter for a reaction volume of 0.5 liters in a reactor of 2 liters. Simultaneously this solution is cooled with a ramp of linear cooling of -20 ° C / hour. At the temperature of 40 ° C, the medium is seeded with 5 weight percent crystals of osanetant - Form I and the solution obtained is continued to cool down to 0 ° C, with the cooling ramp of -20 ° C / hour. The medium is maintained at 0 ° C, for 6 hours then the crystals formed are filtered. They are washed with isopropanol then dried under vacuum at 80 ° C. The osanetant - crystalline Form I is thus obtained with a yield of 93 percent. EXAMPLE 7 Osanetant - Crystalline Form IA a suspension of 20 grams of osanetant benzenesulfonate, solvate with 0.25 mole of 4-m35yl-2-pentanone, obtained in EXAMPLE 1, step a), in 60 milliliters of 100% ethanol, add 1.2 grams of NaOH in 20 milliliters of 100 percent ethanol. After stirring for one hour at room temperature, the sodium benzenesulfonate formed is filtered and washed with 10 milliliters of 100% ethanol. 50 milliliters of ethanol is distilled under atmospheric pressure, then added to 70 ° C 40 milliliters of water and let it return to room temperature. Since the first crystals appear, it is stirred for 15 hours, then heated to 45-50 ° C for 3 hours, the mixture is cooled to 0 ° C and kept at this temperature for 15 hours. It is filtered and washed precipitate formed by a mixture of ethanol / water (1/1; volume / volume) preferably cooled to 0 ° C. After vacuum drying at 80 ° C, you get 15.14 grams of osanetant, Form I (yield 99.6 percent). EXAMPLE 8 Osanetant - Crystalline Form I Operate as described in EXAMPLE 1, step a), and the first part of step b). After the distillation of the azeotrope dichloromethane / water, the ethanol is added, then the azeotrope dichloromethane / ethanol is removed keeping the volume constant by the addition of ethanol. The ethanol solution thus obtained is concentrated by distillation until200 grams of osanetant in 240 milliliters of ethanol, either a weight concentration of 34.7 percent osanetant.

This solution, whose temperature is close to 70 ° C, is diluted by 160 milliliters of water either a final weight concentration of 22.3 percent in osanetant. This solution, stirred with a stirring mobile with a "propeller" type paddle, is cooled with a linear cooling slope of -15 ° C / hour. At the temperature of 40 ° C, the medium is seeded with 5 weight percent osanetant crystals (Form I) and continue cooling with a cooling ramp of -5 ° C / hour, up to 20 ° C. The medium is maintained at 20 ° C for 4 hours. The suspension of osanetant asi obtained is reheated with a heating ramp of + 14 ° C / hour to 48 ° C, then maintained at 48 ° C for 2 hours. This suspension is cooled to 20 ° C with a cooling ramp of -5 ° C / hour. It is kept at 20 ° C for 4 hours then the crystals formed are filtered. They are washed with an ethanol / water mixture (60/40, volume / volume) then dried in vacuo at 80 ° C. The osanetant is thus obtained. Crystal form I with a yield greater than 90 percent.

Claims (22)

1. CLAIMS 1. Procedure for crystallization of osanetant, characterized in that: i) the osanetant containing less than 20 percent impurities is crystallized in a mixture of ethanol / water or isopropanol to give the crystalline Form I; ii) the osanetant containing less than 20 percent impurities is crystallized from a mixture of ethanol / isopropyl ether / water to give the crystalline Form II. Process according to claim 1, characterized in that the osanetant to be crystallized contains less than 10 percent impurities. 3. Procedure for the preparation of osanetant crystalline form I, according to claim 1 or claim 2, characterized in that the osanetant is crystallized from a mixture of ethanol / water or isopropanol. Method for the preparation of osanetant crystalline form II according to claim 1 or claim 2, characterized in that the osanetant is crystallized from a mixture of ethanol / isopropyl ether. Method according to claim 1 or claim 2, characterized in that: - water is added to a solution of osanetant in ethanol and heated to a temperature less than or equal to reflux temperature of the solvent is then cooled to obtain the osanetant crystalline Form I; or a solution of osanetant in isopropanol is heated to a temperature less than or equal to the reflux temperature of the solvent, then cooled to obtain osanetant in crystalline Form I; - isopropyl ether and water are added to a solution of osanetant in ethanol, heated to a temperature less than or equal to the reflux temperature of the solvent and cooled to obtain osanetant - crystalline form II. Process according to claim 5 for the preparation of osanetant - Crystalline Form I characterized in that: water is added to a solution of osanetant in ethanol and heated to a temperature of 60 ° C to 75 ° C, then cooled; or a solution of osanetant in isopropanol is heated at 60 ° C-80 ° C and cooled. Process according to claim 6, characterized in that water is added to a solution of osanetant in ethanol, heated to a temperature of 60 ° C to 75 ° C, then cooled. 8. Process according to claim 7, characterized in that it is cooled to 20 ° -25 ° C then crystallization starts, or the first crystals are expected appear and then the temperature is increased to 45-50 ° C, then cooled to 0 ° C and maintained at this temperature. Method according to claim 7, characterized in that it is cooled to a neighboring temperature at 40 ° C, crystallization is started, cooling is continued to 20-25 ° C, the osanetant suspension formed is reheated to 45-50 ° C, then it is cooled to 20-25 ° C. 10. Process according to claim 6, characterized in that a solution of osanetant in isopropanol is heated to a temperature of 60-80 ° C, then cooled. 11. Process according to claim 10, characterized in that it is cooled to a temperature comprised between 0 and 50 ° C, then the crystallization is started, then cooled to 0 ° C and maintained at 0 ° C. Method according to claim 5, for the preparation of osanetant - crystalline form II, characterized in that isopropyl ether and water are added to a solution of osanetant in ethanol, heated to reflux, then cooled in a mixture of ethanol / isopropyl ether , add isopropyl ether and water, heat to reflux, then cool. Method according to claim 12, characterized in that a solution of osanetant in a mixture of ethanol / isopropyl ether is heated to reflux, is added isopropyl ether and water, it is allowed to cool to 40-50 ° C, then crystallization is started, or it is expected that the first crystals appear and then cooled to 20-25 ° C. Process according to any of claims 1 to 13, characterized in that the osanetant after crystallization is prepared by neutralizing its benzenesulfonate. 15. Osanetant - Crystal Form I, susceptible to being obtained by a method according to any of claims 1, 2, 5 to 11 and characterized by having - a melting temperature with a peak whose maximum is at 143.6 ± 0.5 ° C - a melting enthalpy of 68.5 ± 0.5 J / g. 16. Osanetant Crystalline form II, capable of being obtained by a process according to any of claims 1, 2, 4, 5, 12 or 13 and characterized in that it has: - a melting temperature with a peak whose maximum is at 141.8 ± 0.5 ° C - a fusion enthalpy of 65.0 ± 0.5 J / g. 17. Osanetant - Crystal form I according to claim 16, characterized in that its X-ray diffractogram of the powder presents characteristic stripes in 2 Bragg's teat at approximately 17.81 °, 11.04 ° and 16.84 °. 18. Osanetant - Crystal form II according to claim 16, characterized in that its X-ray diffractogram of the powder presents characteristic stripes in 2 Bragg's teat at approximately 18.35 °, 18.58 ° and 18.97 °. 19. A pharmaceutical composition containing, as an active ingredient, a compound according to any of claims 15 or 17. 20. A pharmaceutical composition containing, as an active ingredient, a compound according to any of claims 16 or 18. 21. Composition according to claim 20 or claim 21, characterized in that it is in the form of a dosage unit containing 0.5 to 500 milligrams of active principle. 22. The composition according to claim 21, characterized in that said dosage unit contains from 1 to 250 milligrams of active principle.