Crystalline Forms of Picolinamide Fungicide Compounds

Abstract

The present technology relates to a process useful for preparing the crystalline (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoate)-L-alaninate compound (I), which comprises distilling a mixture, which comprises distilling a mixture containing an aprotic organic solvent, a protic organic solvent, the compound (I), and a seed crystal of the compound (I), or which comprises distilling a mixture containing an aprotic organic solvent and the compound (I) and crystallizing the compound (I) by preparing a second mixture containing a protic organic solvent, the compound (I), and a seed crystal of the compound (I). The process disclosed herein describes a more stable and storage-compatible preparation of the compound (I). Preparations of the compound (I) having fewer (trace) impurities are also disclosed.

Description

Technical Field

[0001] The present disclosure relates to the crystalline forms of (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoate)-L-alaninate (Compound I), a known compound for controlling fungal diseases, its compositions and its uses, and to the field of processes for making or manufacturing the crystalline form of (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoate)-L-alaninate.

Background Art

[0002] Fungicides are natural or synthetically derived compounds that act to protect and / or treat plants against damage caused by agriculturally relevant fungi. As a result, research is ongoing to find new fungicides or new forms thereof, and for that process, it is desirable from the perspective of increased biological activity, atom economy of manufacture, chemical stability with respect to composition, or other such advantages that an improved fungicide (form / process) may confer.

[0003] The solid state of a compound - in this case, a fungicidal compound - can be either amorphous (i.e., having no long-range order 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 the compound such that the composition and / or neat preparation of the compound of interest can be stored, transported, and / or is more bioactive, or has more desirable physical properties, such as a lower melting point, lower hygroscopicity, etc., or contains a higher purity, i.e., fewer (undesired) trace compounds are detected in the preparation and thus fewer impurities are found.

[0004] The present disclosure relates to a fungicide: the crystalline form of (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoate)-L-alaninate (Compound I), and a process for making or manufacturing such crystalline forms. Such forms are more stable, provide a cleaner impurity profile, and are active against and / or provide protection against Ascomycetes, Basidiomycetes, and Deuteromycetes.

Summary of the Invention

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

[0006] Compound I is extremely difficult to make in crystalline form. The amorphous material isolated from the work-up of the organic layer containing Compound I, either by column chromatography or salt isolation, results in the formation of an aggregated solid.

[0007] In fact, it has been found that proven methods for increasing the crystallization of organic compounds have not been successful with Compound I. Specifically, increasing the oil concentration of the crude suspension containing Compound I (and seed crystals) did not induce crystallization. The procedure followed was as follows: an acid wash procedure was utilized on the crude reaction mixture containing Compound I, but the oil formed during crystallization increased. Then the temperature was raised during solvent exchange, and again the oil concentration increased. After solvent exchange, the temperature was maintained at 30 °C for 2 hours and then cooled to 8 °C over 12 hours. The next morning, the reaction mixture was completely oily. The resulting sample showed a Compound I concentration of 7.02 wt%. The mixture was easily redissolved and seeded at 25 °C with 1% seed Compound I (relative to Compound I in the mixture). The overall temperature profile (held at 25 °C for 2 hours and cooled to 8 °C over 12 hours) resulted in the formation of aggregates of Compound I clogging the inside of the reactor. After starting the filtration of the solid, the cake was washed and an attempt was made to collect it. Unfortunately, more aggregates were observed throughout the filtered reaction slurry.

[0008] Screening for stable forms of Compound I was carried out. Many screening experiments resulted in either an oil or a gel of Compound I. Two polymorphs were identified and designated as Form A and Form B. It was confirmed that the forms are monotropic. The melting point of each of the two crystalline forms is about 90 °C, while the amorphous form exhibited a glass transition (Tg) event at around 55 °C. The crystalline material is fluid.

[0009] Accordingly, one aspect of the present disclosure includes a process or method of manufacturing to produce one or more crystalline forms of Compound I. Further, one aspect of the present disclosure includes a process of making a composition of Compound I having fewer (trace) impurities, i.e., a high-purity composition of Compound I. One aspect of the present disclosure includes substantially pure Compound I.

[0010] (S)-1,1-Bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoate)-L-alaninate (Compound I) has the following chemical structure:

Chemical formula

[0011] Descriptions of the structure, synthesis, and use of Compound I are found in the specification of International Patent Application No.: PCT / US2015 / 066760, which is hereby incorporated by reference in its entirety into this specification together with all references cited therein. Further, Compound I is a known fungicide that controls various fungal pathogens of economically important crops, including but not limited to the pathogen of barley scald, Rhynchosporium secalis (RHYNSE).

[0012] One preferred embodiment of the present disclosure involves a process for preparing crystalline Compound I. In some embodiments, the process may or may not include converting amorphous Compound I to crystalline Compound I (in other words, Compound I crystallizes directly from the reaction mixture after the final step of its synthesis and is not isolated as a compound in between). In some embodiments, the present disclosure provides a process by which Compound I with an improved impurity profile is synthesized. In some embodiments, the present disclosure provides a process by which Compound I is more stable and does not decompose or decomposes at a much slower rate so as to be storable and transportable.

[0013] In some embodiments, the present disclosure provides a process by which crystalline Compound I has the property of being more fluid.

[0014] One embodiment of the present disclosure includes a method for controlling pathogen-induced diseases in plants at risk of disease from pathogens, which involves contacting a plant or a portion adjacent to the plant with a composition comprising one or more crystalline forms of Compound I.

[0015] One embodiment of the present disclosure includes the use of one or more crystalline forms of Compound I for the protection of plants from attack by phytopathogenic organisms or the treatment of plants invaded by phytopathogenic organisms, which involves the application of one or more crystalline forms of Compound I or a composition comprising one or more crystalline forms of Compound I to soil, plants, plant parts, leaves, and / or seeds.

[0016] One embodiment of the present disclosure includes a composition comprising one or more crystalline forms of Compound I and a botanically acceptable carrier material, which is useful for the protection of plants from attack by phytopathogenic organisms and / or the treatment of plants invaded by phytopathogenic organisms.

[0017] Definitions Various terms used in this specification and the claims are defined as follows unless otherwise defined in the present disclosure. All technical and scientific terms not defined herein have the meanings commonly understood by those skilled in the technical field to which the present invention pertains.

[0018] "Substantially pure or free of" means that one organic compound of interest far exceeds the amount of other minor organic compounds in the mixture as impurities and is at least 80%, 85%, 90%, 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.7%, or at least 99.9% of the desired compound in molar terms in a mixture.

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

[0020] The compounds described herein may exist as solvates, particularly hydrates, and unless otherwise specified, all such solvates and hydrates are intended. Hydrates may be formed during the manufacture of the compound or composition containing the compound, or hydrates may be formed over time due to the hygroscopicity of the compound. The compounds of this technology may exist as organic solvates including, inter alia, DMF, ether, and alcohol solvates. The identification and preparation of any particular solvate are within the skill of those in the art of synthetic organic chemistry.

[0021] Throughout this application, this document refers to various embodiments of the present compounds, compositions, and methods. The various embodiments described mean providing examples as various examples and should not be construed as another kind of explanation. Rather, it should be noted that the descriptions of the various embodiments provided herein may potentially have overlapping ranges. The embodiments discussed herein are merely examples and do not mean to limit the scope of this technology.

[0022] For the purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing quantities, sizes, dimensions, ratios, shapes, formulations, parameters, percentages, parameters, amounts, characteristics, and other numerical values used in this specification and the claims are to be understood as being modified in all instances by the term "about" even if the term "about" does not explicitly appear with that value, amount, or range. Thus, unless otherwise indicated, the numerical parameters set forth in the following specification and the appended claims are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding, measurement error, and other factors known to those of skill in the art, in accordance with the desired properties to be obtained by the subject matter disclosed herein. For example, the term "about" when referring to a value can be meant to encompass variations of, in some embodiments, ±100%, in some embodiments, ±50%, in some embodiments, ±20%, in some embodiments, ±10%, in some embodiments, ±5%, in some embodiments, ±1%, in some embodiments, ±0.5%, and in some embodiments, ±0.1% from the specified amount, as such variations are appropriate for carrying out the disclosed methods or using the disclosed compositions.

DETAILED DESCRIPTION OF THE INVENTION

[0023] Process In some embodiments, the present disclosure provides a process for making or producing crystalline Compound I. In some embodiments, the present disclosure includes a. distilling an aprotic organic solvent from a mixture comprising Compound I; and b. crystallizing Compound I from a protic organic solvent comprising Compound I and seed Compound I, optionally with a protic solvent added in step a.

[0024] In some embodiments, the aprotic organic solvent is dichloromethane. In some embodiments, 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% of residual dichloromethane.

[0025] In some embodiments, the protic organic solvent is added in step a. In some embodiments, the protic organic solvent is isopropyl alcohol.

[0026] In some embodiments, the water content after step a and before step b is less than 1000 ppm and greater than 0.1 ppm, 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, or within the range between any of the numerical concentrations listed herein, i.e., having a content within any range between 1000 ppm - 400 ppm - 300 ppm - 50 ppm - 10 ppm - 5 ppm - 1 ppm - 0.5 ppm - 0.1 ppm as analyzed by the Karl Fischer method.

[0027] In some embodiments, the amount of Compound I before step b during step a 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 within the range between any of the numerical percentages listed herein, for example, having an amount within any range between 15 wt% - 10 wt% - 7 wt%.

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

[0029] In some embodiments, the amount of the seed crystal compound I is 50 wt% or less and 2 wt% or more, 50 wt% or less and 15 wt% or more, 20 wt% or less and 5 wt% or more, 10 wt% or less and 2 wt% or more, or has an amount within any range of the numerical percentages listed herein, for example, within any range of 50 wt% - 20 wt% - 15 wt% - 10 wt% - 5 wt% - 2 wt%.

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

[0031] Impurity Profile and Stability In some embodiments, the present disclosure provides a high-purity compound I. In some embodiments, 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 the numerical percentages listed herein, that is, within 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 embodiments, the present disclosure provides a crystalline compound I having increased stability. In some embodiments, the crystalline compound I is stable at 21 °C for more than 12 hours and less than 24 hours. In some embodiments, the crystalline compound I is stable at 25 °C for more than 12 hours and less than 24 hours. In some embodiments, the crystalline compound I is stable at 30 °C for more than 12 hours and less than 24 hours. In some embodiments, the crystalline compound I is stable at 21 °C for more than 24 hours and less than 36 hours. In some embodiments, the 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 present technology and should not be construed as limiting the scope of the present technology. Although efforts have been made to ensure accuracy with respect to the numerical values used (e.g., amounts, temperatures, etc.), some experimental error and deviation are to be expected, of course. Various modifications of the present technology in addition to those described herein will be apparent to those skilled in the art from the above description and the accompanying drawings. Such modifications are included within the scope of the appended claims. Unless otherwise specified, all temperatures are in degrees Celsius.

[0034] The practice of the present invention, unless otherwise indicated, will employ conventional methods of synthetic organic chemistry, protein chemistry and biochemistry, and agriculture within the scope of the relevant art. Such techniques are well described in the literature. For example, see T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington’s Agricultural Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3 rd Ed. (Plenum Press) Vols A and B (1992), and Organic Reactions, Volumes 1 - 40 (John Wiley, and Sons, 1991).

[0035] In the following examples, the following abbreviations have the following meanings. When an abbreviation is not defined, it has its generally accepted meaning. aq. = aqueous THF = Tetrahydrofuran o / n = overnight r.t. = room temperature DCM = Dichloromethane DMF = Dimethylformamide DMSO = Dimethyl sulfoxide equiv. = equivalent EtOAc = Ethyl acetate EtOH = Ethanol g = gram h = hour HCl = Hydrochloric acid HPLC = High Performance Liquid Chromatography M = Molarity MeOH = Methanol mg = milligram mL = milliliter mmol = millimole mp = Melting point wt% = Weight percent μM = Micromolarity

[0036] Details of the overall experiment Overall Example: Comprehensive overview of the crystallization process The reaction mixture (after workup) typically contains about 2000 ppm of water. Compound I decomposes by the water present. After workup, the organic layer is distilled and then solvent exchange is carried out. In this example transferred to execution, the solvent is dichloromethane (DCM) and the exchange solvent is by isopropyl alcohol (IPA). A typical large-scale, industrial-sized crystallization process - transferred to execution - shows from 60 - 80 kg of crude starting material about 75 g - 100 kg (93 - 99%) of Compound I as an observed as 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 at the top of the column at 1 atmosphere. The mixture begins to boil at about 40 °C and finally reaches about 54 °C. This drives out all the residual water, typically reducing the water content to less than 300 ppm from about 2000 ppm, and also reducing it in DCM.

[0038] After DCM distillation, the jacket temperature is lowered to 30 °C and room temperature isopropyl alcohol (IPA) (water specification value less than 1000 ppm) is loaded. Then the vacuum is set to 180 mmHg and the jacket temperature is set to 55 °C. At 180 mmHg, the mixture begins to boil at around 38 °C and distillation ends at a final bottom temperature of about 51.3 °C when the bottom specification values are met (less than 0.5 wt% residual DCM, 25 - 27 wt% compound I).

[0039] After 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 come out as an oil or an amorphous solid. A 5 - 20% seed loading (seed crystal size D50 < 20 μm, very small, the seed loading is quite high compared to the normal process which is typically less than 1%) can be used for this process. After loading the seeds, the temperature can be maintained at 30 °C for 2 - 6 hours and then lowered to 8 °C over 4 - 7 hours.

[0040] Crystallization is usually filtered when the mother liquor concentration drops below 2.5 wt%. The crystals are filtered and then washed with heptane. Then the wet cake is loosened, trimmed and put into a dryer where it is dried under heating vacuum (45 mmHg and maximum temperature 50 °C).

[0041] Two possible polymorphs are probably formed from compound I. Both polymorphs are crystalline, while the amorphous compound I is not.

[0042] Example 1: Method 1 for crystal formation Synthesis of Crystalline (S)-1,1-Bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoate)-L-alaninate (Compound I) Distillation After work-up, the organic layer (723.18 g) containing Compound I was analyzed by Karl Fischer to determine the water content (1620 ppm). The LC sample of the organic layer was taken after base washing (Compound I wt% = 10.89%). Then the remaining organic layer was transferred to a distillation vessel. The jacket was set at 55 °C for DCM-H2O distillation. The content temperature rose from 10 °C and started boiling at 40 °C. Distillation was stopped at 43 °C (content temperature), and the water content was analyzed by Karl Fischer at that point (257 ppm). The organic layer was cooled to 0 °C and kept in the reactor overnight (16 hours).

[0043] The next morning, distillation was continued until the content temperature reached 54 °C (jacket temperature 65 °C). Then isopropanol (355.05 g, 423 ppm water, 35.1 eq) was added to the bottom. The pressure was set at 180 mmHg (jacket temperature 60 °C). The mixture started boiling at about 38 °C and distillation was completed at a final bottom temperature of about 51.3 °C until the dichloromethane bottom specification was met (less than 0.5 wt% residual DCM). The solution was cooled back to 30 °C and analyzed by HPLC assay - 26.4 wt%.

[0044] Crystallization Then the post-distillation mixture (293.05 g) was transferred to a crystallizer. The seed slurry (15.04 g solid Compound I polymorph A, purity 97%, active ingredient: 14.58 g, d50 - 10 μm; 45.12 g IPA) was transferred 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 was less than 2.5% by weight, the slurry was filtered. The mother liquor was used to rinse the solid reactor. The mother liquor was analyzed by HPLC to determine the Compound I content (244.3 g, 2.22% by weight Compound I, 5.42 g of active lost). The wet cake was held on the filter for 30 minutes and then the reactor was rinsed with heptane wash (102.42 g) to wash the wet cake. When the wet cake (88.42 g) was held on the filter for 30 minutes and then dried overnight in a vacuum oven at 50 °C, a colorless solid was obtained. Based on XRD, the solid formed was polymorph A.

[0046]

Table 1

[0047] Wet cake: 88.42 g Dry cake: 88.38 g LOD: 0.05% by weight of solvent The dry cake was analyzed by HPLC (97.2% by weight). Isolated active substance: 85.91 g Loaded seed crystal active substance: 14.58 g

[0048] Example 2: Method 2 for crystal formation Synthesis of crystalline (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoate)-L-alaninate (Compound I). Distillation After work-up, the organic layer (727.4 g) was analyzed by Karl Fischer to determine the water content (1852 ppm). The LC sample of the organic layer was taken after base washing (Compound I weight% = 10.95%). Then, the residual organic layer was transferred to a distillation vessel.

[0049] Set the jacket to 55 °C for DCM-H2O distillation. The content temperature rose from 10 °C and began to boil at 40 °C. Stop the distillation at 43 °C (content temperature), and then analyze the water content by Karl Fischer at that time (298 ppm). Cool the organic layer to 0 °C and keep it in the reactor overnight (16 hours).

[0050] The next morning, continue the distillation until the content temperature reaches 54 °C (jacket temperature 65 °C). Then, add isopropanol (355.73 g, 355 ppm water) to the bottom. Set the pressure to 180 mmHg (jacket temperature 60 °C). The mixture begins to boil at about 38 °C, and the distillation ends at a final bottom temperature of about 51.3 °C until the dichloromethane bottom specification is met (less than 0.5 wt% residual DCM). Cool the solution back to 30 °C and analyze it by HPLC assay - 26.6 wt%.

[0051] Crystallization Next, transfer the post-distillation mixture (298.1 g) to a crystallizer. Add a seed slurry (15.9 g of solid Compound I polymorph B, purity 97%, active ingredient: 15.42 g, d50 - 20 μm; 48.2 g IPA) to the reactor (at 30 °C) and stir at 500 rpm. The temperature profile used was a stepwise decrease from 30 °C to 8 °C over 24 hours.

[0052] When the concentration of Compound I decreased below 2.5 wt%, filter the slurry. Use the mother liquor to rinse the solid reactor. Analyze the mother liquor by HPLC to determine the Compound I content (215 g, 1.8 wt% Compound I, 3.87 g loss of activity). Hold the wet cake on the filter for 30 minutes, then rinse the reactor and the wet cake using heptane wash (101.6 g). Hold the wet cake (88.1 g) on the filter for 30 minutes and then dry it overnight in a 50 °C vacuum oven to obtain a colorless solid. Based on XRD, the solid formed is polymorph B.

[0053]

Table 2

[0054] Wet cake: 88.1 g Dry cake: 87.2 g LOD: 0.05 wt% solvent The dry cake was analyzed by HPLC (97.5 wt%). Isolated active substance: 85.02 g Loaded seed crystal active substance: 15.42 g

[0055] All references, including publications, patent applications, and patents cited herein, are hereby incorporated by reference in their entirety to the same extent as if each reference had been individually and specifically indicated to be incorporated by reference and set forth in full herein.

[0056] In the context of describing the present invention (particularly in the context of the following claims), the use of the terms "a", "an", "the", and "at least one" and similar referents should be construed to include both the singular and the plural unless specifically indicated otherwise herein or clearly contradicted by the context. The use of the term "at least one" preceding a list of one or more items (e.g., "at least one of A and B") should be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B) unless specifically indicated otherwise herein or clearly contradicted by the context. The terms "comprising", "having", "including", and "containing" should be construed as non-limiting terms (i.e., meaning "including but not limited to") unless otherwise specified. The recitation of a range of values herein is merely intended to serve as a convenient method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. The use of any examples or exemplary language provided herein (e.g., "such as") is merely intended to better illustrate the invention and does not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0057] Preferred embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the present invention. Variations of these preferred embodiments will be apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to appropriately utilize such variations, and the inventors intend for the present invention to be practiced in ways other than those specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Further, unless otherwise indicated herein or clearly contradicted by context, all possible combinations of all of the above-described elements in all possible variations thereof are included in the present invention.

Claims

1. The following formula: 【Chemistry 1】 A process for preparing a crystalline compound, wherein the process is A process of distilling a mixture comprising a non-protic organic solvent, a protic organic solvent, compound I, and seed crystal compound I.

2. The following formula: 【Chemistry 2】 A process for preparing a crystalline compound, wherein the process is a. Distilling a mixture, wherein the mixture comprises an aprotic organic solvent and compound I; b. A process comprising crystallizing compound I from step a by preparing a second mixture containing a protic organic solvent, compound I, and seed crystal compound I.

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

4. The process according to claim 3, wherein the amount of dichloromethane in the mixture after step a is less than 1% by weight and greater than 0.01% by weight of residual dichloromethane.

5. The process according to claim 3, wherein the amount of dichloromethane in the mixture after step a is less than 0.5% by weight and greater than 0.005% by weight of residual dichloromethane.

6. The process according to claim 2, wherein a protic organic solvent is added to the mixture in step a.

7. The process according to claim 2, wherein the mixture after step a and before step b has a water content of less than 1000 ppm and more than 50 ppm as analyzed by the Karl Fischer method.

8. The process according to claim 2, wherein the mixture after step a and before step b has a water content of less than 300 ppm and more than 0.1 ppm as analyzed by the Karl Fischer method.

9. The process according to claim 2, wherein the amount of compound I in the mixture after step a and before step b is less than 15% by weight and greater than 7% by weight.

10. The process according to claim 2, wherein the amount of compound I in the mixture after step a and before step b is less than 15% by weight and greater than 10% by weight.

11. The process according to claim 2, wherein the amount of compound I in the mixture after step a and before step b is less than 10% by weight and greater than 7% by weight.

12. The process according to claim 2, wherein the temperature during step a is in the range of approximately 60°C to approximately 10°C.

13. The process according to claim 1, wherein the amount of seed crystal compound I is less than 50% by weight and greater than 15% by weight.

14. The process according to claim 1, wherein the amount of seed crystal compound I is less than 10% by weight and more than 2% by weight.

15. The process according to claim 2, wherein the temperature during step b is in the range of approximately 50°C to approximately 0°C.

16. The following formula: 【Transformation 3】 A crystalline polymorph of the compound.

17. The aforementioned polymorph has at least the following 2θ reflection positions: Table 1 The polymorph according to claim 16, characterized by a powder X-ray diffraction pattern having the following characteristics.

18. The aforementioned polymorph has at least the following 2θ reflection positions: Table 2 The polymorph according to claim 16, characterized by a powder X-ray diffraction pattern having the following characteristics.

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