Crystalline RET inhibitors

Abstract

Provided herein are crystalline forms of selpercatinib, and methods of making the crystalline forms, that are useful for the treatment and prevention of diseases that can be treated with RET kinase inhibitors, including RET-associated diseases and disorders.

Description

[Background technology]

[0001] Selpercatinib (LOXO-292 or RETEVMO™) is a RET inhibitor approved in the United States for use in treating patients with metastatic RET fusion-positive NSCLC, RET mutant medullary thyroid cancer, and RET fusion-positive thyroid cancer. Selpercatinib, or 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, has the following chemical structure: [ka]

[0002] Although U.S. Patent No. 10,584,124 describes several crystalline forms of selpercatinib, including a crystalline form designated "Form A," a new, thermodynamically more stable crystalline form and a method for making this crystalline form are disclosed herein. This new crystalline form can be incorporated into formulations such as tablets, capsules, and suspensions to provide benefits to patients. Summary of the Invention

[0003] This disclosure relates to a new crystalline form of selpercatinib, referred to throughout as "Form B," and methods for making this thermodynamically stable polymorph. In a general sense, this disclosure provides methods for its preparation, isolation, and characterization.

[0004] As described in more detail below, the compound of formula I (selpercatinib) can be provided in polymorphic forms (form A and form B), and surprisingly, certain processes and methods are effective to provide selpercatinib in its most thermodynamically stable polymorphic form B. As described below and demonstrated by the illustrative examples, processes and methods for producing and preparing selpercatinib in specific polymorphic forms can include converting (i.e., reacting, contacting, and / or treating) a compound of formula I provided in one or more polymorphic forms under crystallization conditions effective to produce form B or convert another polymorph (i.e., form A) to form B. In other aspects, processes and methods for producing form B of selpercatinib can include a synthetic route (i.e., a direct synthetic route) that includes reacting one or more intermediate or precursor compounds under conditions effective to produce form B of selpercatinib.

[0005] Form B has (a) an x-ray powder diffraction (XRPD) pattern that includes a peak at 21.1° and one or more peaks at 17.1°, 17.7°, and 19.8°±0.2° 2θ, when measured using an x-ray wavelength of 1.5418 A; or (b) peaks at 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (each ±0.2 ppm) referenced to the high magnetic resonance of adamantane (δ=29.5 ppm). 13 C solid-state NMR spectrum.

[0006] Also provided is a method of using Form B and pharmaceutical compositions thereof to treat cancer, such as cancer with aberrant RET expression (e.g., a RET-associated cancer, such as medullary thyroid cancer or a RET fusion lung cancer), comprising administering a therapeutically effective amount of Form B to a patient in need thereof.

[0007] Also provided herein is Form B for use in therapy. Further provided herein is Form B for use in the treatment of cancer, particularly cancers associated with aberrant RET expression (e.g., RET-associated cancers such as medullary thyroid cancer or RET fusion lung cancer).

[0008] Also provided herein is the use of Form B in the manufacture of a medicament for treating cancer, particularly for use in treating cancers associated with aberrant RET expression (e.g., RET-associated cancers such as medullary thyroid cancer or RET fusion lung cancer).

[0009] A method for converting selpercatinib form A to selpercatinib form B is also disclosed.

[0010] Also detailed herein is a method of converting serpercatinib form A to serpercatinib form B, comprising combining serpercatinib form A with a C1-C5 alcohol to produce a slurry, and isolating serpercatinib form B from the slurry.

[0011] 1. A method for converting selpercatinib form A to selpercatinib form B, comprising: a. dissolving selpercatinib form A in a solvent comprising DMSO to form a solution; b. adding water to the solution, thereby forming a slurry; c. isolating selpercatinib form B.

[0012] Also described is a process for converting selpercatinib form A to form b, the process comprising combining selpercatinib form A with methanol to form a slurry and stirring the pre-slurry until >99% by weight of form A is converted to form B.

[0013] Another method described herein is a method of converting selpercatinib form A to form B, comprising dissolving selpercatinib form A in DMSO at about 60-80° C. to form a solution having a concentration of about 10-15 mL / g DMSO per gram of form A, cooling the solution to about 40-60° C., adding water, optionally seeding the resulting mixture with seed crystals of form B, stirring the mixture, adding more water, heating the mixture to about 60-80° C., cooling the mixture, and isolating form B.

[0014] Selpercatinib as polymorphic form B of formula I; [ka] or a pharma- ceutically acceptable salt thereof, comprising the steps of: This process produces a compound of the structure: [ka] or a salt thereof in a solvent containing 6-methoxynicotinaldehyde in the presence of an acid and a reducing agent to prepare selpercatinib form B or a pharma- ceutically acceptable salt thereof.

[0015] A compound having the structure [3], which is 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile: [ka] or a pharma- ceutically acceptable salt thereof, are described herein. [Brief description of the drawings]

[0016] [Figure 1] 1 is an overlay of XRPD data for Form A and Form B up to about 26 degrees two theta (2θ). [Diagram 2] Included are 13C solid state NMR data for Form A, Form B, and an overlay comparing Form A to Form B from about 25 to 60 ppm. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Described herein is selpercatinib Form B. This crystalline form of selpercatinib can be used to treat disorders associated with aberrant RET activity, such as IBS or cancer, particularly cancers resulting from excessive RET signaling (i.e., RET-associated cancers). More specifically, this crystalline form of selpercatinib may be used to treat RET-associated 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, bronchiolopulmonary cell carcinoma, multiple endocrine neoplasia type 2A or 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, ganglioneuromatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer.

[0018] Form B is characterized by having an x-ray powder diffraction (XRPD) pattern including a peak at 21.1° and one or more peaks at 17.1°, 17.7°, and 19.8°±0.2° 2θ when measured using an x-ray wavelength of 1.5418 A. Form B also includes peaks referenced to the high magnetic resonance of adamantane (δ=29.5 ppm) at 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (each ±0.2 ppm). 13 C solid-state NMR spectrum is shown.

[0019] Form B may be further characterized by having an x-ray powder diffraction (XRPD) pattern including a peak at 21.1° and one or more peaks at 7.5°, 12.0°, 13.2°, 17.1°, 17.7°, and 19.8°±0.2° 2θ, when measured using an x-ray wavelength of 1.5418A.

[0020] Additionally, Form B may be characterized by having an x-ray powder diffraction (XRPD) pattern including 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, when measured using an x-ray wavelength of 1.5418A.

[0021] Form B contains peaks 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 (each ±0.2 ppm) referenced to the high magnetic resonance of adamantane (δ=29.5 ppm). 13 It can be further characterized by C solid-state NMR spectroscopy.

[0022] Additionally, Form B may be further characterized by a C solid state NMR spectrum containing one or more peaks referenced to the high magnetic resonance of adamantane (δ=29.5 ppm) 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, and 163.5 ppm (each ±0.2 ppm).

[0023] Also described herein are pharmaceutical compositions comprising Form B and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0024] A pharmaceutical composition containing Form B comprises 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 selpercatinib. Preferably, the pharmaceutical composition described herein comprises at least 80% of Form B and less than 20% of other crystalline forms of selpercatinib. More preferably, the pharmaceutical composition comprises at least 90% of Form B and less than 10% of other crystalline forms of selpercatinib. Even more preferably, the pharmaceutical composition comprises at least 95% of Form B and less than 5% of other crystalline forms of selpercatinib. Even more preferably, the pharmaceutical composition comprises at least 97% of Form B and less than 3% of other crystalline forms of selpercatinib. More preferably, the pharmaceutical composition contains at least 98% or 99% Form B and less than 2% or 1%, respectively, of other crystalline forms of selpercatinib.

[0025] Form B may be used in a method for treating cancer, comprising administering an effective amount of Form B to a patient in need thereof. Types of cancer that may be treated using the methods described herein include hematological cancer or solid tumor cancer. Examples of types of cancer that may 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, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer. Specifically, the type of cancer may be lung cancer or thyroid cancer. More specifically, the cancer may be non-small cell lung cancer or medullary thyroid cancer.

[0026] Form B for use in therapy is also described herein.

[0027] Form B may be used in the manufacture of a medicament for the treatment of a RET-related disease or disorder, such as IBS or cancer. Cancers that may be treated using such agents are described herein above. The use of Form B in the manufacture of a medicament may also include performing an in vitro assay using a biological sample from a patient to determine the presence of dysregulation of the RET gene, RET kinase, or any of their expression or activity or levels, and administering a therapeutically effective amount of Form B to the patient if dysregulation of the RET gene, RET kinase, or any of their expression or activity or levels is present. In these uses, the biological sample may be a tumor sample, and the tumor sample may be analyzed using methods known to those skilled in the art, such as genomic / DNA sequencing. Furthermore, in these uses, a sample may be obtained from the patient prior to the first administration of Form B. In these uses of Form B, as described herein, the therapy may be based on the patient being selected for treatment by having at least one of the RET gene, RET kinase, or any of their expression or activity or levels dysregulation. Also, in these uses, Form B may be administered to the patient at a dosage of about 1 mg / kg to 200 mg / kg (subranges of effective dosages are described herein above).

[0028] In this specification, the patient is a patient who has been determined to have RET fusion or RET mutation.Therefore, the term "determine RET fusion or RET mutation" means to determine whether RET fusion or RET mutation exists.The method of determining whether RET fusion or RET mutation exists is known to those skilled in the art, for example, see Wang, Yucong et al., Medicine 2019; 98 (3): e14120.

[0029] As used above and throughout the description of the present invention, the following terms shall have the following meanings, unless otherwise indicated.

[0030] A "pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally accepted in the art for delivery of a biologically active agent to a mammal, eg, a human.

[0031] The terms "treatment," "treat," "treating," and the like are meant to include slowing, halting, or reversing the progression of a disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or relieving 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 or reversed.

[0032] "Effective amount" refers to the amount of crystalline form of selpercatinib that induces a biological or medical response in a patient or a desired therapeutic effect in a patient according to the treating clinician. In one example, the crystalline form of selpercatinib inhibits native RET signaling in an in vitro or ex vivo RET enzyme assay. In another example, the crystalline form of selpercatinib inhibits native RET signaling in mouse whole blood from animals treated with different doses of the compound.

[0033] As used herein, the term "patient" refers to a human.

[0034] The effective amount can be easily determined by the attending diagnostician, such as one skilled in the art, by using known techniques and by observing results obtained under similar circumstances. In determining the effective amount for a patient, the attending diagnostician will take into account a number of factors, including, but not limited to, the race of the patient; the size, age, and general health of the patient; the particular disease or disorder involved; the extent or involvement or severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing regimen; the use of concomitant drugs; and other relevant circumstances.

[0035] Form B is preferably formulated as a pharmaceutical composition to be administered by any route that makes the compound bioavailable, including oral, intravenous, and transdermal routes. More preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing them are well known in the art. (See, for example, Remington: The Science and Practice of Pharmacy (DB Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006).

[0036] As used herein, "granular composition" refers to a composition in granular form, which is a precursor to a pharmaceutical composition in a pharmaceutical manufacturing process.

[0037] As used herein, "manufacturing vessel" refers to a vessel used in the manufacture of pharmaceutical products, but not used in a medicinal chemistry laboratory. Examples of manufacturing vessels include, but are not limited to, hopper collectors, beds, dryer beds, granulator beds, dryer trays, granulator buckets, and mixing bowls.

[0038] In some embodiments, form B material is prepared from form A material. In one embodiment, a method for converting form A to form B comprises combining selpercatinib form A with a C1-C5 alcohol to form a slurry and isolating selpercatinib form B from the slurry. In some embodiments, the method is carried out at a temperature of about 10-80°C, about 10-30°C, about 15-25°C, or about 20°C.

[0039] In some embodiments, the C1-C5 alcohol comprises methanol. A preferred C1-C5 alcohol comprises 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.

[0040] In other embodiments, the method comprises combining selpercatinib form A with water to form a slurry and isolating from the slurry selpercatinib form B. In some embodiments, the method is carried out at a temperature of about 10-80°C, about 10-30°C, about 15-25°C, or about 20°C.

[0041] In some embodiments, the method includes stirring, mixing, or agitating the slurry for a period of time ranging from 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 of time can be about 8-12 hours. In some further embodiments, the period of time is at least 10 minutes.

[0042] In some embodiments, the method may further comprise isolating the selpercatinib form B produced by the method. In some embodiments, the isolation may comprise vacuum filtration. In some embodiments, the isolation may comprise centrifugation.

[0043] In some further embodiments, the methods may further comprise drying the produced selpercatinib form B. Drying may be accomplished using vacuum and / or thermal means.

[0044] In another embodiment, the method comprises dissolving selpercatinib 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 selpercatinib form B produced in the slurry.

[0045] In some embodiments, the method comprises adding about 1 gram of selpercatinib form A to about 10-15 mL / g of DMSO. In some further embodiments, the method comprises adding about 1 equivalent of selpercatinib 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 g of form A in about 12-13 mL of DMSO.

[0046] In some embodiments of the method, forming a solution comprising DMSO and selpercatinib form A comprises heating a solvent comprising selpercatinib form A and 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 further embodiments, the method comprises cooling the solution to a temperature of about 50° C.

[0047] In some embodiments of this method, adding water comprises adding about 0.1 to about 1 mL / g of water per gram of Form A to the solution. In some further embodiments, adding water comprises adding about 0.3 mL / g of water per gram of Form A to the solution.

[0048] In some embodiments of this method, adding water may further comprise adding about 1 to about 15 wt % seed crystals of Form B to the slurry. In some further embodiments, about 1 to about 10 wt % seed crystals of Form B may be added to the slurry. In yet further embodiments, about 5 wt % seed crystals of Form B may be added to the slurry.

[0049] In some embodiments of the method, after the water is added, the slurry is stirred for about 6 hours to about 72 hours, hi some embodiments, the slurry is stirred for at least 12 hours.

[0050] In some embodiments, the method may further include adding a second water to the slurry formed by the addition of the first water. In some embodiments, the second water may be added to the slurry in an amount of about 0.5 to about 3 mL / g of water added to the slurry.

[0051] In some embodiments of the method, the slurry formed by the addition of water is cooled to about 20-30°C.

[0052] In some embodiments, isolating selpercatinib form B comprises filtration. In some embodiments, the isolated selpercatinib form B may be washed with a solvent comprising methanol, ACN, MTBE, or water. In some further embodiments, the isolated selpercatinib form B is washed with a solvent comprising methanol. In still further embodiments, the isolated selpercatinib form B is washed with methanol until the isolated selpercatinib form B contains less than 0.5% DMSO by weight.

[0053] In some of the above aspects and embodiments, the disclosure provides a method for converting selpercatinib form A to form B, the method comprising combining selpercatinib form A with 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 about 18-24 hours. In still further embodiments, the concentration of selpercatinib form A in methanol is about 8 mL / g.

[0054] In some of the above aspects and embodiments, the disclosure provides a method for converting selpercatinib form A to form B, comprising dissolving selpercatinib form A in DMSO at about 60-80° C. to produce a solution having form A at a concentration of about 10-15 mL / g of DMSO per gram of form A, cooling the solution to about 40-60° C., and adding a first amount of water, optionally seeding the resulting mixture with seed crystals of form B, stirring the mixture, adding a second amount of water, heating the mixture to about 60-80° C., cooling the mixture, and isolating form B. In some embodiments of the method, 5% by weight of seed crystals of form B are added to the mixture. In still further embodiments, the first water addition is about 0.1 mL / g of form A to about 0.5 mL / g of form A. In still further embodiments, the second water addition is about 1.0-1.5 mL / g of form A.

[0055] In another aspect, the present disclosure relates to selpercatinib as polymorphic form B of formula I: [ka] or a pharma- ceutically acceptable salt thereof, the process comprising reacting a compound of the structure: [ka] or a salt thereof is reacted with 6-methoxynicotinaldehyde in a solvent in the presence of an acid and a reducing agent to prepare selpercatinib form B or a pharma- ceutically acceptable salt thereof. A stoichiometric amount of acid may be used, but non-stoichiometric amounts are also acceptable. In structure [3], the oxygen bears a TMS group. Although not explicitly shown, it is understood that other alcohol protecting groups may be used. As described herein, other silyl groups may be used in addition to TMS.

[0056] In some embodiments of this aspect, the process further comprises preparing a compound of structure [3], or a salt thereof, having the following structure: [ka] or a salt thereof, wherein R1 is an amine protecting group, is reacted with a deprotecting agent to form a compound of structure [3] or a salt thereof.

[0057] In some embodiments, 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. In some further embodiments, the deprotecting agent is selected from the group consisting of sulfuric acid, p-toluenesulfonic acid, and acetyl chloride.

[0058] In some embodiments, 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, hi some further embodiments, the reducing agent is selected from the group consisting of sodium triacetoxyborohydride (STAB), sodium borohydride, and sodium cyanoborohydride.

[0059] In some embodiments, R1 is selected from the group consisting of formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butyloxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitroveratryloxycarbonyl, p-methoxybenzyl, and tosyl. In some embodiments, R1 is tert-butyloxycarbonyl (Boc).

[0060] In some embodiments, the acid is selected from the group consisting of pivalic acid and acetic acid. In some further embodiments, the acid is pivalic acid. In still further embodiments, a catalytic amount of pivalic acid is used.

[0061] In some embodiments, the reaction of compound [3] is carried out in an aprotic solvent. Examples of protic solvents include ethers such as anisole.

[0062] In another aspect, the present disclosure provides a compound of structure [3]: 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; [ka] or a pharma- ceutically acceptable salt thereof.

[0063] In some embodiments, the present disclosure provides methods of preparing a compound of structure [3] according to the aspects and embodiments described herein.

[0064] In some embodiments of any of the above aspects, the method includes preparing selpercatinib Form B as a free amine.

[0065] Selpercatinib Form A (Form A) may contain a portion of the more thermodynamically stable polymorphic selpercatinib Form B (Form B). While both polymorphic forms are crystalline, high melting, anhydrous, stable and do not interconvert under normal storage or preparation conditions, these polymorphic forms have different properties and characteristics that allow Form A to be distinguished from Form B. Since Form B is more thermodynamically stable, it is necessary to understand how to convert Form A to Form B.

[0066] definition Unless otherwise defined, 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. As used herein, the following terms have the meanings ascribed to them unless otherwise specified.

[0067] As used herein, the term "polymorph" refers to crystals of the same compound that have different physical properties as a result of the ordering of molecules within the crystal lattice. Different polymorphs of a single compound (i.e., compounds of formula I) have one or more different chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties from each other. The differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in the manufacture of compositions and products), dissolution rate (a key factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, moisture sorption, compaction, and particle morphology. Differences in stability can be due to changes in chemical reactivity (e.g., differential oxidation such that a dosage form discolors more rapidly when composed of one polymorph than when composed of another polymorph) or mechanical changes (e.g., changes in crystals on storage as a kinetically favored polymorph transforms to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than the other). As a result of differences in solubility / degradation, some transitions affect efficacy and toxicity. Furthermore, 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 wash free of impurities (i.e., the particle shape and size distribution may be different between one polymorph compared to another). As used herein, "polymorph" does not include amorphous forms of a compound. In some particular embodiments, the polymorphs of the compound of formula I (i.e., selpercatinib form A and selpercatinib form B) comprise the characteristics described herein.

[0068] As used herein, "amorphous" refers to a non-crystalline form of a compound, which may 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 form of a compound) that lacks a regular repeating arrangement of molecules or external planes.

[0069] The term "anhydrous" as used herein refers to a crystalline form of the compound of formula (I) that does not contain a stoichiometric amount of water associated with the crystal lattice. Typically, anhydrous Form A and anhydrous Form B have 1% or less water by weight. For example, 0.5% or less, 0.25% or less, or 0.1% or less water by weight.

[0070] The term "solvate" as used herein refers to a crystalline form of a compound of formula (I) in which the crystal lattice contains one or more solvents.

[0071] The term "hydrate" or "hydrated polymorphic form" refers to a crystalline form of a compound of formula (I), such as a polymorphic form of a compound in which the crystal lattice contains water. Unless otherwise specified, the term "hydrate" as used herein refers to a "stoichiometric hydrate". Stoichiometric hydrates contain water molecules as an integral part of the crystal lattice. In contrast, non-stoichiometric hydrates contain water, but changes in water content do not cause significant changes in the crystal structure. During drying of non-stoichiometric hydrates, a significant proportion of water can be removed without significantly disturbing the crystal network, and the crystals can then be rehydrated to yield the original non-stoichiometric hydrated crystal form. Unlike stoichiometric hydrates, dehydration and rehydration of non-stoichiometric hydrates does not involve a phase transition, so all hydration states of non-stoichiometric hydrates represent the same crystal form.

[0072] "Purity," when used in reference to a composition comprising a polymorph of the compound of formula (I), refers to the percentage of one particular polymorphic form relative to another polymorphic form or amorphous form of the compound of formula (I) in the referenced composition. For example, a composition comprising polymorphic form 1 having a purity of 90% comprises 90 parts by weight of form 1 and 10 parts by weight of the other polymorphic form and / or amorphous form of the compound of formula (I).

[0073] As used herein, a compound or composition is "substantially free" of one or more other components when the compound or composition does not contain a significant amount of such other components. For example, a composition may contain less than 5%, 4%, 3%, 2%, or 1% by weight of other components. Such components may include starting materials, residual solvents, or other impurities that may result from the preparation and / or isolation 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 polymorph of a compound of formula (I) is "substantially free" of other polymorphs when it constitutes at least about 95% by weight of the compound of formula (I) in which the particular polymorph exists. In some embodiments, a particular polymorph of a compound of formula (I) is "substantially free" of other polymorphs when it constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the compound of formula (I) in which the particular polymorph exists. 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.

[0074] As used herein, "substantially pure" when used in reference to a polymorphic form of the compound of formula (I) refers to a sample of the polymorphic form of the compound having a purity of greater than 90%, including greater than 90%, including 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% of the compound and even equal to about 100%, based on the weight of the compound. The remaining material includes other forms of the compound and / or reaction impurities and / or process impurities resulting from its preparation. For example, a polymorphic form of the compound of formula (I) may be considered to be substantially pure in that the purity of the polymorphic form of the compound of formula (I) is greater than 90%, and the remaining less than 10% of the material includes other forms of the compound of formula (I) and / or reaction impurities and / or process impurities, as measured by means currently known and generally accepted in the art. The presence of reaction impurities and / or process impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy.

[0075] To provide a more concise description, some of the quantitative expressions herein are recited as a range from about X to about Y. When a range is recited, the range is not limited to the recited upper and lower limits, but rather includes the entire range from about X to about Y, or any range therein.

[0076] "Room temperature" or "RT" refers to a typical laboratory ambient temperature, which is usually about 25°C.

[0077] The term "excipient" as used herein refers to any material 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, anti-adherents, glidants, dispersants or wetting agents, dissolution retarders or enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavorings, and sweeteners.

[0078] 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. The use of such media and agents for pharmaceutically active materials is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic formulations is contemplated. Supplementary active agents can also be incorporated into the formulation. In addition, various excipients as commonly used in the art may be included. These and other such compounds are described in the literature, for example, in Merck Index, Merck & Company, Rahway, NJ. Considerations for including various ingredients 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.

[0079] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0080] As used herein, ranges and amounts may be expressed as "about" a particular value or range. About includes the exact amount. Thus, "about 5 grams" also means "about 5 grams" and "5 grams." Ranges expressed herein are also understood to include integers and fractions thereof within the range. For example, the range of 5 to 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 the range, including but not limited to 5.25, 6.5, 8.75, and 11.95 grams. The term "about" preceding values ​​for DSC, TGA, TG, or DTA are reported as degrees Celsius and have an allowable variation of + / - 5°C.

[0081] As used herein, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples when the event or circumstance occurs as well as examples when it does not occur. For example, a reaction mixture "optionally containing a catalyst" means that the reaction mixture either contains a catalyst or does not contain a catalyst.

[0082] 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, e.g., NaOH. Certain strong bases can even deprotonate very weakly acidic CH groups 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 a strong base. In some embodiments, potassium hydroxide is used as a strong base.

[0083] 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 about 6 to about 11. Many such weak bases are known and are exemplified by those listed in Handbook of Biochemistry and Molecular Biology, Vol. 1, 3rd ed., G.D.Fassman, CRC Press, 1976, pp. 305-347. Weak bases can be water-soluble or water-insoluble. 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, e.g., trimethylamine, triethylamine, tripropylamine, and tributylamine, benzyldiethylamine, pyridine, quinoline, N-methylmorpholine, aniline, and the like.

[0084] As used herein, "non-nucleophilic base" refers to a base that does not act as a nucleophile, i.e., does not donate an electron pair to an electrophile to form a chemical bond associated with the reaction. Typically, non-nucleophilic bases are bulky and sterically hindered so that a proton can be bound to the basic center, but alkylation and complexation are prevented. 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.

[0085] As used herein, the term "amine protecting group" refers to any group known in the art of organic synthesis for the protection of 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: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclopentyloxycarbonyl (Cbz) and substituted benz ... (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanes such as trimethylsilane; (7) thiol-containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and benzyl, and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl, and trialkylsilane types such as trimethylsilane.

[0086] The term "deprotecting agent" as used herein refers to a reagent or reagent system (reagent(s) and solvent) useful for removing a protecting group. The deprotecting agent may be an acid, a base, or a reducing agent. For example, removal of a benzyl (Bn) group may be achieved by reduction (hydrogenolysis), removal of a carbamate (e.g., Boc group) may be achieved by use of an acid (e.g., HCl, TFA, H2SO4, etc.), optionally with gentle heating, and removal of a silyl group may be achieved by use of a weak acid or a halide (e.g., a fluoride, such as provided by tetra-n-butylammonium fluoride (TBAF)), optionally with gentle heating.

[0087] As used herein, the phrase "reducing agent" generally refers to any species that can reduce another species while being itself oxidized. As used herein, the phrase "oxidizing agent" or "oxidant" generally refers to any species that can oxidize another species while being itself reduced.

[0088] As used herein, the term "triflating reagent" refers to a compound useful in the reaction in which a triflate group is attached to a hydroxy group to form a triflate ester. Triflating agents are sources of trifluoroacetyl groups. Triflating reagents include, but are not limited to, trialkylsilyl triflates, trialkylstannyl triflates, triflic anhydride (trifluoromethanesulfonic anhydride), N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf2), N-(5-chloro-2-pyridyl)triflimide, and N-(2-pyridyl)triflimide.

[0089] As used herein, an "acrylonitrile derivative" is a compound derived from acrylonitrile having the formula CH2CHCN, in which one or more of the 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.

[0090] As used herein, the term "dilute" when used in reference to an acidic solution refers to a solution having an acid concentration of less than about 0.1 N.

[0091] The terms "hydrogen" and "H" are used interchangeably herein.

[0092] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0093] As used herein, the term "alkyl" refers to a hydrocarbon chain, which may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C 1~6 indicates that the group can have 1 to 6 (inclusive) carbon atoms in it. Examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl.

[0094] As used herein, the term "alkylamine" refers to an amine containing one or more alkyl groups. An alkylamine can be a primary amine, a secondary amine, or a tertiary amine. For example, a secondary alkylamine is an amine containing two alkyl groups. Examples include diisopropylethylamine.

[0095] A salt can be formed from a compound in any manner well known to one of ordinary skill in the art, and thus a statement "forming a compound or a salt thereof" includes embodiments in which a compound is formed and the salt is subsequently formed from the compound in a manner well known to one of ordinary skill in the art.

[0096] 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.

[0097] All combinations of embodiments with respect to aspects described herein, to the extent that every combination is inclusive of possible aspects, are specifically encompassed by the present invention as if each combination were expressly recited individually. Furthermore, all subcombinations of embodiments within an aspect described herein, and all subcombinations of embodiments within every other aspect described herein, are also specifically encompassed by the present invention as if each and every subcombination of all embodiments were expressly recited herein.

[0098] Crystallization method. Disclosed herein is a method for converting selpercatinib form A to selpercatinib form B. Although selpercatinib form A can be converted to form B using a variety of different methods, disclosed herein is a crystallization-based method for converting selpercatinib form A to selpercatinib form B.

[0099] 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.

[0100] In one aspect, a method for converting selpercatinib form A to selpercatinib form B is disclosed herein.

[0101] In another aspect, disclosed herein is a method for converting serpercatinib form A to serpercatinib form B, the method comprising combining serpercatinib form A with a C1-C5 alcohol to produce a slurry, and isolating serpercatinib form B from the slurry.

[0102] In yet another embodiment, there is provided a method for converting selpercatinib form A to selpercatinib form B, the method comprising: a. dissolving selpercatinib form A in a solvent comprising DMSO to form a solution; b. adding water to the solution, thereby forming a slurry; c. isolating selpercatinib form B.

[0103] In another aspect, disclosed herein is a method of converting selpercatinib form A to form B, the method comprising combining selpercatinib form A with methanol to form a slurry, and agitating the slurry until >99% by weight of form A is converted to form B.

[0104] Form A has unique XRPD peaks at 4.9, 9.7, and 15.5 degrees 2θ, and Form B has unique XRPD peaks at 7.5, 10.9, and 12.0 degrees 2θ. The 2θ values ​​and / or peak intensities of other peaks also differ between the two forms, as can be seen in Table 1 below. For clarity, all XRPD peaks disclosed herein are ±0.2 degrees 2θ unless expressly specified otherwise. [Table 1]

[0105] In Table 1, all peaks with a relative intensity less than 1.00 are not included in the list.

[0106] XRPD patterns of Form A and Form B were obtained on a Bruker D4 Endeavor x-ray powder diffractometer equipped with a CuKα source (λ=1.54180A) and a Vantec detector operating at 35 kV and 50 mA. Samples are scanned from 4 to 40 2θ° with a 1.0 mm divergence slit, a 6.6 mm fixed anti-scatter slit, and an 11.3 mm detection slit at a step size of 0.008 2θ° and a scan rate of 0.5 sec / step. Dry powder is loaded into a quartz sample holder and a glass slide is used to obtain a smooth surface. Crystalline form diffraction patterns are collected at ambient temperature and relative humidity. Crystalline peak positions are determined in MDI-Jade after shifting the entire pattern based on an internal NIST675 standard with peaks at 8.853 and 26.774 2θ°. It is well known in the field of crystallography that for any given crystalline form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and crystal habit. When the effect of preferred orientation is present, the peak intensities change, but the characteristic peak positions of the polymorph do not. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. It is also well known in the crystallography art that for any given crystalline form, the angular peak positions may vary slightly. For example, peak positions may shift due to variations in the temperature at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In this case, a peak position variability of ±0.2 2θ° is estimated to take into account these potential variations without preventing unambiguous identification of the indicated crystalline form. Confirmation of a crystalline form may be based on any unique combination of prominent peaks.

[0107] DSC-TGA analysis of anhydrous crystalline form A showed an onset of melting at 207.6°C and two endotherms, the first corresponding to the melting of form A followed by an exothermic recrystallization of form B and then the melting of form B. DSC-TGA analysis of anhydrous crystalline form B showed a single endotherm with an onset of melting at 213.3°C.

[0108] Forms A and B are anhydrous polymorphs, although form A is slightly more hygroscopic than form B.

[0109] Forms A and B have similar solubilities. Both have low solubility at 25° C. in many organic solvents, including methyl ethyl ketone (MEK), acetone, and many alcohol-based solvents, and moderate solubility (3-30 mg / ml) in dichloromethane (DCM), dimethyl sulfoxide (DMSO), and THF. Form B is practically insoluble in anisole.

[0110] Form A and Form B 13 The C solid state NMR spectra are shown in Figure 2. Figure 2 also includes an overlay of portions of the spectra, showing that form A has a peak at 30.9 ppm not observable in form B, and form B has a peak at 48.0 ppm not observable in form A. Both spectra were referenced to the high magnetic resonance of adamantane (δ=29.5 ppm).

[0111] A Bruker Avance III HD 400 MHz wide-bore NMR spectrometer operating at a carbon frequency of 100.62 MHz and a proton frequency of 400.13 MHz and equipped with a Bruker 4 mm double resonance probe was used. 13 C cross-polarization / magic angle spinning NMR (solid-state NMR or ssNMR) spectra are acquired. TOSS sideband suppression is used with SPINAL64 decoupling and cross-polarization using a RAMP100 type H-nucleus CP pulse. Acquisition parameters are 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 recycle delay of 3 seconds is used, with 2655 scans. Chemical shifts are referenced to adamantane (δ=29.5 ppm) in a separate experiment. Representative for Form B 13CssNMR 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.

[0112] The above data establishes that Forms A and B 1) have several distinct properties, 2) can be easily distinguished, and 3) Form A can be converted to Form B.

[0113] A variety of different solvents can be used to convert form A to form B. Solvents that can be used to convert form A to form B include 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 of ACN combined with 19 mL of MeOH), wet ethyl acetate, cyclopentyl methyl ether (CPME), 1,2-dimethoxyethane, ethyl acetate, ethyl formate, methyl isobutyl ketone (MIBK), nitrobenzene, and the like. Examples of solvents include, but are not limited to, fluoromethane, 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 includes C1-C5 alcohols, water, DMSO, MTBE, ACN, and mixtures of two or more thereof. In yet other embodiments, the solvent includes methanol, ethanol, water, DMSO, MTBE, ACN, or mixtures of two or more thereof.

[0114] As mentioned above, selpercatinib can form solvates and metastable solid forms, both of which are generally not stable upon drying. Observed solvates include acetone solvates, chloroform solvates, 1,4-dioxane solvates, methyl ethyl ketone (MEK) solvates, dichloromethane (DCM) solvates, 2-butanol solvates, 1-butanol solvates, ethanol solvates, dimethylsulfoxide (DMSO)-water solvates, DMSO solvates, and tetrahydrofuran (THF) solvates. The solvates and metastable forms usually revert to Form A during isolation and / or drying, although films or amorphous material may form. The chloroform and 1,4-dioxane solvates were stable upon isolation / drying.

[0115] Form A used in the methods described herein may contain some Form B. The amount of Form B, if present, ranges from at least about 0.1% to no more than about 25% by weight, or from about 0.5% to about 17% by weight, or from about 1% to about 16% by weight.

[0116] Some non-limiting methods for converting Form A to Form B are described below.

[0117] Conversion method 1 In a preferred embodiment, the method includes combining selpercatinib form A with a solvent, such as a C1-C5 alcohol, to produce a slurry, and isolating selpercatinib form B from the slurry. When the slurry is stirred or otherwise agitated, selpercatinib 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. Except for the difference in temperature, these two embodiments are similar and are described below.

[0118] solvent Examples of C1-C5 alcohols include methanol, ethanol, isopropanol, propanol, butanol, 2-butanol, 3-butanol, and 1-pentanol. In some embodiments, methanol is the preferred C1-C5 alcohol.

[0119] 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.

[0120] Aqueous alcohols may also be used, with the amount of water present being from about 0.1% to about 70% by weight, or from about 1% to about 50% by weight, or from about 2% to about 30% by weight. In other embodiments, the amount of water present is from about 0.5% to about 20% by weight, or from about 1% to about 15% by weight, or from about 2% to about 12% by weight, or from about 10% by weight, or less than about 10% by weight. In one embodiment, the alcohol comprises at least 90% by weight of methanol. In another embodiment, the alcohol comprises about 90% by weight of methanol and about 10% by weight of water. In another embodiment, the alcohol comprises at least 95% by weight of methanol and about 5% by weight of water. Other solvents may be present in the alcohol mixture. In some embodiments, up to about 3% by weight of one or more other solvents may be present.

[0121] temperature Temperature affects the rate at which Form A is converted to Form B, with lower temperatures taking longer than higher temperatures. Although it is possible to stir the Form A and solvent slurry at sub-ambient temperatures, this is usually avoided as it will prolong the conversion of Form A to Form B.

[0122] 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 may be at the desired temperature before the Form A material is added, or the temperature may be adjusted after the Form A material is added.

[0123] 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, that is, outside air temperature. Form A converts to Form B upon stirring in a room temperature solvent, such as methanol, but the conversion is more rapid when the mixture of Form A and the solvent is heated.

[0124] When the slurry is heated to the point where all of Form A has dissolved, the resulting solution can be filtered to remove any insoluble material. After stirring, the solution is stirred and cooled as detailed below.

[0125] time 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 typically not stirred or otherwise agitated for longer than 72 hours, although, if desired, the slurry can be stirred or otherwise agitated for longer than 72 hours. In some embodiments, the slurry is stirred for about 1-12 hours.

[0126] cooling When the mixture of Form A and alcohol has been heated for the period stated above, the heating is stopped and the slurry is allowed to cool for about 4 to 24 hours, or for about 6 to 18 hours, or for about 12 hours.

[0127] Isolation of Form B The Form B material may be isolated using any method known in the art. In one embodiment, the separation comprises gravity filtration. In another embodiment, the separation comprises vacuum filtration. In yet another embodiment, the separation comprises the use of a centrifuge.

[0128] Fresh solvent such as ethanol, methanol, ACN, MTBE, water, or a combination of two or more thereof may be used to wash the Form B material. More preferably, methanol, ACN, MTBE, water, or a combination of two or more thereof is used to wash the Form B material. Even more preferably, a solvent comprising methanol is used. The fresh solvent may be cooled to a temperature of about 0° C. to less than about 20° C. before using it to wash the Form B material.

[0129] The isolated selpercatinib form B may be dried using methods known in the art. Typical methods include heating, passing an inert gas over the solid, and / or using subatmospheric pressure.

[0130] In a further embodiment of this example, the C1-C5 alcohol is combined with selpercatinib form A and the resulting slurry is stirred or otherwise agitated for a length 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 24 hours or longer. Heating the mixture increases the rate of conversion of form A to form B.

[0131] In another embodiment of this method, the method comprises combining selpercatinib form A with methanol to form a slurry and stirring the slurry until >95% by weight, >96% by weight, >97% by weight, >98% by weight, or >99% by weight of form A is converted to form B. The slurry is stirred for about 12-48 hours or about 18-24 hours. The concentration of selpercatinib 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.

[0132] Conversion method 2 In another embodiment, the method includes mixing selpercatinib form A with a solvent, and heating and stirring the resulting mixture until form A dissolves in the solvent. Once a solution is formed, the mixture may be filtered if any insoluble impurities are removed. The mixture is then cooled and water is added. If seed crystals are used, seed crystals may be added at this point. 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 then the form B material is isolated.

[0133] solvent A variety of different solvents may be used. Importantly, the solvent should not form selpercatinib solvates, but rather should provide the desired Form B. Examples of suitable solvents include, but are not limited to, DMSO, C1-C5 alcohols, ACN, MTBE, water, or combinations 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% water by weight.

[0134] The amount of solvent used depends on the solvent used. Typically, 1 g 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.

[0135] temperature Temperature affects the rate at which Form A is converted to Form B, with lower temperatures taking longer than higher temperatures.

[0136] The mixture containing Form A and the solvent is heated to a temperature of about 30°C to about 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 may 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 temperature of the solution is reduced by about 15-35°C. The temperature may 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.

[0137] 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.

[0138] In another embodiment, the solvent is not heated, i.e., stirred at ambient temperature. In these embodiments, the conversion of Form A to Form B takes longer.

[0139] First Tranche of Water When the first aliquot of water (first stage 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 is added (mL of water per g of Form A). In some embodiments, the first aliquot 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.

[0140] The first aliquot of water is added over a period of about 30 seconds to about 15 minutes, or about 1 to 10 minutes, or about 4 to 6 minutes, or about 5 minutes. Longer periods of time may be utilized if desired.

[0141] seed crystal When seed crystals of Form B are added to the mixture, about 0.1 to 15 wt. %, or about 1 to about 10 wt. %, or about 5 wt. % of seed crystals of Form B are used.

[0142] In some embodiments, about 1 wt%, 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% seed crystals are added.

[0143] The seed crystals may be prepared using the methods described herein.

[0144] time After heating the mixture to dissolve the Form A material, reducing the temperature of the mixture by 50-110° C., and adding seed crystals, the mixture is stirred for about 1-96 hours, or about 6-72 hours, or about 8-24 hours if seed crystals are used. 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.

[0145] Second Tranche of Water After stirring for 1-96 hours, a second aliquot of water (stage 2 water) is slowly added. The amount of water in the second aliquot is about 0.3-6 mL / g, 0.50-3.0 mL / g (mL of water per gram of Form A), about 0.75-1.5 mL / g, or about 0.9-1.20 mL / g. In some embodiments, the second aliquot 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 1.06 mL / g, about 1.08 mL / g, about 1.10 mL / g, about 1.12 mL / g, about 1.16 mL / g, about 1.18 mL / g, about 1.19 mL / g, about 1.20 mL / g, about 1.22 mL / g, about 1.26 mL / g, about 1.28 mL / g, about 1.29 mL / g, about 1.30 mL / g, about 1.31 mL / g, about 1.32 mL / g, about 1.33 mL / g, about 1.34 mL / g, about 1.35 mL / g, about 1.36 mL / g, about 1.37 mL / g, about 1.38 mL / g, about 1.39 mL / g, about 1.40 mL / g, about 1.41 mL / g, about 1.42 mL / 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, 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, and about 1.20 mL / g.

[0146] The second aliquot of water is added slowly, i.e., it takes about 0.5 to 24 hours or about 1 to 12 hours to add the entire second aliquot 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 aliquot of water.

[0147] cooling After the second aliquot of water is added, the mixture is cooled to 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, yields tend to be slightly lower than when lower temperatures are used.

[0148] After the second aliquot 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, about 20° C. / hr.

[0149] After reaching the desired temperature, the mixture is stirred for about 1 to about 72 hours, or for 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.

[0150] Isolation of Form B Form B is isolated as described above.

[0151] Fresh solvent such as ethanol, methanol, ACN, MTBE, water, or a combination of two or more thereof may be used to wash the Form B material. More preferably, methanol, ACN, MTBE, water, or a combination of two or more thereof is used to wash the Form B material. Even more preferably, a solvent comprising methanol is used. The fresh solvent may be cooled to a temperature of about 0° C. to less than about 20° C. before using it to wash the Form B material.

[0152] In embodiments where the solvent comprises DMSO, the isolated selpercatinib form B is washed with methanol until the isolated selpercatinib form B contains less than 0.5% DMSO by weight.

[0153] In a further example of this method, selpercatinib form A is dissolved in a room temperature solvent containing DMSO to form a solution having a concentration of about 10-15 mL / g DMSO per gram of form A. Water is then added. The mixture is then allowed to stand, during which time form B is formed. Form B can then be isolated, or additional water can be added and after further stirring (as above), form B can be isolated.

[0154] In another example of this method, selpercatinib form A is dissolved in DMSO at about 60-80° C. or about 70° C. to form a solution having a concentration of about 10-15 mL / g DMSO 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 seed crystals of form B, the mixture is stirred, more water is added, 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 of form A to about 0.5 mL / g of form A, or about 0.3 mL / g of form A. The amount of seed crystals that can be used ranges from about 1-10% by weight, or about 5% by weight, based on the amount of form A. The seed crystal-containing mixture is stirred for about 8-24 hours or about 12 hours. The second addition / division of water is about 1.0-1.5 mL / g, or about 1.10-1.15 mL / g, or about 1.14 mL / g of Form A. The second addition / division of water is added over about 3-8 hours or about 5 hours. After the second addition / division of water is added, the slurry is cooled to about 20-30° C. or about 25° C. The rate of cooling the slurry from about 70° C. to about 25° C. is about 10° C. / hour until it reaches about 25° C. The slurry at about 25° C. 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 to 8 hours, or about 2 hours, selpercatinib form B is isolated, for example, by filtration.

[0155] Crystallization methods effective for the conversion of Form A to Form B are further illustrated in the exemplary embodiments described in the Examples.

[0156] Direct Synthesis of Form B of Compound of Formula I. In another aspect, the present disclosure provides a compound of formula I (i.e., selpercatinib) as Form B, [ka] or a process for preparing a pharma- ceutically acceptable salt thereof.

[0157] In embodiments, the process for preparing selpercatinib form B includes the synthesis of one or more precursor compounds by synthetic methods such as those disclosed and described elsewhere (e.g., U.S. Pat. No. 10,112,942, which is incorporated herein by reference in its entirety). The following exemplary schemes 1 and 2 show general methods for preparing selpercatinib form B and key intermediate compounds [3] from precursor compounds [2]. [ka]

[0158] Detailed descriptions of synthetic methods that can provide the precursor 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) are disclosed, for example, in U.S. Pat. Nos. 10,745,419 and 10,112,942, and International Patent Publication No. 2018 / 071447, each of which is incorporated herein by reference in its entirety. In a brief summary of one non-limiting embodiment, compound [2] is prepared by reacting 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile, 3,6-diaza-bicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester, and KCO in DMSO.3(s) (1:1:6.67 molar equivalents) with stirring under heat (e.g., 90° C. for 12 hours). The resulting viscous slurry is diluted with additional DMSO and stirred under heat (e.g., 90° C. for an additional 12 hours). After reaction, the mixture is cooled to ambient temperature and diluted with water, and the resulting aqueous mixture is washed with dichloromethane. The combined organic extracts are washed with anhydrous MgSO 4(s) The mixture is dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. The resulting residue is purified by silica chromatography (EtOAc / Hexanes as gradient eluent system) to provide compound [2] in high yield. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize compound [2]. Those skilled in the art will further appreciate that compound [2] may contain amine protecting groups other than Boc, including non-limiting examples of formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitroveratryloxycarbonyl, p-methoxybenzyl and tosyl. In some embodiments, the protecting group is tert-butyloxycarbonyl (Boc).

[0159] In general, a method for the Direct Synthesis of Form B selpercatinib according to the present disclosure involves (1) removing 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]) under conditions effective to remove the protecting group. 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 such as anisole.

[0160] The silyl moiety (e.g., TMS in some exemplary embodiments) is removed under conditions effective for deprotection, such as, for example, the addition of a fluoride source (e.g., tetrabutylammonium fluoride (TBAF)). After reaction and removal of the silyl protecting group, the pH of the reaction mixture is adjusted with a base and cooled to allow for the formation and isolation of crystalline form B selpercatinib.

[0161] In some embodiments, conditions effective for removing the protecting group and for silylation may include a solvent selected from 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 generate an HCl solution), esters (e.g., ethyl acetate), ethers (e.g., anisole), and combinations thereof. In some embodiments, the reaction includes a deprotecting agent that may include trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, aluminum trichloride, 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 time ranging from about 1 hour to about 8 hours or more (e.g., overnight, or about 12 hours).

[0162] In some embodiments, the silyl group used in the reaction may include trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), isopropyldimethylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBS / TBDMS), tetraisopropyldisiloxane ylidene (TIPDS), di-t-butylsilylene (DTBS), or triisopropylsilyl (TIPS). The presence of a silyl group (e.g., a TMS group on compound [3]), in addition to acting as a protecting group, provides additional solubility of the compound in the solvent anisole, which may be considered a poor solvent for selpercatinib form B, compound [2], and the non-silylated derivatives of compound [3].

[0163] Silyl groups can be added using methods known in the art.

[0164] In some embodiments, the reaction of compound [3] with 6-methoxy-3-pyridinecarboxaldehyde is carried out using anisole as a solvent, assuming that compound [3] is more soluble in anisole than the 2-hydroxy-2-methyl-propoxy form of [3]. In some embodiments, the reducing agent may include an alkali metal borohydride, a hydrazine compound, citric acid, a citrate salt, succinic acid, a succinate salt, ascorbic acid, and an ascorbate salt. In some embodiments, the reducing agent is selected from sodium borohydride, lithium borohydride, nickel borohydride, and potassium borohydride. In some embodiments, the lithium borohydride is selected from lithium borohydride and lithium triethylborohydride. In some embodiments, the 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 inorganic acids (e.g., HCl, H2SO4, etc.) or organic acids that are water soluble (e.g., acetic acid, pivalic acid, etc.). In some embodiments, the acid includes pivalic acid.

[0165] 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., selpercatinib). In some embodiments, deprotection of the silyl group is accomplished by adding a fluoride source (e.g., tetrabutylammonium fluoride (TBAF), pyridine (HF) or a fluoride derivative (e.g., tetrabutylammonium fluoride (TBAF) or pyridine (HF)) to the reaction in an amount effective to react with the silyl group. x Deprotection step conditions include the addition of a buffered fluoride source, trimethylamine trihydrofluoride (Et3N 3HF), hydrofluoric acid, tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), ammonium fluoride (H4NF), or a weak acid. Conditions for the deprotection step may include a buffered fluoride source and may be empirically determined, while keeping conditions mild enough to avoid decomposition reactions.

[0166] After the reaction, the pH of the reaction mixture is adjusted with a base (e.g., a KCO slurry) and cooled to allow for the formation and isolation of crystalline form B selpercatinib. In some embodiments, the crystallization can further include the addition of a small amount of seed crystals of selpercatinib form B. In some further embodiments, the crystallization can include any of the crystallization techniques described herein that can be effective to convert the remaining amount of selpercatinib form B to form A.

[0167] Although specific starting materials and reagents are shown in the following schemes and associated description, other starting materials, reaction conditions, and reagents can be substituted to obtain the target compound (i.e., selpercatinib Form B) in accordance with the present disclosure.

[0168] In some embodiments of this aspect, the synthetic method comprises the general reaction scheme shown in Scheme 1. [ka]

[0169] In some embodiments of this aspect, the process comprises the general reaction scheme shown in Scheme 2. [ka]

[0170] Whether selpercatinib Form B is obtained by direct synthesis or conversion from selpercatinib (i.e., amorphous selpercatinib or another polymorphic form of selpercatinib) according to aspects and embodiments of the present disclosure, it may further be provided as a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, and may exhibit higher thermodynamic stability compared to other polymorphs and / or amorphous selpercatinib. Selpercatinib Form B retains its activity as a RET inhibitor, and the activity may be evaluated and assessed by any assay known in the art, including, for example, the assays described in PCT Publication No. 2018 / 071447 and U.S. Patent Application Publication No. 2018 / 0134702, each of which is incorporated by reference in its entirety.

[0171] The following examples are provided solely for the purposes of illustrating and describing certain embodiments within the scope of the methods described and claimed herein. EXAMPLES

[0172] The selpercatinib (6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-5 3,6-diazabicyclo[3.1.1]heptan-3)-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile) used in the crystallization procedures described herein was made using the techniques and methods described in U.S. Pat. No. 10,112,942.

[0173] Example 1: Cooling Crystallization 264 mg of Form A was dissolved in 20 mL of DCM and (15) dispensed into equal portions in 8 mL vials. These 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 solvent (see Table 2) was added at 50° C. with shaking. The heat source was switched 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 followed by air drying. The vials without solids were placed in the refrigerator for 3 days and, if no precipitation occurred, were removed and allowed to evaporate in a fume hood for 1 day. XRPD data was collected on the wet solids (if possible). Approximately 10 minutes after the experiment, 10 minutes was left in the refrigerator for 3 days and 10 minutes was left in the fume hood for 3 days. 2 / 3 (approximately 66%) yielded metastable solvates upon isolation and drying. These metastable solvates (except for the chloroform solvate) were quickly converted to form A upon removal from the mother liquor. 81% ACN-MeOH gave form B, and anisole gave form A. [Table 2]

[0174] Example 2: Evaporation and Vapor Diffusion Crystallization Evaporation plates were prepared by dissolving 5 mg of Form A in 0.9–12 mL of solvent (33) in a vial. The evaporation solution was manually syringe filtered into a clean vial, covered with parafilm with a pinhole, and allowed to evaporate to dryness at room temperature (RT) and ambient humidity in a fume hood. The solution for vapor diffusion was placed in a 20 mL chamber containing 5 mL of antisolvent and tightly capped.

[0175] Approximately half of the crystallization experiments produced solvates or mixtures of solvates and Form A. A significant number of solvates were converted to Form A upon desolvation. It is believed that template effects due to structural similarity may direct the nucleation of the metastable form. Form B was obtained from only two crystallization experiments using ACN and 5:1 MeOH-THF. X-ray diffraction amorphous forms / films were obtained from five solvent systems (THF, 11:1 IPA:acetic acid, benzyl alcohol, acetic acid, and 10:1 EtOH:DMF). The chloroform and 1,4-dioxane solvates were stable upon isolation and solid state characterization data was collected. IPA is isopropyl alcohol, THF is tetrahydrofuran, and DMF is dimethylformamide.

[0176] Vapor diffusion experiments yielded a variety of solvates or amorphous material. Five solvates, namely DCM, 1-BuOH, EtOH, THF, and DMSO, were metastable and gave form A upon isolation. DMSO / heptane mixtures gave a mixture of form A and form B.

[0177] Example 3: Antisolvent crystallization (29) Antisolvent addition experiments were prepared by dissolving various amounts (9–36 mg) of Form A in 1–15 mL of solvent in 4 mL vials. For the first 17 vials, the antisolvent was syringe-filtered into the filtered solution until either 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 solids were isolated by vacuum filtration and air-dried. Vials in which no precipitate was observed were allowed to evaporate for periods up to 2 weeks. 71% of antisolvent additions produced Form A or an unstable solvate leading to Form A. Form B appeared in 24% of the experiments (one result was amorphous). Reverse antisolvent additions yielded Form A or a solvate in 83% of the experiments and Form B in 17% of the experiments.

[0178] Example 4: Slurry Crystallization Form A vial slurries were prepared with 10 mg of Form A in 4 mL vials. Solvents were added according to the solubility of Form A in these solvents to produce a certain slurry density. The slurries were shaken on a shaker block at 500 rpm at 22° C. for approximately 3 days. The solids were analyzed as wet cakes by XRPD. The majority of the slurry screens yielded solids consistent with Form A or solvates that converted to Form A during isolation / drying.

[0179] 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 slurries were shaken at 22° C. for 24 hours on a shaker block at 500 rpm. After 24 hours, the mother liquor in each vial was replaced with fresh respective solvent. The slurries were then stirred for 15 days. The solids were analyzed wet and dry by XRPD. Approximately 10 minutes after the experiment, 10 minutes of Form A was shaken at 22° C. for 24 hours ... 2 / 3 Form B was observed in approximately 66% of the remaining experiments. 1 / 3 In about 33% of cases, a mixture of forms A and B or form A and a solvate (1 case) was obtained. These results suggest that equilibrium was not reached, which may be due to 1) the solubility limit of form A in the solvents tested or 2) minimal thermodynamic driving force for phase transformation near the transition point. In the slurry crystallization experiments, anisole again gave form A. [Table 3]

[0180] In Table 3 above, the slurries were stirred for 15 days unless another time is stated.

[0181] Example 5: Solvent-assisted Milling Two experiments using solvent-assisted mechanical milling were carried out 1 In one experiment, when DMSO was used as the solvent, form B was observed. When water was used as the solvent, there was no change in form, i.e., form A was not observed.

[0182] Example 6: Conversion of Form A to Form B Selpercatinib (2.0 g) is suspended in methanol (200 mL) and stirred at 750 rpm at 55° C. The suspension is stirred at 55° C. for 60 minutes. Heating is stopped and the suspension is allowed to cool to room temperature naturally. The solid is collected by filtration and dried under vacuum for 4 hours to give crystals of the title compound (1.72 g, 86%).

[0183] Example 7: Conversion of Form A to Form B Selpercatinib Form A (152.0 g) is suspended in methanol (1.5 L) and stirred at room temperature at 750 rpm. The suspension is stirred overnight at room temperature (about 20° C.). The solid is collected by filtration under vacuum. The solid is dried under full house vacuum with a nitrogen purge at 45° C. to give crystals of the title compound (148.28 g, 97.6%).

[0184] Example 8: Conversion of Form A to Form B Stir selpercatinib form A in methanol (8 mL / g) at room temperature for 18-24 hours. Isolate the solid by filtration. Dry the solid under vacuum at 45 °C with a slight N2 purge.

[0185] Example 9: Conversion of Form A to Form B Dissolve Form A in DMSO (13 mL / g) with stirring at 70° C. to obtain a clear solution. Cool the solution to 50° C. Add water (0.3 mL / g) and then seed the solution with Form B seed crystals (5 wt %, based on the amount of Form A used). Stir for 12 hours and then add water (1.14 mL / g) over 5 hours. Cool the slurry to 25° C. at 10° C. / h. Stir for at least 2 hours. Heat the slurry to 73° C. and stir for 1 hour. Cool the slurry to 25° C. at 10° C. / h. Stir for at least 2 hours. Isolate the solid by filtration. Wash the wet cake three times with MeOH (8 mL / g). Dry the solid under vacuum at 45° C. with a slight N2 purge.

[0186] Example 10: Synthesis of Form B [ka] This synthetic route to form B of the compound of formula I (i.e., selpercatinib) can include any synthetic route that produces the compound tert-butyl-3-[5-[3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl]-2-pyridyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [2].

[0187] To a round-bottom flask (three-neck) equipped with an overhead stirrer, condenser, and thermocouple, methanol (200 mL, 100%) and acetyl chloride (3.1 mL, 44 mmol, 100%) are added. The mixture is allowed to react before adding tert-butyl 3-[5-[3-cyano-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridin-4-yl]-2-pyridyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [2], (9.9965 g, 19.81 mmol, 100%). Upon addition, the reaction is heated to approximately 60° C. (63° C.). The temperature was adjusted to reduce the amount of observable off-gassing and to avoid the possibility of overdriving the attached condenser. The reaction was assayed to determine complete conversion (approximately 2 hours) after which the solvent was removed. Acetonitrile (ACN) (about 100 mL) was added to the mixture to rinse the sides of the reaction vessel. The solvent mixture was again removed and kept under a nitrogen atmosphere.

[0188] Additional ACN (300 mL, 100%) and hexamethyldisilazane ("HMDS" 25 mL, 119 mmol, 100%) are added to the reaction vessel. The reaction is stirred at ambient temperature for approximately 1 hour prior to the first sampling of the reaction mixture, yielding approximately 1.6% of the title compound based on the amount of [2]. The reaction is allowed to proceed overnight at ambient temperature. Following sampling of the overnight reaction, the mixture is heated to 40° C. and sampled after 1 hour at that temperature. Heating of the reaction increases to 56° C. During the temperature increase, the mixture refluxes and bubbles, presumably indicating the evolution of ammonia. After approximately 1-1.25 hours at that temperature, the reaction is sampled with continued observable reflux. The reaction is maintained at that temperature for an additional 3 hours and sampled again. The reaction solvent is removed and aqueous potassium carbonate (100 mL, 50.45 mmol, 5 wt %) is slurried into the reaction vessel. The resulting mixture is washed with water (25 mL) and dried to give 7.89 g of the title compound [3] (78% yield). (Mass spectrometry, m / z = 477.20, 477.30 (M+H). 1 H NMR (400MHz, (DMSO-d6)d:8.55(s,1H), 8.06(d,1H), 7.82(dd,1H), 7.66(dd,1H).

[0189] Alternative process. In a reaction vessel equipped with an overhead stirrer, condenser, and thermocouple, tert-butyl 3-[5-[3-cyano-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridin-4-yl]-2-pyridyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [2], (9.9965 g, 19.81 mmol, 100%), and p-toluenesulfonic acid (2.1 eq.) are added in 10 volumes of organic solvent. The mixture is allowed to react for 1 hour, after which pyridine (2.1 eq.) and hexamethyldisilazane ("HMDS" 6 eq.) are added. The reaction mixture is stirred for an additional hour to give the title compound [3]. [ka]

[0190] In a reaction vessel equipped with a magnetic stirrer, add 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile[3] (0.9981 g, 2.094 mmol, 100 wt%), 6-methoxy-3-pyridinecarboxaldehyde (i.e., 6-methoxynicotinaldehyde, 0.4909 mg, 0.003401 mmol, 95 wt%), pivalic acid (0.5328 mg, 0.005217 mmol, 100 wt%), and anisole (10 mL, 91.8 mmol, 100 wt%) and stir to form a slurry. Heat with stirring until a homogeneous solution mixture is obtained. The solution is cooled to ambient temperature and remains a homogeneous solution. Once cooled, sodium triacetoxyborohydride (1.0840 g, 5.1147 mmol, 100% by weight) 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.

[0191] After completion of the reaction, the method can be continued to remove the TMS protection and crystallize form B. To the mixture, water (1 mL, 55.5099 mmol, 100% by weight) and tetrabutylammonium fluoride trihydrate (0.6070 g, 2.322 mmol, 100% by weight) and, optionally, a quantity (about 10 mg) of seed crystals of the title compound as form B are 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 and checked as complete, but no crystallization is observed. The pH of the mixture (slightly acidic) is adjusted by the addition of potassium carbonate (5% by weight in water) as a slurry in 1 mL aliquots until the observed bubbling ceases and the pH tests basic. The mixture is stirred overnight and sampled to give the title compound without detectable impurities, obtained in an overall isolated yield of 54%. (Mass spectrometry, m / z=526.30(M+H). 1 H NMR (400MHz, DMSO-d6d:8.55(s,1H), 8.06(d,1H), 7.82(dd,1H), 7.66(dd,1H)

[0192] Alternative process. In a reaction vessel equipped with a magnetic stirrer, add 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile[3] (1.00 g, 2.10 mmol), 6-methoxy-3-pyridinecarboxaldehyde (1.6 eq.), pivalic acid (approximately 5 eq. by volume), sodium triacetoxyborohydride (2.5 eq.), anisole (10 mL, 91.8 mmol, 100% by weight) and react for approximately 1 hour. Add water (10 mL) to the reaction mixture. Filter the mixture through Celite (diatomaceous earth, filter aid). Add saturated sodium chloride solution (10 mL) to the organic layer and separate the layers. Separate the layers. 5N HCl (1 mL) is added to the organic layer. The mixture is heated at 95° C. for 3 hours. After the reaction, the pH of the mixture (acidic) is adjusted to pH 9 by adding potassium carbonate. The mixture is cooled and allowed to crystallize. The resulting crystals of selpercatinib form B are filtered, washed with methyl tert-butyl ether (MTBE) and dried to obtain the pure title compound.

[0193] Example 11 The physical and chemical stability of Form B is an important attribute not only for ensuring solubility and dissolution, but also for API and dosage form drug development and manufacturing operations (drying, storage, shipping, transfer, etc.). Not all crystalline forms have the necessary stability to enable drug development. A crystalline form that is stable to both temperature and humidity is desired. Accelerated stability studies are performed to evaluate the stability of the crystalline forms of selpercatinib. Samples of Form B are weighed into 20 mL scintillation vials and placed in bell jars (open dishes) with saturated salt solution in an oven at the temperatures and for the times specified in Table 4. Form B is analyzed before and after the accelerated stability studies and collected on a Bruker D8 Advance XRPD equipped with a CuKα source (wavelength=1.54056A) and Linxeye detector, operating at 40 kV and 40 mA, with a 0.2 mm divergence slit. Each sample is scanned from 4° to 30° 2θ at a rate of 0.2 seconds per step, in 0.02° steps. Assay for starting material and impurities are evaluated using an Agilent 1260 HPLC system equipped with a diode array detector. Samples are prepared at appropriate concentrations in 50 / 50 0.1% TFA in water / 0.1% TFA in ACN and evaluated using the following HPLC conditions: Column Zorbax Bonus-RP, 75x4.6mm id, 3.5 microns, Mobile phase A is 0.1% TFA in water, Mobile phase B is 0.1% TFA in ACN, Gradient is 95% A at time 0, 23% A at time 9.5-12.1 min, 5% A at time 13-16 min, Flow rate of 1.5mL / min, 95% A at time 16.1-20 min, Column temperature of 30°C, UV detection wavelength of 210 nm, injection volume of 3μL. The stability of Form B is characterized and found to be chemically and physically stable under the test conditions (Table 4). [Table 4]

[0194] Example 12: Solubility Solubility studies were completed for the crystalline forms of selpercatinib described herein. These studies used aqueous media and three simulated fluids covering the physiological pH range. A sufficient amount of solid compound to saturate the volume of the solvent is weighed into a vessel containing approximately 1 mL of the specified solvent. The samples are mixed at 37°C in an incubator shaker set at 100 rpm. After equilibration, the samples are transferred to a centrifugal filter (Durapore PVDF, 0.22 μm pore size) and centrifuged at 10,000 rpm for 3 minutes while maintaining the temperature at 37°C. A 100 μL aliquot is then taken from each sample and diluted with 900 μL of 50:50 acetonitrile:water. The pH of the filtrate is recorded using a calibrated scientific pH device. The solution concentration of the compounds is determined by HPLC using an Agilent Zorbax Bonus-RP 4.6x75mm, 3.5μm column under the following conditions: temperature 30°C, injection volume 4μL, UV detection at 238nm, flow rate 1.5mL / min, autosampler temperature 25°C, mobile phase A is 0.1% trifluoroacetic acid in water, mobile phase B is 0.1% trifluoroacetic acid in acetonitrile. The HPLC gradient is 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; 20 min-95% A, 5% B. The table below (Table 3) details the equilibrium solubility data and equilibrium pH reported as an average of two sample preparations. The solid form of the residual solids from the centrifuged samples was verified by XRPD as shown in Table 5. [Table 5] The invention as originally claimed in the present application is set forth below. [1] A crystalline form of selpercatinib, (a) an x-ray powder diffraction (XRPD) pattern, when measured using an x-ray wavelength of 1.5418 A, that includes a peak at 21.1° and one or more peaks at 17.1°, 17.7°, and 19.8°±0.2° 2θ; or (b) Peaks at 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (each ±0.2 ppm) referenced to the high magnetic resonance of adamantane (δ=29.5 ppm). 13 C solid-state NMR spectrum, A crystalline form of selpercatinib characterized by at least one of the following: [2] The crystalline form of selpercatinib described in [1], characterized in that the crystalline form has an x-ray powder diffraction (XRPD) pattern including a peak at 21.1° and one or more peaks at 7.5°, 12.0°, 13.2°, 17.1°, 17.7°, and 19.8°±0.2° 2θ, when measured using an x-ray wavelength of 1.5418A. [3] The crystalline form of selpercatinib described in [1], characterized in that the crystalline form has an x-ray powder diffraction (XRPD) pattern with characteristic 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. [4] The crystalline form includes peaks 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 (each ±0.2 ppm) based on the high magnetic resonance of adamantane (δ=29.5 ppm). 13 A crystalline form of selpercatinib described in [1], characterized by a C solid-state NMR spectrum. [5] The crystalline form includes 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, and 163.5 ppm (each ±0.2 ppm) based on the high magnetic resonance of adamantane (δ=29.5 ppm). 13 A crystalline form of selpercatinib described in [1], characterized by a C solid-state NMR spectrum. [6] A pharmaceutical composition comprising a crystalline form of selpercatinib described in any one of [1] to [5] and a pharma- ceutically acceptable carrier, diluent or excipient. [7] The pharmaceutical composition described in [6], wherein the composition contains less than about 20% by weight of other crystalline forms of selpercatinib. [8] The pharmaceutical composition described in [6], wherein the composition contains less than about 10% by weight of other crystalline forms of selpercatinib. [9] The pharmaceutical composition described in [6], wherein the composition contains less than about 5% by weight of other crystalline forms of selpercatinib.

[10] A method for treating cancer in a patient, comprising administering to a patient in need of such treatment an effective amount of selpercatinib described in any of [1] to [9].

[11] The pharmaceutical composition according to any one of [6] to [9] for use in therapy.

[12] The pharmaceutical composition described in any one of [6] to [9] for use in treating cancer.

[13] The pharmaceutical composition for use according to

[12] , wherein the cancer is selected from the group consisting of 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, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer.

[14] The pharmaceutical composition for use according to

[13] , wherein the cancer is medullary thyroid cancer.

[15] The pharmaceutical composition for use according to

[13] , wherein the cancer is lung cancer, and the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiolopulmonary carcinoma, RET fusion lung cancer, or lung adenocarcinoma.

[16] The pharmaceutical composition for use according to

[15] , wherein the cancer is RET fusion lung cancer.

[17] A process for producing the crystalline form of selpercatinib according to [1], comprising: (a) suspending selpercatinib in a solvent; (b) heating the suspension to 50°C to 60°C while stirring for 30 to 90 minutes; (c) removing heat and cooling the suspension to room temperature to form solid crystals; (d) recovering said solid crystals. A process including.

[18] The process of

[17] , wherein the solvent comprises methanol.

[19] The process of

[17] or

[18] , wherein the suspension is heated to 55°C.

[20] The process described in any one of

[17] to

[19] , wherein the suspension is stirred for 60 minutes.

[21] The process according to any one of

[17] to

[20] , wherein the solid crystals are recovered by vacuum filtration.

[22] A method for converting selpercatinib form A to selpercatinib form B.

[23] The method comprises converting selpercatinib form A to C. 1 ~C 5 with an alcohol to produce a slurry; and isolating selpercatinib form B from the slurry.

[24] Said C 1 ~C 5 The method according to

[22] or

[23] , wherein the alcohol is at about 10°C to about 30°C.

[25] Said C 1 ~C 5 The method according to any one of

[22] to

[24] , wherein the alcohol is at about 15 to 25°C.

[26] Said C 1 ~C 5 The method according to any one of

[22] to

[25] , wherein the alcohol is at about 20°C.

[27] Said C 1 ~C 5 The method according to

[22] or

[23] , wherein the alcohol is at about 10°C to about 80°C.

[28] Said C 1 ~C 5 The method according to any one of

[22] to

[27] , wherein the alcohol comprises methanol.

[29] C 1 ~C 5 The method according to any one of

[22] to

[28] , wherein the alcohol contains at least 90% by weight of methanol.

[30] The method of any one of

[22] to

[29] , wherein the slurry is stirred or otherwise agitated for at least about 10 minutes.

[31] The method according to any one of

[22] to

[30] , wherein isolating form B comprises vacuum filtration.

[32] The method according to any one of

[22] to

[31] , wherein isolating form B comprises centrifugation.

[33] The method according to any of

[22] to

[32] , further comprising drying the selpercatinib form B.

[34] The method, a. dissolving said selpercatinib form A in a solvent comprising DMSO to form a solution; b. adding water to the solution, thereby forming a slurry; c. isolating said selpercatinib form B.

[35] The method according to

[34] , wherein the concentration of Form A dissolved in DMSO is about 10-15 mL / g.

[36] The method according to

[34] or

[35] , wherein the concentration of Form A dissolved in DMSO is about 12-13 mL / g.

[37] The method according to any of

[34] to

[36] , wherein forming the solution in step a comprises heating a solvent containing the selpercatinib form A and the DMSO to about 50°C to about 70°C.

[38] The method according to any one of

[34] to

[37] , wherein the solution is cooled to a temperature less than about 70°C and greater than about 20°C.

[39] The method of

[37] , wherein the solution is cooled to a temperature of about 50°C.

[40] The method of any of

[34] to

[39] , wherein step b comprises adding about 0.1 to about 1 mL of water per gram of Form A to the solution.

[41] The method of any of

[34] to

[40] , wherein step b comprises adding about 0.3 mL of water per gram of Form A to the solution.

[42] The method according to any one of

[34] to

[41] , wherein step b further comprises adding about 1 to about 15 wt% seed crystals of form B.

[43] The method according to any one of

[34] to

[42] , wherein step b further comprises adding about 1 to about 10 wt% seed crystals of form B.

[44] The method of

[42] or

[43] , wherein about 5% by weight of seed crystals of Form B are added.

[45] The method according to any one of

[34] to

[44] , wherein after the water is added in step b, the slurry is stirred for about 6 hours to about 72 hours.

[46] The method according to any one of

[34] to

[45] , wherein the slurry is stirred for at least 12 hours.

[47] The method of any of

[34] to

[46] , wherein step b further comprises adding a second aliquot of water to the slurry.

[48] ​​The method of

[47] , wherein about 0.5 to about 3 mL of water per gram of Form A is added to the slurry.

[49] The method according to any one of

[34] to

[48] , wherein the slurry in step b is cooled to about 20 to 30°C.

[50] The method according to any one of

[34] to

[49] , wherein step c includes filtration.

[51] The method according to any of

[34] to

[50] , wherein the isolated selpercatinib form B from step c is washed with a solvent comprising methanol, ACN, MTBE, or water.

[52] The method of

[51] , wherein the isolated selpercatinib form B is washed with a solvent comprising methanol.

[53] The method of

[52] , wherein the isolated selpercatinib form B is washed with methanol until the isolated selpercatinib form B contains less than 0.5% by weight of DMSO.

[54] The method of

[22] , the method comprising combining selpercatinib form A with methanol to form a slurry and stirring the slurry until >99% by weight of the form A is converted to form B.

[55] The method according to

[54] , wherein the slurry is stirred for about 18 to 24 hours.

[56] The method of

[54] or

[55] , wherein the concentration of the selpercatinib form A in the methanol is about 8 mL / g.

[57] The method of

[22] , the method comprising: dissolving selpercatinib form A in DMSO at about 60-80°C to form a solution having a concentration of about 10-15 mL / g DMSO per gram of form A; cooling the solution to about 40-60°C; adding water; optionally seeding the resulting mixture with seed crystals of form B; stirring the mixture; adding more water; heating the mixture to about 60-80°C; cooling the mixture; and isolating form B.

[58] The method of

[57] , wherein 5 wt. % seed crystals of Form B are added to the mixture.

[59] The method of

[57] or

[58] , wherein the first water addition is from about 0.1 mL / g of Form A to about 0.5 mL / g of Form A.

[60] The method of any of

[57] to

[59] , wherein the second water addition is about 1.0 to 1.5 mL / g of Form A.

[61] Selpercatinib as polymorphic form B of formula I;

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[62] The method according to claim 1, further comprising preparing a compound of structure [3], or a salt thereof, said process comprising preparing a compound of the following structure:

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[63] The process of

[61] or

[62] , 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.

[64] The process of

[62] or

[63] , wherein the deprotecting agent is selected from the group consisting of sulfuric acid, p-toluenesulfonic acid, and acetyl chloride.

[65] The process according to any one of

[61] to

[64] , wherein the reducing agent is selected from the group consisting of alkali metal boron hydrides, hydrazine compounds, citric acid, citrate salts, succinic acid, succinate salts, ascorbic acid, and ascorbate salts.

[66] The process according to any one of

[61] to

[65] , wherein the reducing agent is selected from the group consisting of sodium triacetoxyborohydride (STAB), sodium borohydride, and sodium cyanoborohydride.

[67] R 1 is selected from the group consisting of formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butyloxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitroveratryloxycarbonyl, p-methoxybenzyl, and tosyl.

[68] R 1 The process according to any one of

[61] to

[67] , wherein is tert-butyloxycarbonyl (Boc).

[69] The process according to any one of

[61] to

[68] , wherein the acid is selected from the group consisting of pivalic acid and acetic acid.

[70] The process according to any one of

[61] to

[69] , wherein the reaction is carried out in a solvent, and the solvent comprises anisole.

[71] A compound having the structure [3], which is 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.

change

Claims

1. Selpercatinib as crystalline polymorphic form B of formula I; 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, comprising the steps of: The process comprises producing a compound having the structure: 【Chemistry 2】 or a salt thereof with 6-methoxynicotinaldehyde in the presence of an acid and a reducing agent in a solvent comprising anisole to prepare a crystalline form of selpercatinib form B or a pharma- ceutically acceptable salt thereof.

2. The method further comprises preparing a compound of structure [3], or a salt thereof, the process comprising: 【Chemistry 3】 or a salt thereof (wherein, R １ is an amine protecting group) with a deprotecting agent to form a compound of structure [3] or a salt thereof.

3. 3. The process of claim 1 or 2, 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.

4. 4. The process of any one of claims 1 to 3, 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.

5. 5. The process of any one of claims 1 to 4, wherein the reducing agent is selected from the group consisting of sodium triacetoxyborohydride (STAB), sodium borohydride, and sodium cyanoborohydride.

6. R １ is selected from the group consisting of formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butyloxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitroveratryloxycarbonyl, p-methoxybenzyl, and tosyl.

7. The process of any one of claims 1 to 6, wherein the acid is selected from the group consisting of pivalic acid and acetic acid.

8. A compound having the structure [3], which is 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile, 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

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