TWI471318B - Method for preparing a non-hydratable crystal form - Google Patents

Description

Method for preparing non-hydrated crystal form

The present invention relates to a compound from 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]- A method of preparing a non-hydrated crystalline form of a hydrated crystalline form of 1H-pyrazole-5-carboxyguanamine.

Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-cyano-2-methyl-6-[(methylamine) is disclosed in PCT Patent Publication No. WO 04/067528 and WO 06/062978. The preparation of carbonyl]phenyl]-1H-pyrazole-5-carboxamide (Compound 1), and the use of this compound as an insecticide. WO 06/062978 further discloses the purification of compound 1 by recrystallization from 1-propanol.

It is known in the art that certain crystalline compounds may exist as polymorphs. The term "polymorph" means a specific crystal form of a compound which can be crystallized into different crystal forms, and the molecules within these forms have different arrangements and/or configurations. Although polymorphs may have the same chemical composition, they may differ in composition due to the presence or absence of co-crystallized water or other molecules that may be weakly or strongly bound within the crystal lattice. Polymorphs can vary in chemical, physical, and biological properties, such as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate, and bioavailability.

Until now, it has been impossible to predict the occurrence and quantity of any single compound crystalline polymorph, nor to predict the physicochemical properties of any particular polymorph. Most importantly, the thermal stability is in the living body after administration.

The present invention is a method of preparing polymorph A of compound 1, wherein polymorph A is characterized by an X-ray diffraction pattern having at least 2θ reflection positions of 6.78, 11.09, 19.94, 20.99, 26.57, 26.98 and 31.52; Heating the mixture at a temperature between about 40 ° C and the boiling point of the solvent, the mixture comprising: (a) selected from the group consisting of water, n-heptane, 1-chlorobutane, 1-chloropentane, toluene, 1-butanol, 1-pentyl a solvent of the group consisting of a mixture of an alcohol and any of the above solvents, and (b) a polymorph B of the compound 1, wherein the polymorph B is characterized by an X-ray diffraction pattern having at least 2θ reflection positions of 7.43, 9.89, 18.68. 19.36, 22.16, 23.09 and 25.70.

The terms "comprising," "comprising," "having," or "said" or "comprising", as used herein, are intended to encompass non-exclusive inclusions. For example, a set of compounds, processes, methods, articles, or devices containing the plural elements listed in the list are not necessarily limited to the elements listed in the list, but may include, but not explicitly listed, Process, method, article or other element inherent in the device. In addition, unless expressly stated otherwise, “or” means an inclusive “or” rather than an exclusive “or”. For example, any of the following conditions satisfies condition A or B: A is true (or exists) and B is false (or non-existent), A is false (or non-existent) and B is true ( Or existing), and A and B are both true (or exist).

Similarly, the indefinite articles "a" and "an" Thus, the word "a" or "an" is intended to include the singular, and the s

Compound 1 is 3-bromo-1- (3-chloro-2-pyridinyl) - N - [4- cyano-2-methyl-6 - [(methylamino) carbonyl] phenyl] -1 H - Pyrazole-5-carboxamide, which has the following chemical structure:

Compound 1 may be present in more than one crystal form (i.e., polymorph). It will be apparent to those skilled in the art that a polymorph of Compound 1 exhibits advantageous effects relative to other polymorphs or polymorphs of Compound 1 (e.g., suitable for the preparation of useful formulations, improved biological properties). Differences in chemical stability, filterability, solubility, hygroscopicity, melting point, solid density, and fluidity can have a significant impact on the development of manufacturing methods and formulations and the quality and efficiency of plant treatments.

A process for preparing a non-hydrated polymorph (polymorph A) of Compound 1 from a hydrated polymorph (Compound B) of Compound 1, which is typically formed first by the step of preparing Compound 1, has been found. The water content of polymorph B is significantly altered as it is exposed to different atmospheric humidities. Unlike polymorph B, polymorph A does not increase or lose considerable water when faced with changes in atmospheric humidity. Furthermore, polymorph A is typically not converted to polymorph B during long-term storage. This amazing stability helps Compound 1 to have a more consistent analysis. These properties also make the polymorph A of Compound 1 very suitable for the manufacture of long-lasting stable solid formulations which specify a stable active ingredient content.

Furthermore, polymorph A has a physical form that can be more effectively filtered than polymorph B. At the stage of large-scale synthesis and separation, polymorph A, which is easier to separate, can reduce the processing cost.

The crystalline phase of both polymorphs A and B of Compound 1 was identified by powder X-ray diffraction. Data were acquired using a Philips X'PERT automated powder diffractometer (Model 3040) to characterize polymorphs A and B. Samples at room temperature were operated in batch mode using a PW 1775 or PW 3065 (Model PW 1775 or Model PW 3065) multi-position sample conversion unit. The diffractometer is equipped with an automatic variable slit, a helium proportional meter and a graphite monochromator. The radiation is Cu (Kα), 45 kV, 40 milliamperes (mA). The sample was prepared by dry coating on a low background glass sample holder. Data was collected using a continuous scan between 2 theta angles from 2 to 60 degrees, with an equivalent step of 0.03 degrees and a count time of 2.0 seconds per step. Using the MDI/Jade software, the data is identified by the database of the International Diffraction Center, and the diffraction patterns of the samples are compared by reference.

The X-ray diffraction pattern of the polymorph A of Compound 1 is shown in Fig. 1. The corresponding 2θ values are listed in Table 1.

The X-ray diffraction pattern of the polymorph B of Compound 1 is shown in Fig. 2. The corresponding 2θ values are listed in Table 2.

The crystalline polymorph of Compound 1 can also be characterized by IR spectroscopy. The infrared spectrum was measured using an FTS 3000 FTIR spectrometer (Varian, USA) suitable for a solid gold gate ATR accessory. The infrared spectrum contains the maximum spectral bands shown below in Table 3 (polymorph A) and Table 4 (polymorph B).

The crystalline polymorphs of Compound 1 can also be characterized by IR spectroscopy and by Raman and Near Infrared Spectroscopy.

Embodiments of the invention include:

Example 1. The method is disclosed in the Summary of the Invention wherein the solvent is n-heptane.

Embodiment 1a. The method of embodiment 1, wherein the temperature is between about 40 and about 100 °C.

Example 2. The method is disclosed in the Summary of the Invention wherein the solvent is toluene.

Embodiment 2a. The method of embodiment 2 wherein the temperature system is between about 40 and about 111 °C.

Example 3. The process is disclosed in the Summary of the Invention wherein the solvent is 1-chlorobutane or 1-chloropentane.

Example 3a. The method is disclosed in the Summary of the Invention wherein the solvent is 1-chlorobutane.

Example 3b. The method is disclosed in the Summary of the Invention wherein the solvent is 1-chloropentane.

Embodiment 3c. The method of Embodiment 3a wherein the temperature system is between about 40 and about 77 °C.

Example 4. The method is disclosed in the Summary of the Invention wherein the solvent is 1-butanol or 1-pentanol.

Example 4a. The method is disclosed in the Summary of the Invention wherein the solvent is 1-butanol.

Example 4b. The method is disclosed in the Summary of the Invention wherein the solvent is 1-pentanol.

Embodiment 4c. The method of any of embodiments 4 to 4b wherein the temperature system is between about 40 and about 100 °C.

Example 5. The method is disclosed in the Summary of the Invention wherein the solvent is water.

Embodiment 5. The method of Embodiment 5 wherein the temperature is between about 60 and about 100 °C.

Embodiment 5b. The method of Embodiment 5a wherein the temperature is between about 70 and about 100 °C.

Embodiment 5c. The method of Embodiment 5a wherein the temperature is between about 70 and about 90 °C.

Embodiment 5d. The method of any of embodiments 5 to 5c wherein the mixture is heated for at least about 2 hours.

Embodiment 5. The method of Embodiment 5d wherein the mixture is heated for no more than about 48 hours.

Embodiment 5f. The method of Embodiment 5e wherein the mixture is heated for no more than about 24 hours.

Embodiment 5. The method of Embodiment 5f wherein the mixture is heated for no more than about 12 hours.

Embodiment 6. The method of any one of embodiments 5 to 5, wherein the mixture comprises at least about 30% water by weight.

Embodiment 6a. The method of embodiment 6, wherein the mixture comprises at least about 40% water by weight.

Embodiment 6b. The method of Embodiment 6a wherein the mixture comprises at least about 80% water by weight.

Embodiment 6c. The method of Embodiment 6b wherein the mixture comprises at least about 90% water by weight.

Embodiment 6d. The method of Embodiment 6c wherein the mixture comprises at least about 95% water by weight.

Embodiment 6e. The method of Embodiment 6d wherein the mixture comprises at least about 98% water by weight.

Embodiment 7. The method is disclosed in the present invention or any of the methods 1 to 6e, wherein about 0.1 to 10% of polymorph A (compound 1) based on the weight of the polymorph B is added before the mixture is heated.

Embodiment 7a. The method of embodiment 7, wherein about 0.2 to 5% of polymorph A (compound 1) relative to the weight of polymorph B is added prior to heating the mixture.

The polymorph B of compound 1 can be converted into polymorph A of compound 1 by heating in the presence of a liquid phase, the liquid phase comprising a solvent selected from certain organic solvents (ie, a solvent containing at least one carbon atom in the molecule) ). Only certain organic solvents meet the requirements of this conversion, and it is not possible to predict beyond homologous homologues, so identifying a class suitable for organic solvents requires experimentation. However, it has been found that a class of organic solvents which are generally used to convert polymorph B to polymorph A to function well include: C ₃ -C ₈ n-alkyl alcohols (e.g., n-propanol, n-butanol, n-pentanol). ), C ₄ -C ₆ n-alkyl chloride (eg n-butyl chloride or n-pentyl chloride), C ₆ -C ₁₀ alkane (eg n-hexane, hexanes, n-heptane, Heptane), C ₆ -C ₁₀ naphtheane, optionally substituted with up to 2 substituents each independently selected from C ₁ -C ₂ alkyl (eg cyclohexane, methylcyclohexane, A The base cycloheptane), and benzene, are optionally substituted with up to three groups of substituents each selected from a C ₁ -C ₂ alkyl group (eg, benzene, toluene, xylene). Since the mixture comprises (a) a solvent selected from the group consisting of water, n-heptane, 1-chlorobutane, 1-chloropentane, toluene, 1-butanol and 1-pentanol, and (b) Form B, more than one solvent may be present in the mixture. For example, in addition to the second suitable solvent, the liquid phase may contain water, n-heptane, 1-chlorobutane, 1-chloropentane, toluene, 1-butanol or 1-pentanol, and the second A suitable solvent may be water, n-heptane, 1-chlorobutane, 1-chloroheptane, toluene, 1-butanol or 1-heptanol, but is not limited thereto. For example, the liquid phase may contain water with another component, such as an alcohol, which may be, for example, methanol or ethanol, or the liquid phase may be a mixture of 1-butanol and 1-pentanol.

Since polymorph B typically contains water (such as water of hydration and water remaining therein, such as a wet cake) and polymorph A is anhydrous, water will be released upon conversion. Water is often removed from the polymorph conversion mixture using azeotropic distillation.

In the heated liquid phase for converting polymorph B to polymorph A, water has been found to be a very effective solvent. This is unexpected because polymorph B, which can accept a significant amount of water in its crystal lattice, is expected to be more advantageous in aqueous media than anhydrous polymorph A. However, water is currently found to be particularly suitable for use in forming the liquid phase used for the conversion of polymorph B to polymorph A. In a commercially convenient time, and at temperatures not exceeding 100 ° C (ie, the normal boiling point of water), the conversion will proceed to near 100% completion with high yields. Not only is water cheaper than organic solvents, but because polymorph A has low solubility in water, it can be easily separated by filtration. Alternatively, if the concentration of polymorph A in water is high, polymorph A can be separated by evaporation of water.

Unlike organic solvents, water evaporated from the mixture does not need to be collected. In an embodiment of the method, the mixture comprising polymorph B and water (along with an increased amount of polymorph A) comprises a solid phase connected to the same liquid phase, the solid phase comprising a reduced number of polymorphs B and an increased number Form A, the liquid phase contains water and other solvents as needed. Typically, other solvents are optionally selected from the group consisting of water-soluble organic solvents, although organic solvents having lower water solubility can also be used. Thus in this embodiment of the process, typically the liquid phase of the mixture comprises at least about 50% water by weight, and more typically at least about 80%, 90% or 95% water, and most typically At least about 98% water.

The method of the above examples provides a method of converting the polymorph B of the compound 1 into the polymorph A of the compound 1, by heating a mixture comprising the polymorph B of the compound 1 and water. Typically, a mixture of solid polymorph B of Compound 1 and water, in the form of a suspension or slurry, is placed in a suitably sized container which is configured to mix and heat the mixture. The mixture is then heated and mixed for a sufficient time to complete the conversion of polymorph B to polymorph A. The mixing method can be internal (eg, a stir bar or overhead stirrer) or external (eg, rotating or shaking the reaction vessel). It is generally advantageous to add the seed crystal of polymorph A to the mixture containing polymorph B prior to heating. The addition of seed crystals reduces the total conversion time and, in some cases, reduces the temperature required for the transition to occur. After the polymorph B is converted to polymorph A, the mixture is cooled and the product is isolated. Depending on the relative amounts of solid phase and liquid phase, the detachment of the product may involve further slurry drying, or if the mixture is a suspension, further filtration may be involved, followed by washing as needed and then drying.

The amount of water in the mixture can be varied to accommodate different processing equipment. For example, the use of a large amount of excess water (i.e., where water is in the liquid phase and the polymorph B crystal is suspended therein) makes it easier to agitate conventional equipment such as overhead stirrers. However, this suspension requires significant energy to heat to the desired temperature. After the conversion of the polymorph A of Compound 1 is completed, the suspension can be filtered to separate the solid product. The wet solid product or wet cake may be further dried to obtain a crystalline product which is suitable for the preparation of a formulation which is free of water, or which may be used directly to prepare an aqueous formulation composition (e.g., an aqueous suspension concentrate).

A preferred embodiment of the process comprises preparing a mixture of Polymorph B of Compound 1 and water as a slurry containing only the amount of water required to promote mixing. It is advantageous to use a smaller amount of water because less energy is required to heat the slurry to the desired temperature. In addition, a separate filtration step of the polymorph A crystal is not required because the polymorph A crystal can be easily separated by drying the slurry. Depending on the form of the container used for the conversion of polymorph B into polymorph A, it may be advantageous to perform this drying process directly within the container. On a large number of commercialization procedures, the need to transfer solids from one container to another is eliminated, resulting in significant cost savings.

Alternatively, the polymorph A crystal can be transferred to another container suitable for further drying. Thus, in a preferred embodiment of the invention, the crystals of Polymorph B of Compound 1 can be combined with water to form a slurry which typically contains from about 20 to 60% by weight water, more typically from 30 to 50. The water content of % is most typically about 40% water content.

Even without further elaboration, it is believed that those skilled in the art using the foregoing description will be able to make the most of the invention. Therefore, the following examples are to be construed as illustrative only and not in any way limiting. The initial feedstock for each example may not need to be routed by the same preparation. Percentages are by weight unless otherwise stated.

Specific examples of the conversion of the polymorph B of the compound 1 into the polymorph A of the compound 1 are explained below.

Example 1 Preparation of Polymorph A of Compound 1 (Using Slurry in Water)

A 250 ml flat-bottomed sheathed cylindrical reactor (close to 6 cm inner diameter, Wilmad-LabGlass) was placed with the water wet cake of Compound 1 polymorph B (67.8 g, according to the example in PCT Patent Publication No. WO 06/062978) The procedure of 15 was obtained except that the isolated product cake was washed with additional water; the wet cake was not dried and was used without further treatment). The wet cake of water has a total water content of approximately 40% by weight, including approximately 1% residual acetonitrile. Next, 2.0 g of seed crystal of polymorph A of Compound 1 (prepared by heating and azeotropic drying of the slurry of polymorph B in heptane; 97.4% polymorph A in near-infrared analysis) was added. Overhead agitation was installed with glass, four blades, a 45-degree impeller with a total diameter of 4.5 cm and a projection blade height of approximately 2.2 cm. The reactor is capped and a thermocouple is inserted through a lid opening. All other lid openings are plugged with a plug to prevent water from evaporating from the mixture. Stirring starts at 21 revolutions per minute. The hot oil from the circulating heater/freezer was maintained at 83 ° C, circulated through the jacket of the reactor, and the contents of the reactor were allowed to heat and mix for 6.25 hours, after which time the contents of the reactor were cooled and allowed to It is left to be left unmixed all night. The next day, reheat and mix under the same conditions and maintained for 7.25 hours. After the stirring was stopped and the reactor lid was removed during heating, the sample was withdrawn from the reactor. Prior to taking each sample, the reactor contents were thoroughly mixed by hand with a spatula to ensure uniformity. A sample having a weight of between 1 and 3 grams was withdrawn, then placed in a vacuum oven and dried overnight at a flow of tiny nitrogen of approximately 50 ° C and 17 to 40 kPa. The sample was then analyzed for its crystal form by near infrared ray. The crystal shape analysis results of the samples are as follows:

(a) Determination by near infrared spectroscopy

After heating for a total of 13.5 hours, the reactor was cooled to 25 ° C, the reactor contents were transferred to a drying tray, and dried in a vacuum oven at 50 ° C and a small nitrogen flow of 17 to 40 kPa. Over the course of the night, 28.2 g of dry compound 1 polymorph A (purity by HPLC analysis of 92.3%, Karl Fischer titration 0.1% H ₂ O) was produced.

Example 2 Preparation of Polymorph A of Compound 1 (Using a Suspension of Water)

Polymorph B of Compound 1 (5.00 g, placed in a 100 ml round bottom flask, prepared according to the procedure of Example 15 of PCT Patent Publication No. WO 06/062978, was not recrystallized from 1-propanol, and was analyzed by near-infrared analysis to 4.2. % polymorph A), polymorph A of compound 1 (prepared according to the procedure of Example 15 of WO 06/062978, comprising recrystallization from 1-propanol, 0.05 g, 97.0% polymorph A in near-infrared analysis) and water ( 15 ml). The mixture was spun in a water bath heated to 70 ° C for 4 hours. After cooling to 25 ° C, the mixture was filtered, washed with a small portion of water, dried in a vacuum oven at 60 ° C and 17 to 40 kPa (kPa), and provided with Compound 1 polymorph A (in near-infrared analysis) 96.8% polymorph A), 4.74 g (93.9% yield), melted at 218-220 °C.

Example 3 Preparation of Polymorph A of Compound 1 (using a suspension of n-heptane)

A 6-liter glass-sheathed cylindrical reactor equipped with an overhead stirrer, thermocouple, sample tilting tube, nitrogen inlet, distillation reflux head and reflux condenser was placed with Compound 1 polymorph B (906.1 g of water wet filter) Cake; nearly 40% humidity is determined by weight loss after drying; prepared according to the procedure of Example 15 of PCT Patent Publication No. WO 06/062978, without recrystallization from 1-propanol, and without drying; polymorph B is surrounded by X-rays The measurement was carried out in which the reflux condenser was cooled with a closed loop recirculation freezer filled with 50:50 glycol:water. The freezer temperature was set to 5 °C. After the reactor was flushed with nitrogen, the reactor was charged with 500 ml of fresh n-heptane and 2000 ml of n-heptane recovered from a procedure similar to that described in this example. The reactor was again flushed with nitrogen, stirring was started, and the reaction mixture was heated to a jacket set point of 97.5 °C. When the reaction temperature reached about 80 ° C at atmospheric pressure, the reaction mixture began to boil, and the condensate (ie, condensed vapor) was directly transferred from the reflux condenser to a 1000 ml graduated cylinder, and the modified cylinder bottom was removed. The condensate forms two separate layers of clear liquid. The lower layer timing of the condensate consisting of water is removed from the cylinder and weighed. Approximately 350 ml of fresh n-heptane was added back to the reactor to compensate for the loss of n-heptane movement through the condensate collection cylinder. The temperature of the reaction mixture gradually increases as the water is removed from the system. When the temperature of the reaction mixture reached 90 ° C, the jacket set point was raised to 110 ° C and the reaction mixture was heated to reflux for an additional 2 hours. A sample of the reaction mixture was sampled periodically via a sample tilt tube. These samples were filtered, and the resulting wet cake was recovered, dried in a vacuum oven, and measured by near infrared spectroscopy. The crystal shape analysis results of the samples are as follows:

(a) Determination of the initial appearance of the condensate

(b) Determination by near infrared spectroscopy

The total volume of the aqueous layer removed from the distillate was 363 ml. The reactor was cooled to 25 ° C and allowed to stand overnight. The reaction mixture was stirred briefly to help the crystal slurry drain to a coarse glassy filter funnel and the slurry was vacuum filtered. The filtrate was recovered and used to rinse the residual product from the reactor to the filter. The wet cake was dried overnight in a vacuum oven at 80 ° C with a small stream of nitrogen to produce 529.5 grams of product. By near-infrared analysis and X-ray diffraction (97.1% polymorph A in near-infrared analysis), the dried product was observed to be polymorph.

Example 4 Preparation of Polymorph A of Compound 1 (Using a suspension of 1-chlorobutane)

A glass screw cap vial was placed in the polymorph B of compound 1 (0.509 g), polymorph A of compound 1 (0.503 g, prepared from polymorph B in a similar procedure to Example 3) and 1-chlorobutane (5.8). g). Add a magnetic stir bar and cover the vial. Place the vial on an aluminum pan on a heated magnetic stir plate. The aluminum pan was heated to 45 ° C and the reaction mixture was stirred at this temperature for about 27 hours. Take B The chner funnel was vacuum filtered through the reaction mixture. The filter cake was air dried for about 30 minutes and then transferred to a new vial. The vial was covered with a cloth and placed in a vacuum oven maintained at 60 to 70 ° C and 17 to 40 kPa for about 3 days. The dried solid was analyzed by near-infrared light and found to be 97.4% polymorph A.

Example 5 Preparation of Polymorph A of Compound 1 (suspension with toluene)

Polymorph B of Compound 1 was placed in a 1000 ml glass cylindrical sheathed reactor equipped with an overhead stirrer, a Dean-Stark trap and a reflux condenser, a thermocouple and an additional funnel (100 g, published from PCT patent) The procedure of Example 15 of WO 06/062978 was carried out except that the isolated product cake was slurried with an acetonitrile/water mixture, filtered and dried; polymorph B was confirmed by X-ray diffraction). After flushing the reactor with nitrogen, the reactor was placed with 500 ml of toluene and the contents of the reactor were mixed to form a slurry. The slurry was heated by raising the temperature of the sheath fluid to 120 °C. When the slurry reached 102.6 ° C, the condensate was collected and collected in a Dean-Stark trap. After about 1 hour of reflux, 4.4 grams of the lower (water) layer was removed from the trap. After a further 20 minutes, the slurry became thinner and consisted of large solid particles which quickly precipitated to the bottom of the reactor when the agitation was temporarily stopped. After refluxing for a total time of 2 hours, the reaction mixture was cooled to 20 °C. The reaction mixture was released and filtered under vacuum to give a wet cake with a sand appearance. The product cake was rinsed in a total of 150 ml and divided into two portions of fresh toluene and then transferred to a dry dish. The product cake was dried in a vacuum oven at 100 ° C and a slight nitrogen flow of 17 to 40 kPa for 3 days. The dried product was determined to be polymorph A of compound 1 (92.2 g) by X-ray diffraction; near-infrared analysis showed that the product was 95.6% polymorph A.

Example 6 Preparation of Polymorph A of Compound 1 (Using a suspension of 1-butanol)

Glass screw cap vial was placed into Compound 1 Polymorph B (0.572 g), Compound 1 Polymorph A (0.578 g, prepared from Polymorph B in a similar procedure to Example 3) and 1-butanol (4.0 g) ). Add a magnetic stir bar and cover the vial. The vial was placed in an aluminum pan on a heated magnetic stir plate. The aluminum pan was heated to 60 ° C and the reaction mixture was stirred at this temperature for about 24 hours. Take B The chner funnel was vacuum filtered through the reaction mixture. The filter cake was air dried for about 30 minutes and then transferred to a new vial. The vial was covered with cloth and placed in a vacuum oven at about 60 ° C, 17 to 40 kPa for about 3 days. The solid was dried by near-infrared analysis and found to be 96.7% polymorph A.

Example 7 Preparation of Polymorph A of Compound 1 (Using a suspension of 1-pentanol)

A glass screw cap vial was placed in the polymorph B of compound 1 (0.611 g), polymorph A of compound 1 (0.605 g, prepared from polymorph B in a similar procedure to Example 3) and 1-pentanol (4.0 g) ). Add a magnetic stir bar and cover the vial. The vial was placed in an aluminum pan on a heated magnetic stir plate. The aluminum pan was heated to 60 ° C and the reaction mixture was stirred at this temperature for about 24 hours. Take B The chner funnel was vacuum filtered through the reaction mixture. The filter cake was air dried for about 30 minutes and then transferred to a new vial. The vial was covered with cloth and placed in a vacuum oven at about 60 ° C, 17 to 40 kPa for about 3 days. The solid was dried by near-infrared analysis and found to be 97.2% polymorph A.

Figure 1 is an X-ray diffraction pattern of Polymorph A of Compound 1, showing a map of absolute intensity count versus 2θ reflectance.

2 is an X-ray diffraction pattern of polymorph B of Compound 1, which shows a map of absolute intensity count versus 2θ reflection position.

Claims (15)

For the preparation of one kind of 3-bromo-1- (3-chloro-2-pyridinyl) - N - [4- cyano-2-methyl-6 - [(methylamino) carbonyl] phenyl] -1 H a method of polymorph A of pyrazole-5-carboxamide, comprising heating a mixture comprising: (a) one selected from the group consisting of water, n-heptane, 1-chlorobutane, 1-chloropentane, the solvent of the group consisting of toluene, 1-butanol, 1-pentanol and a mixture of any of the above solvents, and (b) 3- bromo-1- (3-chloro-2-pyridinyl) - N - [ Polymorph B of 4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1 H -pyrazole-5-carboxyguanamine wherein polymorph B has at least 2θ reflection Characterization of the position of the X-ray diffraction pattern Temperature in the range between about 40 ℃ and the boiling point of the solvent, thereby preparing 3-bromo-1- (3-chloro-2-pyridinyl) - N - [4- cyano-2-methyl-6 - [(methylamino Polymorph A of amino)carbonyl]phenyl]-1 H -pyrazole-5-carboxyguanamine wherein polymorph A is characterized by an X-ray diffraction pattern having at least 2θ reflection positions The method of claim 1, wherein the solvent is n-heptane. The method of claim 1, wherein the solvent is toluene. The method of claim 1, wherein the solvent is 1-chlorobutane. The method of claim 1, wherein the solvent is 1-butanol or 1-pentanol. The method of claim 1, wherein the solvent is water. The method of claim 6, wherein the temperature range is between about 60 and about 100 °C. The method of claim 7, wherein the temperature range is between about 70 and about 100 °C. The method of claim 8, wherein the temperature range is between about 70 and about 90 °C. The method of claim 6, wherein the mixture is heated for at least about 2 hours. The method of claim 10, wherein the mixture is heated for no more than about 48 hours. The method of claim 11, wherein the mixture is heated for no more than about 24 hours. The method of claim 12, wherein the mixture is heated for no more than about 12 hours. The method of claim 6, wherein the mixture is added to about 0.1 to 10% of the polymorph A relative to the weight of the polymorph B before heating. The method of claim 14, wherein the mixture is added to about 0.2 to 5% of the polymorph A relative to the weight of the polymorph B prior to heating.