Crystalline RET inhibitors

Abstract

Provided herein are a crystalline form of selpatinib useful for treating and preventing diseases treatable with RET kinase inhibitors, including RET-related diseases and disorders, and methods for preparing the crystalline form.

Description

[0001] background

[0002] Serpatinib (LOXO-292 or RETEVMO TM ) is a RET inhibitor approved in the United States for the treatment of patients with metastatic RET fusion-positive NSCLC, RET-mutant medullary thyroid cancer, and RET fusion-positive thyroid cancer. Serpatinib or 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile has the following chemical structure:

[0003] (Formula I).

[0004] While U.S. Patent No. 10,584,124 describes several crystalline forms of serpatinib, including a crystalline form referred to as "Form A," this document discloses a new, more thermodynamically stable crystalline form and methods for preparing the crystalline form. This new crystalline form can be incorporated into formulations such as tablets, capsules, and suspensions to benefit patients.

[0005] Overview

[0006] The present disclosure relates to a new crystalline form of selpatinib and methods for preparing this thermodynamically stable polymorph, which is referred to throughout as "Form B." In general, the present disclosure provides methods for its preparation, isolation, and characterization.

[0007] As described in more detail below, the compound of Formula I (serpatinib) is available as polymorphic forms (Form A and Form B), and surprisingly, certain processes and methods are effective in providing serpatinib in its most thermodynamically stable polymorph, Form B. As described below and demonstrated by exemplary working examples, processes and methods for generating and preparing specific polymorphic forms of serpatinib may comprise converting (i.e., reacting, contacting, and / or treating) a compound of Formula I provided as one or more polymorphic forms under crystallization conditions effective to generate Form B or to convert other polymorphs (i.e., Form A) to Form B. In other aspects, processes and methods for generating serpatinib Form B may comprise a synthetic route comprising reacting one or more intermediate or precursor compounds under conditions effective to generate serpatinib Form B (i.e., a direct synthetic route).

[0008] Form B is characterized by at least one of the following: (a) an x-ray powder diffraction (XRPD) pattern comprising a peak at 21.1° and one or more peaks at 17.1°, 17.7°, and 19.8° ± 0.2° 2θ as measured using an x-ray wavelength of 1.5418 Å, or (b) an XRPD pattern comprising peaks at 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (each ± ​​0.2 ppm) referenced to an upfield resonance (δ = 29.5 ppm) of adamantane. 13 C solid-state NMR spectrum.

[0009] Also provided are methods of using Form B and pharmaceutical compositions thereof to treat cancer, such as cancers with aberrant RET expression (e.g., RET-associated cancers, such as medullary thyroid cancer or RET fusion lung cancer). The methods comprise administering a therapeutically effective amount of Form B to a patient in need thereof.

[0010] Also provided herein is Form B for use in therapy. Further provided herein is Form B for use in treating cancer, particularly for treating cancer with aberrant RET expression (eg, RET-associated cancer, such as medullary thyroid cancer or RET fusion lung cancer).

[0011] Also provided is the use of Form B in the preparation of a medicament for treating cancer, particularly for treating cancer with aberrant RET expression (eg, RET-associated cancer, such as medullary thyroid carcinoma or RET fusion lung cancer).

[0012] Also disclosed are methods of converting serpatinib Form A to serpatinib Form B.

[0013] Also described herein is a method for converting serpatinib Form A to serpatinib Form B, comprising combining serpatinib Form A with a C1-C5 alcohol to form a slurry and isolating serpatinib Form B from the slurry.

[0014] Also described is a method of converting serpatinib Form A to serpatinib Form B, the method comprising:

[0015] a. dissolving serpatinib Form A in a solvent comprising DMSO to form a solution;

[0016] b. adding water to the solution and thereby forming a slurry;

[0017] c. Isolation of Serpatinib Form B.

[0018] Further described is a method for converting serpatinib Form A to Form B, comprising: combining serpatinib Form A and methanol to form a slurry, and stirring the slurry until >99 wt% of Form A is converted to Form B.

[0019] Another method described herein is a method for converting selpatinib Form A to Form B, wherein selpatinib Form A is dissolved in DMSO at about 60-80°C to form a solution having a DMSO concentration of about 10-15 mL / g per gram of Form A; the solution is cooled to about 40-60°C, water is added; the resulting mixture is optionally seeded with Form B seeds; the mixture is stirred; more water is added; the mixture is heated to about 60-80°C; the mixture is cooled and Form B is isolated.

[0020] Also described is a process for preparing selpatinib of Formula I or a pharmaceutically acceptable salt thereof as polymorph Form B:

[0021] (Formula I)

[0022] The method comprises reacting a compound of the following structure or a salt thereof with 6-methoxynicotinaldehyde in a solvent in the presence of an acid and a reducing agent:

[0023]

[0024] To prepare selpatinib form B or a pharmaceutically acceptable salt thereof.

[0025] Described herein is a compound having the structure [3], namely 4-[6-(3,6-diazabicyclo[3.1.1]hept-3-yl)-3-pyridinyl]-6-(2-methyl-2-trimethylsilyloxy-propyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile:

[0026]

[0027] or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Overlay of Form A and Form B XRPD data out to approximately 26° 2 theta (2 ϴ).

[0030] Figure 2 Containing form A and form B 13 C Solid-state NMR data and overlay comparing Form A and Form B from approximately 25 to 60 ppm.

[0031] Details

[0032] Serpatinib Form B is described herein. This crystalline form of serpatinib can be used to treat disorders associated with aberrant RET activity, such as IBS or cancer, particularly cancers caused by overactive RET signaling (i.e., RET-related cancers). More specifically, this crystalline form of serpatinib can be used to treat RET-related cancers, such as lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland tumor, lung adenocarcinoma, bronchiolar lung cell carcinoma, multiple endocrine neoplasia type 2A or type 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, breast tumor, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma, inflammatory myofibroblastic tumor, or cervical cancer.

[0033] Form B is characterized by an x-ray powder diffraction (XRPD) pattern comprising a peak at 21.1° and one or more peaks at 17.1°, 17.7°, and 19.8° ± 0.2° 2θ as measured using an x-ray wavelength of 1.5418 Å. Form B also exhibits an upfield resonance (δ = 29.5 ppm) referenced to adamantane comprising peaks at 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (± 0.2 ppm, respectively). 13 C solid-state NMR spectrum.

[0034] Form B is further characterized by having an x-ray powder diffraction (XRPD) pattern comprising a peak at 21.1° and one or more peaks occurring at 7.5°, 12.0°, 13.2°, 17.1°, 17.7°, and 19.8° ± 0.2° 2θ as measured using an x-ray wavelength of 1.5418 Å.

[0035] Additionally, Form B can be characterized by having an x-ray powder diffraction (XRPD) pattern comprising a peak at 21.1° and one or more peaks occurring at 7.5°, 10.9°, 12.0°, 13.2°, 17.1°, 17.7°, 18.2°, 19.8°, 21.1°, and 24.5° ± 0.2° 2θ as measured using an x-ray wavelength of 1.5418 Å.

[0036] Form B can be further characterized by peaks comprising an upfield resonance (δ = 29.5 ppm) referenced to adamantane at 26.4, 28.0, 42.0, 43.9, 48.0, 56.3, 69.5, 80.4, 102.3, 106.8, 115.2, 120.8, 130.2, 134.9, 140.6, 149.5, 152.5, and 163.5 ppm (± 0.2 ppm, respectively). 13 C solid-state NMR spectrum.

[0037] Additionally, Form B can be characterized by comprising one or more peaks at 26.4, 27.4, 28.0, 42.0, 43.4, 43.9, 48.0, 53.9, 56.3, 58.3, 69.5, 77.9, 80.4, 102.3, 106.8, 113.6, 115.2, 118.2, 120.8, 125.2, 130.2, 134.9, 136.9, 140.6, 148.4, 149.5, 151.2, 152.5, 158.2, 163.5 ppm (each + 0.2 ppm) referenced to an upfield resonance (δ = 29.5 ppm) of adamantane. 13 C solid-state NMR spectrum.

[0038] Also described herein are pharmaceutical compositions comprising Form B and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0039] Pharmaceutical compositions containing Form B comprise at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% by weight of Form B compared to other crystalline forms of selpatinib. The pharmaceutical compositions described herein preferably comprise at least 80% Form B and less than 20% other crystalline forms of selpatinib. More preferably, the pharmaceutical compositions comprise at least 90% Form B and less than 10% other crystalline forms of selpatinib. Even more preferably, the pharmaceutical compositions comprise at least 95% Form B and less than 5% other crystalline forms of selpatinib. Even more preferably, the pharmaceutical compositions comprise at least 97% Form B and less than 3% other crystalline forms of selpatinib. More preferably, the pharmaceutical compositions comprise at least 98% or 99% Form B and less than 2% or 1%, respectively, of other crystalline forms of selpatinib.

[0040] Form B can be used in a method of treating cancer comprising administering an effective amount of Form B to a patient in need thereof. Types of cancer that can be treated using the methods described herein include hematological cancers or solid tumor cancers. Examples of types of cancer that can be treated using Form B include lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or type 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma, and cervical cancer. Specifically, the type of cancer can be lung cancer or thyroid cancer. More specifically, the cancer can be non-small cell lung cancer or medullary thyroid cancer.

[0041] Also described herein is Form B for use in therapy.

[0042] Form B can be used to prepare a medicament for treating a RET-related disease or disorder, such as IBS or cancer. Cancers that can be treated using such medicaments are described above. Use of Form B in the preparation of a medicament can also include the steps of performing an in vitro assay using a biological sample from a patient to determine the presence of dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any thereof, and, if dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any thereof is present, administering a therapeutically effective amount of Form B to the patient. In these uses, the biological sample can be a tumor sample, and the tumor sample can be analyzed using methods known to those skilled in the art, such as genomic / DNA sequencing. Alternatively, in these uses, the sample can be obtained from the patient prior to the first administration of Form B. These therapeutic uses of Form B as described herein can be based on selecting a patient for treatment based on at least one dysregulation of the expression, activity, or level of the RET gene, RET kinase, or any thereof. Furthermore, in these uses, Form B can be administered to the patient at a dose of approximately 1 mg / kg to 200 mg / kg (with subranges of effective doses as described above).

[0043] In this context, a patient is a patient in whom a RET fusion or RET mutation has been identified. Thus, the term "identifying a RET fusion or RET mutation" refers to determining whether a RET fusion or RET mutation is present. Methods for determining whether a RET fusion or RET mutation is present are known to those of ordinary skill in the art, for example, see Wang, Yucong et al., Medicine 2019;98(3) :e14120.

[0044] As used above and throughout the specification of the present invention, unless otherwise indicated, the following terms shall be understood to have the following meanings:

[0045] A "pharmaceutically acceptable carrier, diluent or excipient" is an art-recognized vehicle for delivering a biologically active agent to a mammal, such as a human.

[0046] The terms "treating," "treating," and the like are intended to include slowing, halting, or reversing the progression of a disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or lessening one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and even if the progression of the disorder or condition itself is not slowed, halted, or reversed.

[0047] An "effective amount" refers to an amount of the crystalline form of selpatinib that elicits a biological or medical response in a patient, or a therapeutic effect desired by a clinician. In one example, the crystalline form of selpatinib inhibits native RET signaling in an in vitro or ex vivo RET enzyme assay. In another example, the crystalline form of selpatinib inhibits native RET signaling in whole blood from mice treated with different doses of the compound.

[0048] As used herein, the term "patient" refers to a human being.

[0049] The attending physician, as a skilled practitioner, can readily determine an effective amount by using known techniques and observing the results obtained under similar circumstances. In determining an effective amount for a patient, the attending physician considers many factors, including, but not limited to: the species of the patient; the size, age, and general health of the patient; the specific disease or disorder involved; the degree of involvement or severity of the disease or disorder; the response of the individual patient; the specific compound being administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; concomitant medications; and other relevant circumstances.

[0050] Form B is preferably formulated as a pharmaceutical composition for administration by any route that makes the compound bioavailable, including oral, intravenous, and transdermal routes. Such compositions are most preferably for oral administration. Such pharmaceutical compositions and methods for their preparation are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, edited by DB Troy, 21st edition, Lippincott, Williams & Wilkins, 2006).

[0051] As used herein, a "granular composition" refers to a composition in granular form, which is a precursor composition of a pharmaceutical composition in the pharmaceutical process.

[0052] As used herein, "manufacturing vessel" refers to a container used in drug product manufacturing rather than in a medicinal chemistry laboratory. Examples of manufacturing vessels include, but are not limited to, hopper collectors, beds, drying beds, granulation beds, dryer trays, granulator barrels, and mixing tanks.

[0053] In some embodiments, Form B material is prepared from Form A material. In one embodiment, a method of converting Form A to Form B comprises combining serpatinib Form A with a C1-C5 alcohol to form a slurry and isolating serpatinib Form B from the slurry. In some embodiments, the method is performed at a temperature of about 10-80°C, about 10-30°C, about 15-25°C, or about 20°C.

[0054] In some embodiments, the C1-C5 alcohol comprises methanol. Preferred C1-C5 alcohols comprise methanol, and in some embodiments, the methanol is at least about 90%, or 92%, or 94%, or 96%, or 98%, or 99% by weight methanol.

[0055] In other embodiments, the method comprises combining serpatinib Form A with water to form a slurry and isolating serpatinib Form B from the slurry. In some embodiments, the method is performed at a temperature of about 10-80°C, about 10-30°C, about 15-25°C, or about 20°C.

[0056] In some embodiments, the method comprises stirring, mixing, or agitating the slurry for a period of at least about 5 minutes (e.g., at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, or at least 60 minutes). In some embodiments, the period can be about 8-12 hours. In some further embodiments, the period is at least 10 minutes.

[0057] In some embodiments, the method may further comprise isolating selpatinib Form B produced by the method. In some embodiments, isolating may comprise vacuum filtration. In some embodiments, isolating may comprise centrifugation.

[0058] In some further embodiments, the method may further comprise drying the resulting selpatinib Form B. Drying may be achieved using vacuum and / or thermal means.

[0059] In other embodiments, the method comprises dissolving serpatinib Form A in a solvent comprising DMSO to form a solution; adding water to the solution in an amount to form a slurry; and isolating serpatinib Form B formed in the slurry.

[0060] In some embodiments, the method comprises adding about 1 gram of selpatinib Form A to about 10-15 mL / g of DMSO. In some further embodiments, the method comprises adding about 1 equivalent of selpatinib Form A to about 12-13 mL / g of DMSO, such that the concentration of Form A dissolved in DMSO is about 12-13 mL / g, or 1 gram of Form A in about 12-13 milliliters of DMSO.

[0061] In some embodiments of the method, forming a solution comprising DMSO and selpatinib Form A comprises heating selpatinib Form A and a solvent comprising DMSO to about 50° C. to about 70° C. In some further embodiments, the method comprises cooling the solution to a temperature less than about 70° C. and greater than about 20° C. In yet further embodiments, the method comprises cooling the solution to a temperature of about 50° C.

[0062] In some embodiments of the method, adding water comprises adding about 0.1 to about 1 mL / g of water to the solution per gram of Form A. In some further embodiments, adding water comprises adding about 0.3 mL / g of water per gram of Form A to the solution.

[0063] In some embodiments of the method, the addition of water may further comprise adding about 1 to about 15 weight percent of Form B seeds to the slurry. In some further embodiments, about 1 to about 10 weight percent of Form B seeds may be added to the slurry. In yet further embodiments, about 5 weight percent of Form B seeds may be added to the slurry.

[0064] In some embodiments of the method, after the water is added, the slurry is stirred for about 6 to about 72 hours. In some embodiments, the slurry is stirred for at least 12 hours.

[0065] In some embodiments, the method may further comprise adding a second addition of water to the slurry formed from the first addition of water. In some embodiments, the second addition of water may be added to the slurry in an amount of about 0.5 to about 3 mL / g water.

[0066] In some embodiments of the method, the slurry formed by adding water is cooled to about 20-30°C.

[0067] In some embodiments, isolation of serpatinib Form B comprises filtration. In some embodiments, isolated serpatinib Form B can be washed with a solvent comprising methanol, ACN, MTBE, or water. In some further embodiments, isolated serpatinib Form B is washed with a solvent comprising methanol. In yet further embodiments, isolated serpatinib Form B is washed with methanol until isolated serpatinib Form B contains less than 0.5 wt% DMSO.

[0068] In some of the aforementioned aspects and embodiments, the present disclosure provides a method for converting serpatinib Form A to Form B, comprising: combining serpatinib Form A and methanol to form a slurry, and stirring the slurry until >99% by weight of Form A is converted to Form B. In some embodiments of the method, the slurry is stirred for approximately 18-24 hours. In yet further embodiments, the concentration of serpatinib Form A in methanol is approximately 8 mL / g.

[0069] In some of the aforementioned aspects and embodiments, the present disclosure provides a method for converting selpatinib Form A to Form B, wherein selpatinib Form A is dissolved in DMSO at about 60-80°C to form a solution having a DMSO concentration of about 10-15 mL / g per gram of Form A; the solution is cooled to about 40-60°C, a first amount of water is added; the resulting mixture is optionally seeded with Form B seeds; the mixture is stirred; a second amount of water is added; the mixture is heated to about 60-80°C; the mixture is cooled, and Form B is isolated. In some embodiments of the method, 5 wt% of Form B seeds are added to the mixture. In yet further embodiments, the first amount of water added is about 0.1 mL / g Form A to about 0.5 mL / g Form A. In yet further embodiments, the second amount of water added is about 1.0-1.5 mL / g Form A.

[0070] In another aspect, the present disclosure provides a method for preparing selpatinib of Formula I or a pharmaceutically acceptable salt thereof as polymorph Form B:

[0071] (Formula I)

[0072] The method comprises reacting a compound of the following structure or a salt thereof with 6-methoxynicotinaldehyde in a solvent in the presence of an acid and a reducing agent:

[0073]

[0074] To prepare serpatinib Form B or a pharmaceutically acceptable salt thereof. Although a stoichiometric amount of acid may be used, non-stoichiometric amounts are also acceptable. In structure [3], a TMS group is present on the oxygen. Although not explicitly shown, it is understood that other alcohol protecting groups may be used. In addition to TMS, other silyl groups as described herein may also be used.

[0075] In some embodiments of this aspect, the method further comprises preparing a compound of structure [3] or a salt thereof, comprising reacting a compound of structure [3] or a salt thereof with a deprotecting agent to form a compound of structure [3] or a salt thereof

[0076]

[0077] wherein R1 is an amine protecting group.

[0078] In some embodiments, the deprotecting agent is selected from trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, aluminum chloride and boron trifluoride. In some further embodiments, the deprotecting agent is selected from sulfuric acid, p-toluenesulfonic acid and acetyl chloride.

[0079] In some embodiments, the reducing agent is selected from alkali metal borohydrides, hydrazine compounds, citric acid, citrate salts, succinic acid, succinate salts, ascorbic acid, and ascorbate salts. In some further embodiments, the reducing agent is selected from sodium triacetoxyborohydride (STAB), sodium borohydride, and sodium cyanoborohydride.

[0080] In some embodiments, R1 is selected from formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, nitrovarachnyloxycarbonyl, p-methoxybenzyl, and toluenesulfonyl. In some further embodiments, R1 is tert-butoxycarbonyl (Boc).

[0081] In some embodiments, the acid is selected from pivalic acid and acetic acid. In some further embodiments, the acid is pivalic acid. In yet further embodiments, a catalytic amount of pivalic acid is used.

[0082] In some embodiments, the reaction of compound [3] is carried out in an aprotic solvent. Examples of protic solvents include ethers, such as anisole.

[0083] In another aspect, the present disclosure provides a compound of structure [3], 4-[6-(3,6-diazabicyclo[3.1.1]hept-3-yl)-3-pyridinyl]-6-(2-methyl-2-trimethylsilyloxy-propyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile:

[0084]

[0085] or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the present disclosure provides a method of preparing a compound of structure [3] according to aspects and embodiments described herein.

[0087] In some embodiments of any of the aforementioned aspects, the method comprises preparing selpatinib Form B as the free amine.

[0088] Serpatinib Form A (Form A) may contain some of its more thermodynamically stable polymorph, Serpatinib Form B (Form B). Although both polymorphs are crystalline, high-melting, anhydrous, stable, and do not interconvert under typical storage or manufacturing conditions, these polymorphs have different properties and characteristics that allow Form A to be distinguished from Form B. Because Form B is thermodynamically more stable, it is desirable to understand how Form A is converted to Form B.

[0089] definition

[0090] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified, the following terms used herein have the meanings ascribed to them below.

[0091] As used herein, the term "polymorph" refers to crystals of the same compound that have different physical properties due to the ordering of molecules in the crystal lattice. Different polymorphs of a single compound (i.e., a compound of Formula I) have one or more chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties that differ from one another. Differences in the physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in composition and product preparation), dissolution rate (a factor important in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water absorption, compaction, and particle morphology. Differences in stability can arise from changes in chemical reactivity (e.g., differential oxidation, resulting in a dosage form composed of one polymorph changing color more quickly than one composed of another), mechanical changes (e.g., crystal changes during storage when a kinetically favorable polymorph transforms into a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). Due to differences in solubility / dissolution, some transformations affect efficacy and / or toxicity. In addition, the physical properties of the crystals may be important in processing; for example, one polymorph may be more likely to form solvates or may be difficult to filter and clean from impurities (i.e., particle shape and size distribution may differ between polymorphs). As used herein, "polymorph" does not include an amorphous form of the compound. In some specific embodiments, the polymorphs of the compound of Formula I (i.e., selpatinib Form A and selpatinib Form B) comprise the characteristics described herein.

[0092] As used herein, "amorphous" refers to a non-crystalline form of a compound, which can be a solid state form of the compound or a solubilized form of the compound. For example, "amorphous" refers to a compound (e.g., a solid state form of a compound) that does not have a regular repeating arrangement of molecules or external face planes.

[0093] As used herein, the term "anhydrous" refers to a crystalline form of the compound of Formula (I) that does not contain a stoichiometric amount of water bound to the crystal lattice. Typically, Anhydrous Form A and Anhydrous Form B have 1% by weight or less of water. For example, 0.5% by weight or less, 0.25% by weight or less, or 0.1% by weight or less of water.

[0094] As used herein, the term "solvate" refers to a crystalline form of a compound of formula (I) wherein the crystal lattice includes one or more solvents.

[0095] The term "hydrate" or "hydrated polymorph form" refers to a crystalline form of a compound of formula (I) in which the crystal lattice includes water, such as a polymorphic form of the compound. Unless otherwise specified, the term "hydrate" as used herein refers to a "stoichiometric hydrate". Stoichiometric hydrates contain water molecules as part of the crystal lattice. In contrast, non-stoichiometric hydrates contain water, but changes in the water content do not cause significant changes in the crystal structure. During the drying process of non-stoichiometric hydrates, a considerable proportion of the water can be removed without significantly disturbing the crystal network, and the crystals can subsequently rehydrate to obtain the original non-stoichiometric hydrated crystalline form. Unlike stoichiometric hydrates, dehydration and rehydration of non-stoichiometric hydrates are not accompanied by phase changes, and therefore all hydration states of non-stoichiometric hydrates represent the same crystalline form.

[0096] "Purity" when used in reference to a composition comprising polymorphs of a compound of Formula (I) refers to the percentage of one particular polymorphic form of the compound of Formula (I) relative to another polymorphic form or amorphous form in the composition in question. For example, a composition comprising polymorphic Form 1 at 90% purity comprises 90 parts by weight of Form 1 and 10 parts by weight of other polymorphs and / or amorphous forms of the compound of Formula (I).

[0097] As used herein, a compound or composition is "substantially free of" other components if it does not contain a significant amount of one or more other components. For example, the composition may contain less than 5%, 4%, 3%, 2%, or 1% by weight of other components. Such components may include raw materials, residual solvents, or any other impurities that may be derived from the preparation and / or separation of the compounds and compositions provided herein. In some embodiments, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorphic form of a compound of formula (I) is "substantially free of" other polymorphic forms if the particular polymorphic form constitutes at least about 95% by weight of the compound of formula (I) present. In some embodiments, a particular polymorphic form of a compound of formula (I) is "substantially free of" other polymorphic forms if the particular polymorphic form constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the compound of formula (I) present. In certain embodiments, a particular polymorph of the compound of Formula (I) is "substantially free" of water if the amount of water constitutes no more than about 2%, about 1%, or about 0.5% by weight of the polymorph.

[0098] As used herein, "substantially pure" when used to refer to a polymorphic form of a compound of formula (I) means that a sample of the polymorphic form of the compound has a purity greater than 90%, including greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99%, and also includes about 100% of the compound. The remaining material comprises other forms of the compound, and / or reaction impurities and / or processing impurities derived from its preparation. For example, when a polymorphic form of a compound of formula (I) is measured to have a purity greater than 90% by means currently known and recognized in the art, the polymorphic form of the compound of formula (I) can be considered to be substantially pure, wherein less than 10% of the remaining material comprises other forms of the compound of formula (I) and / or reaction impurities and / or processing impurities. The presence of reaction impurities and / or processing impurities can be determined by analytical techniques known in the art, such as chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry or infrared spectroscopy.

[0099] To provide a more concise description, some quantitative expressions herein are listed as ranging from about amount X to about amount Y. It is to be understood that when a range is listed, the range is not limited to the upper and lower limits listed, but includes the entire range from about amount X to about amount Y, or any range therein.

[0100] "Room temperature" or "RT" refers to the ambient temperature of a typical laboratory, which is usually about 25°C.

[0101] As used herein, the term "excipient" refers to any substance required to formulate a composition into a desired form. For example, suitable excipients include, but are not limited to, diluents or fillers, binders or granulating agents or adhesives, disintegrants, lubricants, antiadherents, glidants, dispersants or wetting agents, dissolution retardants or enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, and sweeteners.

[0102] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, cosolvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are not biologically or otherwise undesirable. Such media and agents are well known in the art for use with pharmaceutically active substances. Any conventional media or agents are contemplated for use in therapeutic formulations unless they are incompatible with the active ingredient. Supplementary active ingredients may also be incorporated into the formulation. In addition, various excipients commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, NJ. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0103] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0104] As used herein, ranges and amounts may be expressed as "about" a particular value or range. "About" also includes the exact amount. Thus, "about 5 grams" means "about 5 grams" as well as "5 grams." It is also to be understood that ranges expressed herein include integers and fractions within that range. For example, a range between 5 grams and 20 grams includes integer values ​​such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 grams, as well as fractions within that range, including, but not limited to, 5.25, 6.5, 8.75, and 11.95 grams. The term "about" preceding a DSC, TGA, TG, or DTA value (reported in ° C) has an allowable variability of + / - 5 ° C.

[0105] As used herein, "optional" or "optionally" means that the subsequently described event or circumstance does or does not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, a reaction mixture that "optionally includes a catalyst" means that the reaction mixture contains the catalyst or it does not contain the catalyst.

[0106] As used herein, "strong base" refers to a basic compound that can deprotonate a weak acid in an acid-base reaction. Examples of strong bases include, but are not limited to, hydroxides, alkoxides, and ammonia. Common examples of strong bases are hydroxides of alkali metals and alkaline earth metals, such as NaOH. Certain strong bases can deprotonate very weakly acidic C--H groups even in the absence of water. Strong bases include, but are not limited to, sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide, lithium hydroxide, and rubidium hydroxide. In some embodiments, NaOH is used as the strong base. In some embodiments, potassium hydroxide is used as the strong base.

[0107] As used herein, the term "weak base" refers to inorganic and organic bases that are only partially ionized in aqueous solution. Weak bases typically have a pKa of between about 6 and about 11. Many such weak bases are known and are exemplified by those listed in Handbook of Biochemistry and Molecular Biology, Volume 1, 3rd Edition, G.D. Fassman, CRC Press, 1976, pages 305-347. Weak bases may be soluble or insoluble in water. Suitable weak bases include, but are not limited to, alkali metal carbonates and bicarbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate; ammonia; primary amines, such as methylamine; secondary amines; and tertiary amines, such as trialkylamines, for example, trimethylamine, triethylamine, tripropylamine, and tributylamine, benzyldiethylamine, pyridine, quinoline, N-methylmorpholine, aniline, and the like.

[0108] As used herein, "non-nucleophilic base" refers to a base that does not act as a nucleophile, i.e., a base that does not donate an electron pair to an electrophile to form a chemical bond associated with the reaction. Typically, a non-nucleophilic base is bulky and sterically hindered, so that a proton can be attached to the basic center, but prevents alkylation and complexation. Examples of non-nucleophilic bases include, but are not limited to, amines and nitrogen heterocycles, such as triethylamine and pyridine, amidines, lithium compounds, and phosphazenes. Other examples of non-nucleophilic bases include sodium hydride and potassium hydride.

[0109] The term "amine protecting group" as used herein refers to any group known in the art of organic synthesis for protecting amine groups. Such amine protecting groups include those listed in Greene, "Protective Groups in Organic Synthesis," John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3," Academic Press, New York (1981). Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: (1) acyl groups such as formyl, trifluoroacetyl, phthaloyl, and p-toluenesulfonyl; (2) aromatic carbamate groups such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethoxycarbonyl (Fmoc); (3) aliphatic carbamate groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cycloalkylcarbamate groups such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl groups such as trityl and benzyl; (6) trialkylsilanes such as trimethylsilane; (7) thiol-containing groups such as phenylthiocarbonyl and dithiosuccinyl; and (8) Alkyl types such as triphenylmethyl, methyl and benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl and tert-butyl; and trialkylsilane types such as trimethylsilane.

[0110] As used herein, the term "deprotecting agent" refers to an agent or reagent system (reagent and solvent) that can be used to remove a protecting group. The deprotecting agent can be an acid, a base, or a reducing agent. For example, the removal of a benzyl (Bn) group can be achieved by reduction (hydrogenolysis), while the removal of a carbamate (e.g., a Boc group) can be achieved by using an acid (e.g., HCl, TFA, H2SO4, etc.), and the removal of a silyl group can be achieved by using a weak acid or a halide (e.g., a fluoride, such as provided by tetra-n-butylammonium fluoride (TBAF)), optionally under mild heating.

[0111] As used herein, the term "reducing agent" generally refers to any species capable of reducing another species while being oxidized itself. As used herein, the term "oxidizing agent" generally refers to any species capable of oxidizing another species while being reduced itself.

[0112] As used herein, the term "triflating reagent" refers to a compound useful in a reaction in which a trifluoromethanesulfonic acid group is attached to a hydroxyl group to form a triflate. The triflating reagent is a source of trifluoroacetyl groups. Triflating reagents include, but are not limited to, trialkylsilyl trifluoromethanesulfonates, trialkylstannyl trifluoromethanesulfonates, trifluoromethanesulfonic anhydride, N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf2), N-(5-chloro-2-pyridyl)trifluoromethanesulfonimide, and N-(2-pyridyl)trifluoromethanesulfonimide.

[0113] As used herein, "acrylonitrile derivatives" are compounds derived from acrylonitrile having the formula CH2CHCN in which one or more hydrogen atoms have been replaced by another atom or group. An example of an acrylonitrile derivative is 2-chloroacrylonitrile in which one of the hydrogen atoms of acrylonitrile has been replaced by a chlorine atom.

[0114] As used herein, the term "dilute," when applied to acid solutions, refers to solutions having an acid concentration of less than about 0.1 N.

[0115] The terms "hydrogen" and "H" are used interchangeably herein.

[0116] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0117] The term "alkyl" as used herein refers to a hydrocarbon chain containing the specified number of carbon atoms, which may be straight or branched. 1-6 = means that the group may have from 1 to 6 (inclusive) carbon atoms. Examples include methyl, ethyl, isopropyl, tert-butyl and n-hexyl.

[0118] As used herein, the term "alkylamine" refers to an amine containing one or more alkyl groups. Alkylamines can be primary, secondary, or tertiary amines. For example, a secondary alkylamine is an amine containing two alkyl groups. One example includes diisopropylethylamine.

[0119] Salts may be formed from compounds in any manner familiar to the skilled person. Thus, the recitation "to form a compound or a salt thereof" includes embodiments in which the compound is formed and then a salt is formed from the compound in a manner familiar to the skilled person.

[0120] It will be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0121] The present invention specifically encompasses all combinations of embodiments related to the aspects described herein, as if each combination were expressly enumerated individually, provided such combinations include possible aspects. Furthermore, the present invention also specifically encompasses all subcombinations of embodiments encompassed within an aspect described herein, and all subcombinations of embodiments encompassed within all other aspects described herein, as if each subcombination of all embodiments were expressly enumerated individually.

[0122] Crystallization method .

[0123] Disclosed herein are methods for converting serpatinib Form A to serpatinib Form B. Although serpatinib Form A can be converted to Form B using a variety of different methods, disclosed herein are crystallization-based methods for converting serpatinib Form A to serpatinib Form B.

[0124] Suitable methods for converting Form A to Form B include cooling crystallization, evaporative crystallization, vapor diffusion, crystallization using one or more antisolvents (including reverse antisolvent addition), and slurry crystallization. These methods are discussed herein.

[0125] In one aspect, disclosed herein is a method of converting selpatinib Form A to selpatinib Form B.

[0126] In another aspect, disclosed herein is a method of converting serpatinib Form A to serpatinib Form B, the method comprising: combining serpatinib Form A with a C1-C5 alcohol to form a slurry and isolating serpatinib Form B from the slurry.

[0127] In yet another aspect, disclosed herein is a method of converting serpatinib Form A to serpatinib Form B, the method comprising:

[0128] a. dissolving serpatinib Form A in a solvent comprising DMSO to form a solution;

[0129] b. adding water to the solution and thereby forming a slurry;

[0130] c. Isolation of Serpatinib Form B.

[0131] In another aspect, disclosed herein is a method for converting selpatinib Form A to Form B, comprising: combining selpatinib Form A and methanol to form a slurry, and stirring the slurry until >99 wt% of Form A is converted to Form B.

[0132] Form A has unique XRPD peaks at 4.9, 9.7, and 15.5° 2θ, while Form B has unique XRPD peaks at 7.5, 10.9, and 12.0° 2θ. As can be seen in Table 1 below, the 2θ values ​​and / or peak intensities of other peaks also differ between the two forms. It should be understood that all XRPD peaks disclosed herein are ± 0.2° 2θ unless explicitly stated otherwise.

[0133] Table 1. X-ray powder diffraction peak analysis, Form A and Form B

[0134]

[0135]

[0136] In Table 1, not all peaks with relative intensities less than 1.00 are listed.

[0137] XRPD patterns of Form A and Form B (described above) were obtained on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKα source (λ = 1.54180 Å) and a Vantec detector, operating at 35 kV and 50 mA. The sample was scanned between 4 and 40 2θ° with a step size of 0.008 2θ° and a scan rate of 0.5 sec / step, using a 1.0 mm divergence, a fixed anti-scatter of 6.6 mm, and an 11.3 mm detector slit. The dry powder was mounted on a quartz sample holder and a glass slide was used to obtain a smooth surface. Crystalline diffraction patterns were collected at ambient temperature and relative humidity. Crystalline peak positions were determined in MDI-Jade after whole pattern shifting based on the NIST 675 internal standard with peaks at 8.853 and 26.774 2θ°. It is well known in the field of crystallography that for any given crystal form, the relative intensity of the diffraction peaks may be different due to the preferred orientation caused by factors such as crystal morphology and habit. If there is a preferred orientation effect, the peak intensity changes, but the characteristic peak position of the polymorph remains unchanged. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. In addition, it is also well known in the field of crystallography that for any given crystal form, the angular peak position may be slightly different. For example, the peak position may move due to temperature changes, sample displacement, or the presence or absence of an internal standard when analyzing the sample. In this case, a peak position variability of ± 0.22θ° is assumed to account for these potential changes without hindering the clear identification of the crystal form shown. A crystal form can be confirmed based on any unique combination of characteristic peaks.

[0138] DSC-TGA analysis of anhydrous crystalline Form A showed a melting onset of 207.6°C and exhibited two endotherms, wherein the first endotherm corresponded to melting of Form A, followed by exothermic recrystallization of Form B, and then melting of Form B. DSC-TGA analysis of anhydrous crystalline Form B showed a single endotherm with a melting onset of 213.3°C.

[0139] Although Forms A and B are anhydrous polymorphs, Form A is slightly more hygroscopic than Form B.

[0140] Forms A and B have similar solubility. Both exhibit poor solubility at 25°C in many organic solvents, including methyl ethyl ketone (MEK), acetone, and many alcohol-based solvents, while having moderate solubility (3-30 mg / ml) in dichloromethane (DCM), dimethyl sulfoxide (DMSO), and THF. Form B is almost insoluble in anisole.

[0141] Forms A and B 13 C solid-state NMR spectrum shows Figure 2 middle. Figure 2 Also included is an overlay of a portion of the spectrum showing that Form A has a peak at 30.9 ppm that is not observed in Form B, while Form B has a peak at 48.0 ppm that is not observed in Form A. Both spectra are referenced to the upfield resonance of adamantane (δ = 29.5 ppm).

[0142] The above-cited data were obtained using a Bruker Avance III HD 400 MHz wide-aperture NMR spectrometer operating at a carbon frequency of 100.622 MHz and a proton frequency of 400.13 MHz and equipped with a Bruker 4 mm double resonance probe. 13 C cross-polarization / magic angle spinning NMR (solid-state NMR or ssNMR) spectroscopy. SPINAL64 decoupling and RAMP100 shaped H-nuclear CP pulses were used, with TOSS sideband suppression employed in conjunction with cross-polarization. Acquisition parameters were as follows: 4.0 μs proton pulse, 1.5 ms contact time, 5 kHz MAS frequency, 30.2 kHz spectral width, and 34 ms acquisition time. A 3 s recycle delay and 2655 scans were used. Chemical shifts are referenced to adamantane (δ = 29.5 ppm) in a separate experiment. Representative of Form B 13C ss NMR resonances include: 26.44, 27.37, 28.00, 41.98, 43.43, 43.91, 48.04, 53.92, 56.31, 58.32, 69.48, 77.90, 80.38, 102.32, 106.77, 113.58, 115.24, 118.23, 120.76, 125.23, 130.23, 134.86, 136.93, 140.59, 148.42, 149.50, 151.20, 152.45, 158.22, and 163.52 ppm.

[0143] The above data establish that Forms A and B: 1) have somewhat distinct properties, 2) can be readily identified, and 3) Form A can be converted to Form B.

[0144] A variety of solvents can be used to convert Form A to Form B. Solvents that can be used to convert Form A to Form B include, but are not limited to, C1-C5 alcohols (such as methanol or ethanol), water, acetonitrile (ACN), methyl tert-butyl ether (MTBE), heptane, n-butyl acetate (n-BuOAC), 81% ACN-MeOH (81 ml ACN combined with 19 ml MeOH), wet ethyl acetate, cyclopentyl methyl ether (CPME), 1,2-dimethoxyethane, ethyl acetate, ethyl formate, methyl isobutyl ketone (MIBK), nitromethane, n-propyl acetate (NPA), 1-pentanol, toluene, 1:1 MeOH:water, 1:1 EtOH:water, ACN:water, DMSO / heptane mixtures, or DMSO / water mixtures. In some embodiments, the solvent comprises a C1-C5 alcohol, water, DMSO, MTBE, ACN, and mixtures of two or more thereof. In other embodiments, the solvent comprises methanol, ethanol, water, DMSO, MTBE, ACN, or mixtures of two or more thereof.

[0145] As mentioned above, selpatinib can form solvates; it can also form metastable solid forms, both of which are generally unstable upon drying. Observed solvates include acetone solvate, chloroform solvate, 1,4-dioxane solvate, methyl ethyl ketone (MEK) solvate, dichloromethane (DCM) solvate, 2-butanol solvate, 1-butanol solvate, ethanol solvate, dimethyl sulfoxide (DMSO)-water solvate, DMSO solvate, and tetrahydrofuran (THF) solvate. Solvates and metastable forms generally revert to Form A upon isolation and / or drying, although films or amorphous material may occasionally form. Chloroform and 1,4-dioxane solvates are stable upon isolation / drying.

[0146] Form A used in the methods described herein may contain some Form B. If present, Form B is present in an amount of at least about 0.1% to a maximum of about 25%, or about 0.5% to about 17%, or about 1% to about 16%.

[0147] Several non-limiting methods for converting Form A to Form B are described below.

[0148] Transformation method 1

[0149] In a preferred embodiment, the method comprises combining serpatinib Form A with a solvent, such as a C1-C5 alcohol, to form a slurry, and isolating serpatinib Form B from the slurry. When the slurry is stirred or otherwise agitated, serpatinib Form B is formed. In some embodiments, the alcohol is maintained at ambient temperature. In other embodiments, the slurry is heated, which increases the rate of Form B formation. Aside from the temperature difference, these two embodiments are similar and are described below.

[0150] solvent

[0151] Examples of C1-C5 alcohols include methanol, ethanol, isopropanol, propanol, butanol, 2-butanol, 3-butanol, and 1-pentanol. In some embodiments, methanol is a preferred C1-C5 alcohol.

[0152] Examples of C1-C5 alcohols include methanol, ethanol, isopropanol, propanol, butanol, 2-butanol, and 3-butanol. In certain embodiments, the alcohol comprises methanol and / or ethanol. In one embodiment, the alcohol comprises methanol.

[0153] Also can use aqueous alcohol, the amount of water wherein existing is about 0.1 weight % to about 70 weight %, or about 1 weight % to about 50 weight %, or about 2 weight % to about 30 weight %.In another embodiment, the amount of water existing is about 0.5 weight % to about 20 weight %, or about 1 weight % to about 15 weight %, or about 2 weight % to about 12 weight %, or about 10 weight % or less than 10 weight %.In one embodiment, alcohol comprises at least 90 weight % methanol.In another embodiment, alcohol comprises about 90 weight % methanol and about 10 weight % water.In another embodiment, alcohol comprises at least 95 weight % methanol and about 5 weight % water.In alcohol mixture, may there be other solvents.In some embodiments, may there be one or more other solvents of about 3 weight % at most.

[0154] temperature

[0155] Temperature affects the rate at which Form A converts to Form B, with lower temperatures requiring longer times than higher temperatures. While it is possible to stir a slurry of Form A and solvent at subambient temperatures, this prolongs the conversion of Form A to Form B and is therefore generally avoided.

[0156] The temperature of the alcohol, such as a C1-C5 alcohol, is about 10-80° C., or about 20-60° C., or about 55° C. The C1-C5 alcohol can be at the desired temperature before adding the Form A material, or the temperature can be adjusted after adding the Form A material.

[0157] In other embodiments, the temperature of the alcohol, such as a C1-C5 alcohol, is 10-30° C., or about 15-25° C., or about 20° C. In other embodiments, the temperature is ambient temperature, which is the external temperature. Although Form A will convert to Form B when stirred in a room temperature solvent, such as methanol, the conversion is faster if the Form A and solvent mixture is heated.

[0158] If the slurry is heated to the point where all of Form A is dissolved, the resulting solution can be filtered to remove any insoluble material. After stirring, the solution will be stirred and cooled as detailed below.

[0159] time

[0160] The slurry is stirred or otherwise agitated for at least about 5 minutes or at least about 10 minutes. In some embodiments, the slurry is not typically stirred or otherwise agitated for more than 72 hours, but if desired, the slurry can be stirred or otherwise agitated for more than 72 hours. In some embodiments, the slurry is stirred for about 1-12 hours.

[0161] cool down

[0162] If the Form A and alcohol mixture is heated for the times indicated above, the heat is removed and the slurry is allowed to cool for about 4 to 24 hours, or about 6-18 hours, or about 12 hours.

[0163] Isolated Form B

[0164] The Form B material can be isolated using any method known in the art. In one embodiment, the isolation comprises gravity filtration. In another embodiment, the isolation comprises vacuum filtration. In yet another embodiment, the isolation comprises the use of a centrifuge.

[0165] Fresh solvents, such as ethanol, methanol, ACN, MTBE, water, or a combination of two or more thereof, can be used to wash the Form B material. More preferably, methanol, ACN, MTBE, water, or a combination of two or more thereof are used to wash the Form B material. Even more preferably, a solvent comprising methanol is used. The fresh solvent can be cooled to a temperature of about 0° C. to less than about 20° C. before being used to wash the Form B material.

[0166] Isolated selpatinib Form B can be dried using methods known in the art. Typical methods include heating, passing an inert gas over the solid, and / or using subatmospheric pressure.

[0167] In a further embodiment of this example, a C1-C5 alcohol and selpatinib Form A are combined and the resulting slurry is stirred or otherwise agitated for a period of time sufficient to convert Form A to Form B. Typical stirring times are at least about 10 minutes up to about 36 hours, or about 24 hours, but typically at least about 30 minutes, or at least about 1 hour, or at least about 4 hours, or at least about 6 hours, or at least about 8 hours, or at least about 12 hours. If desired, the mixture may be stirred and / or agitated for more than 24 hours. Heating the mixture will increase the rate at which Form A converts to Form B.

[0168] In another embodiment of this method, the method comprises combining selpatinib Form A and methanol to form a slurry, and stirring the slurry until >95%, >96%, >97%, >98%, or >99% by weight of Form A is converted to Form B. The slurry is stirred for about 12 to 48 hours or about 18-24 hours. The concentration of selpatinib Form A in methanol is about 6-14 mL / g or about 8-12 mL / g. In some methods, it is about 8 mL / g.

[0169] Conversion Method 2

[0170] In another embodiment, the method comprises combining selpatinib Form A with a solvent and heating and stirring the resulting mixture until Form A is dissolved in the solvent. Once a solution is formed, the mixture can be filtered to remove any insoluble impurities. The mixture is then cooled and water is added. If seed crystals are used, they can be added at this time. After stirring, additional water is slowly added. The mixture is then cooled to room temperature. After cooling to room temperature, the mixture is stirred and the Form B material is then isolated.

[0171] solvent

[0172] A variety of solvents can be used. Importantly, the solvent should not form a selpatinib solvate; instead, it should provide the desired Form B. Examples of suitable solvents include, but are not limited to, DMSO, C1-C5 alcohols, ACN, MTBE, water, or a combination of two or more thereof. Preferred C1-C5 alcohols include ethanol and / or methanol. In some embodiments, DMSO is a preferred solvent. In some embodiments, the solvent contains at least 2% by weight water.

[0173] The amount of solvent used depends on the solvent used. Typically, 1 gram of Form A is dissolved in about 8-20 mL, or about 10-15 mL, or about 11-14 mL, or about 12-13 mL of the solvent used. In some embodiments, 1 gram of Form A is dissolved in 10-15 mL / g of DMSO or 1 gram of Form A is dissolved in about 12-13 mL / g of DMSO.

[0174] temperature

[0175] Temperature affects the rate at which Form A converts to Form B, with lower temperatures requiring longer times than higher temperatures.

[0176] The mixture comprising Form A and a solvent is heated to a temperature of about 30°C up to the boiling point of the solvent. Typically, the mixture is heated to a temperature of about 50-110°C or about 50°C to about 70°C. In some embodiments, the mixture can be heated to about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, or about 110°C. After the mixture is heated to the desired temperature and the Form A material is dissolved, the solution temperature is reduced by about 15-35°C. The temperature can be reduced by about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C. In one embodiment, the solution is cooled to a temperature less than about 70°C and greater than about 20°C.

[0177] In some embodiments, the solvent comprises DMSO and is heated to about 50° C. to about 70° C. In further embodiments, the DMSO is then cooled to about 50° C.

[0178] In alternative embodiments, the solvent is not heated, ie, it is allowed to stir at ambient temperature. In these embodiments, the conversion of Form A to Form B takes longer.

[0179] The first batch of water

[0180] When the first batch of water is added to the solution, about 0.1-1.0 mL / g, or about 0.2-0.6 mL / g, or about 0.3 mL / g of Form A (milliliters of water per gram of Form A) is added. In some embodiments, the first batch of water is about 0.1 mL / g or about 0.2 mL / g, about 0.3 mL / g, about 0.4 mL / g, about 0.5 mL / g, or about 0.6 mL / g.

[0181] The first batch of water is added over a period of about 30 seconds to about 15 minutes, or about 1-10 minutes, or about 4-6 minutes, or about 5 minutes. Longer times can be used if desired.

[0182] seed crystal

[0183] If Form B seeds are added to the mixture, about 0.1-15 weight percent, or about 1 to about 10 weight percent, or about 5 weight percent, of Form B seeds are used.

[0184] In some embodiments, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about 11 wt %, about 12 wt %, about 13 wt %, about 14 wt %, or about 15 wt % of seeds are added.

[0185] Seed crystals can be prepared using the methods described herein.

[0186] time

[0187] After the mixture is heated and the Form A material dissolves and the temperature of the mixture is reduced by 50-110° C. and seed crystals, if used, are added, the mixture is stirred for about 1-96 hours, or about 6-72 hours, or about 8-24 hours. In some embodiments, the mixture is stirred for at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, or at least 24 hours.

[0188] The second batch of water

[0189] After stirring for 1-96 hours, a second batch of water is slowly added. The amount of water in the second batch is about 0.3-6 mL / g, 0.50-3.0 mL / g (milliliters of water / grams of Form A), about 0.75-1.5 mL / g, or about 0.9-1.20 mL / g. In some embodiments, the second batch of water is about 0.90 mL / g, about 0.91 mL / g, about 0.92 mL / g, about 0.93 mL / g, about 0.94 mL / g, about 0.95 mL / g, about 0.96 mL / g, about 0.97 mL / g, about 0.98 mL / g, about 0.99 mL / g, about 1.00 mL / g, about 1.01 mL / g, about 1.02 mL / g, about 1.03 mL / g, about 1.04 mL / g, about 1.05 mL / g, about 1.06 mL / g, about 1.07 mL / g, about 1.08 mL / g, about 1.09 mL / g, about 1.10 mL / g, about 1.11 mL / g, about 1.12 mL / g, about 1.13 mL / g, about 1.14 mL / g mL / g, about 1.15 mL / g, about 1.16 mL / g, about 1.17 mL / g, about 1.18 mL / g, about 1.19 mL / g, about 1.20 mL / g Form A.

[0190] The second batch of water is added slowly, i.e., it takes about 0.5-24 hours or about 1-12 hours to add the entire second batch of water. In some embodiments, it takes about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours to add the entire second batch of water.

[0191] cool down

[0192] After the second batch of water is added, the mixture is cooled by about 15-30°C to a temperature of about 20-30°C. In some embodiments, the mixture is cooled to about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, or about 30°C. In one embodiment, the final temperature after cooling is room temperature. In other embodiments, the mixture is cooled to a temperature of about 30-55°C. In these embodiments, the yield tends to be slightly lower when lower temperatures are used.

[0193] After the second batch of water is added, the mixture is cooled at a rate of about 1-20°C / hr, or about 3-17°C / hr, or about 5-15°C / hr, until the desired temperature is reached. In one embodiment, the cooling rate is about 1°C / hr, about 2°C / hr, about 3°C / hr, about 4°C / hr, about 5°C / hr, about 6°C / hr, about 7°C / hr, about 8°C / hr, about 9°C / hr, about 10°C / hr, about 11°C / hr, about 12°C / hr, about 13°C / hr, about 14°C / hr, about 15°C / hr, about 16°C / hr, about 17°C / hr, about 18°C / hr, about 19°C / hr, or about 20°C / hr.

[0194] After reaching the desired temperature, the mixture is stirred for about 1 to about 72 hours or about 2 to 48 hours. In some embodiments, the mixture is stirred for at least 2 hours. In other embodiments, the mixture is stirred for less than 72 hours.

[0195] Isolated Form B

[0196] Form B was isolated as described above.

[0197] Fresh solvents, such as ethanol, methanol, ACN, MTBE, water, or a combination of two or more thereof, can be used to wash the Form B material. More preferably, methanol, ACN, MTBE, water, or a combination of two or more thereof are used to wash the Form B material. Even more preferably, a solvent comprising methanol is used. The fresh solvent can be cooled to a temperature of about 0° C. to less than about 20° C. before being used to wash the Form B material.

[0198] In embodiments where the solvent comprises DMSO, the isolated serpatinib Form B is washed with methanol until the isolated serpatinib Form B contains less than 0.5 wt% DMSO.

[0199] In a further example of this method, selpatinib Form A is dissolved in a room temperature solvent comprising DMSO to form a solution having a DMSO concentration of approximately 10-15 mL / g per gram of Form A. Water is then added. The mixture is then allowed to stand, during which time Form B forms. Form B can then be isolated, or additional water can be added, and after further stirring (as described above), Form B can be isolated.

[0200] In another example of this method, selpatinib Form A is dissolved in DMSO at about 60-80°C or about 70°C to form a solution having a DMSO concentration of about 10-15 mL / g per gram of Form A; the mixture is cooled to about 40-60°C or about 50°C; water is added; the resulting mixture is seeded with Form B seeds, the mixture is stirred, more water is added, and the mixture is heated; the mixture is cooled and Form B is isolated. The initial amount of water added is about 0.1 mL / g Form A to about 0.5 mL / g Form A, or about 0.3 mL / g Form A. The amount of seed crystals that can be used is about 1-10 wt%, or about 5 wt%, based on the amount of Form A. The seeded mixture is stirred for about 8-24 hours or about 12 hours. A second addition / second batch of water is about 1.0-1.5 mL / g Form A, or about 1.10-1.15 mL / g, or about 1.14 mL / g. The second addition / second batch of water is added over about 3-8 or about 5 hours. After the second addition / second batch of water is added, the slurry is cooled to about 20-30°C or about 25°C. The slurry is cooled from about 70°C to about 25°C at a rate of about 10°C / hour until it reaches about 25°C. The approximately 25°C slurry is stirred for at least about 2 hours, then heated to about 60-80°C, or 70-75°C, or about 73°C and stirred for about 1 hour. The slurry is then cooled again to about 20-30°C or about 25°C. The slurry is cooled from about 73°C to about 25°C at a rate of about 10°C / hour. After stirring for at least about 30 minutes to about 8 hours, or about 1-8 hours, or about 2 hours, serpatinib Form B is isolated, for example, by filtration.

[0201] Crystallization methods that effectively convert Form A to Form B are further exemplified in the exemplary embodiments described in the Examples.

[0202] Direct synthesis of Form B of the compound of Formula I.

[0203] In another aspect, the present disclosure relates to a method for preparing a compound of Formula I (i.e., selpatinib) or a pharmaceutically acceptable salt thereof as Form B

[0204] (Formula I).

[0205] In embodiments, the method of preparing serpatinib Form B comprises synthesizing one or more precursor compounds by synthetic methods, such as those disclosed and described elsewhere (e.g., U.S. Patent No. 10,112,942, the entirety of which is incorporated herein by reference). The following exemplary Schemes 1 and 2 show general methods for preparing serpatinib Form B and key intermediate compounds [3] from precursor compounds [2]:

[0206] .

[0207] Detailed descriptions of the synthesis methods of the precursor compound [2] (tert-butyl 3-(5-(3-cyano-6-(2-hydroxy-2-methyl-propyloxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate) are disclosed, for example, in U.S. Patents 10,745,419 and 10,112,942 and International Patent Publication No. WO2018 / 071447, each of which is incorporated herein by reference in its entirety. In a brief overview of one non-limiting embodiment, compound [2] can be prepared by reacting 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate and KCO with stirring under heating (e.g., at 90°C for 12 hours). 3(s) The reaction was prepared by a reaction of 1:1:6.67 molar equivalents in DMSO. The resulting thick slurry was diluted with additional DMSO and stirred under heating (e.g., at 90°C for another 12 hours). After the reaction, the mixture was cooled to ambient temperature and diluted with water, and the resulting aqueous mixture was washed with dichloromethane. The combined organic extracts were purified by anhydrous MgSO 4(s) The mixture is dried, filtered and concentrated in vacuo. The resulting residue is purified by silica gel chromatography (EtOAc / hexane as a gradient elution system) to provide compound [2] in high yield. One skilled in the art will recognize that other synthetic routes can be used to synthesize compound [2]. One skilled in the art will further recognize that compound [2] may contain an amine protecting group other than Boc, including, but not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, nitroveratroxycarbonyl, p-methoxybenzyl and toluenesulfonyl. In some embodiments, the protecting group is tert-butyloxycarbonyl (Boc).

[0208] Generally, the method for the direct synthesis of Form B serpatinib according to the present disclosure comprises reacting compound [2] (tert-butyl 3-(5-(3-cyano-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate) under conditions effective for (1) removal of a protecting group (e.g., Boc, as shown in [2]) and (2) silylation of the hydroxyl group on the 2-hydroxy-2-methyl-propoxy substituent (e.g., TMS, as shown in [3]). The silylated and deprotected compound [3] is then reacted with 6-methoxy-3-pyridinecarboxaldehyde in the presence of a reducing agent and an acid in an organic solvent (e.g., anisole).

[0209] The silyl moiety (e.g., TMS in some exemplary embodiments) is removed under conditions effective for deprotection, such as by the addition of a fluorine source (e.g., tetrabutylammonium fluoride (TBAF)). Following the reaction and removal of the silyl protecting group, the pH of the reaction mixture is adjusted with a base and cooled to form and isolate crystalline Form B serpatinib.

[0210] In some embodiments, conditions effective for removing protecting groups and silylation may include a solvent selected from the group consisting of polar organic solvents, such as alcohols (e.g., MeOH, EtOH), organic acids (e.g., arylsulfonic acids, such as p-toluenesulfonic acid), aprotic solvents (e.g., acetonitrile), acyl halides in alcohols (e.g., acetyl chloride in methanol to produce an HCl solution), esters (e.g., ethyl acetate), ethers (e.g., anisole), and combinations thereof. In some embodiments, the reaction comprises a deprotecting agent, which may include trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, aluminum chloride, and boron trifluoride. In some embodiments, the deprotecting agent is sulfuric acid, acetyl chloride, or p-toluenesulfonic acid. In some embodiments, the conditions may include heating the reaction mixture, optionally to reflux, for a period of about 1 hour to about 8 hours or longer (e.g., overnight, or about 12 hours).

[0211] In some embodiments, the silyl group used in the reaction may comprise trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), isopropyldimethylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBS / TBDMS), tetraisopropyldisiloxaneidene (TIPDS), di-tert-butylsilylene (DTBS), or triisopropylsilyl (TIPS). The presence of a silyl group (e.g., the TMS group on compound [3]), in addition to acting as a protecting group, also increases the solubility of the compound in the solvent anisole (which can be considered an antisolvent for the non-silylated derivatives of serpatinib Form B, compound [2], and compound [3]).

[0212] Silyl groups can be added using methods known in the art.

[0213] In some embodiments, the reaction of compound [3] with 6-methoxy-3-pyridinecarboxaldehyde is carried out using anisole as a solvent, considering that the solubility of compound [3] in anisole is higher than that of the 2-hydroxy-2-methyl-propoxy form of [3]. In some embodiments, the reducing agent in the reaction may include an alkali metal borohydride, a hydrazine compound, citric acid, a citrate, succinic acid, a succinate, ascorbic acid, and an ascorbate. In some embodiments, the reducing agent is selected from sodium borohydride, lithium borohydride, nickel borohydride, and potassium borohydride. In some embodiments, lithium borohydride is selected from lithium borohydride and lithium triethylborohydride. In some embodiments, sodium borohydride is selected from sodium triacetoxyborohydride (STAB), sodium borohydride, and sodium cyanoborohydride. In some embodiments, the reducing agent is STAB. In some embodiments, the acid in the reaction acts as a catalyst for the reaction and may include an inorganic acid (e.g., HCl, H2SO4, etc.), or a water-soluble organic acid (e.g., acetic acid, pivalic acid, etc.). In some embodiments, the acid comprises pivalic acid.

[0214] The resulting compound is deprotected under conditions sufficient to remove the silyl group (e.g., TMS) but not so harsh as to react with and decompose the reaction product (i.e., selpatinib). In some embodiments, the deprotection of the silyl group comprises adding a fluorine source (e.g., tetrabutylammonium fluoride (TBAF), pyridine·(HF) x , trimethylamine trihydrofluoride (Et3N·3HF), hydrofluoric acid, tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), ammonium fluoride (H4NF), or a weak acid is added to the reaction in an amount effective to react with the silyl group. The conditions used for the deprotection step may include a buffered fluorine source and can be determined empirically, with the conditions being sufficiently mild to avoid decomposition reactions.

[0215] After the reaction, the pH of the reaction mixture is adjusted with a base (e.g., K2CO3 slurry) and cooled to form and isolate crystalline Form B serpatinib. In some embodiments, the crystallization may further comprise adding a small amount of seed crystals of serpatinib Form B. In some further embodiments, the crystallization may comprise any crystallization technique described herein that is effective to convert any remaining amount of serpatinib Form A to Form B.

[0216] Although specific starting materials and reagents are depicted in the following schemes and associated description, other starting materials, reaction conditions, and reagents can be substituted in accordance with the present disclosure to provide the target compound (ie, serpatinib Form B).

[0217] In some embodiments of this aspect, the synthetic method comprises the general reaction scheme depicted in Scheme 1.

[0218]

[0219] In some embodiments of this aspect, the method comprises the general reaction scheme depicted in Scheme 2.

[0220]

[0221] Regardless of whether serpatinib Form B is obtained by direct synthesis or converted from serpatinib (i.e., amorphous serpatinib or another polymorphic form of serpatinib) according to aspects and embodiments of the present disclosure, it can be further provided as a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and can exhibit higher thermodynamic stability than another polymorphic form and / or amorphous form of serpatinib. Serpatinib Form B retains its activity as a RET inhibitor and can be evaluated and assessed for activity by any assay known in the art, including, for example, those described in PCT Publication No. WO2018 / 071447 and U.S. Patent Application Publication No. US20180134702 (each of which is incorporated herein by reference in its entirety).

[0222] The following examples are merely intended to illustrate and describe certain embodiments that fall within the scope of the methods described herein and are encompassed by the claims. Example

[0223] Serpatinib (6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-5-(3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile) used in the crystallization procedures described herein was prepared using the techniques and methods described in U.S. Patent No. 10,112,942.

[0224] Example 1: Crystallization by Cooling

[0225] 264 mg of Form A was dissolved in 20 mL of DCM and aliquoted into (15) 8 mL vials. The vials were then placed in a vacuum oven at 70°C to remove the solvent. Birefringent white solids were observed in all vials. The respective solvents (see Table 2) were added at 50°C with shaking. The heat was turned off and the samples were allowed to cool naturally to room temperature (RT). The samples were stirred overnight and the resulting solids were isolated by vacuum filtration and then air-dried. The vials without solids were placed in the refrigerator for 3 days and then evaporated in a fume hood for 1 day if no precipitation occurred. XRPD data were collected on wet solids (if possible). Approximately 2 / 3 (~66%) of the experiments produced solvates that were metastable after isolation and drying. These metastable solvates (except the chloroform solvate) converted to Form A upon removal from the mother liquor. 81% ACN-MeOH provided Form B, while anisole provided Form A.

[0226] Table 2 . Summary of Cooling Crystallization Experiment

[0227] solvent antisolvent Temperature product DMSO MTBE RT Form B 4:1 toluene-DMF MTBE 50 Form B acetone heptane 50 Form B THF heptane 50 Form B MeOH MTBE 50 Form B + Form A (Secondary) DCM n-BuOAc 50 Form A / / Form B

[0228] Example 2: Evaporation & Vapor Diffusion Crystallization

[0229] Prepare an evaporation plate by dissolving 5 mg of Form A in 0.9-12 mL of solvent in (33) vials. The evaporated solution is manually syringe filtered into clean vials, covered with needle-pierced parafilm, and allowed to evaporate to dryness in a fume hood at room temperature (RT) and ambient humidity. The solution for vapor diffusion is placed in a 20 mL chamber containing 5 mL of antisolvent and capped.

[0230] Approximately half of the crystallization experiments produced solvates or mixtures of solvates and Form A. The majority of the solvates converted to Form A upon desolvation. It is suspected that template effects due to structural similarity may have guided the nucleation of the metastable form. Form B was only obtained from two crystallization experiments using ACN and 5:1 MeOH-THF. X-ray diffraction amorphous forms / thin films were obtained from five solvent systems (THF, 11:1 IPA:acetic acid, benzyl alcohol, acetic acid, and 10:1 EtOH:DMF). Chloroform and 1,4-dioxane solvates were stable upon isolation and solid-state characterization data were collected. IPA is isopropyl alcohol, THF is tetrahydrofuran, and DMF is dimethylformamide.

[0231] Vapor diffusion experiments afforded various solvates or amorphous materials. Five solvates, namely DCM, 1-BuOH, EtOH, THF, and DMSO, were metastable and afforded Form A upon isolation. DMSO / heptane mixtures afforded a mixture of Form A and Form B.

[0232] Example 3: Antisolvent Crystallization

[0233] Antisolvent addition experiments were prepared by dissolving various amounts (9-36 mg) of Form A in 1-15 mL of solvent in (29) 4 mL vials. For the first 17 vials, the antisolvent was added dropwise to the syringe filtered solution until precipitation occurred or the volume of antisolvent was equal to or greater than the volume of solvent. For the second 12 vials, the solution was syringe filtered into a clean vial containing 5 mL of antisolvent. The solid was isolated by vacuum filtration and air dried. Vials in which no precipitation was observed were evaporated for up to 2 weeks. 71% of the antisolvent additions produced Form A or an unstable solvate of Form A. Form B appeared in 24% of the experiments (one result was amorphous). For reverse antisolvent addition, 83% of the experiments produced Form A or a solvate and 17% of the experiments produced Form B.

[0234] Example 4: Slurry crystallization

[0235] A Form A slurry vial was prepared using 10 mg of Form A in a 4 mL vial. Solvents were added to establish the slurry density based on the solubility of Form A in these solvents. The slurry was shaken on a 500 rpm shaker block at 22°C for approximately 3 days. The solid was analyzed by XRPD as a wet cake. Most of the slurry sieve yielded a solid consistent with Form A or a solvate that converted to Form A during the isolation / drying process.

[0236] Another slurry plate containing 10 mg of Form A in a 4 mL vial was prepared in a similar manner as described in the previous paragraph. The slurry was shaken on a 500 rpm shaker block at 22°C for 24 hours. After 24 hours, the mother liquor in each vial was replaced with fresh solvent. The slurry was then stirred for 15 days. The wet solids and dry solids were analyzed by XRPD. At approximately 2 / 3 rd In 66% of the experiments, form B was observed. rd In experiments with a low (~33%) yield, mixtures of Forms A and B or Form A and a solvate (in one case) were obtained. These results suggest that equilibrium was not reached, which could be due to: 1) limited solubility of Form A in the tested solvents, or 2) minimal thermodynamic driving force for the phase transition near the transition point. In slurry crystallization experiments, anisole again provided Form A.

[0237] Table 3 Summary of slurry conditions and results

[0238] solvent Temperature (℃) Final form wet (XRPD) Final form dry (XRPD) MeOH RT Form B Form B EtOH RT Form B Form B ACN RT Form B Form B Wet EtOAc RT Form B Form B nBuOAc RT Form A+B Form A + B CPME RT Form B Form B 1,2-Dimethoxyethane RT Form B Form B EtOAc RT Form B Form B Ethyl formate RT Form B Form B heptane RT Form A + B Form A + B MIBK RT Form B Form B Nitromethane RT Amorphous Form B + A (Secondary) NPA RT Amorphous Form A + B (Secondary) 1-Pentanol RT Amorphous Form A + B Toluene RT Form A + B Form A + B 1:1 MeOH-water RT Form B Form B 1:1 EtOH-water RT Form B Form B DMSO RT Amorphous Form B water RT Amorphous Form A + B Methanol RT (2 hours) Form B Form B Methanol:water (aw = 0.5) RT (1 day) Form B Form B Acetonitrile:water (aw = 0.8) RT (1 day) Form B Form B water RT (5 days) Form A+ B (Minor) Form A+ B (Minor) water RT (7 days) Form A+ B (Minor) Form A+ B (Minor)

[0239] In Table 3 above, if a different time is not described, the slurry was stirred for 15 days.

[0240] Example 5: Solvent-Assisted Grinding

[0241] Two experiments using solvent-assisted mechanical milling were performed. In one experiment, Form B was observed when DMSO was used as the solvent. No form change, i.e., Form A was observed when water was used as the solvent.

[0242] Example 6: Conversion of Form A to Form B

[0243] Serpatinib (2.0 g) was suspended in methanol (200 ml) and stirred at 750 rpm at 55°C. The suspension was stirred at 55°C for 60 minutes. Heating was removed and the suspension was allowed to cool naturally to room temperature. The solid was collected by filtration and dried under vacuum for 4 hours to provide crystals of the title compound (1.72 g, 86%).

[0244] Example 7: Conversion of Form A to Form B

[0245] Serpatinib Form A (152.0 g) was suspended in methanol (1.5 L) and stirred at 750 rpm at room temperature. The suspension was stirred at room temperature (approximately 20°C) overnight. The solid was collected by vacuum filtration. The solid was dried at 45°C under full house vacuum with a nitrogen purge to provide crystals of the title compound (148.28 g, 97.6%).

[0246] Example 8: Conversion of Form A to Form B

[0247] Serpatinib Form A was stirred in methanol (8 mL / g) at room temperature for 18-24 hours. The solid was isolated by filtration and dried under vacuum at 45°C with a slight N2 purge.

[0248] Example 9: Conversion of Form A to Form B

[0249] Form A was dissolved in DMSO (13 mL / g) at 70°C with stirring to obtain a clear solution. The solution was cooled to 50°C. Water (0.3 mL / g) was added, and the solution was seeded with Form B seeds (5 wt % based on the amount of Form A used). Stirred for 12 hours, and then water (1.14 mL / g) was added over 5 hours. The slurry was cooled to 25°C at a rate of 10°C / h. Stirred for at least 2 hours. The slurry was heated to 73°C and stirred for 1 hour. The slurry was cooled to 25°C at a rate of 10°C / h. Stirred for at least 2 hours. The solid was isolated by filtration. The wet cake was washed three times with MeOH (8 mL / g). The solid was dried under vacuum at 45°C with a slight N2 purge.

[0250] Example 10: Synthesis of Form B

[0251]

[0252] 4-[6-(3,6-diazabicyclo[3.1.1]hept-3-yl)-3-pyridinyl]-6-(2-methyl-2-trimethylsilyloxy-propyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile[3]

[0253] This synthetic route to Form B of the compound of Formula I (i.e., selpatinib) may comprise any synthetic route that produces the compound 3-[5-[3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl]-2-pyridinyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester [2].

[0254] To a round-bottom flask (three-necked) equipped with an overhead stirrer, condenser, and thermocouple was added methanol (200 mL, 100%) and acetyl chloride (3.1 mL, 44 mmol, 100%). The mixture was allowed to react, and then tert-butyl 3-[5-[3-cyano-6-(2-hydroxy-2-methyl-propyloxy)pyrazolo[1,5-a]pyridin-4-yl]-2-pyridinyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate[2] (9.9965 g, 19.81 mmol, 100%) was added. Following the addition, the reaction was heated to approximately 60°C (63°C). The temperature was adjusted to reduce the amount of outgassing observed and to avoid possible overdriving of the incidental condenser. After the reaction was assayed to determine complete conversion (approximately 2 hours), the solvent was removed. Acetonitrile (ACN) (approximately 100 mL) was added to the mixture to rinse the sides of the reaction vessel. The solvent mixture was again removed and maintained under a nitrogen atmosphere.

[0255] To the reaction vessel was added additional ACN (300 mL, 100%) and hexamethyldisilazane ("HMDS" 25 mL, 119 mmol, 100%). The reaction was stirred at ambient temperature for approximately 1 hour prior to initial sampling of the reaction mixture to form approximately 1.6% of the title compound based on the amount of [2]. The reaction was allowed to continue at ambient temperature overnight. After sampling the overnight reaction, the mixture was heated to 40°C and sampled after 1 hour at this temperature. The reaction heat was raised to 56°C. During the temperature increase, the mixture refluxed and foamed, which is believed to indicate the release of ammonia. After approximately 1-1.25 hours at this temperature, the reaction was sampled with reflux still observed. The reaction was maintained at temperature for an additional 3 hours and sampled again. The reaction solvent was removed and an aqueous solution of potassium carbonate (100 mL, 50.45 mmol, 5% by mass) was slurried in the reaction vessel. The resulting mixture was washed with water (25 mL) and dried to provide 7.89 g of the title compound [3] (78% yield). (Mass spectrometry, m / z = 477.20, 477.30 (M+H). 1 H NMR (400 MHz, DMSO-d6) d: 8.55 (s, 1H), 8.06 (d, 1H), 7.82 (dd, 1H), 7.66 (dd, 1H).

[0256] Alternative method. To a reaction vessel equipped with an overhead stirrer, condenser, and thermocouple was added tert-butyl 3-[5-[3-cyano-6-(2-hydroxy-2-methyl-propyloxy)pyrazolo[1,5-a]pyridin-4-yl]-2-pyridinyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [2] (9.9965 g, 19.81 mmol, 100%) and p-toluenesulfonic acid (2.1 eq) in 10 volumes of organic solvent. The mixture was allowed to react for 1 hour, after which pyridine (2.1 eq) and hexamethyldisilazane ("HMDS" 6 eq) were added. This reaction mixture was stirred for an additional approximately 1 hour to provide the title compound [3].

[0257]

[0258] 6-(2-Hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Form B)

[0259] 4-[6-(3,6-diazabicyclo[3.1.1]hept-3-yl)-3-pyridinyl]-6-(2-methyl-2-trimethylsilyloxy-propyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile[3] (0.9981 g, 2.094 mmol, 100 mass%), 6-methoxy-3-pyridinecarboxaldehyde (i.e., 6-methoxynicotinaldehyde, 0.4909 mg, 0.003401 mmol, 95 mass%), pivalic acid (0.5328 mg, 0.005217 mmol, 100 mass%), and anisole (10 mL, 91.8 mmol, 100 mass%) were added to a reaction vessel equipped with a magnetic stirrer and stirred to form a slurry. Heat was applied under stirring until a homogeneous solution mixture was obtained. The solution was cooled to ambient temperature and maintained as a homogeneous solution. Once cooled, sodium triacetoxyborohydride (1.0840 g, 5.1147 mmol, 100 mass %) was added and allowed to react. Analysis of the reaction after 2 hours indicated the formation of the TMS-protected derivative of the title compound.

[0260] After the reaction is complete, the process can be continued to remove the TMS protection and crystallize Form B. Water (1 mL, 55.5099 mmol, 100 mass%) and tetrabutylammonium fluoride trihydrate (0.6070 g, 2.322 mmol, 100 mass%) are added to the mixture, and a seed amount (~10 mg) of Form B title compound is optionally added. If no crystals are observed after a period of time, the mixture can be warmed to 50°C. After maintaining the elevated temperature overnight, the reaction is sampled to confirm completion, but no crystallization is observed. The pH of the (slightly acidic) mixture is adjusted by adding potassium carbonate (5 mass% in water) as a slurry in 1 mL aliquots until any observed bubbling ceases and the pH tests basic. The mixture is stirred overnight and sampled to provide the title compound free of detectable impurities; it is obtained in an overall isolated yield of 54%. (Mass spectrometry, m / z = 526.30 (M+H). 1 H NMR (400 MHz, DMSO-d6) d:8.55 (s, 1H), 8.06 (d, 1H), 7.82 (dd, 1H), 7.66 (dd, 1H)

[0261] Alternative method4-[6-(3,6-diazabicyclo[3.1.1]hept-3-yl)-3-pyridinyl]-6-(2-methyl-2-trimethylsilyloxy-propyloxy)pyrazolo[1,5-a]pyridine-3-carbonitrile[3] (1.00 g, 2.10 mmol), 6-methoxy-3-pyridinecarboxaldehyde (1.6 equivalents), pivalic acid (~5 volume equivalents), sodium triacetoxyborohydride (2.5 equivalents), and anisole (10 mL, 91.8 mmol, 100 mass %) were added to a reaction vessel equipped with a magnetic stirrer and allowed to react for approximately 1 hour. Water (10 mL) was added to the reaction mixture. The mixture was filtered through Celite (diatomaceous earth, filter aid). The layers were separated, and saturated sodium chloride solution (10 mL) was added to the organic layer. The layers were separated. 5N HCl (1 mL) was added to the organic layer. The mixture was heated to 95°C for 3 hours. After the reaction, the pH of the mixture (acidic) was adjusted to pH 9 by adding potassium carbonate. The mixture was cooled to allow crystallization. The resulting crystals of serpatinib Form B were filtered, washed with methyl tert-butyl ether (MTBE), and dried to obtain the pure title compound.

[0262] Example 11

[0263] The physical and chemical stability of Form B are important properties—not only for ensuring dissolution and solubility, but also for API and dosage form drug development and manufacturing operations (drying, storage, transport transfer, etc.). Not all crystalline forms possess the stability required for drug development. Crystal forms that are stable to both temperature and humidity are desirable. To evaluate the stability of crystalline forms of selpatinib, accelerated stability studies were conducted. Samples of Form B were weighed into 20 mL scintillation vials and placed in a bell jar (open dish) with a saturated saline solution in an oven at the temperature and time specified in Table 4. Form B was analyzed before and after the accelerated stability study and collected on a Bruker D8 Advance XRPD equipped with a CuKα source (wavelength = 1.54056 Å) and a Linxeye detector, operating at 40 kV and 40 mA, with a 0.2 mm divergence slit. Each sample was scanned from 4° to 30° 2θ at a rate of 0.2 sec / step with a step size of 0.02°. Assays and impurities were evaluated relative to the starting material using an Agilent 1260 HPLC System with a diode array detector. Samples were prepared at appropriate concentrations in a 50 / 50 0.1% TFA-water / 0.1% TFA-ACN mixture and evaluated using the following HPLC conditions: Zorbax Bonus-RP column, 75 x 4.6 mm id, 3.5 micron column, mobile phase A: 0.1% TFA-water, mobile phase B: 0.1% TFA-ACN, gradient: 95% A at time 0, 23% A from time 9.5 to 12.1 minutes, 5% A from time 13 to 16 minutes, and 95% A from time 16.1 to 20 minutes, flow rate: 1.5 mL / min, column temperature: 30°C, UV detection at 210 nm, and injection volume: 3 µL. The stability of Form B was characterized and found to be chemically and physically stable under the conditions tested (Table 4).

[0264] Table 4: Stability of crystalline forms of serpatinib

[0265]

[0266] 1 Note: The crystal form is compared to the XRPD of the unstressed (time 0) sample; NC = no change.

[0267] 2 Note that this measurement is determined in comparison to an unstressed (time 0) sample.

[0268] Example 12: Solubility

[0269] Solubility studies were performed on the crystalline forms of selpatinib described herein. Aqueous media covering the physiological pH range and three simulated fluids were used in these studies. An amount of solid compound sufficient to saturate the solvent volume was weighed into a container with approximately 1 mL of the designated solvent. Samples were mixed at 37°C on an incubator shaker set to 100 rpm. After equilibration, the samples were transferred to centrifugal filters (Durapore PVDF, 0.22 µm pore size) and centrifuged at 10,000 rpm for 3 minutes while maintaining at 37°C. A 100 µL aliquot was then withdrawn from each sample and diluted with 900 µL of 50:50 acetonitrile:water. The pH of the filtrate was recorded using a calibrated scientific pH instrument. Solution concentrations of the compounds were determined by HPLC using an Agilent Zorbax Bonus-RP 4.6 x 75 mm, 3.5 µm column under the following conditions: temperature, 30°C; injection volume, 4 µL; UV detection at 238 nm; flow rate, 1.5 mL / min; autosampler temperature, 25°C; mobile phase A, 0.1% trifluoroacetic acid in water; and mobile phase B, 0.1% trifluoroacetic acid in acetonitrile. The HPLC gradient was as follows: 0 min – 95% A, 5% B; 9.5 min – 23% A, 77% B; 12.1 min – 23% A, 77% B; 13 min – 5% A, 95% B; 16 min – 5% A, 95% B; 16.1 min – 95% A, 5% B; and 20 min – 95% A, 5% B. The following table (Table 5) details the equilibrium solubility data and equilibrium pH, reported as the average of replicate sample preparations. As noted in Table 5, the solid form of the residual solid from the centrifuged samples was verified by XRPD.

[0270] Table 5: Solubility of crystalline forms of Serpatinib at 37°C after 24 hours of equilibrium

[0271] <![CDATA[Solvent 1 > Solubility (mg / mL) Balanced pH water 0.0036 7.146 <![CDATA[0.1N HCl 2 ]]> ≥ 10 1.297 0.01N HCl 4.7700 3.634 pH 4.0 Citrate / Phosphate 0.7116 4.134 pH 4.5 Acetate (USP) 0.1694 4.496 pH 6.0 Phosphate (USP) 0.0086 6.027 pH 7.5 Phosphate (USP) 0.0022 7.526 0.01N NaOH 0.0011 9.985 <![CDATA[SGF 3 ]]> <![CDATA[1.440 4 ]]> 2.644 <![CDATA[FaSSIF 5 ]]> 0.0096 6.445 <![CDATA[FeSSIF 6 ]]> 0.2277 4.928

[0272] 1 Descriptions are consistent with USP, Ph.Eur. and Japanese Pharmacopoeias.

[0273] 2 The solubility in 0.1 N HCl was measured at 21.5°C (ambient temperature).

[0274] 3 SGF: simulated gastric fluid (0.01N HCl / sodium lauryl sulfate 0.05% / NaCl 0.2%).

[0275] 4XRPD of the residual solid showed non-crystalline material.

[0276] 5 FaSSIF: fasting simulated intestinal fluid (NaH2PO4 28.66 mM, sodium taurocholate 3 mM, lecithin 0.75 nM, NaCl 105.8 mM, pH 6.5).

[0277] 6 FeSSIF: fed simulated intestinal fluid (acetic acid 144.04 mM, sodium taurocholate 15 mM, phosphatidylcholine 3.75 mM, NaCl 203.17 mM, pH 5.0).

[0278] The low solubility at higher pH and moderate to high solubility in acidic media are consistent with a weak free base with low intrinsic solubility. The results indicate that this crystalline form of selpatinib has a low intrinsic solubility (approximately 0.001 mg / mL).

Claims

1. A crystalline form of serpatinib, characterized in that: An x-ray powder diffraction (XRPD) pattern comprising peaks at 7.5°, 12.0°, 13.2°, 17.1°, 17.7°, 19.8°, and 21.1° ± 0.2° 2θ with relative intensities of 18.2%, 20.3%, 21.9%, 44.4%, 19.4%, 18.8%, and 100.0%, respectively, measured using an x-ray wavelength of 1.5418 Å.

2. The crystalline form of selpatinib according to claim 1, wherein the crystalline form is characterized by an x-ray powder diffraction (XRPD) pattern having additional peaks at 10.9°, 18.2°, and 24.5° ± 0.2° 2θ.

3. A pharmaceutical composition comprising the crystalline form of selpatinib according to claim 1 or 2 and a pharmaceutically acceptable carrier, diluent or excipient.

4. The pharmaceutical composition according to claim 3, wherein the composition contains less than 20% by weight of other crystalline forms of selpatinib.

5. The pharmaceutical composition according to claim 3, wherein the composition contains less than 10% by weight of other crystalline forms of selpatinib.

6. The pharmaceutical composition according to claim 3, wherein the composition contains less than 5% by weight of other crystalline forms of selpatinib.

7. Use of the crystalline form of selpatinib according to any one of claims 1-2 or the pharmaceutical composition according to any one of claims 3-6 for preparing a medicament for treating cancer.

8. The method according to claim 7, wherein the cancer is selected from the group consisting of lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, multiple endocrine neoplasia type 2A or type 2B, pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal ganglioneuroma and cervical cancer.

9. The use according to claim 8, wherein the cancer is medullary thyroid cancer.

10. The use according to claim 8, wherein the cancer is lung cancer, and the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiolar lung cell carcinoma, RET fusion lung cancer or lung adenocarcinoma.

11. The use according to claim 8, wherein the cancer is RET fusion lung cancer.

12. The use according to claim 8, wherein the differentiated thyroid cancer is refractory differentiated thyroid cancer.

13. A method for preparing the crystalline form of serpatinib according to claim 1, comprising the steps of: (a) suspending selpatinib in a solvent; wherein the solvent comprises methanol; (b) heating the suspension to between 50° C. and 60° C. for 30 to 90 minutes while stirring; (c) removing heat and allowing the suspension to cool to room temperature to form solid crystals; and (d) Collect the solid crystals.

14. A method of converting selpatinib Form A comprising XRPD peaks having relative intensities of 100.0%, 41.6%, 16.0%, 15.5%, 18.0%, 16.5%, 23.9%, 17.2%, 24.3% and 14.4% at 4.9°, 9.7°, 14.8°, 15.5°, 16.5°, 16.8°, 18.0°, 18.5°, 18.8° and 25.5°±0.2°2θ, respectively, as measured using an x-ray wavelength of 1.5418 Å. A method for preparing selpatinib Form B comprising XRPD peaks at 7.5°, 12.0°, 13.2°, 17.1°, 17.7°, 19.8°, and 21.1°±0.2° 2θ with relative intensities of 18.2%, 20.3%, 21.9%, 44.4%, 19.4%, 18.8%, and 100.0%, respectively, as measured by an x-ray wavelength of 40.8 Å, the method comprising: combining serpatinib Form A with a C1-C5 alcohol to generate a slurry; and isolating serpatinib Form B from the slurry, wherein the C1-C5 alcohol comprises methanol and / or ethanol.

15. The method according to claim 14, wherein the C1-C5 alcohol is 10°C to 30°C, and the C1-C5 alcohol comprises methanol.

16. The process according to any one of claims 14 to 15, wherein the C1-C5 alcohol comprises at least 90% by weight of methanol.

17. A method of converting selpatinib Form A comprising XRPD peaks having relative intensities of 100.0%, 41.6%, 16.0%, 15.5%, 18.0%, 16.5%, 23.9%, 17.2%, 24.3% and 14.4% at 4.9°, 9.7°, 14.8°, 15.5°, 16.5°, 16.8°, 18.0°, 18.5°, 18.8° and 25.5°±0.2°2θ, respectively, as measured using an x-ray wavelength of 1.5418 Å. A method for preparing selpatinib Form B comprising XRPD peaks at 7.5°, 12.0°, 13.2°, 17.1°, 17.7°, 19.8°, and 21.1°±0.2° 2θ with relative intensities of 18.2%, 20.3%, 21.9%, 44.4%, 19.4%, 18.8%, and 100.0%, respectively, as measured by an x-ray wavelength of 40.8 Å, the method comprising: a. dissolving serpatinib Form A in a solvent comprising DMSO to form a solution; b. adding water to the solution and thereby forming a slurry; c. Isolation of Serpatinib Form B.

18. The method according to claim 17, wherein the concentration of Form A dissolved in DMSO is 10-15 mL / g.

19. The method according to claim 17, wherein the concentration of Form A dissolved in DMSO is 12-13 mL / g.

20. The method according to claim 18, wherein forming the solution of step a comprises heating selpatinib Form A and a solvent comprising DMSO to 50°C to 70°C.

21. The method according to claim 18, wherein the solution of step a is cooled to a temperature of less than 70°C and greater than 20°C.

22. The method according to claim 17, wherein step b comprises adding 0.1 to 1 ml of water per gram of Form A to the solution.

23. The method according to claim 17, wherein step b comprises adding 0.3 ml of water per gram of Form A to the solution.

24. The method according to claim 17, wherein step b further comprises adding 1 to 15 wt% of Form B seeds.

25. The method of claim 17, wherein after adding water in step b, the slurry is stirred for 6 to 72 hours.

26. The method of claim 17, wherein step b further comprises adding a second amount of water to the slurry.

27. The method according to claim 26, wherein 0.5 to 3 ml of water per gram of Form A is added to the slurry.

28. The method according to claim 17, wherein the slurry of step b is cooled to 20-30°C.

29. The process according to claim 17, wherein the isolated selpatinib Form B from step c is washed with a solvent comprising methanol, ACN, MTBE or water.

30. The method according to claim 29, wherein the isolated serpatinib Form B is washed with methanol until the isolated serpatinib Form B contains less than 0.5 wt% DMSO.

31. A method of converting selpatinib Form A comprising XRPD peaks having relative intensities of 100.0%, 41.6%, 16.0%, 15.5%, 18.0%, 16.5%, 23.9%, 17.2%, 24.3% and 14.4% at 4.9°, 9.7°, 14.8°, 15.5°, 16.5°, 16.8°, 18.0°, 18.5°, 18.8° and 25.5°±0.2°2θ, respectively, as measured using an x-ray wavelength of 1.5418 Å. A method for preparing selpatinib Form B comprising XRPD peaks at 7.5°, 12.0°, 13.2°, 17.1°, 17.7°, 19.8°, and 21.1°±0.2° 2θ with relative intensities of 18.2%, 20.3%, 21.9%, 44.4%, 19.4%, 18.8%, and 100.0%, respectively, as measured by an x-ray wavelength of 40.8 Å, the method comprising: Serpatinib Form A and methanol were combined to form a slurry, and the slurry was stirred until >99 wt% of Form A was converted to Form B, wherein the concentration of serpatinib Form A in methanol was 8 mL / g.

32. A method of converting selpatinib Form A comprising XRPD peaks having relative intensities of 100.0%, 41.6%, 16.0%, 15.5%, 18.0%, 16.5%, 23.9%, 17.2%, 24.3% and 14.4% at 4.9°, 9.7°, 14.8°, 15.5°, 16.5°, 16.8°, 18.0°, 18.5°, 18.8° and 25.5°±0.2°2θ, respectively, as measured using an x-ray wavelength of 1.5418 Å. A method for preparing serpatinib Form B comprising XRPD peaks with relative intensities of 18.2%, 20.3%, 21.9%, 44.4%, 19.4%, 18.8% and 100.0% at 7.5°, 12.0°, 13.2°, 17.1°, 17.7°, 19.8° and 21.1°±0.2° 2θ, respectively, as measured by an x-ray wavelength of 30 Å, the method comprising dissolving serpatinib Form A in DMSO at 60-80°C to form a solution having a DMSO concentration of 10-15 mL / g per gram of Form A; cooling the solution to 40-60°C, adding water; optionally seeding the resulting mixture with Form B seeds; stirring the mixture; adding more water; heating the mixture to 60-80°C; cooling the mixture and isolating Form B.

33. The process according to claim 32, wherein 5 wt% of Form B seeds are added to the mixture.

34. The method according to claim 32 or 33, wherein the first amount of water added is from 0.1 mL / g Form A to 0.5 mL / g Form A.

35. The method of claim 32, wherein the second addition of water is in an amount of 1.0-1.5 mL / g Form A.

36. A method of preparing selpatinib of Formula I or a pharmaceutically acceptable salt thereof as polymorph Form B comprising XRPD peaks at 7.5°, 12.0°, 13.2°, 17.1°, 17.7°, 19.8°, and 21.1° ± 0.2° 2θ with relative intensities of 18.2%, 20.3%, 21.9%, 44.4%, 19.4%, 18.8%, and 100.0%, respectively, as measured using an x-ray wavelength of 1.5418 Å: (Formula I) The method comprises reacting a compound of the following structure or a salt thereof with 6-methoxynicotinaldehyde in a solvent in the presence of an acid and a reducing agent: To prepare selpatinib Form B or a pharmaceutically acceptable salt thereof, wherein the solvent comprises anisole.

37. The method of claim 36, further comprising preparing a compound of structure [3] or a salt thereof, the method comprising reacting a compound of structure [3] or a salt thereof with a deprotecting agent to form a compound of structure [3] or a salt thereof wherein R1 is an amine protecting group.

38. The method of claim 37, wherein the deprotecting agent is selected from the group consisting of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, aluminum trichloride, and boron trifluoride.

39. The method of claim 36, wherein the reducing agent is selected from the group consisting of alkali metal borohydrides, hydrazine compounds, citric acid, citrate salts, succinic acid, succinate salts, ascorbic acid, and ascorbate salts.

40. The method of claim 36, wherein the reducing agent is selected from the group consisting of sodium triacetoxyborohydride (STAB), sodium borohydride, and sodium cyanoborohydride.

41. The method of claim 37, wherein R1 is selected from the group consisting of formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, nitroveratroxycarbonyl, p-methoxybenzyl, and toluenesulfonyl.

42. The method of claim 36, wherein the acid is selected from the group consisting of pivalic acid and acetic acid.

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