2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-A]pyridine-6-yl)-3-isopropyl-1H-indole-5-yl)piperidine-1-yl)acetamide and its crystalline form

Abstract

The free base hemihydrate and free base anhydride of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-A]pyridine-6-yl)-3-isopropyl-1H-indole-5-yl)piperidine-1-yl)acetamide, and their crystalline forms are disclosed.

Description

Technology Field

[0001] Cross-reference

[0002] This application claims the benefit of U.S. provisional application serial number 63 / 598,169 filed on November 13, 2023, the full text of which is incorporated herein by reference.

[0003] Field of invention

[0004] The present invention relates to 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-3-isopropyl-1H-indole-5-yl)piperidine-1-yl)acetamide, which is generally a free base hemihydrate, and the crystalline form thereof. Background Technology

[0005] The compound 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)-3-isopropyl-1H-indole-5-yl)piperidine-1-yl)acetamide has the structure of chemical formula (I) and:

[0006]

[0007] Referred herein as “Compound (I)”. Compound (I) is disclosed as Example 15 of WO 2018 / 005586 A1, which was assigned to the assignee. Compound (I) has the generic name afimethoran.

[0008] Compound (I) is an inhibitor of Toll-like receptors 7 and 8 (TLR7 / 8), and clinical trials for the treatment of lupus are currently underway.

[0009] In synthesizing chemical compounds intended for pharmaceutical use, it is necessary to isolate and purify the compound upon completion of the synthesis process and before further processing to provide the compound as a pharmaceutical formulation. The isolation and purification steps, which may be combined or separate consecutive steps, provide the compound as a purified solid while minimizing yield loss during isolation from other components of the reaction mixture and / or during purification to remove impurities from the isolated compound sample.

[0010] In preparing a pharmaceutical composition, a form of the active ingredient is required in which desirable characteristics, such as dissolution rate, solubility, bioavailability, and / or storage stability, are balanced. For example, the form of the active ingredient is required to possess sufficient stability, solubility, and bioavailability to prevent the form from converting to another form having an undesirable solubility and / or bioavailability profile during the production, preparation, and / or storage of the pharmaceutical composition. Additionally, a form that is stable under ambient temperature and humidity conditions and has low hygroscopicity is required.

[0011] It is desirable to isolate the purified compound in a physically and chemically stable solid form under various storage conditions, such as different temperature and humidity conditions.

[0012] The applicant has discovered a form of compound (I) that is physically and chemically stable under various storage conditions.

[0013] Furthermore, the applicant has discovered a crystalline form of compound (I) that provides a solid form of compound (I) that is physically and chemically stable under various storage conditions.

[0014] The present invention also relates to other important aspects.

[0015] The present invention provides compound (I) as a free base. The present invention also provides compound (I) as a free base hemihydrate of crystalline form B and compound (I) as a free base anhydride of crystalline forms N, O, and P. Brief explanation of the drawing

[0016] Figure 1 shows the observed powder X-ray diffraction pattern of the free base hemihydrate crystalline form B of compound (I) (CuKα, λ = 1.54178 Å at T = 25°C). Figure 2 shows a differential scanning calorimetry (DSC) thermogram of the crystalline form B of the free base hemihydrate having an endotherm peak at approximately 275°C. Figure 3 shows the thermogravimetric analysis (TGA) thermogram of the free base hemihydrate crystalline form B. Figure 4 shows the water-adsorption isotherm for the crystalline form B of the free base hemihydrate at a temperature of 25°C. Figure 5 shows the observed powder X-ray diffraction pattern of the free base anhydride crystalline form N of compound (I) (CuKα, λ = 1.54178 Å at T = 25°C). Figure 6 shows the observed powder X-ray diffraction pattern of the free base anhydride crystalline form O of compound (I) (CuKα, λ = 1.54178 Å at T = 25°C). Figure 7 shows the observed powder X-ray diffraction pattern of the free base anhydride crystalline form P of compound (I) (CuKα, λ = 1.54178 Å at T = 25°C). Specific details for implementing the invention

[0017] The features and advantages of the present invention can be more easily understood by those skilled in the art by reading the following detailed description. For clarity, it should be recognized that specific features of the present invention described above and below in the context of separate embodiments may also be combined to form a single embodiment. Conversely, for brevity, various features of the present invention described in the context of a single embodiment may also be combined to form sub-combinations thereof.

[0018] The designations used herein to determine the characteristics of a specific form, e.g., "Form B," are merely identifiers to be interpreted in accordance with the characteristic determination information presented herein and are not limited to excluding any other substances having similar or identical physical and chemical properties. The designations of specific forms should also be understood as simple identifiers to be interpreted in accordance with the characteristic determination information presented herein.

[0019] The definitions set forth herein shall take precedence over any definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0020] Where the word “about” precedes any number indicating the amount of a component, weight percentage, temperature, etc., it should be understood merely as an approximation, and even if a variation slightly higher or lower than the stated number is used, substantially the same result as the stated number can be achieved. Therefore, unless otherwise indicated, numeric parameters preceded by the word “about” are approximations that may vary depending on the desired characteristics to be obtained. At the very least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numeric parameter should be interpreted by taking into account at least the number of recorded significant figures and applying general rounding techniques.

[0021] All measurements are subject to experimental error and are within the scope of the present invention.

[0022] As used herein, "polymorph" refers to a crystalline form having the same chemical structure but differing in the spatial arrangement of molecules and / or ions that form the crystal.

[0023] As used herein, "amorphous" refers to a solid form of molecules and / or ions that is not crystalline. Amorphous solids do not exhibit a distinct X-ray diffraction pattern with sharp maxima.

[0024] As used herein, “substantially pure” means, when used in relation to the crystalline form, a compound having a purity of greater than 90 weight%, comprising more than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 weight% of compound (I) based on the weight of the compound, and also comprising about 100 weight%. The remainder of the material comprises other form(s) of the compound and / or reaction impurities and / or processing impurities arising from the manufacturing process. For example, the crystalline form of compound (I) may be considered substantially pure if its purity exceeds 90 weight% as measured by means known and generally accepted in the art, wherein the remainder of less than 10 weight% of the material comprises amorphous and / or other form(s) of compound (I) and / or reaction impurities and / or processing impurities.

[0025] A powder x-ray diffraction (PXRD) pattern “containing” a plurality of peaks selected from the specified group of peaks as used herein is intended to include a PXRD pattern having additional peaks not included in the specified group of peaks. For example, a PXRD pattern containing four or more, preferably five or more, 2θ values ​​selected from A, B, C, D, E, F, G, and H is intended to include (a) four or more, preferably five or more, 2θ values ​​selected from A, B, C, D, E, F, G, and H, and (b) a PXRD pattern having zero or more peaks that are not one of peaks A, B, C, D, E, F, G, and H.

[0026] The presence of reaction impurities and / or processing impurities can be determined by analytical techniques known in the field, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, and / or infrared spectroscopy.

[0027] As used herein, the unit cell parameter "molecules per unit cell" refers to the number of molecules of compound (I) within the unit cell.

[0028] A first aspect of the present invention provides a compound (I) as a free base hemihydrate solid form. This solid form has a stoichiometry of 0.5 molecules of water for each molecule of compound (I).

[0029] In one embodiment, the compound (I), which is in the form of a free base hemihydrate, is provided as a crystalline material.

[0030] In one embodiment, the compound (I), which is in the form of a free base hemihydrate, is provided as a clean crystalline material.

[0031] Form B of compound (I) which is a free base hemihydrate

[0032] In one embodiment, a compound (I) that is a free base hemihydrate is provided as a crystalline material comprising form B. The crystalline form B of the free base hemihydrate compound (I) is a crystalline hemihydrate form. The crystalline form B is also referred to herein as “form B”.

[0033] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is characterized by unit cell parameters approximately the same as the following, and

[0034] a = 39.16 ± 0.10 Å

[0035] b = 7.50 ± 0.10 Å

[0036] c = 16.77 ± 0.10 Å

[0037] α = 90.0 ± 1.0°

[0038] β = 93.2 ± 1.0°

[0039] γ = 90.0 ± 1.0°

[0040] Space group: C 2 / c

[0041] Molecules per unit cell (Z): 8

[0042] Unit cell volume = 4920 ± 20 Å 3

[0043] Calculated density 1.225 g / cm³ 3

[0044] Here, the unit cell parameters of form B of compound (I), which is a free base hemihydrate, are measured at a temperature of about 296 K.

[0045]

[0046] ​In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is characterized by a powder x-ray diffraction pattern containing four or more 2θ values ​​(CuKα λ=1.5418 Å) selected from 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2 and 21.3 ± 0.2, wherein the PXRD pattern of form B is measured at a temperature of about 25°C.

[0047] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is characterized by a powder x-ray diffraction pattern containing five or more 2θ values ​​(CuKα λ=1.5418 Å) selected from 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2 and 21.3 ± 0.2, wherein the PXRD pattern of form B is measured at a temperature of about 25°C.

[0048] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is characterized by a powder x-ray diffraction pattern containing at least six 2θ values ​​(CuKα λ=1.5418 Å) selected from 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2 and 21.3 ± 0.2, wherein the PXRD pattern of form B is measured at a temperature of about 25°C.

[0049] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is characterized by a powder X-ray diffraction pattern observed substantially as shown in FIG. 1.

[0050] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is characterized by a differential scanning calorimetry (DSC) thermogram as substantially as shown in FIG. 2.

[0051] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is characterized by an endothermic peak in the range of 273°C to 277°C.

[0052] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is characterized by (i) a powder x-ray diffraction pattern including 2θ values ​​(CuKα λ=1.5418 Å) at 16.1±0.2 and 21.3±0.2 measured at a temperature of about 25°C and (ii) a differential scanning calorimetry (DSC) thermogram substantially consistent with that shown in FIG. 2.

[0053] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is characterized by (i) a powder x-ray diffraction pattern including four or more 2θ values ​​(CuKα λ=1.5418 Å) selected from 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2 and 21.3 ± 0.2, where the PXRD pattern of form B is measured at a temperature of about 25°C, and (ii) a melting point in the range of 273°C to 275°C.

[0054] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, exhibits a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG. 3.

[0055] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is characterized by a thermogravimetric analysis (TGA) thermogram having a weight loss of about 2.3 to 2.7 weight percent based on the weight of the sample of form B when heated to a temperature of about 220°C.

[0056] In one embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, substantially exhibits a moisture-adsorption isotherm as shown in FIG. 4. In FIG. 4, for the crystalline form B of compound (I), which is a free base hemihydrate, a change of approximately 0.3 weight% was observed at relative humidity of 5 to 95%.

[0057] In a more specific embodiment, the crystalline form B of compound (I), which is a free base hemihydrate, is substantially pure.

[0058] In another embodiment, the crystalline form of compound (I) which is a free base hemihydrate essentially consists of form B. The crystalline form of this embodiment may comprise at least about 90 weight%, preferably at least about 95 weight%, and more preferably at least about 99 weight% of form B of compound (I) which is a free base hemihydrate, based on the weight of the crystalline form.

[0059] One embodiment provides a composition comprising a compound (I) which is a free base hemihydrate, wherein at least 95 weight%, preferably at least 97 weight%, and more preferably at least 99 weight% of the free base hemihydrate, said compound (I) exists in a crystalline form B.

[0060] Form N of compound (I) which is a free base anhydride

[0061] In one embodiment, the free base compound (I) is provided as a crystalline material comprising form N. The crystalline form N of the free base compound (I) is an anhydride crystalline form. The crystalline form N is also referred to herein as “form N”.

[0062]

[0063] In one embodiment, the crystalline form N of compound (I), which is a free base anhydride, is characterized by a powder x-ray diffraction pattern containing four or more 2θ values ​​(CuKα λ=1.5418 Å) selected from 8.7 ± 0.2, 10.0 ± 0.2, 10.6 ± 0.2, 11.2 ± 0.2, 13.2 ± 0.2, 14.0 ± 0.2, 14.6 ± 0.2, 15.9 ± 0.2, 17.1 ± 0.2, 19.2 ± 0.2, 20.0 ± 0.2, 23.1 ± 0.2 and 24.4 ± 0.2, wherein the PXRD pattern of form N is measured at a temperature of about 25°C.

[0064] In one embodiment, the crystalline form N of compound (I), which is a free base anhydride, is characterized by a powder x-ray diffraction pattern containing five or more 2θ values ​​(CuKα λ=1.5418 Å) selected from 8.7 ± 0.2, 10.0 ± 0.2, 10.6 ± 0.2, 11.2 ± 0.2, 13.2 ± 0.2, 14.0 ± 0.2, 14.6 ± 0.2, 15.9 ± 0.2, 17.1 ± 0.2, 19.2 ± 0.2, 20.0 ± 0.2, 23.1 ± 0.2 and 24.4 ± 0.2, wherein the PXRD pattern of form N is measured at a temperature of about 25°C.

[0065] In one embodiment, the crystalline form N of compound (I), which is a free base anhydride, is characterized by a powder x-ray diffraction pattern containing at least six 2θ values ​​(CuKα λ=1.5418 Å) selected from 8.7 ± 0.2, 10.0 ± 0.2, 10.6 ± 0.2, 11.2 ± 0.2, 13.2 ± 0.2, 14.0 ± 0.2, 14.6 ± 0.2, 15.9 ± 0.2, 17.1 ± 0.2, 19.2 ± 0.2, 20.0 ± 0.2, 23.1 ± 0.2 and 24.4 ± 0.2, wherein the PXRD pattern of form N is measured at a temperature of about 25°C.

[0066] In one embodiment, the crystalline form N of compound (I), which is a free base anhydride, is characterized by a powder X-ray diffraction pattern observed substantially as shown in FIG. 5.

[0067] In one embodiment, the crystalline form N of compound (I), which is a free base anhydride, is substantially pure.

[0068] In another embodiment, the crystalline form of the free base anhydride compound (I) essentially consists of form N. The crystalline form of this embodiment may comprise at least about 90 weight%, preferably at least about 95 weight%, and more preferably at least about 99 weight% of the free base anhydride compound (I) based on the weight of the crystalline form.

[0069] One embodiment provides a composition comprising a compound (I) which is a free base anhydride, wherein at least 95 weight%, preferably at least 97 weight%, and more preferably at least 99 weight% of the free base anhydride compound (I) exists in a crystalline form N.

[0070] Form O of compound (I) which is a free base anhydride

[0071] In one embodiment, the free base compound (I) is provided as a crystalline material comprising form O. The crystalline form O of the free base compound (I) is an anhydride crystalline form. The crystalline form O is also referred to herein as "form O".

[0072]

[0073] In one embodiment, the crystalline form O of the free base anhydride compound (I) is characterized by a powder x-ray diffraction pattern containing four or more 2θ values ​​(CuKα λ=1.5418 Å) selected from 7.0 ± 0.2, 9.3 ± 0.2, 10.4 ± 0.2, 13.3 ± 0.2, 14.1 ± 0.2, 15.0 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.0 ± 0.2, 18.7 ± 0.2, 21.0 ± 0.2, 21.7 ± 0.2 and 22.2 ± 0.2, where the PXRD pattern of form O is measured at a temperature of about 25°C.

[0074] In one embodiment, the crystalline form O of the free base anhydride compound (I) is characterized by a powder x-ray diffraction pattern containing five or more 2θ values ​​(CuKα λ=1.5418 Å) selected from 7.0 ± 0.2, 9.3 ± 0.2, 10.4 ± 0.2, 13.3 ± 0.2, 14.1 ± 0.2, 15.0 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.0 ± 0.2, 18.7 ± 0.2, 21.0 ± 0.2, 21.7 ± 0.2 and 22.2 ± 0.2, where the PXRD pattern of form O is measured at a temperature of about 25°C.

[0075] In one embodiment, the crystalline form O of the free base anhydride compound (I) is characterized by a powder x-ray diffraction pattern containing at least six 2θ values ​​(CuKα λ=1.5418 Å) selected from 7.0 ± 0.2, 9.3 ± 0.2, 10.4 ± 0.2, 13.3 ± 0.2, 14.1 ± 0.2, 15.0 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.0 ± 0.2, 18.7 ± 0.2, 21.0 ± 0.2, 21.7 ± 0.2 and 22.2 ± 0.2, where the PXRD pattern of form O is measured at a temperature of about 25°C.

[0076] In one embodiment, the crystalline form O of the free base anhydride compound (I) is characterized by a powder X-ray diffraction pattern observed substantially as shown in FIG. 6.

[0077] In one embodiment, the crystalline form O of compound (I), which is a free base anhydride, is substantially pure.

[0078] In another embodiment, the crystalline form of the free base anhydride compound (I) essentially consists of form O. The crystalline form of this embodiment may comprise at least about 90 weight%, preferably at least about 95 weight%, and more preferably at least about 99 weight% of the free base anhydride compound (I) based on the weight of the crystalline form.

[0079] One embodiment provides a composition comprising a compound (I) which is a free base anhydride, wherein at least 95 weight%, preferably at least 97 weight%, and more preferably at least 99 weight% of the free base anhydride compound (I) exists in a crystalline form O.

[0080] Form P of compound (I) which is a free base anhydride

[0081] In one embodiment, the free base compound (I) is provided as a crystalline material comprising form P. The crystalline form P of the free base compound (I) is an anhydride crystalline form. The crystalline form P is also referred to herein as “form P”.

[0082]

[0083] In one embodiment, the crystalline form P of compound (I), which is a free base anhydride, is characterized by a powder x-ray diffraction pattern containing four or more 2θ values ​​(CuKα λ=1.5418 Å) selected from 6.0 ± 0.2, 8.1 ± 0.2, 8.8 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 12.1 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 21.5 ± 0.2, 22.2 ± 0.2 and 23.8 ± 0.2, wherein the PXRD pattern of form P is measured at a temperature of about 25°C.

[0084] In one embodiment, the crystalline form P of compound (I), which is a free base anhydride, is characterized by a powder x-ray diffraction pattern containing five or more 2θ values ​​(CuKα λ=1.5418 Å) selected from 6.0 ± 0.2, 8.1 ± 0.2, 8.8 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 12.1 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 21.5 ± 0.2, 22.2 ± 0.2 and 23.8 ± 0.2, wherein the PXRD pattern of the crystalline form P is measured at a temperature of about 25°C.

[0085] In one embodiment, the crystalline form P of compound (I), which is a free base anhydride, is characterized by a powder x-ray diffraction pattern containing at least six 2θ values ​​(CuKα λ=1.5418 Å) selected from 6.0 ± 0.2, 8.1 ± 0.2, 8.8 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 12.1 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 21.5 ± 0.2, 22.2 ± 0.2 and 23.8 ± 0.2, wherein the PXRD pattern of the crystalline form P is measured at a temperature of about 25°C.

[0086] In one embodiment, the crystalline form P of compound (I), which is a free base anhydride, is characterized by a powder X-ray diffraction pattern observed substantially as shown in FIG. 6.

[0087] In one embodiment, the crystalline form P of compound (I), which is a free base anhydride, is substantially pure.

[0088] In another embodiment, the crystalline form P of the free base anhydride compound (I) essentially consists of form P. The crystalline form P of this embodiment may comprise at least about 90 weight%, preferably at least about 95 weight%, and more preferably at least about 99 weight% of the free base anhydride compound (I) based on the weight of the crystalline form.

[0089] One embodiment provides a composition comprising a compound (I) which is a free base anhydride, wherein at least 95 weight%, preferably at least 97 weight%, and more preferably at least 99 weight% of the free base anhydride compound (I) exists in a crystalline form P.

[0090] Crystalline forms can be produced by various methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid-state transition from another phase, crystallization from a supercritical fluid, and jet injection. Techniques for crystallizing or recrystallizing crystalline forms from a solvent mixture include, for example, evaporation of the solvent, cooling of the solvent mixture, crystal seeding of molecules and / or salts into a supersaturated solvent mixture, freeze-drying of the solvent mixture, and addition of an antisolvent (countersolvent) to the solvent mixture. High-throughput crystallization techniques may be used to produce crystalline forms containing polymorphs.

[0091] The crystals of drugs containing polymorphs, manufacturing methods, and characteristics of drug crystals are based on the literature Solid-State Chemistry of Drugs , SR Byrn, RR Pfeiffer and JG Stowell, 2 nd It is discussed in Edition, SSCI, West Lafayette, Indiana (1999).

[0092] In the case of solvent-based crystallization techniques, the selection of a solvent or solvents typically depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. A combination of solvents may be used; for example, after a compound is dissolved in a first solvent to provide a solution, an antisolvent may be added to reduce the solubility of the compound in the solution and form crystals. An antisolvent is a solvent in which the compound has low solubility.

[0093] One method of preparing crystals is to suspend the compound in a suitable solvent and / or stir it to provide a slurry, which may be heated to promote dissolution. As used herein, the term "slurry" refers to a saturated solution of the compound, which may also contain additional amounts of the compound to provide a heterogeneous mixture of the compound and the solvent at a given temperature.

[0094] Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of specific polymorphs or to control the grain size distribution of crystalline products. Therefore, the calculation of the required amount of seed is, for example, in the literature "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, As described in 1971, 26, 369-377, it depends on the size of the available seed and the desired size of the average product particle. Generally, small-sized seeds are required to effectively control the growth of crystals within a batch. Small-sized seeds can be produced by sieving, milling, or pulverizing large crystals, or by microcrystallizing the solution. Care must be taken to ensure that milling or pulverizing the crystals does not cause any change in crystallinity from the desired crystal form (i.e., change into an amorphous or another polymorph).

[0095] The cooled crystallization mixture is filtered under vacuum, and the isolated solid is washed with a suitable solvent, such as a low-temperature recrystallization solvent, and dried under a nitrogen purge to provide a desired crystalline form. The isolated solid can be analyzed by suitable spectroscopic or analytical techniques, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, or powder X-ray diffraction, to ensure that a desired crystalline form of the product is formed. The resulting crystalline form is typically produced with an isolation yield of more than about 70 wt%, preferably more than 90 wt%, based on the weight of the compound originally used in the crystallization process. If necessary, the product may be co-milled or passed through a mesh screen to remove delumps of the product.

[0096] The crystalline form can be prepared directly from the reaction medium of the final process for preparing compound (I). This can be achieved, for example, by using a solvent or a mixture of solvents in which compound (I) can be crystallized at the final process step. Alternatively, the crystalline form can be obtained by distillation or solvent addition techniques. Solvents suitable for this purpose include the aforementioned nonpolar and polar solvents, including, for example, protic polar solvents such as alcohols and aprotic polar solvents such as ketones.

[0097] The presence of more than one polymorph within a sample can be determined by techniques such as powder X-ray diffraction (PXRD) or solid-state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks when comparing experimentally measured PXRD patterns with simulated PXRD patterns may indicate more than one polymorph within the sample. Simulated PXRD can be calculated from single-crystal X-ray data. Smith, DK, " A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns,"See Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0098] The form of compound (I) can be characterized using various techniques, the operation of which is known to those skilled in the art. The form can be characterized and distinguished using single-crystal X-ray diffraction based on unit cell measurements of a single crystal at a fixed analysis temperature. A detailed description of the unit cell is provided in Chapter 3 of the literature Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), which is incorporated herein by reference. Alternatively, another means of characterizing the crystalline structure is by powder X-ray diffraction analysis, where the diffraction profile is compared with a simulated profile representing a pure powder material, both profiles are measured (run) at the same analysis temperature, and the measurements for the target form are characterized by a series of 2θ values ​​(typically four or more).

[0099] Other means of determining the characteristics of a form may include, for example, solid-state nuclear magnetic resonance (ssNMR), differential scanning calorimetry, thermal analysis, and vibrational spectroscopy. These parameters may also be used in combination to determine the characteristics of the target form.

[0100] usefulness

[0101] The free base hemihydrate of compound (I) can be used to isolate compound (I) from other components at the completion of the synthesis process and / or to purify compound (I) by one or a series of crystallization steps.

[0102] Crystalline form B of the free base hemihydrate of compound (I) may be used to isolate compound (I) from other components and / or to purify compound (I) by one or a series of crystallization steps upon completion of the synthesis process. The isolation and purification steps may be combined or carried out as separate process steps.

[0103] The free base hemihydrate of compound (I) can be formulated into a pharmaceutical composition for oral administration.

[0104] The crystalline form B of the free base hemihydrate of compound (I) can be formulated into a pharmaceutical composition for oral administration.

[0105] The free base hemihydrate of compound (I) and its form B are useful as sources of purified compound (I) in the preparation of salts of compound (I).

[0106] Examples

[0107] The present invention will now be described more specifically through the following working example(s), which are preferred embodiments of the invention. All temperatures are in degrees Celsius (°C) unless otherwise indicated. It should be understood that these examples are illustrative and not limiting, and that other embodiments may exist that fall within the spirit and scope of the invention as defined by the claims appended herein.

[0108] The synthesis of compound (I) is disclosed as Example 15 in WO 2018 / 005586.

[0109] Example 1: Preparation of compound (I), which is a free base and is a hemihydrate crystalline form B

[0110] Compound (I) (100 mg) was dissolved in 1 mL of DMF at 41°C. The sample was cooled to room temperature, and 0.2 mL of water was added to the form B slurry. The slurry was stirred at room temperature for 2 days. The solid of the slurry was a free base and a hemihydrate crystalline form B.

[0111] Example 2: Preparation of compound (I) which is a free base and is a hemihydrate crystalline form B

[0112] Compound (I) (1.15 g) was dissolved in 95:5 THF:water (volume:volume) at room temperature. Next, 1 mL of the solution was transferred to vials. The vials were placed in a vacuum concentrator to evaporate the solvent from each vial.

[0113] 1 mL of 90:10 DCM:MeOH (volume:volume) was added to one vial, and the slurry was stirred for 13 days. The solid of the slurry was a free base and a hemihydrate crystalline form B.

[0114] 1 mL of 1 mL MIBK was added to another vial, and the slurry was stirred for 13 days. The solid of the slurry was a free base and a hemihydrate crystalline form B.

[0115] Example 3: Preparation of compound (I) which is a free base and an anhydrous crystalline form N

[0116] Compound (I) (31 g) was added to 420 mL of EtOH in a volumetric flask. The solution was heated until all solids were dissolved, then allowed to cool back to room temperature. The solids were isolated by vacuum filtration and characterized by PXRD.

[0117] Example 4: Preparation of compound (I) which is a free base and an anhydrous crystalline form O

[0118] A sample of compound (I), which is a free base and of form N (Example 3), was heated to 200°C in a pan using a differential scanning calorimeter. The solid was isolated from the pan and analyzed via PXRD.

[0119] Example 5: Preparation of compound (I) which is a free base and an anhydride crystalline form P

[0120] A sample of compound (I), a free base of form N (Example 3), was added to 95:5 v:v THF / water at a concentration of 5 mg / mL and stirred for 1 day in a vial containing a stirring bar. Subsequently, the slurry was dried using a speed vacuum. Next, 1 mL of MeOH was added to the vial to return the concentration to 5 mg / mL. The slurry was stirred with a stirring bar at room temperature for 14 days. The solid was isolated using vacuum filtration and dried for 5 days in a vacuum oven set to 50°C. The solid was analyzed using PXRD.

[0121] The solid-state stability of compound (I), which is a free base hemihydrate and form B, was studied by storing samples as follows.

[0122] (i) 5℃ inside a sealed container

[0123] (ii) 25°C / 60% relative humidity (RH) inside an open container

[0124] (iii) 40°C / 75% relative humidity in an open container, and

[0125] (iv) 50℃ in a sealed container

[0126] Physical stability, characterized by DSC, TGA, and PXRD, and chemical stability, characterized by HPLC, were measured at weeks 2 and 4.

[0127]

[0128] In Table 5, physical stability analyses (PXRD, DSC, and TGA) indicated that form B was physically stable for at least 4 weeks under all harsh conditions.

[0129] In Table 2, chemical stability analysis by HPLC did not show significant degradation of form B of compound (I), which is a free base hemihydrate, for at least 4 weeks under all harsh conditions.

[0130] Figure 4 shows the moisture-adsorption isotherm for compound (I), which is the crystalline form B of the free base hemihydrate, at a temperature of 25°C. In these measurements, the weight change for compound (I), which is the crystalline form B of the free base hemihydrate, was approximately 0.3 wt% change at 5 to 95% relative humidity, which indicates that the crystalline form B of compound (I), which is the free base hemihydrate, is non-hygroscopic.

[0131] Single crystal data

[0132] Single crystal X-ray data of type B were collected using a Bruker X8-Proteum diffractometer equipped with an APEX II CCD detector and a MICROSTAR microfocus rotating anode X-ray generator of monochromatic Cu Kα radiation (λ = 1.54178 Å). The single crystal was at room temperature (approximately 25°C) during data acquisition.

[0133] Indexing and processing of the measured intensity data were performed using the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA).

[0134] The final unit cell parameters were determined using the entire dataset. The structure was solved using the direct method and refined using the total matrix least squares method with the SHELXTL software package (GM Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA). Structure refinement is It involved the minimization of a function defined as, where w is an appropriate weighting factor based on the error of the observed intensity, and F o is a structural factor based on measured reflections, and F c is a structure factor based on calculated reflections. The degree of agreement between the refined crystal structure model and experimental X-ray diffraction data is the residual factor. and Evaluation is performed using [the method]. Difference Fourier maps were examined at every stage of refinement. All non-hydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms were introduced using idealized geometric structures with isotropic temperature factors and included in the calculation of structural factors using fixed parameters.

[0135] Powder X-ray Diffraction (PXRD)

[0136] PXRD data for Type B were acquired using a Bruker D8 Discover DaVinci equipped with an XYZ stage. An IμS X-ray generator was operated at 50 kV and 1 mA using a Cu target (CuKα radiation). The incident beam optical system included a Montel mirror with a 0.3 mm collimator. Photons were counted using an Eiger2 R 500K detector in 2D, 2θ optimized mode. The sample-to-detector distance was set to 140 mm. Samples were measured for 1000 seconds in transmission, snapshot mode with the incident beam at 0° and the detector at 17.5°.

[0137] PXRD data for N, O, and P were obtained using a Bruker C2 GADDS. The radiation was Cu Kα (40 KV, 40 mA). The sample-detector distance was 15 cm. The sample was placed in a sealed glass capillary with a diameter of 1 mm or less. The capillary was rotated during data acquisition. Data were collected at approximately 2 ≤ 2θ ≤ 32° with a sample exposure time of at least 1000 seconds. The generated two-dimensional diffraction arc was integrated to produce a traditional one-dimensional PXRD pattern with a step size of 0.05 2θ in the range of approximately 2 to 32 2θ.

[0138] Differential Scanning Calorimetry (DSC)

[0139] Differential Scanning Calorimetry (DSC) experiments were performed using a TA Instruments Discovery DSC 2500. Samples (approx. 1 to 5 mg) were weighed in Tzero aluminum pans. The weight of the samples was accurately recorded to the nearest 0.01 mg before transferring them to the DSC. The instrument was purged with nitrogen gas at 50 mL / min. Data were collected at room temperature to 350°C at a heating rate of 10°C / min. DSC plots were generated with the endothermic peak pointing downwards.

[0140] Thermogravimetric Analysis (TGA)

[0141] Thermogravimetric analysis (TGA) experiments were performed using a TA Instruments Discovery TGA 5500. Samples (approx. 1 to 10 mg) were pre-washed and placed in a tarred platinum pan. The weight of the samples was accurately measured and recorded to the nearest 0.001 mg by the instrument. The furnace was purged with nitrogen gas at 25 mL / min. Data were collected at room temperature to 400°C at a heating rate of 10°C / min.

[0142] Moisture adsorption isotherm

[0143] Moisture adsorption isotherm data were collected using a VTI SGA-100 symmetric vapor analyzer with approximately 10 mg of sample. The sample was tested at 25°C with decreasing and increasing RH increments, starting from 95% relative humidity (RH) to 5% RH and then back to 95% RH. Equilibrium at each RH was achieved when a change rate of 0.0010 wt% / min was reached over 60 minutes or after a maximum of 120 minutes.

Claims

Claim 1 Free base hemihydrate of the following compound (I): . Claim 2 In claim 1, the free base hemihydrate of compound (I) is crystalline, the free base hemihydrate of compound (I). Claim 3 In paragraph 2, the free base hemihydrate of compound (I) is a pure free base hemihydrate of compound (I). Claim 4 In paragraph 2, the free base hemihydrate of compound (I) exists in crystalline form B. Claim 5 A free base hemihydrate of compound (I), wherein the crystalline form B is characterized by a powder x-ray diffraction pattern (PXRD) containing at least four 2θ values ​​(CuKα λ=1.5418 Å) selected from 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2 and 21.3 ± 0.2, wherein the PXRD pattern of form B is measured at a temperature of about 25°C. Claim 6 A free base hemihydrate of compound (I), wherein the crystalline form B is characterized by a powder x-ray diffraction pattern (PXRD) containing at least five 2θ values ​​(CuKα λ=1.5418 Å) selected from 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2 and 21.3 ± 0.2, wherein the PXRD pattern of form B is measured at a temperature of about 25°C. Claim 7 A free base hemihydrate of compound (I), wherein the crystalline form B is characterized by a powder x-ray diffraction pattern (PXRD) containing at least six 2θ values ​​(CuKα λ=1.5418 Å) selected from 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2 and 21.3 ± 0.2, wherein the PXRD pattern of form B is measured at a temperature of about 25°C. Claim 8 In claim 4, the crystalline form B is a free base hemihydrate of compound (I) characterized by (i) a powder X-ray diffraction pattern including 2θ values ​​(CuKα λ=1.5418 Å) at 16.1±0.2 and 21.3±0.2 measured at a temperature of about 25°C; and (ii) a melting point in the range of 273°C to 277°C. Claim 9 In claim 4, the crystalline form B is a free base hemihydrate of compound (I) characterized by (i) a powder X-ray diffraction pattern including 2θ values ​​(CuKα λ=1.5418 Å) at 16.1±0.2 and 21.3±0.2 measured at a temperature of about 25°C; and (ii) a differential scanning calorimetry (DSC) thermogram substantially consistent with that shown in FIG.

2. Claim 10 In claim 4, the crystalline form B comprises (i) a powder X-ray diffraction pattern including 2θ values ​​(CuKα λ=1.5418 Å) at 16.1±0.2 and 21.3±0.2 measured at a temperature of about 25°C; and (ii) a free base hemihydrate of compound (I) characterized by a weight loss of 0.2 to 0.4 wt% when heated from 25°C to 220°C. Claim 11 In paragraph 4, the free base hemihydrate of compound (I) which is essentially composed of crystalline form B. Claim 12 In paragraph 4, the above form B is a free base hemihydrate of compound (I) which is a substantially pure form. Claim 13 A composition comprising the free base hemihydrate of the compound (I) according to claim 1. Claim 14 A composition according to claim 13, wherein at least 95 weight percent of the free base hemihydrate of the compound (I) exists in the crystalline form B. Claim 15 Crystalline free base anhydride of the following compound (I): . Claim 16 In claim 15, the crystalline free base anhydride of compound (I) exists as a crystalline form N characterized by a powder X-ray diffraction pattern comprising at least four 2θ values ​​(CuKα λ=1.5418 Å) selected from 8.7 ± 0.2, 10.0 ± 0.2, 10.6 ± 0.2, 11.2 ± 0.2, 13.2 ± 0.2, 14.0 ± 0.2, 14.6 ± 0.2, 15.9 ± 0.2, 17.1 ± 0.2, 19.2 ± 0.2, 20.0 ± 0.2, 23.1 ± 0.2, and 24.4 ± 0.2, wherein the PXRD pattern of said crystalline form N is measured at a temperature of about 25°C, the crystalline free base of compound (I). Anhydrous. Claim 17 In claim 15, the crystalline free base anhydride of compound (I) is a crystalline form O characterized by a powder X-ray diffraction pattern comprising at least four 2θ values ​​(CuKα λ=1.5418 Å) selected from 7.0 ± 0.2, 9.3 ± 0.2, 10.4 ± 0.2, 13.3 ± 0.2, 14.1 ± 0.2, 15.0 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.0 ± 0.2, 18.7 ± 0.2, 21.0 ± 0.2, 21.7 ± 0.2 and 22.2 ± 0.2, wherein the PXRD pattern of the crystalline form O is measured at a temperature of about 25°C. Claim 18 In claim 15, the crystalline free base anhydride of compound (I) is a crystalline form P characterized by a powder X-ray diffraction pattern comprising at least four 2θ values ​​(CuKα λ=1.5418 Å) selected from 6.0 ± 0.2, 8.1 ± 0.2, 8.8 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 12.1 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 21.5 ± 0.2, 22.2 ± 0.2 and 23.8 ± 0.2, wherein the PXRD pattern of said crystalline form P is measured at a temperature of about 25°C.

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