Crystalline forms of picolinamide fungicide compounds

Abstract

The present technology relates to a process useful for the preparation of a crystalline (S)-1, 1-bis (4-fluorophenyl) propan-2-yl (3-acetoxy-4-methoxypicolinyl)-L-alanine ester compound (I) comprising: distilling a mixture comprising: an aprotic organic solvent, a protic organic solvent, compound (I) and a seed compound (I), or the process comprises distilling the mixture comprising: an aprotic organic solvent and compound (I), and crystallizing compound (I) by producing a second mixture comprising: a protic organic solvent, compound (I), and seed compound (I). The methods disclosed herein describe more stable, storage compatible formulations of Compound (I). Formulations of Compound (I) with less (trace) impurities are also disclosed.

Description

Technical Field

[0001] The present disclosure relates to the field of crystalline forms of (S)-1,1-bis(4-fluorophenyl)propan-2-yl(3-acetoxy-4-methoxypicolinoyl)-L-alaninate (Compound I), compositions thereof, and uses thereof, as well as methods of preparing or manufacturing crystalline forms thereof; Compound I is a known compound for controlling fungal diseases. Background Art

[0002] Fungicides are compounds of natural or synthetic origin that act to protect and treat plants from damage caused by agriculturally relevant fungi. Therefore, research is ongoing to discover new fungicides or new forms thereof; as well as research on processes thereof - which are desirable from the perspective of increased biological activity, atom economy of manufacture, chemical stability of composition, or other such benefits that the improved fungicide (form / process) may bring.

[0003] The solid state of a chemical compound (in the present case a fungicidal compound) may be amorphous (i.e., not long-range ordered in the positions of the atoms) or crystalline (i.e., the atoms are arranged in an ordered, repeating pattern). Research is ongoing to find improved forms of chemical compounds so that compositions and / or pure preparations of the compound of interest can be stored, transported and / or found to have higher biological activity or have more desirable physical properties, such as lower melting point, hygroscopicity, etc., or contain higher purity, i.e., fewer trace amounts of the compound (unwanted) are detected in the preparation, and therefore fewer impurities are detected.

[0004] The present disclosure relates to a crystalline form of a fungicide: (S)-1,1-bis(4-fluorophenyl)propan-2-yl(3-acetoxy-4-methoxypicolinoyl)-L-alaninate (Compound I), and methods of preparing or making the crystalline form thereof. Such forms are more stable, provide a cleaner impurity profile, and have activity against and / or provide protection against ascomycetes, basidiomycetes, and imperfect fungi. Summary of the invention

[0005] One aspect of the present disclosure provides one or more crystalline forms of Compound 1.

[0006] Compound I is exceptionally difficult to prepare in crystalline form. Amorphous material isolated from workup of an organic layer containing Compound I by column chromatography or by separation of salts results in the formation of an agglomerated solid.

[0007] In fact, it was found that a method that has been proven to be reliable to increase the crystal formation of organic compounds was not successful for compound I. Specifically, increasing the oil concentration of the crude suspension containing compound I (and seeds) does not induce crystallization. The procedure followed is: using an acid wash procedure for the crude reaction mixture containing compound I, which produces more oil during crystallization. Then the temperature is increased during the solvent exchange, which also increases the concentration of the oil. After the solvent exchange, the temperature is maintained at 30°C for 2 hours and then cooled to 8°C within 12 hours. The next morning, the reaction mixture was completely oiled. The resulting sample showed a concentration of 7.02wt% of compound I. The mixture is easily redissolved and seeded with 1% seed compound I (relative to compound I in the mixture) at 25°C. The overall temperature profile (maintained at 25°C for 2 hours and cooled to 8°C within 12 hours) produced agglomerates of compound I stuck in the reactor. After starting to filter the solid, the filter cake was washed and tried to collect. Unfortunately, more agglomerates were observed in the entire filtered reaction slurry.

[0008] Compound I was screened for stable forms. Many screening experiments produced oils or gels of Compound I. Two polymorphs were identified, designated Forms A and B. These forms have been determined to be monotropic. The melting point of each of the two crystalline forms is about 90°C, while the amorphous form exhibits a glass transition (Tg) event near 55°C. The crystalline material is flowable.

[0009] Thus, one aspect of the present disclosure includes a manufacturing process or method for preparing one or more crystalline forms of Compound 1. Additionally, one aspect of the present disclosure includes a method for preparing a composition of Compound 1 having fewer (trace) impurities (i.e., having a high purity of Compound 1). One aspect of the present disclosure includes substantially pure Compound 1.

[0010] The chemical structure of (S)-1,1-bis(4-fluorophenyl)propan-2-yl(3-acetoxy-4-methoxypicolinyl)-L-alaninate (Compound I) is:

[0011] A description of the structure, synthesis, and uses of Compound I is found in International Patent Application No.: PCT / US2015 / 066760, which is hereby incorporated by reference in its entirety along with all references cited therein. In addition, Compound I is a known fungicide and provides control of a variety of fungal pathogens in economically important crops, including but not limited to the causative agent of barley moire disease, Rhynchosporium secalis (RHYNSE).

[0012] One of the preferred aspects of the present disclosure includes a method for preparing crystalline Compound 1. In some aspects, the method may or may not include converting amorphous Compound 1 to crystalline Compound 1 (in other words, Compound 1 is crystallized directly from the reaction mixture after the last step of its synthesis, rather than being isolated as an intermediate compound. In some aspects, the present disclosure provides a method for synthesizing Compound 1 with an improved impurity profile. In some aspects, the present disclosure provides a method for making Compound 1 more stable and not degrading or degrading at a much slower rate, allowing it to be stored and transported.

[0013] In some aspects, the present disclosure provides methods for crystallizing Compound 1 with more flowable properties.

[0014] One aspect of the present disclosure includes a method of controlling a pathogen-induced disease in a plant at risk of infection by a pathogen, the method comprising contacting the plant or an area adjacent to the plant with a composition comprising one or more crystalline forms of Compound I.

[0015] One aspect of the present disclosure includes the use of one or more crystalline forms of Compound 1 for protecting plants from attack by phytopathogenic organisms or for treating plants infected by phytopathogenic organisms, the use comprising applying one or more crystalline forms of Compound 1 or a composition comprising one or more crystalline forms of Compound 1 to soil, plants, parts of plants, leaves and / or seeds.

[0016] One aspect of the present disclosure includes a composition useful for protecting plants from attack by phytopathogenic organisms and / or for treating plants infested by phytopathogenic organisms, the composition comprising one or more crystalline forms of Compound I and a phytologically acceptable carrier material. definition

[0017] Unless otherwise expressly defined in this disclosure, the definitions of various terms used in the specification and claims herein are set forth below. All technical and scientific terms not defined herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0018] "Substantially pure or free" refers to a mixture in which an organic compound of interest greatly exceeds the amount of other minor organic compounds in the mixture as impurities and is at least 80 mol%, 85 mol%, 90 mol%, 95 mol%, at least 96 mol%, at least 97 mol%, at least 98 mol%, at least 99 mol%, at least 99.5 mol%, at least 99.7 mol%, or at least 99.9 mol% of the desired compound.

[0019] Generally speaking, reference or description of an element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Thus, a group containing deuterium, tritium, 14 C. 32 P and 35 Compounds containing radioactive isotopes of S are within the scope of the present technology. Based on the disclosure herein, procedures for inserting such labels into compounds of the present technology will be apparent to those skilled in the art.

[0020] The compounds described herein may exist as solvates, especially hydrates, and unless otherwise specified, all such solvates and hydrates are contemplated. Hydrates may be formed during the manufacture of compounds or compositions comprising these compounds, or hydrates may be formed over time due to the hygroscopic properties of the compounds. The compounds of the present technology may also exist as organic solvates, including DMF, ether and alcohol solvates, etc. The identification and preparation of any particular solvate is within the skill of those of ordinary skill in the field of synthetic organic chemistry.

[0021] Throughout this application, text relates to various embodiments of compounds, compositions and methods of the present invention. The various embodiments described are intended to provide various illustrative examples and should not be construed as descriptions of alternative substances. On the contrary, it should be noted that the descriptions of the various embodiments provided herein may have overlapping scopes. The embodiments discussed herein are merely illustrative and are not intended to limit the scope of the present invention technology.

[0022] For the purposes of this specification and the appended claims, unless otherwise indicated, all numbers representing the amount, size, dimensions, ratio, shape, formula, parameter, percentage, parameter, quantity, feature and other numerical values ​​used in this specification and claims should be understood to be modified by the term "about" in all cases, even if the term "about" may not appear explicitly with the value, amount or range. Therefore, unless otherwise indicated, the numerical parameters set forth in the following specification and the appended claims are not and need not be precise, but may be approximate and / or larger or smaller as required, reflecting tolerances, conversion factors, rounding, measurement errors, etc. and other factors known to those skilled in the art, depending on the desired characteristics sought to be obtained by the subject matter currently disclosed. For example, the term "about", when referring to a value, can mean to cover changes from the specified amount in some aspects ± 100%, in some aspects ± 50%, in some aspects ± 20%, in some aspects ± 10%, in some aspects ± 5%, in some aspects ± 1%, in some aspects ± 0.5% and in some aspects ± 0.1%, because such changes are suitable for carrying out the disclosed method or using the disclosed composition. DETAILED DESCRIPTION method

[0023] In some aspects, the present disclosure provides a method for preparing or manufacturing crystalline Compound 1. In some aspects, the present disclosure provides a method comprising a. distilling an aprotic organic solvent from a mixture containing Compound 1; and b. crystallizing Compound 1 from a protic organic solvent containing Compound 1 and a seed Compound 1, optionally wherein a protic solvent is added in step a.

[0024] In some aspects, the aprotic organic solvent is dichloromethane. In some aspects, the amount of dichloromethane after step a is less than 1 wt% and greater than 0.01 wt%, less than 0.5 wt% and greater than 0.005 wt%, less than 1 wt% and greater than 0.005 wt%, less than 0.75 wt% and greater than 0.005 wt%, or less than 1 wt% and greater than 0.001 wt% residual dichloromethane.

[0025] In some aspects, a protic organic solvent is added in step a. In some aspects, the protic organic solvent is isopropanol.

[0026] In some aspects, the water content after step a and before step b is: less than 1000 ppm and greater than 0.1 ppm, less than 1000 ppm and greater than 50 ppm, less than 400 ppm and greater than 0.1 ppm, less than 400 ppm and greater than 50 ppm, less than 300 ppm and greater than 0.1 ppm, less than 300 ppm and greater than 0.5 ppm, less than 300 ppm and greater than 1 ppm, less than 300 ppm and greater than 10 ppm, less than 300 ppm and greater than 5 ppm as analyzed by the Karl Fisher method, or has a content within a range between any numerical concentrations recited herein, that is, any range between 1000 ppm-400 ppm-300 ppm-50 ppm-10 ppm-5 ppm-1 ppm-0.5 ppm-0.1 ppm.

[0027] In some aspects, the amount of Compound I in step a and prior to step b is less than 15 wt% and greater than 7 wt%, less than 15 wt% and greater than 10 wt%, less than 10 wt% and greater than 7 wt%, or an amount within a range between any numerical percentages recited herein, for example, any range between 15 wt%-10 wt%-7 wt%.

[0028] In some aspects, the temperature during step a is carried out in the range of about 60°C to about 10°C.

[0029] In some aspects, the amount of seed compound I is: less than or equal to 50 wt% and greater than or equal to 2 wt%, less than or equal to 50 wt% and greater than or equal to 15 wt%, less than or equal to 20 wt% and greater than or equal to 5 wt%, less than or equal to 10 wt% and greater than or equal to 2 wt%, or an amount within the range of any numerical percentages listed herein, for example, any range of 50 wt%-20 wt%-15 wt%-10 wt%-5 wt%-2 wt%.

[0030] In some aspects, the temperature during step b is carried out in the range of about 50°C to about 0°C. Impurity profile and stability

[0031] In some aspects, the present disclosure provides high purity Compound I. In some aspects, the purity is ≥97.0%, ≥97.5%, ≥97.9%, ≥98.0%, ≥98.1%, ≥98.5%, ≥99.0%, ≥99.1%, ≥99.5%, ≥99.7%, ≥99.9%, ≥99.99%, or has a purity within any range of numerical percentages recited herein, i.e., any range of 97.0%-97.5%-97.9%-98.0%-98.1%-98.5%-99.0%-99.1%-99.5%-99.7%-99.9%-99.99%.

[0032] In some aspects, the present disclosure provides crystalline compound I with increased stability. In some aspects, crystalline compound I is stable at 21°C for more than 12 hours and less than 24 hours. In some aspects, crystalline compound I is stable at 25°C for more than 12 hours and less than 24 hours. In some aspects, crystalline compound I is stable at 30°C for more than 12 hours and less than 24 hours. In some aspects, crystalline compound I is stable at 21°C for more than 24 hours and less than 36 hours. In some aspects, crystalline compound I is stable at 21°C for more than 36 hours and less than 48 hours. Examples

[0033] The following examples are provided to illustrate the technology of the present invention, and these examples are not interpreted as limiting the scope of the technology of the present invention in any way. With regard to the numbers used (such as amounts, temperatures, etc.), efforts have been made to ensure their accuracy, but some experimental errors and deviations should still be allowed. According to the foregoing description and the accompanying drawings, in addition to those described herein, various modifications of the technology of the present invention are obvious to those skilled in the art. Such modifications fall within the scope of the appended claims. Unless otherwise stated, all temperatures are in degrees Celsius.

[0034] The practice of the present invention will employ, unless otherwise indicated, conventional methods of synthetic organic chemistry, protein chemistry and biochemistry, and agriculture, which are within the skill of the art. Such techniques are fully explained in the literature. See, e.g., T. C. Reighton, Proteins: Structures and Molecular Properties (W. H. Freeman and Company, 1993); A. Lehninger, Biochemistry (Worth Publishers, Inc., latest edition); Methods In Enzymology (S. Colowick and N. Kaplan, eds., Academic Press, Inc.); Remington's Agricultural Sciences, 18th ed. (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry, 3rd ed. (Springer Science Press, Plenum Press), Vols. A and B (1992), and Organic Reactions, Vols. 1-40 (Johnson, ed.). Wiley, and Sons, 1991).

[0035] In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has the generally accepted meaning. aq.=water-based THF = Tetrahydrofuran o / n = overnight rt = room temperature DCM = dichloromethane DMF = dimethylformamide DMSO = dimethyl sulfoxide equiv.=equivalent EtOAc = Ethyl acetate EtOH = ethanol g = grams h = hours HCl = Hydrochloric acid HPLC = High Performance Liquid Chromatography M = mole MeOH = methanol mg = milligrams mL = milliliters mmol = millimole mp = melting point wt% = weight percentage μM = micromolar General experimental details: Generic Example: General Overview of the Crystallization Process

[0036] The reaction mixture (aftertreatment) typically contains about 2000ppm of water. Compound I degrades in the presence of water. After aftertreatment, the organic layer is distilled and then solvent exchange is performed. In the example of the present invention put into practice, the solvent is dichloromethane (DCM) and the exchange solvent is isopropyl alcohol (IPA). Typical large-scale, industrial-scale crystallization processes (which have been put into practice) have demonstrated that from 60-80kg of crude starting material, about 75g-100kg (93%-99%) of Compound I are obtained as the observed yield from the crystallization process.

[0037] In another general but more specific example, the process uses distillation to first remove the solvent: 80%-85% of the feed volume (DCM, water) is distilled overhead at 1 atmosphere. The mixture begins boiling at about 40°C and eventually reaches about 54°C. This drives off any residual water, typically reducing the water content from about 2000 ppm to <300 ppm of water, and drives off the DCM.

[0038] After the DCM distillation, the jacket temperature was lowered to 30°C and loaded with room temperature isopropyl alcohol (IPA) (water specification <1000 ppm). The vacuum was then set to 180 mm Hg and the jacket temperature was set to 55°C. At 180 mm Hg, the mixture began to boil at about 38°C and the distillation was ended at a final bottoms temperature of about 51.3°C when the bottoms specifications (<0.5 wt% residual DCM, 25-27 wt% compound I) were met.

[0039] After the solvent exchange, the distillation bottoms are cooled to 30°C and transferred to a crystallizer. If the transfer occurs at a lower temperature, Compound I may appear as an oil or an amorphous solid. A seed loading of 5% to 20% (seed size D50 < 20 μm, very small, very high compared to a normal process of typically less than 1%) can be used for this process. After loading the seeds, the temperature is maintained at 30°C for 2-6 hours, and then the temperature can be reduced to 8°C within 4-7 hours.

[0040] When the mother liquor concentration is below 2.5 wt%, the crystals are usually filtered. The crystals are filtered and then washed with heptane. The wet cake is then scooped out and scraped into a dryer where it is dried under heated vacuum (45 mm Hg and 50° C. maximum temperature).

[0041] Two possible polymorphs may be formed from Compound 1. Both polymorphic forms are crystalline, whereas amorphous Compound 1 is not crystalline. Example 1: Crystal formation method 1 Synthesis of crystalline (S)-1,1-bis(4-fluorophenyl)propan-2-yl(3-acetoxy-4-methoxypicolinoyl)-L-alaninate (Compound I). Distillation

[0042] After work-up, the organic layer (723.18 g) containing compound I was analyzed by Karl-Fischer method to determine the water content (1620 ppm). An LC sample of the organic layer was taken after alkaline washing (Compound I wt%=10.89%). The remaining organic layer was then transferred to a distillation vessel. For DCM-H2O distillation, the jacket was set to 55°C. The content temperature increased from 10°C and began to boil at 40°C. The distillation was stopped at 43°C (content temperature), after which the water content (257 ppm) was analyzed by Karl-Fischer method. The organic layer was cooled to 0°C and kept in the reactor overnight (16 hours).

[0043] The next morning, distillation was continued (jacket temperature 65°C) until the content temperature reached 54°C. Isopropyl alcohol (355.05g, 423ppm water, 35.1 equivalents) was then added to the bottom. The pressure was set to 180mmHg (jacket temperature 60°C). The mixture began to boil at about 38°C, and the distillation ended at a final bottom temperature of about 51.3°C until the methylene chloride bottom specification (<0.5wt% residual DCM) was met. The solution was cooled back to 30°C and analyzed by HPLC determination -26.4wt%. crystallization

[0044] The distilled mixture (293.05 g) was then transferred to a crystallizer. Seed slurry (15.04 g of solid Compound I polymorph A, purity 97%, active substance: 14.58 g, d50-10 μm; 45.12 g of IPA) was added to the reactor (at 30° C.) and stirred at 500 rpm. The temperature profile used was a stepwise decrease from 30° C. to 8° C. over 24 hours.

[0045] When the concentration of Compound I dropped to less than 2.5wt%, the slurry was filtered. The mother liquor was used to rinse the solid in the reactor. The mother liquor was analyzed by HPLC to determine the content of Compound I (244.3g, 2.22wt% of Compound I, 5.42g of active substance loss). The wet cake was kept on the filter for 30 minutes, and then heptane washings (102.42g) were used to rinse the reactor and wash the wet cake. The wet cake (88.42g) was kept on the filter for 30 minutes, and then dried overnight in a vacuum oven at 50°C to obtain a colorless solid. Based on XRD, the solid formed is polymorph A. 2θ d Peak height 5.97 14.792 219.1 10.69 8.2692 409.8 14.17 6.2452 161 14.71 6.0172 831.7 16.19 5.4703 132.6 16.99 5.2145 1000 17.69 5.0097 319.7 18.31 4.8414 251.8 19.41 4.5695 422 20.01 4.4338 277.5 20.67 4.2937 164 21.17 4.1934 229.7 23.21 3.8292 803.8 23.81 3.7341 313.5 25.01 3.5576 185.6 25.83 3.4464 134.3 27.21 3.2746 138.8 28.57 3.1218 168.5 31.27 2.8582 94 32.51 2.7519 85 Wet cake: 88.42g Dry filter cake: 88.38g LOD: 0.05wt% solvent The dry cake was analyzed by HPLC (97.2 wt%). Isolated active substance: 85.91 g, Active material loaded: 14.58 g Example 2: Crystal formation method 2 Synthesis of crystalline (S)-1,1-bis(4-fluorophenyl)propan-2-yl(3-acetoxy-4-methoxypicolinoyl)-L-alaninate (Compound I). Distillation

[0046] After work-up, the organic layer (727.4 g) was analyzed by Karl-Fischer method to determine the water content (1852 ppm). An LC sample of the organic layer was taken after the alkaline wash (Compound I wt% = 10.95%). The remaining organic layer was then transferred to a distillation vessel.

[0047] For DCM-H2O distillation, the jacket was set to 55°C. The content temperature increased from 10°C and started boiling at 40°C. The distillation was stopped at 43°C (content temperature), after which the water content was analyzed by Karl-Fischer method (298 ppm). The organic layer was cooled to 0°C and kept in the reactor overnight (16 hours).

[0048] The next morning, distillation was continued (jacket temperature 65°C) until the content temperature reached 54°C. Isopropyl alcohol (355.73g, 355ppm water) was then added to the bottom. The pressure was set to 180mmHg (jacket temperature 60°C). The mixture began to boil at about 38°C, and the distillation was terminated at a final bottom temperature of about 51.3°C until the methylene chloride bottom specification (<0.5wt% residual DCM) was met. The solution was cooled back to 30°C and analyzed by HPLC determination -26.6wt%. crystallization

[0049] The distilled mixture (298.1 g) was then transferred to a crystallizer. Seed slurry (15.9 g of solid Compound I polymorph B, purity 97%, active substance: 15.42 g, d50-20 μm; 48.2 g of IPA) was added to the reactor (at 30° C.) and stirred at 500 rpm. The temperature profile used was a stepwise decrease from 30° C. to 8° C. over 24 hours.

[0050] When the concentration of Compound I dropped to less than 2.5wt%, the slurry was filtered. The mother liquor was used to rinse the solid in the reactor. The mother liquor was analyzed by HPLC to determine the content of Compound I (215g, 1.8wt% of Compound I, 3.87g of active material loss). The wet cake was kept on the filter for 30 minutes, and then heptane washings (101.6g) were used to rinse the reactor and wash the wet cake. The wet cake (88.1g) was kept on the filter for 30 minutes, and then dried overnight in a vacuum oven at 50°C to obtain a colorless solid. Based on XRD, the solid formed is polymorph B. Wet cake: 88.1g Dry filter cake: 87.2g LOD: 0.05wt% solvent The dry cake was analyzed by HPLC (97.5 wt%). Isolated active substance: 85.02 g, Active material loaded: 15.42 g

[0051] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0052] Unless otherwise indicated herein or clearly contradictory to the context, the terms "a and an" and "the" and "at least one" and similar indicators used in the context of describing the present invention (particularly in the context of the following claims) should be interpreted as including both the singular and the plural. Unless otherwise indicated herein or clearly contradictory to the context, the use of the term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") should be interpreted as meaning any combination of one item selected from the listed items (A or B) or two or more of the listed items (A and B). Unless otherwise indicated, the terms "including", "having", "including" and "containing" should be interpreted as open terms (i.e., meaning "including, but not limited to"). Unless otherwise indicated herein, the recitation of a range of values ​​herein is intended only to be used as a shorthand method of individually referencing each individual value falling within the range, and each individual value is incorporated into this specification as if it were individually recited herein. Unless otherwise indicated herein or otherwise clearly contradictory to the context, all methods described herein may be performed in any suitable order. Unless otherwise indicated, the use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention and is not intended to limit the scope of the present invention. No language in this specification should be construed as indicating that any unclaimed element is essential to the practice of the present invention.

[0053] Preferred embodiments of the present invention are described herein, including the best modes of implementing the present invention known to the inventors. After reading the foregoing description, the variations of those preferred embodiments are apparent to those of ordinary skill in the art. The inventors expect that skilled technicians will adopt these variations as appropriate, and the inventors intend to practice the present invention in other ways different from those specifically described herein. Therefore, with the permission of applicable law, the present invention includes all modifications and equivalent forms of the subject matter listed in the appended claims. In addition, unless otherwise indicated in the text or otherwise clearly contradictory to the context, the present invention encompasses any combination of the above-mentioned elements in all possible variations thereof.

Claims

1. A method for preparing a crystalline compound having the formula: The method comprises: A mixture is distilled, the mixture comprising: an aprotic organic solvent, a protic organic solvent, Compound I and a seed Compound I.

2. A method for preparing a crystalline compound having the formula: The method comprises: a. distilling a mixture, the mixture comprising: an aprotic organic solvent and a compound I; b. crystallizing Compound I from step a by producing a second mixture comprising: a protic organic solvent, Compound I, and seed Compound I.

3. The method according to claim 1 or claim 2, wherein: The aprotic organic solvent is dichloromethane.

4. The method of claim 3, wherein: The amount of dichloromethane in the mixture after step a is less than 1 wt % and greater than 0.01 wt % of residual dichloromethane.

5. The method of claim 3, wherein: The amount of dichloromethane in the mixture after step a is less than 0.5 wt % and greater than 0.005 wt % residual dichloromethane.

6. The method according to any one of claims 1 to 5, wherein: In step a, a protic organic solvent is added to the mixture.

7. The method according to any one of claims 1 to 6, wherein: After step a and before step b the mixture has a water content of less than 1000 ppm and greater than 50 ppm as analyzed by the Karl-Fischer method.

8. The method according to any one of claims 1 to 6, wherein: After step a and before step b the mixture has a water content of less than 300 ppm and greater than 0.1 ppm as analyzed by the Karl-Fischer method.

9. The method according to any one of claims 1 to 8, wherein: The amount of compound I in the mixture after step a and before step b is less than 15 wt % and greater than 7 wt %.

10. The method according to any one of claims 1 to 8, wherein: The amount of compound I in the mixture after step a and before step b is less than 15 wt % and greater than 10 wt %.

11. The method according to any one of claims 1 to 8, wherein: The amount of compound I in the mixture after step a and before step b is less than 10 wt % and greater than 7 wt %.

12. The method according to any one of claims 1 to 11, wherein: The temperature during step a is carried out in the range of about 60°C to about 10°C.

13. The method according to any one of claims 1 to 11, wherein: The amount of the seed compound I is less than 50 wt % and greater than 15 wt %.

14. The method according to any one of claims 1 to 11, wherein: The amount of the seed compound I is less than 10 wt % and greater than 2 wt %.

15. The method according to any one of claims 1 to 14, wherein: The temperature during step b is carried out in the range of about 50°C to about 0°C.

16. A crystalline polymorph of a compound having the formula:

17. The polymorph of claim 16, wherein: The polymorph is characterized by a powder X-ray diffraction pattern having at least a 2θ reflection position: 。 18. The polymorph of claim 16, wherein: The polymorph is characterized by a powder X-ray diffraction pattern having at least a 2θ reflection position:

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