MXPA99005563A - Method of purifying carbazole ester precursors of 6-chloro-alpha-methyl-carbazole-2-acetic acid - Google Patents

Abstract

A process of purifying a (6-chloro-2-carbazolyl)methyl-malonic acid di(C1 -C6 alkyl) ester of Formula (I):áááwherein Ra and Rb must be the same and are selected from the group consisting of C1 -C6 alkyl;comprises phase separating one or more impurities from said carbazole ester at least once wherein the solvent used to carry out said phase separation is acetic acid. In a preferred embodiment said acetic acid is glacial acetic acid which is maintained at a temperature of from about 30ºto about 110ºC and said carbazole ester is obtained in a purity of at least 99. 90%by weight, so that the amount of impurities present therein is 0.10%or less by weight. In a more preferred embodiment of said process, said temperature is from about 50ºto about 70ºC, and said phase separation is carried out only once.

Description

PROCEDURE FOR PURIFYING CARBAZOL ESTERS PRECURSORS OF ß-CHLORINE-a-METILCARBAZOL-2-ACETIC ACID BACKGROUND OF THE INVENTION The present invention is in the field of methods of purifying organic compounds, including, but not limited to, those organic compounds that are the final and intermediate products, especially the latter, produced by synthetic processes in organic chemistry. In particular, the processes are for purifying alkyl esters of organic compounds which are carboxylic acids. The present invention relates to an improved process for the purification by phase separation of di (C1-C4 alkyl) esters of (6-chloro-2-carbazolyl) methyl-malonic acid, especially the diethyl ester, which is hereinafter referred to as sometimes in the present specification "carbazole ester", although this term is also used as a general reference for all di (C 1 -C 4 alkyl) esters involved in the process of the present invention. The carbazole ester is the starting material for a process of making carprofen, a very effective and selective anti-inflammatory drug of COX-2, approved by the Food and Drug Administration, Committee of Medicine (FDA / CVM), to be used in dogs in the United States. It is known that the carbazole ester starting material potentially contains at least one impurity created during a step of a related manufacturing process, which can constitute as much as 0.9% by weight of the carbazole ester starting material. The composition of this impurity is discussed in detail below, but it is contemplated that the purification process of the present invention includes, within its scope, not only this impurity but also other impurities. To obtain the final product carprofen in sufficiently pure form for use as an animal drug, all these impurities must be minimized.

BRIEF DESCRIPTION OF THE STATE OF THE ART Zwahlen, in US 264,500, describes a process for preparing 6-chloro-methylcarbazole-2-acetic acid. The final intermediate for the final product is the diethyl ester of (6-chloro-2-carbazolyl) methylmalonic acid which, according to the description of Zwahlen, is converted by hydrolysis and decarboxylation into the final product. It is said that the conversion steps are carried out alternatively in situ or after isolating the said penultimate intermediate in a known manner, for example, by crystallization. However, in the Zwahlen patent there is no suggestion on a method of purifying said intermediate as provided by the present invention nor on the surprisingly high yields obtained according to the process of the present invention.

SUMMARY OF THE INVENTION In accordance with the more general aspects of the present invention, there is provided a process for purifying a di (C? -C alkyl) ester of (6-chloro-2-carbazolyl) methylmalonic acid of formula (I) (I) wherein Ra and R must be the same and are selected from the group consisting of C -? - C4 alkyl; which comprises separating, by phrase separation, one or more impurities from said ester at least once, wherein the solvent used to perform said phase separation is acetic acid. In accordance with the present invention, there is further provided the above described method of purifying said ester of formula (I), wherein said ester is obtained with a purity of at least 99.80% by weight so that the amount of impurities of impurities present therein is 0.20% by weight or less; and wherein further said acetic acid is glacial acetic acid maintained at a temperature of about 30 to about 110 ° C; and wherein the aforementioned phase separation is optionally carried out two or more times. Also, according to the present invention, the above described method of purifying said ester of formula (I), wherein said ester is the diethyl ester, is provided.; and wherein further said ester of formula (I) is obtained with a purity of at least 99.90% by weight so that the amount of impurity present therein is 0.10% by weight or less; and wherein further said acetic acid is glacial acetic acid which are preferably maintained at a temperature of from about 40 to about 90 ° C, more preferably from about 45 to about 75 ° C, and most preferably from about 50 to about 70 ° C; and in which in addition said phase separation is performed only once. According to more restricted but not less preferred embodiments of the present invention, said di (C6-C6 alkyl) ester of the (6-dloro-2-carbazolyl) methylmalonic acid of formula (I) which has been purifying is present in the form of a dispersed solid, either amorphous or crystalline, which predominantly forms a suspension thereof in the glacial acetic acid solution. Furthermore, it is included that said impurities can be produced directly or indirectly in the course of a process for preparing said ester and can comprise one or more of the starting materials, synthesis intermediates, reagents, byproducts of the reaction, products of degradation, solvents in which various stages of the reactions of said preparation process or undesired analogues of chemical structure closely related to that of the said ester of formula (I) have been carried out. It is particularly envisaged that said impurities can be derived indirectly from said preparation process as a result of carrying out said procedure inappropriately or on a suboptimal basis. It is also included that said impurities can be inadvertently derived from sources that do not include production directly or indirectly during said process of preparing said ester of formula (I), for example, by contamination of the equipment in which it is made said method of preparation, by contamination of the starting materials, solvents or synthesis aids used in the aforementioned preparation process, by contaminants existing in the surrounding atmosphere, that is, in the environment surrounding the aforementioned preparation process, which are absorbed in said process, or by contamination of said ester of formula (I) when stored or handled after its preparation. In a particularly preferred embodiment of the purification process of the present invention, the intermediate to be purified is the (diethyl) ester of carbazole and the impurity to be eliminated is a dimer of formula (IV): (IV) DETAILED DESCRIPTION OF THE INVENTION The di (C? -C6 alkyl) ester of the above-described (6-chloro-2-carbazolyl) methylmalonic acid of formula (I): (I) wherein Ra and Rb must be the same and are selected from the group consisting of C1-C4 alkyl, which is to be purified according to the methods of the present invention, is the final intermediate in the synthesis of cofen. Cofen, as already described, is an approved anti-inflammatory drug, especially useful in the treatment of pain and inflammation in dogs. It is required that Ra and Rb be the same and that they be selected from the group consisting of C1-C4 alkyl. If Ra and Rb represent different alkyl groups, for example, methyl and ethyl, whereby mixed diesters result, then the malonic acid carbon is a chiral center, yielding (S) and (R) enantiomers of the ester of formula (I) . This result would complicate and probably completely fail the satisfactory purification of the ester of formula (I) precursor. For example, it would then be necessary to use known phase separation methods of the diastereomers formed from the racemic mixture by combination with an optically pure molecule, for example, tartaric acid and its derivatives. In the present specification, Ra and R are used as different substituent dentifiers in spite of the fact that the radicals they represent must be the same. The purpose of this different identification is to emphasize that the potential impurities that must be removed from the ester of formula (I) include mixed esters that may be produced by the improper execution of a preparation process or by any other unknown or unforeseen circumstance. R a and R b are selected from C 1 -C 4 alkyl, which may be linear or branched, and include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tere-butyl. Of these representative species, methyl and ethyl, and particularly ethyl, are preferred.

Cofen, 6-chloro-a-methyl-9H-carbazole-2-acetic acid, which is prepared from a precursor, the ester of formula (I), can be represented by formula (I), can be represented by the formula (II): (II) It should be noted that the active agent cofen of formula (II) differs from its precursor, the ester of formula (I), in that it has been hydrolyzed and monodecarboxylated. In a preferred process of making cofen, the precursor, carbazole ester of formula (I), has its own intermediate, shown below in formula (III). The precursor, carbazole ester of formula (I), in turn, differs from the intermediate of formula (III) which precedes it by having been flavored by introduction of two additional double bonds in the phenyl ring to which the acid radical is attached to -methylacetic This can be easily appreciated by the following representation of the intermediate of formula (III): (lll) The aforementioned modifications of the carbazole ester of formula (I) and its preceding intermediate of formula (III) take place in a preferred process for the manufacture of cofen which is carried out according to the synthesis steps described in the document US 4,264,500 of Zwahlen mentioned above. The first stage in the synthesis of Zwahlen is to aromatize the intermediate of formula (III) by treating it with chlorine. This step is preferably carried out in an aprotic solvent, methylene chloride or ethylene chloride, at an elevated temperature, such as the reflux temperature of the reaction mixture, while slowly adding chlorine to said mixture.

The addition of color takes place preferably in a period of time of 2 to 8 hours. In a typical manner of carrying out this step, toluene is used as the solvent and the reaction is carried out at 75 ° C for 4 hours. The resulting aromatic compound is the carbazole ester precursor represented by the formula (I): (0) The aromatization of the ester of the formula (III) produces the intermediate carbazole ester represented by the formula (I) above, which is then subjected to hydrolysis and decarboxylation to produce the final product carprofen. In a preferred embodiment of this step mentioned above, the intermediate of formula (I) is hydrolyzed and decarboxylated according to known processes involving acid treatment, for example, with a combination of glacial acetic acid and hydrochloric acid. The synthesis transformations described above can be represented according to the following reaction scheme: According to the present invention, it is generally contemplated that the impurity or impurities that are separated from the ester precursors of formula (I) can vary significantly in character and can be derived from different origins. Intrinsically, the purification performed in the present invention is based on the basic nature of purification processes which generally, as a preferred embodiment, is a phase separation process. Such known processes can achieve very high separation levels, even of compounds having a closely related structure, as explained in more detail below. The parameters of the purification process of the present invention have been chosen in such a way that said procedure does not owe its operationality and selectivity superior to the structure of the impurities that must be separated. It is not contemplated, therefore, that the present invention is limited in any way by the nature of said impurities. An investigation of one of the most molar impurities found with respect to the most troublesome carbazole ester found with respect to the carbazole ester of formula (I) precursor has been undertaken. This impurity appears with time as a precipitate in solutions of said precursor ester as well as in solutions of the final product carprofenose of formula (II). The impurity has been identified by x-ray crystallography and other analytical data as a dimeric form of spirooxindol of the precursor carbazole ester, which is produced during the aromatization step involving the chlorination of the intermediate of formula (lili) represented above in the scheme of synthesis. The structure of the spirooxindole dimer can be represented by the formula (IV): The dimeric impurity has crystallization properties that pose a challenge to conventional purification procedures, which can be canceled by coprecipitation. Initial attempts to achieve the required levels of purification obtained by the purification process of the present invention using conventional solvent systems were not successful. Acetone, acetonitrile, ethanol, propanol, butanol, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, methyl isobutyl ketone and combinations of these solvent systems gave rise to increased levels of dimeric impurity due to the kinetic effects of crystallization before mentioned of these solvent systems. More acceptable results were achieved using toluene / methanesulfonic acid and toluene / butane as the solvent system. The yields (75-85%) and product quality (<0.1% dimer impurity) obtained with toluene / methanesulfonic acid as solvent system were satisfactory while the yields with toluene / butanol as the solvent system were lower. The purification was then carried out with the toluene / methanesulfonic acid system under stress conditions to stimulate those that could be encountered during actual manufacture. The purification was carried out at elevated temperatures (60-65 ° C) for prolonged times (> 2 hours). These stress conditions produced a degradation product that could not be isolated or eliminated. Satisfactory results were also obtained initially with a recrystallization in ethanol / isopropyl ether, which gave a high yield and good elimination of impurities. However, when this purification system was subjected to experiments under tension using long granulation times, the production results were unacceptable. The crystallization was kinetic in nature first crystallized the product, and then the dimer impurity, in 1 hour. This time interval in which the dimeric impurity also crystallized is too short for commercial scale production. The solvent system which was successful and on which the present invention is based was that which involves hot acetic acid. The pulp of the system with hot acetic acid, that is, the suspension of the phase preparation, underwent under stress experiments that were considered in prolonged granulation time (> 36 hours), prolonged heating time (> 12 hours) and heating excessive (> 70 ° C). Then the scale of the solvent system based on acetic acid was increased to produce quantities of up to 40 kg, which implied changes in cycle times as well as in the equipment.

The production was carried out with great success, producing only 0.02% dimer impurity, determined by high resolution liquid chromatography (HPLC) assay. In addition to the aforementioned dimeric spiroxindole impurity, other potential impurities can obviously exist. These impurities can be produced directly or indirectly in the course of a process for preparing said carbazole ester of formula (I) precursor and can comprise any one or more of starting materials, synthesis intermediates, reagents, byproducts of the reaction , degradation products, solvents in which various stages of reactions have been carried out of said preparation process or undesired analogues of chemical structure closely related to that of the said carbazole ester of formula (I). Most typically, said impurities will originate during the ordinary procedures involved in the particular preparation process that has been employed and, therefore, will be considered herein as "directly" related to the said preparation process. However, it is often the case that a preparation procedure is improperly designed in terms of basic chemical engineering, using inadequate starting materials, reagents or solvents or requiring inappropriate process parameters, such as the time and temperature of performing the reaction . On the other hand, a preparation procedure can be based on a perfectly appropriate chemical engineering but some involuntary error is made in the course of its execution. For example, a wrong starting material or an inappropriate amount of reagent may be used at the temperature at which the reaction is performed may be too high or too low. Such execution errors can also produce impurities together with the desired final product. Impurities of this type originate outside the scope of the processes involved in the preparation process that is employed and, therefore, will be considered as related herein. "indirectly" with the aforementioned preparation procedure. It is also possible that the impurities are not directly or indirectly related to the preparation procedure. Instead, said impurities can be inadvertently derived from different sources, for example, by contamination of the equipment in which the process of preparation of the starting materials, solvents or synthesis aids used in the preparation process is carried out, by contaminants existing in the surrounding atmosphere, that is, in the environment surrounding the preparation process. The impurities of these origins can be absorbed in the procedures of the preparation process. After the preparation process has been completed, it is necessary to separate the final product and then manipulate or store it in some preparatory manner to its formulation in a pharmaceutical composition according to known procedures. Thus, impurities can be caused as a result of contamination of said ester of formula (I) by contact with the origin of said impurities, while it is stored or handled after its preparation. The purification process of the present invention provides a yield of the carbazole ester of formula (I) precursor sufficiently high, so that the impurity of said final product, the precursor carbazole ester, is at least 99.80% by weight which the weight of impurities present therein is 0.20% by weight or less. The percentage indicated by weight is based on the weight of the precursor ester in the final product divided by the weight of said final product and multiplied by 100. However, it is often more convenient to calculate the percentage of purity from the results of an analysis quantitative of the final product that determines the amount of impurity present, from which the purity percentage is calculated afterwards. Said quantitative analytical procedures are well known and one or more of them can be adapted to the needs of the process described herein. In a preferred embodiment of the present invention, said carbazole ester of formula (I) precursor is the diethyl ester and said precursor carbazole ester is obtained with a purity of at least 99.90% by weight so that the amount of impurities present in it is 0.10% by weight or less. Also in another more preferred embodiment of the present invention, said carbazole ester of formula I precursor is the diethyl ester and said precursor carbazole ester is obtained with a purity of at least 99.95% by weight so that the amount of impurities present in it is 0.05% by weight or less. The acetic acid used can be in the form of a highly concentrated non-aqueous solution, in which acetic acid is the predominant component significantly. However, said non-aqueous solution of acetic acid will normally be associated with lower levels of purity in the final product, the carbazole ester of formula (I) precursor. Accordingly, in preferred embodiments of the present invention said acetic acid is glacial acetic acid. The purification process of the present invention, in a preferred embodiment thereof, uses hot acetic acid as solvent, which is applied to a solid product comprising the carbazole ester of formula (I) precursor and the impurities contained therein. The impurities to be removed are very soluble in this solvent based on hot acetic acid but the final product, the carbazole ester precursor, has a very low solubility in the hot acetic acid used as the solvent. The insolubility of the carbazole ester of formula (I) precursor in the hot acetic acid used as solvent is in the order of about 85% by weight, that is, only about 15% of the precursor carbazole ester will dissolve in hot acetic acid. The remainder of the precursor carbazole ester is present as a solid which is dispersed in the hot acetic acid used as the solvent and, therefore, can be described exactly as a precipitate or paste. After the hot acetic acid used as solvent has been precipitated as much as possible of the precursor carbazole ester, this and the already dispersed precursor carbazole ester which has not dissolved in the solvent are separated from the solvent. This separation constitutes a phase separation in which the solid phase, the precursor carbazole ester, is separated from the liquid phase in which the impurities are dissolved. The acetic acid used as the solvent is maintained at a temperature of from about 30 to about 110 ° C, preferably at a temperature of from about 35 to about 90 ° C, more preferably from about 40 to about 75 ° C, and most preferably from about 45 to about 70 ° C. The precipitation process, that is, the phase separation process that includes the mass of the precursor carbazole ester in the form of a suspension, can be carried out as many times as desired. Although each phase separation operation will yield a purer product, this will be achieved at the expense of spending additional energy and thus reducing efficiency. However, one of the surprising advantages of the present invention is that it can be achieved with a single phase separation a purity as high as at least 99.90% by weight and as high as 99.95% by weight or more, including even 99.98% in weigh. Performing the phase separation procedure twice is usually all that is required to obtain a final product of the high purity required for commercial distribution as an animal sanity drug.

It is also contemplated that the purification process of the present invention can be carried out in a series of different embodiments with respect to the character and history of the process of the carbazole ester of formula (I) precursor to be purified. For example, it is contemplated that the aforementioned carbazole ester material precursor may be in the form of an isolated solid as an intermediate in a preparation process as described above in more detail. Said precursor carbazole ester material may be isolated as a solid to allow its storage for further processing at the same manufacturing site or transportation to a different manufacturing plant for finishing. Said isolated solid intermediate represents an excellent opportunity to conveniently remove impurities that are present since the processing of the precursor carbazole ester according to the present invention will be fully compatible with the sequence of manufacturing synthesis steps that are being used. Said carbazole ester, isolated solid intermediate precursor, can be directly treated with the hot acetic acid used as solvent in the phase separation process of the present invention. In a less preferred embodiment, said carbazole ester, isolated solid intermediate precursor, can first be dissolved in a non-aqueous solvent that is compatible with the acetic acid to be added later. The purification process of the present invention is to be performed not only according to the description herein, but also according to principles of purification procedures, especially phase separation procedures, which are well known in the art. These principles are described below to summarize those considerations that most often play a role in modifications of the purification process of the present invention made by those skilled in the art. The summary of these principles also serves to underline the unpredictable nature of the results of phase separation procedures in general and the unexpected success of the method of the present invention in particular. Thus, for example, purification by phase separation according to the present invention involves not only the presence of the precursor ester in dispersed form, in suspension, but also some precipitation of the precursor ester, which must take place while the impurities remain dissolved. in the acetic acid used as a solvent. It is normally considered that precipitation consists essentially of the process of separating solid particles from a previously transparent solution by physical or chemical changes. This has to be differentiated from the presence of the precursor ester in the dispersed state from the beginning of the purification process of the present invention. One of the most important uses of phase separation is in the purification of solids, which can be referred to as precipitation in general. In its simplest aspect, phase separation involves an impure solid that is dissolved in a suitable solvent at elevated temperatures and, upon cooling, most of the impurities remain solubilized while the precipitated product is separated from them and, therefore, Therefore, it is purified. In the case of precursor esters of formula (I), the product has a low solubility, even in the presence of the acetic acid solvent at elevated temperatures, resulting in the initial formation of a suspension. The phase separation process of the present invention can be repeated several times, if desired, and the acetic acid solvent can be used at various temperatures. The solid precursor ester of formula (I), which is the product of the purification by the phase separation process of the present invention, it can be in amorphous form or in the form of crystals or both. If it is in amorphous form, the final solid product may comprise any one of a number of different shapes and sizes and these amorphous particles may also agglomerate or flocculate together to form larger masses. If it is in crystalline form, the final solid product may comprise more than one crystalline form and these may also appear combined. The size of the crystalline particles can vary over a large range of sizes. In more specific terms, phase separation or crystallization refers to the production of a solid, single-component, amorphous or crystalline phase, from a fluid phase of several components and, in the case of the present invention, the said fluid phase is a solution of acetic acid in which undesired impurities are dissolved. When the object of phase separation or crystallization is to prepare a pure dry solid, which is the case in some of the embodiments of the present invention, it will be necessary to separate the solid from said fluid phase and this is usually achieved by centrifugation or filtration. , followed by drying. The advantageous properties of said dry, amorphous or crystalline solid product include ease of handling, stability, good flow properties and attractive appearance. Generally, phase separation or crystallization is carried out in jacketed or stirred vessels and the conditions necessary to obtain the purity, yield and possibly the appropriate crystalline form must be determined by experimentation. When the separation of phases involves crystalline dispersed particles or crystallization in solution, it will take place in three basic stages: induction of supersaturation, formation of nuclei and growth of crystals. At a given temperature and concentration, a solution can be saturated by cooling or by solvent removal. It is also possible to add a third component that reduces the solubility of the solute or perform a chemical reaction in a solvent in which the resulting product has a low solubility. Upon cooling or concentrating more, one enters the metastable supersaturated region. It is unlikely that low levels of supersaturation will produce the spontaneous formation of crystal nuclei but the growth of crystals can be initiated by adding seeds. At lower temperatures or at higher concentrations found in the curve that limits the metastable region, spontaneous nucleation is virtually certain and crystal growth also occurs under these conditions. When the border of the metastable region is crossed, the nucleation rate rapidly increases and the crystallization process becomes uncontrolled. Consequently, it is desirable to maintain the state of the solution within the metastable region. The width of the surface under the curve of the metastable zone is affected, most importantly, by the agitation, the cooling rate, the presence of soluble additives, the solvent and the thermal history of the particular solution. Nucleation causes the formation of small nuclei around which crystals grow. Therefore, without crystalization, crystal growth can not occur. When a material crystallizes in a solution, the nucleation and growth of the crystals occur simultaneously over a wide temperature range. Nucleation depends on the degree of supercooling, resulting in low supercooling degrees or little or no nucleation. However, the nucleation rate increases to a maximum and then falls, so that excessive cooling can decrease the rate of crystallization by limiting the number of nuclei formed. Spontaneous nucleation occurs when sufficient molecules of low kinetic energy are united in a context in which their mutual attraction is sufficient to overcome their individual momentum. Once a certain size has been reached, the nuclei become stable in the existing conditions and, as the temperature drops, there are more low energy molecules and the nucleation speed increases. These circumstances partially characterize the formation of the dimeric impurity previously theorized which is especially troublesome in solutions of the precursor ester of formula (I) as described above. The formation of nuclei of crystals or nucleation is also a process that determines the size of the crystals of the product and also plays a substantial role in determining a series of physical properties of the aforementioned crystals and, more importantly in the present case, its purity. With respect to the growth of the crystals, at higher temperatures the molecules have too much energy to remain captive in the crystal lattice while at lower temperatures more molecules are retained and the rate of growth is increased. Finally, however, the diffusion and orientation towards the surface of the crystals decreases at even lower temperatures. Deposition on the faces of the crystal causes the number of molecules in the immediate vicinity to decrease. Therefore, the driving force of the growth of the crystals is provided by the scheme of the concentration gradient, from supersaturation in the solution to lower concentrations on the face of the crystals. Consequently, a high level of supersaturation favors a high speed of crystal growth. Correct positioning and proper orientation with respect to the crystal lattice cause a loss of kinetic energy in the molecules involved. The aggregates as well as the heat of crystallization must be eliminated, that is, transferred to a surface from the entire solution, and therefore the rate of crystal growth is influenced by both the rate of heat transfer and the changes that they take place on the aforementioned surface. For example, it is well known that the agitation of the system increases the heat transfer by reducing the thermal resistance of the liquid layers adjacent to the crystal until changes in the face of the crystals become the controlling effect.

Initially, the agitation rapidly increases the growth rate by decreasing the thickness of this boundary layer and the resistance by diffusion. However, when agitation intensifies, a limit value determined by the kinetics of the reaction on the surface is reached. The various phases through which units or growth precursors pass during the growth of the crystals reveal additional critical factors, for example, transport through the entire solution to a shock site that is not necessarily the site of crystal growth, absorption in the shock where the precursors pour solvent molecules and the solvent is transported back to the solution, diffusion on the precursors from the shock site to a growth site and incorporation into the crystal lattice after the desolvation during It is also possible that the solvent is absorbed before escaping to the solution. All these processes depend on the morphology of the interfacial region.

Various crystal growth models have been used in the art to identify the growth mechanisms of a face of a crystal and consequently also the interfacial processes. For example, volume diffusion and surface diffusion models are used, as well as two-dimensional and spiral growth models. Also, total growth rates are measured in the art according to different procedures but, from the point of view of crystal growth theory, the linear rate of growth of the plane of a crystal is most often used. In addition, nucleation rates and kinetics of nucleation are measured by different methods. One of these is to measure the period of induction, which is the time that elapses between the achievement of supersaturation and the appearance of a solid phase in the system under study. It is considered that the induction period is inversely proportional to the nucleation speed. In a crystallizer, nucleation and crystal growth compete in supersaturation and both contribute to the size distribution of the final product. In order to obtain crystals of great uniformity of composition and, therefore, of high purity, it is important to maintain the linear growth rate constant throughout the advancing phase, that is, that the shape of the crystal remains unchanged during growth. Soluble impurities from which the precipitate of the final product crystallizes out can increase or decrease the nucleation rate. For example, insoluble materials can act as nuclei and thus favor crystallization. Impurities can also affect the shape of the crystals. Due to the presence of these impurities, the composition of the solid precipitate differs from the composition of the coexisting fluid during crystallization. This phenomenon is called segregation and is important for the growth of crystals for various reasons, the central issue being in each case the extent to which the composition of the crystals reflects the composition of the nutrient in which it grows. Depending on their contributions to the Gibbs free energy of the crystal, the impurities are partially rejected or adsorbed preferentially by the advancing interface. Therefore, a segregation coefficient based on the interfacial transfer of the impurity is defined. Furthermore, it is known that the impurity-solvent interaction and the formation of complexes give rise to a complicated dependence on the concentration of the segregation coefficient. Segregation is also important with respect to the kinetics of crystal growth, since impurities can greatly influence the kinetics of growth. When a crystal grows in an impure solution, it will generally reject the impurity if it is less soluble in the crystal than in the solution. When the filter moves, the impurity can be rejected in the solution more quickly than what can be eliminated by diffusion. Consequently, the concentration of impurities in the solid will be determined by the concentration of impurities in the diffusion-enriched layer and not by the average concentration in the solution. Accordingly, the segregation performed in a controlled manner can be advantageously employed for the purification of materials. It is well known in the art that large differences in the maximum speeds obtainable from supersaturation and crystal nucleation can result from an appropriate choice of the solvent-solute system. In addition, there are significant differences in the maximum obtainable supersaturation,? Cma ?, when the solvent is changed from polar to non-polar and there is an obvious correlation between? Cmax and solubility. The higher the solubility, the lower the supersaturation at which nucleation occurs; therefore, nucleation is easier when the solution is more concentrated. The choice of solvent also has a significant influence on the growth of the crystals. The growth kinetics of crystals growing in a solution is determined by two factors related to the nature of the growth factor: the degree of molecular irregularity and the nature of the adsorption of the solvent on the surface. When the desired parameters for phase separation procedures are chosen according to the principles discussed above and described herein and then applied to the process of the present invention, then the specific embodiments resulting from the purification process must be performed in a suitable apparatus to obtain the desired result. The purpose of the process of phase separation or crystallization itself is to optimally produce amorphous or crystalline particles of the shape, size distribution, purity and yield required. When crystallization is involved, this is achieved by maintaining a degree of supersaturation in which the nucleation and the growth of the crystals proceed at appropriate speeds. In addition to solute solubility and temperature, other important factors include the thermal stability of the solute, the nature of the impurities present and the degree of hydration required. The solute precursor ester in the process of the present invention is substantially insoluble in the hot acetic acid solvent from the beginning of the process. However, the precursor ester that is dissolved in this step will increase substantially when the temperature is increased, and the supersaturation and deposition of a large proportion of the solute will normally occur in a suitable crystallizing apparatus upon cooling a hot concentrated solution. Therefore, the mother liquor from a crystallization by evaporation can be cooled to give a new crop of crystals. As an alternative, a crystallizing apparatus employing instantaneous evaporation can be used. In said apparatus, a hot solution is passed to a vacuum chamber in which both evaporation and cooling take place. Optimally, the crystallizer used will produce crystals of uniform size, which facilitates the separation of the mother liquor and washing. If large amounts of the liquor are occluded in the crystal mass, drying will yield an impure product unacceptable in terms of the present invention. An additional advantage is that the caking of crystals of uniform size during storage is less likely. The discontinuous production of large uniform crystals can be achieved using stirred reactors in which a slowly controlled or totally natural cooling takes place. When the crystallization takes place, the degree of supersaturation and the concentration of the solute fall, reaching saturation when the growth stops. A more precise control of this process can be obtained by artificially seeding the supersaturated solution in the absence of natural nucleation. The continuous production of large uniform crystals can be achieved using Oslo or Krytal crystallizers in which a metastable supersaturated solution is released at the bottom of a mass of growing crystals on which the solute is deposited. The crystals are fluidized by the circulation and the classification of the solution, that is to say, the stratification in this zone allows the separation of sufficiently large crystals from the bottom of the crystallizer. The crystallizers are usually classified by the way in which a solution supersaturates a solution, for example, cooling crystallizers or evaporation crystallizers. The two processes occur in a vacuum crystallizer. The discontinuous crystallization in a cooling crystallizer is carried out in closed tanks stirred by agitators, in which both the specific heat of the solution and the heat of crystallization are removed by means of shirts or coils through which recirculated cooling water is passed. The agitation is important to avoid temperature gradients in said deposits, opposite to the sedimentation and growth of irregular crystals in the bottom of the deposit, and to facilitate the growth of the crystals. When it is desired to carry out the crystallization process continuously, the crystallizing apparatus can take the form of a cooled tank in the same manner described above for the tanks. The solution enters at one end and the crystals and liquid are discharged at the other end. Agitation in said apparatus can be achieved by using a slow-moving screw that works in the solution and raises crystals from the cooling surface to distribute them throughout the solution and transport them slowly through the tub. It is possible to balance the entire tank and jointly use screens that increase the residence time of the solution in the tank. These two types of crystallizers are characterized by low heat transfer coefficients and a faster heat exchange can be achieved by using a double pipe arrangement in which the fluid that crystallizes circulates through the central pipe in countercurrent with the refrigerant circulating through the pipe. the annular space between the pipes. Agitation in this type of apparatus is sometimes achieved by using an axis that rotates in the central pipe and that carries blades that scrape the heat transfer surface, allowing to obtain high heat transfer coefficients.

The evaporation crystallizers can be simple arrangements in the form of stirred plates or reactors. For higher production levels, calenders are used to heat and the vertical down tube, which must be large enough to contain the flow of the suspension, will commonly house an impeller, increasing the forced circulation heat transfer to the boiling liquid. A continuous process can be carried out in which precise control of the size of the crystalline product is important using an Oslo crystallizer, which saturates the solution by evaporation. In a vacuum crystallizer, a hot concentrated solution is typically fed to a stirred crystallization chamber maintained at low pressure. The solution boils and cools adiabatically to the boiling point corresponding to the operating pressure of the crystallizer.

The crystallization follows the concentration and the product is separated from the bottom of the container.

BRIEF DESCRIPTION OF A PREFERRED EMBODIMENT A working example of an embodiment of the present invention is immediately set forth below for the purpose of further illustrating the same, but without any intention to limit the scope of the present invention, to which the appended claims are directed.

EXAMPLE 1 Purification of the precursor carbazole ester .0g of a batch of a specific production of carbazole ester precursor [diethyl ester of (6-chloro-2-carbazolyl) methylmalonic acid]], which had been previously determined to be 0.6% by weight, was added to a reactor. of a dimeric impurity of spirooxindol that had the following structure: The precursor carbazole ester material was combined with 90 ml of glacial acetic acid and heated to 50 ° C with stirring. A fine suspension was developed which was stirred for about 2.5 hours at that temperature. The suspension was cooled slowly to 20-25 ° C, stirred for a further 2 hours and then filtered and dried. The yield of final product, carbazole ester, obtained was 23.14 g (77%), which contained 0.028% by weight of the dimeric impurity of spirooxindol.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for purifying a di (CI-CT alkyl) ester of (6-chloro-2-carbazolyl) methylmalonic acid of formula (I)

(I) wherein Ra and Rb must be the same and are selected from the group consisting of alkyl C-I-CT; which comprises separating, by phase separation, one or more impurities from said carbazole ester at least once, wherein the solvent used to perform said phase separation is acetic acid. 2. A process according to claim 1, wherein said acetic acid is glacial acetic acid which is maintained at a temperature of about 30 to about 1 10 ° C.

3. A method according to claim 2, wherein said temperature is from about 50 to about 70 ° C and the aforementioned phase separation is carried out only once.

4. - A process according to claim 1, wherein said carbazole ester of formula (I) is diethyl ether. 5. A process according to claim 4, wherein said carbazole ester is obtained with a purity of at least 99.55% by weight, so the amount of impurities present in it is of a

0. 05% by weight or less.

6. A process according to claim 5, wherein said carbazole ester of formula (I) to be purified is present in the form of an isolated crystalline solid.

7. A process according to claim 1, wherein said one or more impurities are produced directly or indirectly in the course of a process for preparing said ester and comprise one or more of the starting materials, synthesis intermediates. , reagents, byproducts of the reaction, degradation products, solvents in which various steps of the reactions of the said preparation process or undesired analogues of chemical structure closely related to that of the said carbazole ester of formula (I) have been carried out .

8. A method according to claim 7, wherein said one or more impurities originate indirectly in said preparation process as a result of the said procedure being performed improperly or on a suboptimal.

9. - A method according to claim 1, wherein said one or more impurities are unintentionally produced by contamination of the equipment in which a process for preparing said carbazole ester of formula (I) is carried out, by contamination of the starting materials, solvents or synthesis aids used in said separation process, by contaminants existing in the environment surrounding the aforementioned preparation process and which are absorbed in said process or by contamination of said carbazole ester. Formula (I) when stored or handled after its preparation by the aforementioned preparation procedure.

10. A process according to claim 1, wherein said one or more impurities comprise a spirooxindole dimer of formula (IV): (IV)