UA129813C2 - CRYSTALLINE FORM OF RET INHIBITOR - Google Patents

Abstract

Provided herein is a crystalline form of selpercatinib useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders, and methods of making this crystalline form.

Description

Prerequisites for creating an invention

Selpercatinib (zeiIregsaiyipib) ((0OXO-292 or KETEMMO "M) is a KET inhibitor approved in

United States for use in the treatment of patients with KET fusion-positive metastatic non-small cell lung cancer (MSLC), KET-mutant medullary thyroid cancer, and KET fusion-positive thyroid cancer. Selpercatinib, or 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((b-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:

WITH

Ministry of Education, Culture, Sports, Science and Technology,

M what is it (Formula I).

While U.S. Patent No. 10,584,124 describes several crystalline forms of selpercatinib, including a crystalline form referred to as "Form A," the present disclosure discloses a novel, thermodynamically more stable crystalline form and methods for preparing this crystalline form. This novel crystalline form can be incorporated into dosage forms such as tablets, capsules, and suspensions for the benefit of patients.

The essence of the invention

This disclosure relates to a novel crystalline form of selpercatinib and methods for preparing this thermodynamically stable polymorph, referred to herein as "Form B." In general, this disclosure discloses methods for preparing, isolating, and characterizing it.

As described in more detail below, the compound of Formula I (selpercatinib) may be provided as polymorphic forms (Form A and Form B) and, surprisingly, certain processes and methods are effective for obtaining selpercatinib in its most thermodynamically stable polymorphic Form B. As described below and demonstrated by illustrative working examples, processes and methods for generating and obtaining selpercatinib in a particular polymorphic form can involve transforming (i.e., reacting, contacting, and/or treating) a compound of Formula I, provided as one or more polymorphic forms, under crystallization conditions that are effective for generating or converting other polymorphs (i.e.,

Form A) to Form B. In other aspects, processes and methods for preparing selpercatinib Form B can involve a synthetic route that involves reacting one or more chemical intermediates or precursor compounds under conditions that are effective to prepare selpercatinib Form B (i.e., direct synthetic routes).

Form B is characterized by at least one of the following: (a) an X-ray powder diffraction (XPD) pattern that contains a peak at 21.1", and one or more peaks at 17.17", 17.77 and 19.87-0.27 26, as determined using X-rays with a wavelength of 1.5418 Å (0.15418 nm), or (B) a solid-state "C NMR spectrum that contains peaks associated with the adamantane resonance in the presence of a strong magnetic field (5-29.5 million") at: 28.0 million", 48.0 million", 80.4 million", 106.8 million", 130.2 million" and 134.9 million" (70.2 million), respectively.

Also provided are methods of using Form B and pharmaceutical compositions comprising said Form B for the treatment of cancer, such as cancer with aberrant KET expression (e.g.,

EET-associated cancer, such as medullary thyroid cancer or lung cancer with fusion

KET). Said methods include administering a therapeutically effective amount of Form B to a patient in need thereof.

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

Also provided is the use of Form B in the manufacture of a medicament for the treatment of cancer, in particular for use in the treatment of cancer with aberrant KET expression (e.g., KET-

associated cancer, such as medullary thyroid cancer or lung cancer with fusion

KET).

Methods for converting selpercatinib Form A to selpercatinib Form B are also disclosed.

This description also details a method for converting selpercatinib Form A to selpercatinib Form B, said method comprising: combining selpercatinib Form A

A with a C1-C5 alcohol to obtain a suspension, and isolating selpercatinib Form B from said suspension.

Also described is a method for converting selpercatinib Form A to selpercatinib Form B, which comprises: a) dissolving selpercatinib Form A in a solvent containing OM5O to form a solution; b) adding water to said solution, thereby forming a suspension; c) isolating selpercatinib Form B.

Also described is a method for converting selpercatinib Form A to Form B, said method comprising: combining selpercatinib Form A and methanol to form a suspension, and stirring said suspension until >99% (w/w) of Form A is converted to Form B.

Another method disclosed herein is a method for converting selpercatinib Form A to selpercatinib Form B, wherein selpercatinib Form A is dissolved in OM5O at about 60-80°C to form a solution with a concentration of about 10-15 mL/g OM5O per 1 g of Form A; cooling said solution to about 40-60°C, adding water; optionally introducing seed crystals of Form B into the resulting mixture; mixing said mixture; adding additional water; heating said mixture for about 60-80 seconds; cooling said mixture, and isolating Form B.

This description also discloses a method for preparing selpercatinib as nolimorph Form B.

Formula I:

M- m more

DE no | u ko | M osn y M y | Z

M that is (Formula II) or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound having the structure

Formulas:

M-

What else | EM o NE ko | M rya

M

MN

ISI or its salts in a solvent with b-methoxynicotinaldehyde in the presence of an acid and a reducing agent, and obtaining selpercatinib Form B or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a compound which is 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxypropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile, and which has the structure:

M- and -

I" I -I M o ko y | M r

M a

ISI or a pharmaceutically acceptable salt thereof.

Brief description of the figures

Figure 1 shows an overlay of X-ray powder diffraction data of Form A and Form B up to approximately 26" two theta (29).

Figure 2 shows solid-state HF NMR spectral data for Form A and Form B, and an overlay from approximately 25 million to 60 million comparing Form A to Form B.

Detailed description

This specification describes selpercatinib Form B. This crystalline form of selpercatinib can be used to treat disorders associated with abnormal KET activity, such as irritable bowel syndrome or cancer, particularly cancer caused by excessive KET signaling (i.e., KET-associated cancer). More specifically, this crystalline form of selpercatinib can be used to treat cancers associated with KET, such as lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine neoplasm, lung adenocarcinoma, lung bronchiole cell carcinoma, multiple endocrine neoplasia type 2A or 28 (MEM2A or MEM2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, breast carcinoma, breast neoplasm, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastric mucosa, inflammatory myofibroblastic tumor or cervical cancer.

Form B is characterized by an X-ray powder diffraction (XRD) pattern containing a peak at 21.17, 0) and one or more peaks at 17.17, 17.77 and 19.87-0.27 26, as determined using X-rays at a wavelength of 1.5418 Å (0.15418 nm). Form B also exhibits a solid-state "C NMR spectrum containing peaks associated with the resonance of adamantane in the presence of a strong magnetic field (5-29.5 million") at: 28.0 million", 48.0 million", 80.4 million", 106.8 million", 130.2 million" and 134.9 million" (10.2 million), respectively.

Form B can be further characterized using an X-ray powder diffraction (XRD) pattern that contains a peak at 21.17, and one or more peaks at 7.57, 12.07, 13.27, 17.17, 17.77, and 19.87-0.27 26, as determined using X-rays at a wavelength of 1.5418 Å (0.15418 nm).

In addition, Form B can be characterized using an X-ray powder diffraction (XPD) pattern that contains a peak at 21.1", and one or more peaks at 7.5", 10.97, 12.07, 13.27, 17.17, 17.77, 18.27, 19.87, 21.17 and 24.570.27 26, as determined using X-rays at a wavelength of 1.5418 Å (0.15418 nm).

Form B can also be characterized by a solid-state C NMR spectrum, which contains peaks associated with the adamantane resonance in the presence of a strong magnetic field (5-29.5 million") at: 26.4 million", 28.0 million", 42.0 million", 43.9 million", 48.0 million", 56.3 million", 69.5 million", 80.4 million", 102.3 million", 106.8 million", 115.2 million", 120.8 million", 130.2 million", 134.9 million", 140.6 million", 149.5 million- 1, 152.5 million" and 163.5 million" (x50.2 million), respectively).

In addition, Form B can be characterized by a solid-state C NMR spectrum containing one or more peaks associated with the adamantane resonance in the presence of a strong magnetic field (0-29.5 million) at: 26.4 million, 27.4 million, 28.0 million, 42.0 million, 43.4 million, 43.9 million, 48.0 million, 53.9 million, 56.3 million, 58.3 million, 69.5 million, 77.9 million, 80.4 million, 102.3 million, 106.8 million, 113.6 million, 115.2 million, 118.2 million, 120.8 million, 125.2 million, 130.2 million, 134.9 million-1, 136.9 million, 140.6 million, 148.4 million", 149.5 million", 151.2 million", 152.5 million", 158.2 million", 163.5 million" (10.2 million", respectively).

Also described herein is a pharmaceutical composition comprising Form B and one or more pharmaceutically acceptable carriers, diluents, or excipients.

A pharmaceutical composition comprising Form B comprises at least 5 95 (wt.), 10 90 (wt.), 20 95 (wt.), 30 95 (wt.), 40 95 (wt.), 50 95 (wt.), 60 95 (wt.), 70 95 (wt.), 80 95 (wt.), 90 95 (wt.), 95 95 (wt.), 96 95 (wt.), 97 95 (wt.) 98 95 (wt.), 99 95 (wt.) or 100 95 (wt.)

Form B, compared to other crystalline forms of selpercatinib. In a preferred embodiment, the pharmaceutical compositions disclosed herein contain at least 80 95

Form B and less than 20 95 other crystalline forms of selpercatinib. More preferably, the pharmaceutical compositions contained at least 90 95 Form B and less than 10 95 other crystalline forms of selpercatinib. More preferably, the pharmaceutical compositions contained at least 95 95 Form B and less than 595 other crystalline forms of selpercatinib. More preferably, the pharmaceutical compositions contained at least 97 95 Form B and less than 3 905 other crystalline forms of selpercatinib. More preferably, the pharmaceutical compositions contained at least 98 95 or 99 95 Form B and less than 2 95 or 1 95, respectively, other crystalline forms of selpercatinib.

Form B can be used in a method of treating cancer, which comprises administering an effective amount of Form B to a patient in need thereof. Types of cancer that can be treated using the methods disclosed herein include hematological cancers or solid cancers. Examples of types of cancer that can be treated using Form B include lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 28 (MEM2A or MEM2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastric mucosal ganglioneuromatosis, and cervical cancer. In particular, the types of cancer can be lung cancer or thyroid cancer. More specifically, the cancer may be non-small cell lung carcinoma or medullary thyroid cancer.

This description also discloses Form B for use in therapy.

Form B can be used in the manufacture of a medicament for the treatment of diseases or disorders associated with KET, such as irritable bowel syndrome or cancer. Cancers that can be treated with such a medicament are described above. The use of Form B in the manufacture of a medicament can also include the step of conducting an in vitro study using a biological sample from a patient, determining whether there is dysregulation of the KET gene, KET kinase or the expression, activity or level of any of them, and administering a therapeutically effective amount of Form B to the patient if there is dysregulation of the KET gene, KET kinase or the expression, activity or level of any of them. In these cases, the biological sample can be a tumor sample, and the tumor sample can be investigated using methods known to those skilled in the art, such as genome/DNA sequencing.

Additionally, in these cases, a sample may be obtained from the patient prior to the first administration.

Forms B. In these instances of using Form B as disclosed herein, therapy may be based on selecting a patient for treatment in the presence of at least one dysregulation of the KET gene, KET kinase, or the expression, activity, or level of any of them.

In addition, in these applications, Form B can be administered to a patient at a dose of from about 1 mg/kg to 200 mg/kg (effective dosage subranges are noted above).

In this case, the patient is one who has been identified as having a KET fusion or a KET mutation. Thus, the term "identifying a KET fusion or a KET mutation" means identifying the presence of a fusion

KET or KET mutations. Methods for determining the presence of a KET fusion or KET mutation are known to those skilled in the art, for example, see Umapod, Wisopoa, et al., Medicine 2019;98(3):e14120.

As used above and throughout the specification, the following terms, unless otherwise indicated, have the meanings set forth below. "Pharmaceutically acceptable vehicle, diluent, or excipient" refers to a medium commonly used in the art for delivering biologically active agents to mammals, e.g., humans.

AND

The terms "treatment", "treat", "course of treatment", etc., encompass slowing, stopping or reversing the progression of a disorder. These terms also encompass alleviating, reducing the intensity of, alleviating, eliminating or reducing 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, stopped or reversed.

The term "effective amount" refers to the amount of a crystalline form of selpercatinib that will elicit a biological or medical response or cause a therapeutic effect desired by the clinician in a patient. In one example, a crystalline form of selpercatinib inhibits native KET signaling in an in vitro or in vivo KET enzyme assay. In another example, a crystalline form of selpercatinib inhibits native KET signaling in whole blood of mice from animals receiving various doses of the compound.

The term "patient" in this description refers to a human.

An effective amount can be readily determined by a diagnostician skilled in the art using known methods and by observing results obtained under similar circumstances. In determining an effective amount for a patient, the diagnostician will consider a number of factors, including, but not limited to: the type of patient; the size, age, and general health of the patient; the particular disease or disorder; 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 drug administered; the dosage regimen selected; the use of concomitant medications; and other relevant circumstances.

Form B is preferably provided in the form of pharmaceutical compositions that are administered by any route that makes the compound bioavailable, including oral, intravenous, and transdermal routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and methods for their preparation are well known in the art. (See, e.g., Keptipdiop: Te 5siepse apa Pragasiisei oi Rpaptasu (O.V. Tou, Eayog, 2151 Eayog,

Pripsoy, UMiShatv»e 5 MLIKip5, 2006).

As used herein, the term "granulated composition" refers to a composition in granular form which, in the pharmaceutical manufacturing process, constitutes a precursor composition to a pharmaceutical composition.

As used herein, the term "production container" refers to a container used in the manufacture of pharmaceuticals, but not in a medicinal chemistry laboratory. Examples of production containers include, but are not limited to, a collection hopper, a tray, a drying tray, a granulator tray, a drying tray, a granulator ladle, and a mixing bowl.

In some embodiments of the present invention, the Form B material is obtained from a material

Form A. In one embodiment of the present invention, a method for converting Form A to

Form B comprises: combining selpercatinib Form A with a C1-C5 alcohol to form a suspension, and isolating selpercatinib Form B from the suspension. In some embodiments of the present invention, the method is carried out at a temperature of about 10-80°C, about 10-15°C, about 15-25°C, or about 20°C.

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

In other embodiments of the present invention, said method comprises: combining selpercatinib Form A with water to form a suspension, and isolating selpercatinib Form A.

In some embodiments of the present invention, 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.

In some embodiments of the present invention, the method includes mixing or stirring the suspension for a period of time that is at least about 5 minutes (e.g., at least 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or at least 60 minutes). In some embodiments of the present invention, the period of time can be about 8-12 hours. In other embodiments of the present invention, the period of time is at least 10 minutes.

In some embodiments of the present invention, the method may also include isolating the selpercatinib Form B obtained by the method. In some embodiments of the present invention, the isolating may include vacuum filtration. In some embodiments of the present invention, the isolating may include separation by centrifugation.

In some other embodiments of the present invention, the method may also include drying the resulting selpercatinib Form B. Drying may be accomplished using vacuum and/or thermal means.

In other embodiments of the present invention, said method comprises dissolving selpercatinib Form A in a solvent containing OM5O to form a solution; adding water to said solution in an amount to form a suspension; and isolating selpercatinib Form B formed in the suspension.

In some embodiments of the present invention, the method comprises adding about 1 g of selpercatinib Form A to about 10-15 mL/L of OM5O. In some other embodiments of the present invention, the method comprises adding about 1 eq. of selpercatinib Form A to about 12-13 mL/g of OM5O, such that the concentration of Form A dissolved in OM5O is about 12-13 mL/g or 1 g of Form A in about 12-13 mL of OM5O.

In some embodiments, the method of preparing a solution comprising OM5O and selpercatinib Form A comprises heating selpercatinib Form A and a solvent comprising OM5O to a temperature of from about 50°C to about 70°C. In some other embodiments, the method comprises cooling said solution to a temperature of less than about 70°C and greater than about 20°C. In other embodiments, the method comprises cooling said solution to a temperature of about 50°C.

In some embodiments, the method of adding water comprises adding from about 0.1 mL/g to about 1 mL/g of water to the solution per 1 g of Form A. In some other embodiments, the method of adding water comprises adding to said solution about 0.3 mL/g of water per 1 g of Form A.

In some embodiments, the method of adding water may further include adding from about 1.95 (w/w) to about 15.95 (w/w) of the game crystals to the suspension.

Form B. In some other embodiments of the present invention, from about 1.95 (w/w) to about 10.95 (w/w) of seed crystals of Form B may be added to said suspension. In other embodiments of the present invention, about 5.95 (w/w) of seed crystals of Form B may be added to said suspension.

In some embodiments of the method, said suspension is stirred for about 6 hours to about 72 hours after adding water. In some embodiments of the present invention, said suspension is stirred for at least 12 hours.

In some embodiments of the present invention, said method may further comprise a second addition of water to the suspension obtained by the first addition of water. In some embodiments of the present invention, in the second addition of water to said suspension, water may be added in an amount of from about 0.5 mg/g to about 3 ml/g.

In some embodiments of the method, the suspension obtained by adding water is cooled to about 20-30°C.

In some embodiments of the present invention, isolating selpercatinib Form B includes filtration. In some embodiments of the present invention, the isolated selpercatinib Form B can be washed with a solvent comprising methanol, ACM, MTBE, or water. In some other embodiments of the present invention, the isolated selpercatinib Form B is washed with a solvent comprising methanol. In other embodiments of the present invention, the isolated selpercatinib Form B is washed with methanol until the isolated selpercatinib Form B contains less than 0.5% (w/w) OM5O.

In some of the above aspects and embodiments, the present invention provides a method of converting selpercatinib Form A to Form B, comprising: combining selpercatinib

Form A and methanol to form a suspension, and stirring said suspension until >99% (w/w) of Form A is converted to Form B. In some embodiments of said method, said suspension is stirred for about 18-24 hours. In other embodiments of the present invention, the concentration of selpercatinib Form A in methanol is about 8 mL/g.

In some of the above aspects and embodiments of the present invention, a method of converting selpercatinib Form A to Form B is provided, wherein selpercatinib Form A is dissolved in

PM5O at about 60-80 "C to obtain a solution with a concentration of about 10-15 ml/g PM5O per 1 g of Form A; cooling said solution to about 40-60 "C, adding 60 of the first amount of water, optionally adding seed crystals of Form A to the resulting mixture

B; stirring said mixture; adding a second amount of water; heating said mixture to about 60-80°C; cooling said mixture, and isolating Form B. In some embodiments of said method, 5-95% by weight of seed crystals of Form B are added to the mixture. In other embodiments of the present invention, the first addition of water is from about 0.1 ml/g of Form A to about 0.5 ml/g of Form A. In other embodiments of the present invention, the second addition of water is from about 1.0-1.5 ml/g of Form A.

In another aspect of the present invention, there is provided a method for preparing selpercatinib as a Form B polymorph having Formula I:

M-- / she

M y som no NO co | M in basic

My | "

M that IM (Formula II) or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound having the structure:

M--

I am a piece

I" M o NE ko | hm rya

M

MN

ISI or its salts, in a solvent with b-methoxynicotinaldehyde in the presence of an acid and a reducing agent to obtain selpercatinib Form B or a pharmaceutically acceptable salt thereof. Although it is possible to use a stoichiometric amount of acid, non-stoichiometric amounts are also acceptable. In the structure of ISI|, the oxygen has a trimethylsilyl (TM5) group.

Although not explicitly shown, it is understood that other alcohol protecting groups may be used. In addition to TM5, other silyl groups may be used as disclosed herein.

In some embodiments of the aforementioned aspect, the method further comprises preparing a compound having the structure Z1, or a salt thereof, which comprises reacting a compound having the structure

M-- u she an no | NOT to | IN

ME

M

Kv "PI or its salts, where Ki represents an amine protecting group, with a deprotecting agent to obtain a compound having the structure of IZI or its salts.

In some embodiments of the present invention, said 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 other embodiments of the present invention, said deprotecting agent is selected from the group consisting of sulfuric acid, p-toluenesulfonic acid, and acetyl chloride.

In some embodiments of the present invention, the reducing agent is selected from the group consisting of alkali metal borohydride, hydrazine compound, citric acid, citric acid salt, succinic acid, succinic acid salt, ascorbic acid, and ascorbic acid salt. In some other embodiments of the present invention, the reducing agent is selected from the group consisting of sodium triacetoxyborohydride (STB), sodium borohydride, and sodium cyanoborohydride.

In some embodiments of the present invention, Ki is selected from the group consisting of formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butyloxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilylethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitroveratriyloxycarbonyl, p-methoxybenzyl, and tosyl. In some other embodiments of the present invention, Ki is tert-butyloxycarbonyl (Boc).

In some embodiments of the present invention, the acid is selected from the group consisting of pivalic acid and acetic acid. In some other embodiments of the present invention, the acid is pivalic acid. In another embodiment of the present invention, a catalytic amount of pivalic acid is used.

In some embodiments of the present invention, the reaction of compound |C| is carried out in an aprotic solvent. Examples of protic solvents include ethers such as anisole.

In another aspect of the present disclosure, there is provided a compound 4-[6-(3,6-diazabicyclo|3.1.1|heptan-3-yl)-3-isopyridyl|-6-(2-methyl-2-trimethylsilyloxyhydroxy)pyrazolo|1,5-a|pyridine-3-carbonitrile having the structure III:

I" " I M o ko 4 | M

F

Men

ISI or a pharmaceutically acceptable salt thereof.

In some embodiments of the present invention, a method of preparing a compound having the structure (III) is provided, in accordance with the aspects and embodiments of the present invention disclosed herein.

In some embodiments of any of the above aspects, the method comprises obtaining selpercatinib Form B as the free amine.

Selpercatinib Form A (Form A) may contain some of its thermodynamically more stable polymorph, selpercatinib Form B (Form B). Although both polymorphic forms are crystalline, low-melting, anhydrous, stable, and non-interconvertible under typical storage or preparative conditions, the polymorphs have different properties and characteristics that distinguish Form A from Form B.

Form B. Since Form B is thermodynamically more stable, it is necessary to understand how to convert Form A to Form B.

Definition

Unless otherwise defined, all technical and scientific terms used in this specification have the meaning commonly understood by one skilled in the art to which this invention belongs. As used in this specification, the following terms have the meanings given to them below unless otherwise specified.

The term "polymorph" as used herein refers to crystals of the same compound that have different physical properties due to the arrangement of the molecules in the crystal lattice. Different polymorphs of the same compound (i.e., compounds of Formula I) have one or more different chemical, physical, mechanical, electrical, thermodynamic, and/or biological properties. The differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important for product formulation and manufacturing), dissolution rate (important for determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water sorption, compaction, and particle morphology. Differences in stability may result from 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., crystal changes during storage as a kinetically favorable polymorph transforms into a thermodynamically more stable polymorph) or both (e.g., one polymorph is more hygroscopic than the other). Due to differences in solubility, some transitions affect efficacy and/or toxicity. In addition, the physical properties of the crystal may be important in processing; for example, one polymorph may be more likely to form solvates or may be difficult to filter and free from impurities (i.e., particle shape and size distribution may differ between one polymorph relative to another). The term "polymorph" as used herein does not include amorphous forms of the compound. In some specific embodiments of the present invention, said polymorph of the compound of Formula I (i.e., selpercatinib Form A and selpercatinib Form B) is

C) has the characteristics disclosed in this description.

As used herein, the term "amorphous" refers to a non-crystalline form of a compound, which may be a solid 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) without a regularly repeating arrangement of molecules or external surface planes. The term "anhydrous" as used herein refers to a crystalline form of a compound of Formula (I) that does not contain stoichiometric amounts of water associated with the crystal lattice. Typically, anhydrous Form A and anhydrous Form B contain water in an amount of 1% by weight or less. For example, 0.5% by weight or less, 0.25% by weight or less, or 0.1% by weight or less.

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

The terms "hydrate" or "hydrated polymorphic form" refer to a crystalline form of a compound of Formula (I), such as a polymorphic form of the compound where the crystal lattice contains water.

Unless otherwise specified, the term "hydrate" as used in this specification refers to a "stoichiometric hydrate". A stoichiometric hydrate contains water molecules as an integral part of the crystal lattice. In comparison, a non-stoichiometric hydrate contains water, but changes in the water content do not cause significant changes in the crystal structure. During drying of non-stoichiometric hydrates, a significant portion of the water can be removed without significant disruption of the crystal lattice, and the crystals can subsequently rehydrate to form the original non-stoichiometric hydrated crystal form. Unlike stoichiometric hydrates, dehydration and rehydration of non-stoichiometric hydrates are not accompanied by a phase transition, and thus all hydration states of a non-stoichiometric hydrate represent the same crystal form.

The term "purity" when used in reference to a composition containing a polymorph of a compound

of Formula (I), means the percentage of one particular polymorphic form relative to another polymorphic form or amorphous form of the compound of Formula (I), in a specified composition. For example, a composition containing a polymorph of Form 1 with a purity of 90-95 would contain 90 parts by weight

Forms 1 and 10 parts by weight of other polymorphic and/or amorphous forms of the compound of Formula (I).

As used herein, a compound or composition is "substantially free" of one or more other components if said compound or composition does not contain a significant amount of such other components. For example, a composition may contain less than 5% by weight, 4% by weight, 3% by weight, 2% by weight, or 1% by weight of other components. Such components may include starting materials, residual solvents, or any other impurities that may result from the preparation and/or isolation of the compounds and compositions provided herein. In some embodiments, a polymorphic form disclosed herein is substantially free of other polymorphic forms. In some embodiments, a particular polymorph of a compound of Formula (I) is "substantially free" of other polymorphs if the particular polymorph constitutes at least about 95% by weight of the compound present.

Formula (I). In some embodiments of the present invention, a particular polymorph of the compound

Formula (I) is "substantially free" of other polymorphs if the particular polymorph constitutes at least about 9795 (wt.), about 9895 (wt.), about 9995 (wt.), or about 99.5 95 (wt.) of the compound of Formula (I) present. In some embodiments of the present invention, a particular polymorph of a compound of Formula (I) is "substantially free" of water if the amount of water constitutes no more than about 2 95 (wt.), about 1 95 (wt.), or about 0.5 95 (wt.) of the polymorph.

As used herein, the term "substantially pure" when used in reference to a polymorphic form of a compound of Formula (I) means a sample of the polymorphic form of the compound having a purity of greater than 90%, including greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, and including equal to or greater than 100% of the compound, based on the weight of the compound. The remainder of the material comprises another form or forms of the compound and/or reaction impurities and/or process impurities arising during its preparation. For example, a polymorphic form of a compound of Formula (I) may be considered substantially pure because it has a purity of greater than 90% of the polymorphic form of the compound.

Formula (I), as determined by means known and generally accepted in the art at this time, wherein the remaining less than 10 95 of the material comprises another form or forms of the compound of Formula (I), and/or reaction impurities, and/or process impurities. The presence of reaction impurities and/or process impurities can be determined by analytical methods known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry or infrared spectroscopy.

For the purpose of providing a more concise description, some of the quantitative statements herein are listed as ranging from about X amount to about Y amount. It is to be understood that when a range is stated, said range is not limited to the stated upper and lower limits, but rather includes the full range from about X amount to about Y amount or any range within that range.

The term "room temperature" or "rt" refers to the ambient temperature of a typical laboratory, which is usually around 25 "C.

As used herein, the term "excipient" refers to any substance necessary to give the composition the desired form. For example, suitable excipients include, but are not limited to, diluents or fillers, binders or granulating agents or adhesives, disintegrants, glidants, anti-adherents, glidants, dispersing or wetting agents, retarders or dissolution enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, and sweeteners.

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 agents and agents that delay absorption, etc., that are not biologically or otherwise undesirable.

The use of such media and vehicles for pharmaceutically active substances is well known in the art. Except where any conventional media or vehicle is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Additional active ingredients may also be included. In addition, various excipients such as those commonly used in the art may be included. These and other such compounds are described in the literature, for example, in MegskKk Ipaech, MetgskK « Sotrapu, Kapmau,

M.U. Considerations regarding the inclusion of various components in pharmaceutical compositions are described, for example, in Siitap, E. A. (Ed.) (2010); boodtap apa Siitap'ye: Te RPagtasoiodisa! Vaviv oi

Tpegaretsiisv, 121p Ed., Tne MsOgam/-NIII Sotrapiev.

As used in this specification, a singular element includes plural elements unless the context clearly dictates otherwise.

As used herein, ranges and amounts may be expressed as "about" with respect to a particular value or range. About also includes an exact amount. Thus, "about 5 g" means "about 5 g" as well as "5 g". It is also intended that ranges expressed herein include whole numbers within the ranges and fractions thereof.

For example, the range of 5 g to 20 g includes whole numbers, such as 5 g, bg, 7 g, 8 g, 9 g, 10 g, 11 g, 12 g, 13 g, 14 g, 15 g, 16 g, 17 g, 18 g, 19 g, and 20 g, and fractions within the range, including, but not limited to, 5.25 g, 6.5 g, 8.75 g, and 11.95 g. The term "about" preceding a value for 60°C (differential scanning calorimetry), TOA (thermogravimetric analysis), TO

(thermogravimetry) or DTA (differential thermal analysis), which are given as degrees

Celsius, has an allowable variability of -5 to 70.

As used herein, the term "optional" or "optionally" means that the event or circumstance described below either occurs or does not occur, and that the description includes instances where the specified event or circumstance occurs and instances where it does not occur. For example, a reaction mixture that "optionally comprises a catalyst" means that the reaction mixture comprises a catalyst or does not comprise a catalyst.

As used herein, the term "strong base" refers to a basic chemical compound that is capable of deprotonating weak acids 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 alkali and alkaline earth metal hydroxides, such as Mahon. Some strong bases are even capable of deprotonating very weakly acidic C-H 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 of the present invention, Mahon is used as the strong base. In some embodiments of the present invention, potassium hydroxide is used as the strong base.

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 in the range of about 6 to about 11. A large number of such weak bases are known, examples of which are those listed in Napabosok Koi Biospetiviku apa Moiliestsiag Bioiodu, Moi. 1, 3rd ed., 05.0. Raztap, SKS Proezz, 1976, pp. 305-347. A weak base may be soluble or insoluble in water. Suitable weak bases include, but are not limited to, alkali metal carbonates and bicarbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate; ammonia; primary amines, such as methylamine; secondary amines; and tertiary amines such as trialkylamines, for example, trimethylamine, triethylamine, tripropylamine and tributylamine, benzyldiethylamine, pyridine, quinoline, N-methylmorpholine, aniline and the like.

The term "non-nucleophilic base" as used herein refers to a base that will not act as a nucleophile, i.e., a base that will not donate an electron pair to an electrophile to form a chemical bond in a reaction. Typically, non-nucleophilic bases are bulky and sterically hindered, such that protons can attach to the basic center, but alkylation and complexation are prevented. Examples of non-nucleophilic bases include, but are not limited to, amines and nitrogenous heterocycles such as triethylamine and pyridine, amidines, lithium compounds, and phosphazenes. Other examples of non-nucleophilic bases include sodium hydride and potassium hydride.

As used herein, the term "amine protecting group" refers to any group known in the art of organic synthesis for protecting amine groups. Such amine protecting groups include those listed in Sage, "Rhoiesiime Sgopre5 i Ogdapis Zupipev, " dopp UmMieu 4 op5, Mem TogK (1981) and "Pe Reriidevh: Apaiuvziz, 5upipevziz, Vioiodu, Moi. 3," Asadetis Rhezv, Mem/

Work (1981). Any amine protecting group known in the art may be used. Examples of amine protecting groups include, but are not limited to, the following groups: (1) acyl-type groups such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate-type groups such as benzyloxycarbonyl (Cb2) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Etos); (3) aliphatic carbamate-type groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate-type groups such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl-type groups such as triphenylmethyl and benzyl; (b) trialkylsilane, such as trimethylsilane; (7) thiol-containing type groups, such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types, such as triphenylmethyl, methyl and benzyl; and substituted alkyl type groups, such as 2,2,2-trichloroethyl, 2-phenylethyl and tert-butyl; and trialkylsilane type groups, such as trimethylsilane.

The term "deprotecting agent" as used herein refers to a reagent or system of reagents (reagent or reagents and solvent) that can be used to remove a protecting group. Deprotecting agents can be acids, bases or reducing agents. For example, removal of a benzyl (Bn) group can be accomplished by reduction (hydrogenolysis), while removal of carbamates (e.g., Boc groups) can be accomplished using acids (e.g., HCl, TEA, H25O4, etc.), while removal of silyl groups can be accomplished using weak acids or halides.

(e.g., a fluoride such as tetra-n-butylammonium fluoride (TBAF)), optionally with mild heating.

As used in this description, the term "reducing agent" refers, within the scope of compounds of the same genus, to compounds of any kind capable of reducing a compound of another species while being oxidized. As used in this description, the term "oxidizing agent" refers, and within the scope of compounds of the same genus, to compounds of any kind capable of oxidizing a compound of another species while being reduced.

As used herein, the term "triflating reagent" refers to a compound that can be used in a reaction in which a triflate group is added to a hydroxy group to form a triflate ester. The triflating reagent is a source of a trifluoroacetyl group. Triflating reagents include, but are not limited to, trialkylsilyl triflates, trialkylstannyl triflates, trifluoromethanesulfonic anhydride (trifluoromethanesulfonic anhydride), N-phenyl-bis(trifluoromethanesulfonimide) (RPMDE), N-(5-chloro-2-pyridyl)triflimide, and N-(2-pyridyl)triflimide.

The term "acrylonitrile derivative", as used herein, is a compound derived from acrylonitrile having the formula CH:CHCH2, where one or more hydrogen atoms are replaced by another atom or group. An example of an acrylonitrile derivative is 2-chloroacrylonitrile, where one of the hydrogen atoms of acrylonitrile is replaced by a chlorine atom.

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

The terms "hydrogen" and "H" are used interchangeably in this description.

The terms "halogen" or "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

As used herein, the term "alkyl" refers to a hydrocarbon chain, which may be straight or branched, containing the specified number of carbon atoms. For example, C-6 indicates that the group may contain from 1 to 6 (inclusive) carbon atoms. Examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl.

The term "alkylamine" as used herein refers to an amine containing one or more alkyl groups. An alkylamine may be a primary amine, a secondary amine, or a tertiary amine. For example, a secondary alkylamine is an amine containing two alkyl groups. An example is diisopropylethylamine.

A salt may be formed from a compound by any method known to one skilled in the art. Accordingly, the phrase "to prepare a compound or a salt thereof" encompasses embodiments of the present invention where the compound is formed and the salt is then formed from the compound by a method known to one skilled in the art.

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

All combinations of embodiments of the present invention relating to the aspects disclosed in this specification are specifically encompassed by this invention as if each combination were separately expressly set forth, to the extent that such combinations encompass possible aspects. In addition, all subcombinations of embodiments of the present invention contained in the aspects disclosed in this specification, as well as all subcombinations of embodiments of the present invention contained in all other aspects disclosed in this specification, are also specifically encompassed by this invention as if each subcombination of all embodiments were expressly set forth in this specification.

Crystallization methods

This description discloses methods for converting selpercatinib Form A to selpercatinib.

Form B. Although selpercatinib Form A can be converted to Form B using various methods, crystallization-based methods are disclosed herein to convert selpercatinib Form A to selpercatinib Form B.

Suitable methods for converting Form A to Form B include crystallization by cooling, crystallization by evaporation, vapor diffusion, crystallization using one or more antisolvents (including back-addition of antisolvents), and suspension crystallization. These methods are discussed herein.

In one aspect, the present disclosure discloses a method for converting selpercatinib Form A to selpercatinib Form B.

In another aspect of the present invention, a method of converting selpercatinib Form A to selpercatinib Form B is disclosed, comprising: combining selpercatinib Form A with a C1-C5 alcohol to form a suspension, and isolating selpercatinib Form B from said suspension.

In another aspect, the present disclosure discloses a method for converting selpercatinib Form A to selpercatinib Form B, comprising: a) dissolving selpercatinib Form A in a solvent containing OM5O to form a solution;

B) adding water to said solution to thereby obtain a suspension; c) isolating selpercatinib Form B.

In another aspect of the present invention, a method for converting selpercatinib Form A to

Form B, which comprises: combining selpercatinib Form A and methanol to form a suspension, and mixing said suspension until 299.95 (w/w) of Form A is converted to Form B.

Form A has unique X-ray powder peaks at 4.9", 9.77 and 15.57 26, while

Form B has unique X-ray powder peaks at 7.5", 10.97 and 12.07 26. The 20 values and/or peak intensities of other peaks also differ between the two forms, as can be seen in Table 1 below. For better understanding, all described herein are X-ray powder peaks at 50.27 28 unless otherwise stated.

Table 1

X-ray powder peak analysis. Form A and Form B 111111 FORMAA GG | | FORMAVG///Z

Peak Position |RelativeIntensity| |Peak Position| Relative Intensity 77717498 | lobo 77777777 17111775 18211 841 17111116base 1 1711111111711111192 11111138 111797 | 46» 4-71 109 | 465 F 7127 |771111122 7771111 120 |7711111120036 1 117138 | 7777145 17777771 1111132 | 7777 21956 17148 | 77771605 17711111 1111143 11111111 1101155... |... 155956.4.ЮИИ.ЮЮБЛШШЯШШЩЧЯЕЮЙЙЦЦ4. | 150. | юЮщщ 735 Ж Пи 117116,65.77. | Jur. 18095 | sh(-B | 162 | (535 F died 117116,8.77 | 77 16595611 17 1111111444 1 11718077 |... 2399 2 shЩ( | B | 177 | 1945 F 1171185... |... 1725 7777771 1718 17711111 655 | 7777771 1186 | 77771711755795 Y |...ЮюююююююююЮ 17126,0.7...Ю. | .ЮюЮюЮЮЮЮживею 11111250... | Юр бл у 71264 | 635 | 2 щ(-: | 265 2 Щ | 205 Ж 11212 | 465 | щЩщ(-: | 267. | -( зЗлж 1171282 | 565 2 щЩщ| (БК | 277 | (205 г КмФШ 7171288... | 77773711 1111280 | 7721, 777.2953 | юю. 165 77777777 1111284 | 7 32 73175 | 715956 юЮюЮЮЇ ююЮщ (БФ | 289 | 415 7322 | 145 | 7777777771171111292 | --:(: 755 ZK 17332 | 77017111 111300 | 77717111 11. 17337 | 7711145 71777771 1711303 17771711 33 1 11111111326 11111111 1111111332 |в

G11111my | 31 1111113 11111131 11111353 11111111lozhv11

Table 1 does not list all peaks that have a relative intensity less than 1.00.

The powder X-ray diffraction patterns of Form A and Form B (above) were obtained using a VgiKeg 04 Epaeamog powder X-ray diffractometer equipped with a source

SikKa (X-1.54180 A (0.154180 nm)) and a Mapies detector operating at 35 kV and 50 mA. The sample was scanned in the range of 4-40" 269 with a step size of 0.008" 26, at a scanning speed of 0.5 s/step, with 0.6 mm separation, a fixed antiscattering level of 6.6 mm and 11.3 mm detector apertures. The dry powder was filled into a quartz sample holder; the surface was smoothed with a glass slide. Diffraction patterns of the crystalline form were obtained at ambient temperature and relative humidity. The positions of the crystalline peaks were determined using the MOI-)ade software after full shift of the powder X-ray pattern based on the internal standard MIZT 675 with peaks at 8.853" and 26.7747 296. It is well known from crystallography that, for any given crystalline form, the relative intensity of the diffraction peaks can also vary due to the preferred orientation, which is a consequence of factors such as the morphology and shape of the crystal. In the presence of preferred orientation effects, the peak intensities change, but the characteristic peak positions of the polymorphic modifications remain unchanged. See, for example, Te Opye Iase5

RPaptasorea 223, Mayop! Eoptiiagu 218, radz 1843-1844, 1995. Furthermore, it is also well known from crystallography that for any given crystalline form the angular positions of the peaks may vary somewhat. For example, the peak positions may shift due to changes in temperature or humidity at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In this case, the peak position variability of 50.2 20 will account for potential changes without interfering with the unambiguous identification of the said crystalline form. Confirmation of the crystalline form may be made on the basis of any unique combination of distinct peaks.

Analysis of the О5С-TOA of anhydrous crystalline Form A demonstrated the onset of melting at 207.6 7С, and showed two endotherms, where the first endotherm corresponds to the melt

Form A, followed by exothermic recrystallization of Form B, and then the melt of Form B.

The 15C-TOA analysis of anhydrous crystalline Form B demonstrated a single endotherm with a melting onset at 213.3°C.

Although Form A and Form B are anhydrous polymorphs, Form A is slightly more hygroscopic than Form B.

Form A and Form B have similar solubility. Both exhibit poor solubility at 25°C in many organic solvents, including methyl ethyl ketone (MEK), acetone, and many alcohol-based solvents, but are moderately soluble (3-30 mg/mL) in dichloromethane (DMSO), dimethyl sulfoxide (DMSO), and THF (tetrahydrofuran). Form B is almost insoluble in anisole.

The solid-state C NMR spectra of Form A and Form B are shown in Fig. 2. Fig. 2 also shows a superposition of a portion of the spectra, which shows that Form A has a peak at 30.9 ppm that was not observed in Form B, while Form B has a peak at 48.0 ppm that was not observed in Form A.

A. Both spectra were assigned to the resonance of adamantane in the presence of a strong magnetic field (5-29.5 million"). sb NMR spectra of cross-polarization/magic angle rotation (solid-state

NMR, or 55MR), mentioned above, were obtained using a large-format VhyKeg Amapse I NO 400 MHz NMR spectrometer, operating at a carbon frequency of 100.62 MHz and a proton frequency of 400.13 MHz, and equipped with a 4 mm VhykKeg double resonance probe.

Total sideband suppression (TO55) was used together with cross-polarization using a ZRIMAI 64 decoupling and a CP pulse of the H nucleus in the form of a QAM 100. The collection parameters were as follows: proton pulse 4.0 μs, contact time 1.5 ms, MA5 frequency 5 kHz, spectral width 30.2 kHz, and collection time 34 ms. A 3-second cycle delay is used and the number of scans is 2655. Chemical shifts are assigned to adamantane (6-29.5 million) in a separate experiment. Representative C 55 NMR resonances for Form B include: 26.44 million, 27.37 million, 28.00 million, 41.98 million, 43.43 million, 43.91 million, 48.04 million, 53.92 million, 56.31 million, 58.32 million, 69.48 million, 77.90 million, 80.38 million, 102.32 million, 106.77 million, 113.58 million, 115.24 million, 118.23 million, 120.76 million, 125.23 million", 130.23 million", 134.86 million, 136.93 million", 140.59 million", 148.42 million", 149.50 million", 151.20 million", 152.45 million", 158.22 million" and 163.52 million".

The above data establishes that Form A and Form B: 1) have slightly different properties, 2) can be easily identified, and 3) Form A can be converted to Form B.

A variety of solvents can be used to convert Form A to Form B.

Solvents that can be used to convert Form A to Form B include, but are not limited to, C. -C. alcohols (such as methanol or ethanol), water, acetonitrile (ACN,

methyl tert-butyl ether (MTBE), heptane, n-butyl acetate (n-BIOAC), 81 U95 ACM-MeOnH (81 ml

AFM in combination with 19 ml Meon), wet ethyl acetate, cyclopentyl methyl ether (CPME), 1,2-dimethoxyethane, ethyl acetate, ethyl formate, methyl isobutyl ketone (MIBE), nitromethane, n-propyl acetate (MPA), 1-pentanol, toluene, 1:11 MeOH':water, 1:11 EOH:water, AFM:water, rumzo/heptane mixtures, or OM5O/water mixtures. In some embodiments of the present invention, the solvents included C.-C5 alcohols, water, OM5O, MTBE, AFM, and mixtures of two or more thereof. In still other embodiments of the present invention, the solvent contained methanol, ethanol, water, OM5O, MTBE,

AFM or mixtures of two or more of them.

As noted above, selpercatinib can form solvates; and it can also form metastable solid forms, both of which are generally not stable upon drying.

The observed solvates include acetone solvate, chloroform solvate, 1,4-dioxane solvate, methyl ethyl ketone (MEK) solvate, dichloromethane solvate (CDM), 2-butanol solvate, 1-butanol solvate, ethanol solvate, dimethyl sulfoxide (DMSO)-water solvate,

PM5O and tetrahydrofuran (THF) solvate. Solvates and metastable forms usually revert to Form A upon isolation and/or drying, although films or amorphous material are sometimes formed. Chloroform and 1,4-dioxane solvates were stable after isolation/drying.

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

Below are some non-limiting ways to convert Form A to Form B.

Conversion method 1

In a preferred embodiment of the present invention, said method comprises combining selpercatinib Form A with a solvent, such as a C-C5 alcohol, to form a suspension and isolating selpercatinib Form B from said suspension. When the suspension is stirred or otherwise agitated, selpercatinib Form B is formed. In some embodiments of the present invention, the alcohol is stored at ambient temperature. In other embodiments of the present invention, the suspension is heated, which increases the rate of formation of Form B. Apart from the temperature difference, these two embodiments are similar to each other and are described below.

Solvents

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

Examples of C4i-C5 alcohols include methanol, ethanol, isopropanol, propanol, butanol, 2-butanol and 3-butanol. In some embodiments of the present invention, said alcohol comprises methanol and/or ethanol. In one embodiment of the present invention, the alcohol comprises methanol.

Hydroalcoholic alcohols can also be used, where the amount of water present is 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 an alternative embodiment of the present invention, 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% to about 10% by weight, or less than 10% by weight. In one embodiment of the present invention, the alcohol contains at least 90% by weight methanol. In another embodiment of the present invention, the alcohol contains about 90% by weight methanol and about 10% by weight water. In another embodiment of the present invention, the alcohol contains at least 95% by weight methanol and about 5% by weight water. Other solvents may be present in the alcohol mixture. In some embodiments of the present invention, up to about 3% by weight of one or more other solvents may be present.

Temperature

Temperature affects the rate at which form A is converted to form B, with the process taking longer at lower temperatures than at higher temperatures.

Although Form A and the solvent suspension can be mixed at temperatures below ambient temperature, this will prolong the conversion.

Form A to Form B, and thus this is usually avoided.

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 prior to addition of the Form A material, or the temperature may be adjusted after addition of the Form A material.

In other embodiments of the present invention, the temperature of the alcohol, such as a C.-C. alcohol, is 10-30 °C, or about 15-25 °C, or about 20 °C. In another embodiment of the present invention, said temperature is ambient temperature, which is the outside temperature. While Form A converts to Form B upon stirring in a room temperature solvent, such as methanol, the conversion occurs more rapidly if the mixture of Form A and the solvent is heated.

If the suspension has been heated to the point where all of the Form A has dissolved, the resulting solution can be filtered to remove any insoluble materials. After stirring, the solution is stirred and cooled as described below.

Time

The suspension was stirred or otherwise agitated for at least about 5 min. or at least about 10 min. In some embodiments of the present invention, the suspension was typically not stirred or otherwise agitated for more than 72 h., but if desired, the suspension can be stirred or otherwise agitated for more than 72 h. In some embodiments of the present invention, the suspension was stirred for about 1-12 h.

Cooling

If the mixture of Form A and alcohol was heated for the above time, the heating was stopped and the suspension was kept under cooling for about 4-24 hours, or for about 6-18 hours, or for about 12 hours.

Highlighting the shape B

Form B material can be isolated using any method known in the art. In one embodiment of the present invention, the isolation includes gravity filtration. In another embodiment of the present invention, the isolation includes vacuum filtration. In yet another embodiment of the present invention, the isolation includes the use of a centrifuge.

Fresh solvents such as ethanol, methanol, ACM, MTBE, water, or combinations of two or more thereof may be used to wash the Form B material. More preferably, methanol, ACM, MTBE, water, or combinations of two or more thereof are used to wash the Form B material. Even more preferably, a solvent containing methanol is used. The fresh solvent may be cooled to a temperature of from about 0°C to less than about 20°C before being used to wash the Form B material.

The isolated Form B of selpercatinib can be dried using methods known in the art. Typical methods include heating, passing an inert gas over the solid, and/or using subatmospheric pressure.

In another embodiment of this example, the C11-C5 alcohol and Form A of selpercatinib were combined, and the resulting suspension was stirred or otherwise agitated for a time sufficient to convert Form A to Form B. A typical stirring time is from at least about 10 min. to about 36 h., or about 24 h., but is typically at least about 30 min., or at least about 1 h., or at least about 4 h., or at least about 6 h., or at least about 8 h., or at least about 12 h. If necessary, the stirring and/or agitation of the mixture can be continued for longer than 24 h. Heating the mixture will increase the rate of conversion of Form A to Form B.

Form B.

In another embodiment of this method, said method comprises: combining selpercatinib Form A and methanol to form a suspension, and stirring the suspension until »95 95 (w/w), »96 95 (w/w), »97 95 (w/w), »98 95 (w/w or »99595 (w/w) of Form A is converted to Form B. The suspension is stirred for about 12 h to 48 h or for about 18-24 h. The concentration of selpercatinib Form A in methanol is about 6-14 mL/g, or about 8-12 mL/gM. In some methods, the concentration is about 8 mL/g.

Conversion method 2

In another embodiment of the present invention, the method comprises combining selpercatinib Form A with a solvent, and the resulting mixture is heated and stirred until Form A dissolves in the solvent. After the solution is formed, the mixture can be filtered if desired to remove any insoluble impurities. The mixture is then cooled and water is added. At this time, seed crystals, if used, can be added. 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 Form B material is isolated.

Solvents

Various solvents may be used. It is important that the solvent does not form a solvate of selpercatinib; rather, it should provide the desired Form B. Examples of acceptable solvents include, but are not limited to, OM5O, C1-C5 alcohols, ACM, MTBE, water, or combinations of two or more thereof. Preferred C1-C5 alcohols include ethanol and/or methanol. In some embodiments of the present invention, OM5O is a preferred solvent. In some embodiments of the present invention, the solvent contains at least 2.95% (w/w) water.

The amount of solvent used depends on the solvent used.

Typically, 1 g of Form A was 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 of the present invention, 1 g of Form A was dissolved in 10-15 mL/g of OM50O, or 1 g of Form A was dissolved in 10-15 mL/g of OM50O.

A was dissolved in approximately 12-13 ml/g of OM5O.

Temperature

Temperature affects the rate at which Form A converts to Form B, with the conversion taking longer at lower temperatures than at higher temperatures.

The mixture containing Form A and the solvent was heated to a temperature ranging from about 30°C to the boiling point of the solvent. Typically, the mixture was heated to a temperature of about 50-110°C, or from about 50°C to about 70°C. In some embodiments of the present invention, the mixture can be heated to about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, or about 110°C.

After heating the mixture to the desired temperature and dissolving the Form A material, the temperature of the solution was reduced by about 15-35°C. The temperature may be reduced by about 15°C, by about 20°C, by about 25°C, by about 30°C, or by about 35°C. In one embodiment of the present invention, the solution was cooled to a temperature less than about 70°C and greater than about 20°C.

In some embodiments of the present invention, the solvent contained OM5O, and was heated to about 50-70°C. In another embodiment of the present invention, the OM5O was then cooled to about 50°C.

In alternative embodiments of the present invention, the solvent was not heated, i.e., it was stirred at ambient temperature. In these embodiments of the present invention, the conversion of Form A to Form B took longer.

First serving of water

When a first portion of water was 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 was added (1 mL of water per 1 g of Form A). In some embodiments of the present invention, the first portion of water is about 0.1 mL/g, or about 0.2 mL/g, or about 0.3 mL/g, or about 0.4 mL/g, or about 0.5 mL/g, or about 0.6 mL/g.

The first portion of water was added over a period of from about 30 seconds to about 15 minutes, or over a period of about 1-10 minutes, or over a period of about 4-6 minutes, or over a period of about 5 minutes. Longer time intervals may be used if necessary.

Seed Crystals If Form B seed crystals were added to the mixture, then about 0.1-15% by weight, or from about 1% by weight to about 10% by weight, or about 5% by weight, of Form B seed crystals was used.

In some embodiments of the present invention, about 1.95 (wt.), 2.95 (wt.), about 3.95 (wt.), about 4.95 (wt.), about 5.95 (wt.), about 6.95 (wt.), about 7.95 (wt.), about 8.95 (wt.), about 9.95 (wt.), about 10.95 (wt.), about 11.95 (wt.), about 12.95 (wt.), about 13.95 (wt.), about 14.95 (wt.), or about 15.95 (wt.) of the starting crystal was added.

Seed crystals can be obtained using the methods described herein.

Time

After heating the mixture, dissolving the Form A material, lowering the temperature of the mixture to 50-110°C, and adding seed crystals, if seed crystals are used, the mixture is stirred for about 1-96 hours, or for about 6-72 hours, or for about 8-24 hours. In some embodiments of the present invention, 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

Second serving of water

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

The second portion of water was added slowly, i.e., it took about 0.5-24 hours, or about 1-12 hours to add the entire second portion of water. In some embodiments of the present invention, the addition of the entire second portion of water 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.

Cooling

After the second portion of water was added, the mixture was cooled by about 15-30°C to about 20-30°C. In some embodiments, the mixture was 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 was cooled to about 30-55°C. In these embodiments, the yield tends to be slightly lower than when lower temperatures are used. o) After adding the second portion of water, the mixture was 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 was reached. In one embodiment of the present invention, the cooling rate was 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/h. or approximately 20 "C/h.

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

Highlighting the shape B

Form B was isolated as described above.

Fresh solvents such as ethanol, methanol, ACM, MTBE, water, or combinations of two or more thereof may be used to wash the Form B material. More preferably, methanol, ACM, MTBE, water, or combinations of two or more thereof may be used to wash the Form B material.

MTBE, water, or combinations of two or more thereof. In a more preferred embodiment, a solvent comprising methanol is used. The fresh solvent may be cooled to a temperature of from about 0°C to less than about 20°C before use to wash the Form B material.

In embodiments of the present invention where the solvent contained 10OM5O, the isolated selpercatinib Form B was washed with methanol until the isolated selpercatinib Form B contained less than 0.5% (w/w) OM5O.

In another embodiment of this method, Form A of selpercatinib was dissolved in a room temperature solvent containing OM5O to obtain a solution with a concentration of approximately 10-15 mL/g OM5O per 1 g of Form A. Water was then added. The mixture was then allowed to settle to form Form B. Form B may then be isolated or additional water may be added, and after further stirring (as described above) Form B may be isolated.

Form B.

In another embodiment of this method, Form A of selpercatinib was dissolved in OM5O at about 60-80°C, or about 70°C, to obtain a solution with a concentration of about 10-15 mL/g OM5O per 1 g of Form A; the mixture was cooled to about 40-60°C, or about 50°C; water was added; seed crystals of Form B were added to the resulting mixture, the mixture was stirred, additional water was added, the mixture was heated; the mixture was cooled, and Form B was isolated. The initial amount of water added was from 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 was from about 1-10 95 (w/w), or was about 5 U (w/w) based on the amount of Form A. The mixture containing the seed crystal was stirred for about 8-24 h, or for about 12 h. The second addition/portion of water was about 1.0-1.5 ml/g of Form A, or about 1.10-1.15 ml/g, or about 1.14 ml/g. The second addition/portion of water was carried out over about 3-8 h, or over about 5 h. After the second portion of water was added, the suspension was cooled to about 20-30 °C, or about 25 °C. The cooling rate of the suspension from about 70°C to about 25°C was about 10°C/hr until a temperature of about 25°C was reached. The suspension at a temperature of about 25°C was stirred for at least about 2 hours, and then it was heated to about 60-80°C, or 70-75°C, or about 73°C, and stirred for about 1 hour. The suspension was then cooled again to about 20-30°C, or about 25°C. The suspension was cooled from about 73°C to about 25°C at a rate of about 10°C/hr. After stirring for at least about 30 minutes to about 8 hours, or about 1-8 hours, or about 2 hours, Form B of selpercatinib was isolated, for example, by filtration.

Crystallization methods effective for converting Form A to Form B are further illustrated in the exemplary embodiments of the present invention disclosed in the Examples section.

Direct synthesis of Form B of a compound of Formula I

In another aspect, the present invention relates to a process for preparing a compound of Formula I (i.e., selpercatinib)

M- /

MOM Evu no aa y ud M dy ! Osn,

M ho im o (Formula II) in the form of Form B or a pharmaceutically acceptable salt thereof.

In embodiments of the present invention, the process for preparing Form B of selpercatinib includes synthesizing one or more precursor compounds using synthetic methods such as those disclosed and described elsewhere (e.g., U.S. Patent No. 10,112,942, which is incorporated herein by reference in its entirety). Illustrative Scheme 1 and Scheme 2 below demonstrate general methods for preparing Form B of selpercatinib, as well as the key chemical intermediate |ZI| from the precursor compound |21:

M- /

MO tEeu no ra 4 | Marya (fr

M

Vos (I)

A detailed description of synthetic methods that can provide the precursor compound |21 (tert-butyl-3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo|1,5-a|pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]|heptane-6-carboxylate) is provided, for example, in U.S. Patent Nos. 10,745,419 and 1,111,111,111.

No. 10,112,942, and International Patent Application Publication No. WO 2018/071447, each of which is incorporated herein by reference in its entirety. In a brief, non-limiting embodiment of the present invention, compound |2| may be prepared by reacting 4-(b-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo|1,5-a|pyridine-

3-carbonitrile; tert-butyl ester of 3,6b-diaza-bicyclo[3.1.1|]heptane-66-carboxylic acid and K2CO3(c) (at 1:1:6.67 molar equiv.) in OM5O with stirring and heating (e.g., 12 h at 90 C). The resulting thick suspension was diluted with additional

OM50O, and stirred with heating (e.g., for an additional 12 hours at 90 C).

After the reaction, the mixture was cooled to ambient temperature, diluted with water, and the resulting aqueous mixture was washed with dichloromethane. The combined organic extracts were dried over anhydrous Mo95O4(35), filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (EtOAc/hexanes as a gradient eluent system) to give compound (21) 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 also appreciate that compounds |2| may contain amine protecting groups other than Boc, including but not limited to formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, trimethylsilyl, 2-trimethylsilylethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitroveratriyloxycarbonyl, p-methoxybenzyl, and tosyl. In some embodiments of the present invention, the protecting group is tert-butyloxycarbonyl (Boc).

Typically, methods for the direct synthesis of Form B of selpercatinib herein involve reacting compound (2) (tert-butyl-3-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo|1,5- a|pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo|3.1.1|heptane-6-carboxylate) under conditions that are effective to (1) remove the protecting groups (e.g., Boc, as shown in (21) and (2) silylate the hydroxyl group on the 2-hydroxy-2-methylpropoxy substituent (e.g., TM5, as shown in (31). The silylated and deprotected compound |C| are then reacted in an organic solvent (e.g., anisole) with b-methoxy-3-pyridinecarboxaldehyde in the presence of reducing agent and acid.

The silyl moiety (e.g., TM5 in some illustrative embodiments) was removed under conditions effective to deprotect, such as, for example, the addition of a fluoride source (e.g., tetrabutylammonium fluoride (TBAF)). Following reaction and removal of the silyl protecting group, the pH of the reaction mixture was adjusted with base, and the mixture was cooled to allow for the formation and isolation of crystalline Form B of selpercatinib.

In some embodiments of the present invention, conditions effective for deprotecting and silylating may include a solvent selected from polar organic solvents such as alcohols (e.g., MeOH, EH), 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 provide an HC solution), esters (e.g., ethyl acetate), ethers (e.g., anisole), and combinations thereof. In some embodiments of the present invention, said reaction mixture contains a deprotecting agent, which may include trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, aluminum trichloride, and boron trifluoride. In some embodiments of the present invention, said deprotecting agent is sulfuric acid, acetyl chloride, or p-toluenesulfonic acid. In some embodiments of the present invention, 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 longer (e.g., overnight or for about 12 hours).

In some embodiments of the present invention, the silyl group used in the reaction may include trimethylsilyl (TM), triethylsilyl (TE5), tert-butyldiphenylsilyl (TVORB), isopropyldimethylsilyl (IPOMB), diethylisopropylsilyl (OBIRB), tert-butyldimethylsilyl (TBMB/TBOMMB), tetraisopropyldisiloxanenylidene (TIPOMB), di-tert-butylsilylene (OTBMB), or triisopropylsilyl (TIPMB). The presence of a silyl group (e.g., the TM5 group in compound |ZI), in addition to acting as a protecting group, provides additional solubility of the compound in the anisole solvent, which can be considered an antisolvent for selpercatinib Form B, compound

II and non-silylated derivative compound |III.

The silyl group can be added using methods known in the art.

In some embodiments of the present invention, the reaction of compound (III) with b-methoxy-3-pyridinecarboxaldehyde is carried out with anisole as a solvent, given that compound (III) exhibits greater solubility in anisole than the 2-hydroxy-2-methyl-propoxy form of (III). In some embodiments of the present invention, the reducing agent in the reaction may be an alkali metal borohydride, a hydrazine compound, citric acid, a citric acid salt, succinic acid, a succinic acid salt, ascorbic acid, and ascorbic acid salt. In some embodiments of the present invention, the reducing agent is selected from sodium borohydride, lithium borohydride, nickel borohydride, and potassium borohydride. In some embodiments of the present invention, the lithium borohydride is selected from lithium borohydride and lithium triethylborohydride. In some embodiments of the present invention, the sodium borohydride is selected from sodium triacetoxyborohydride (STB), sodium borohydride, and sodium cyanoborohydride. In some embodiments of the present invention, the reducing agent is STB. In some embodiments of the present invention, the acid in the reaction acts as a reaction catalyst and may comprise an inorganic acid (e.g.,

HC, Ho5OX, etc.) or a water-soluble organic acid (e.g., acetic acid, pivalic acid, etc.). In some embodiments of the present invention, said acid is pivalic acid.

The resulting compound is subjected to deprotection under conditions that are sufficient to remove the silyl group (e.g., TM5), but not so harsh as to react with and decompose the reaction product (e.g., selpercatinib). In some embodiments of the present invention, deprotection of the silyl group includes adding a fluoride source (e.g., tetrabutylammonium fluoride (TBAF), pyridine-(NH)x, trimethylamine trihydrofluoride (TMH:-NH), hydrofluoric acid, tris(dimethylamino)bisulfonium difluorotrimethylsilicate (TABBE), ammonium fluoride (HAME)) or weak acids to the reaction mixture in amounts effective to react with the silyl group. The conditions for the deprotection step may include a buffered fluoride source and may be determined empirically, with the conditions being kept mild enough to avoid decomposition reactions.

After the reaction is complete, the pH of the reaction mixture is adjusted using a base (e.g., a suspension of KClO3) and cooled to allow for the formation and isolation of crystalline Form B of selpercatinib. In some embodiments of the present invention, the crystallization may also include the addition of a small amount of seed crystals of Form B of selpercatinib. In some other embodiments of the present invention, the crystallization may include any of the crystallization methods described herein that may be effective in converting any residual amount of Form A of selpercatinib to Form B.

Although specific starting materials and reagents are described in the Schemes below and in the accompanying description, other starting materials, reaction conditions, and reagents may be substituted to obtain the target compound (i.e., selpercatinib Form B) as described.

In some embodiments of the aforementioned aspect, the synthesis method includes the general reaction scheme depicted in Scheme 1.

Scheme 1

Mi- I her po, k her - y m 2. Removal of solvent, addition of SAM tur M. w o: - xx m removal - 1 I p - z. removal of solvent, 5 96 KSO" (water ket | tem 21 and 5. filtration, washing (H.O), drying with sho M

M. IZI

Voc MN 1. Pivalic acid, anisole, stirring with heating 2. ZTAV, 2 h. at

Z. TVAR, water "with seed crystal gu 4. Heating, pH adjustment (5 95 KSO") 5. Filtration, optional washing (anisole), drying of water

M- / where are they from?

Main page

M s I z

M s i

IForm VI

In some embodiments of this aspect, said process includes the general reaction scheme depicted in Scheme 2.

Scheme 2

M-- / M- r nn ny a no zh ih -6868686868686366NNTSIkhkNSHOZOZZNCH ko m o x-Zh 3. Removal of solvent, 5 95 K,CO" (aqueous ko M y solution)

I2I and 4. Filtration, washing (N.O), drying IV - M

M

7Voc x 1. Pivalic acid, stirring with heating 2. ZTAV, 2 h. o 3. TVAR, water "with seed crystal gu 4. Heating, pH adjustment (5 95 KSO.) 5. Filtration, optional washing (anisole), drying with bomb

M--

AND

/ My

OK t - M day osn,

M ho im (Form VI

Whether selpercatinib Form B is prepared by direct synthesis or by transformation from selpercatinib (i.e., amorphous selpercatinib or selpercatinib in another polymorphic form) in aspects and embodiments of the present invention, it may also be provided as a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, and may exhibit greater thermodynamic stability compared to selpercatinib in its other polymorphic forms or amorphous forms. Selpercatinib Form B retains its activity as a KET inhibitor, and its activity may be assessed by any assay known in the art, including those described, for example, in M/O2018/071447 and U.S. Patent Application Publication No. 05 20180134702, each of which is incorporated by reference in its entirety.

The examples set forth below are provided solely for the purpose of illustrating and describing certain embodiments of the present invention that fall within the scope of the methods disclosed herein and are encompassed by the claims.

EXAMPLES

Selpercatinib (6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((b-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 disclosed herein, was prepared using the methods and processes described in U.S. Patent No. 10,112,942.

Example 1: Crystallization on Cooling 264 mg of Form A was dissolved in 20 mL of OSM and distributed in equal portions into (15) 8 mL vials. These vials were then placed in a vacuum oven at 70°C to remove the solvent. A birefringent white solid was observed in all vials. The appropriate solvents were added at 50°C with shaking (see Table 2). The heat source was turned off and the samples were allowed to cool to room temperature (RT) naturally. 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 a refrigerator for

From the bottom, and if no precipitate formed, it was left to evaporate in a fume hood for 1 day. Data

The HCRO was collected on a wet solid (where possible). Approximately 2/3 (-66 95) of the experiments gave solvates that remained metastable upon isolation and drying.

These metastable solvates (except the chloroform solvate) were converted to Form A once removed from the mother liquor. 81 95 of the AFM-Meon mixture gave Form B, while anisole gave Form A.

Table 2

Summary of experiments with crystallization during cooling (small amount)

Example 2: Evaporative crystallization and vapor diffusion crystallization

The evaporation plate was prepared by dissolving 5 mg of Form A in 0.9-12 mL of solvent in (33) vials. The evaporated solutions were hand-filtered with a syringe into clean vials, covered with parafilm with pinholes, and allowed to evaporate to dryness in a fume hood at room temperature (RT) and ambient humidity. The vapor diffusion solutions were placed in 20 mL chambers containing 5 mL of antisolvent and tightly capped.

Approximately half of the crystallization experiments yielded solvates or a mixture of solvates with Form A. The majority of the solvates were converted to Form A upon desolvation. It is suspected that a template effect through structural similarity may direct the nucleation of the metastable form. Form B was obtained in only two crystallization experiments using AFM and a (5:1) Meon-TNE mixture. An amorphous form/film with X-ray diffraction was obtained with 5 solvent systems (TNE, (11:1)

IRA (acetic acid, benzyl alcohol, acetic acid, and (10:11) EUN:OME). The chloroform and 1,4-dioxane solvates were stable upon isolation, and solid state characterization data were collected. IRA (isopropyl alcohol), THE (tetrahydrofuran), and OME (dimethylformamide). Vapor diffusion experiments yielded a variety of solvates or amorphous materials. Five solvates, i.e. OSM, 1-BiOH, EN, THE, and OM5O, were metastable and gave Form A upon isolation. A mixture of OM5O/heptane gave a mixture of Form A and Form B.

Example 3: Crystallization with antisolvent

Antisolvent addition experiments were performed by dissolving various amounts (9-36 mg) of Form A in 1-15 mL of solvent in (29) 4 mL vials. For the first 17 vials, the antisolvent was dripped into the syringe-filtered solutions until a precipitate formed or the volume of antisolvent equaled or exceeded 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 drying. Vials where no precipitate was observed were evaporated over a period of up to 2 weeks. 71 90 Addition of antisolvent gave Form A or a labile solvate resulting in Form A.

Form B appeared in 24 of 95 experiments (one result was amorphous). For the reverse addition of the antisolvent, 8395 experiments gave Form A or solvate, and 17 of 95 experiments gave Form B.

Example 4: Suspension Crystallization

Form A vial suspensions were prepared with 10 mg of Form A in 4 mL vials.

The solvent was added according to the solubility of Form A in these solvents to create a suspension density. The suspensions were shaken for approximately 3 days on a shaker at 500 rpm at 22° C. The solids were analyzed as a wet precipitate using HCRO.

Most filtrations of the suspension resulted in solids corresponding to

Form A, or solvates that transformed into Form A during isolation/drying.

Another suspension tablet containing 10 mg of Form A in 4 ml vials was prepared in a similar manner as described in the previous paragraph. The suspensions were shaken for 24 h on a shaker at 500 rpm at 22 °C. After 24 h, the stock solution in each vial was replaced with fresh acceptable diluent. The suspensions were then stirred for 15 days.

The solids were analyzed both wet and dry using HCRO. Form B was observed in approximately 2/3 (766 95) of the experiments. In the remaining 1/3 (-33 95) of the experiments, a mixture of Form A and Form B or Form A and solvate (1 case) was obtained. These results indicated that equilibrium was not reached, which could be due to: 1) the limited solubility of Form A in the solvents tested, or 2) the minimal thermodynamic driving force for phase transformations near the transition points. In the suspension crystallization experiments, anisole re-formed Form A.

Table C

Summary of suspension conditions and results (minor number)

(ami-0.8) day) days) (insignificant number) (insignificant number) days) (insignificant number) (insignificant number)

In the above Table C, the suspensions were stirred for 15 days unless otherwise noted.

Example 5: Solvent-assisted grinding

Two experiments were conducted using mechanical grinding with the use of a solvent. In one experiment, Form B was observed when YUOM5O was used as the solvent. When water was used as the solvent, no change in form was observed, i.e. Form A was observed.

Example 6: Converting Form A to Form B

Selpercatinib (2.0 g) was suspended in methanol (200 mL) and stirred at 55°C at 750 rpm. The suspension was stirred for 60 min at 55°C. The heating was stopped and the suspension was allowed to cool to room temperature naturally. The solid was filtered off and dried under vacuum for 4 h to give crystals of the title compound (1.72 g, 86.95%).

Example 7: Converting Form A to Form B

Selpercatinib Form A (152.0 g) was suspended in methanol (1.5 L) and stirred at room temperature at 750 rpm. The suspension was stirred overnight at room temperature (approximately 20°C). The solid was collected by vacuum filtration.

The solid was dried under full vacuum with nitrogen purge at 45°C to give crystals of the title compound (148.28 g, 97.6% yield).

Example 8: Converting Form A to Form B

Selpercatinib Form A in methanol (8 mL/g) was stirred at room temperature for 18-24 h. Filtered to isolate solids. The solids were dried under vacuum at 45°C with a slight M purge.

Example 9: Converting Form A to Form B

Form A was dissolved in OM5BO (13 ml/g) at 70°C with stirring to obtain a clear solution. The solution was cooled to 50°C. Water (0.3 ml/g) was added, after which seed crystals of Form B (5.95% by weight, based on the amount of Form A used) were added to the solution. Stirring was continued for 12 h, then water (1.14 ml/g) was added over 5 h.

The suspension was cooled to 25°C at a rate of 10°C/h. Stirred for at least 2 h. The suspension was heated to 73°C and stirred for 1 h. The suspension was cooled to 25°C at a rate of 10°C/h. Stirred for at least 2 h. The solids were filtered off. The wet precipitate was washed three times with Meon (8 mL/g). The solids were dried under vacuum at 45°C with a slight M purge.

Example 10: Synthesis of Form B

M- i - what I M o ko XX | M r

M also 4-I6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridylI-6-(2-methyl-2-trimethylsilyloxy-propoxy)pyrazolo|1,5-a|pyridine-3-carbonitrile |C)

This synthetic route to Form B of the compound of Formula I (i.e., selpercatinib) may include any synthetic route that provides 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 (21.

Methanol (200 mL, 100 95) and acetyl chloride (3.1 mL, 44 mmol, 100 965) were added to a round-bottom flask (3-neck) equipped with an overhead stirrer, condenser, and thermocouple.

The mixture was allowed to react before the addition of 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-b-carboxylate (21, (9.9965 g, 19.81 mmol, 100 95). After the addition, the reaction mixture was heated to approximately 60°C (63°C). The temperature was adjusted to reduce the amount of gas evolution observed and to avoid potential overloading of the connected condenser. After analyzing the reaction mixture to determine complete conversion (approximately 2 h), the solvent was removed. Acetonitrile (ACN) (approximately 100 mL) was added to this mixture, rinsing the walls of the reaction vessel. The solvent mixture was again removed, and allowed to stand for 10 min. in a nitrogen atmosphere.

Additional AFM (300 mL, 10095) and hexamethyldisilazane ("HMO5" 25 mL, 119 mmol, 100 95) were added to the reaction vessel. The reaction mixture was stirred at ambient temperature for approximately 1 h before an initial sample of the reaction mixture was taken, yielding approximately 1.695% of the title compound from (2). The reaction mixture was allowed to react overnight at ambient temperature. A sample of the reaction mixture was taken after the mixture was allowed to stand overnight, heated to 40°C, and sampled after 1 h at the same temperature. The reaction mixture was heated to 56°C. As the temperature increased, the mixture refluxed and foamed, which was believed to indicate the evolution of ammonia. After approximately 1-1.25 hours at this temperature, a sample of the reaction mixture was taken, observing continued boiling. The reaction mixture was further maintained at this temperature for 3 hours, and a sample was taken again. The reaction solvent was evaporated, and an aqueous solution of potassium carbonate (100 mL, 50.45 mmol, 5.95 wt.) was suspended in the reaction vessel. The resulting mixture was washed with water (25 mL), and dried to give 7.89 g of the title compound III (78.95 yield), (mass spectrum, m/2-477.20, 477.30 (MAN). 1H NMR (400 MHz,

OM5O-yv) 6: 8.55 (5, 1H), 8.06 (a, 1H), 7.82 (aa, 1H), 7.66 (aa, 1n).

Alternative process. To a reaction vessel equipped with an overhead stirrer, condenser and thermocouple was added tert-butyl-3-[5-(33-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo]1,5-a[pyridin-4-yl]-2-pyridyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (21 (9.9965 g, 19.81 mmol, 100 95) and p-toluenesulfonic acid (2.1 equiv.) in 10 volumes of organic solvent. The mixture was reacted for 1 h, after which pyridine (2.1 equiv.) and hexamethyldisilazane (HMO5, 6 equiv.) were added. This reaction mixture was further stirred for approximately 1 h to give the title compound. |ZI.

M-.- /

MO vu no ra y; in m y / Osn,

M «I 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(b-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[!3.1.1)heptan-3-yl)pyridin-3-yl)pyrazolo|1,5-a|pyridine-3-carbonitrile (Form B)

To a reaction vessel equipped with a magnetic stirrer was added 4-[6-(3,6-diazabicyclo[3.1.1]heptayl-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxypropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile [3]. (0.9981 g, 2.094 mmol, 100 95 (wt.)), 6-methoxy-3-pyridinecarboxaldehyde (i.e. b-methoxynicotinaldehyde, 0.4909 mg, 0.003401 mmol, 95 95 (wt.)), pivalic acid (0.5328 mg, 0.005217 mmol, 100 95 (wt.)) and anisole (10 mL, 91.8 mmol, 100 95 (wt.)), and stirred to form a suspension. Heat with stirring until a homogeneous solution mixture is obtained. The solution is cooled to ambient temperature, and it remains homogeneous. After cooling, sodium triacetoxyborohydride (1.0840 g, 5.1147 mmol, 100% by weight) was added and allowed to react. Analysis of the reaction mixture after 2 h showed the formation of the TM5-protected derivative of the title compound.

After the reaction was complete, the method can be continued to remove TM5 protection and crystallize Form B. To the mixture was added 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 certain amount (710 mg) of seed crystals of the title compound as Form B.

If no crystals were observed after some time, the mixture could be heated to 50°C. After maintaining the elevated temperature overnight, a sample of the reaction mixture was taken, which confirmed the completion of the reaction, but no crystallization was observed. The pH of the mixture (slightly acidic) was adjusted by adding potassium carbonate (5.95 (w/w) in water) as a suspension in 1 mL aliquots until any observed bubbling ceased and the pH became basic. The mixture was stirred overnight, a sample was taken, and the title compound was obtained without any detectable impurities; with a total isolated yield of 54.95. (Mass spectrum, t/2-526.30 (M.N). 1H NMR (400 MHz, OM50-4bv) δ: 8.55 (5, 1H), 8.06 (a, 1H), 7.682 (aa, tn), 7.66 (aa, 1H).

Alternative Process: In a reaction vessel equipped with a magnetic stirrer, 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxypropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile [3] (1.00 g, 2.10 mmol), 6-methoxy-3-pyridinecarboxaldehyde (1.6 equiv.), pivalic acid (55 equiv.), sodium triacetoxyborohydride (2.5 equiv.), and anisole (10 mL, 91.8 mmol, 100 equiv.) were added and allowed to react for approximately 1 h. Water (10 mL) was added to the reaction mixture. The mixture was filtered through celite (diatomaceous earth, filter aid). The layers were separated, saturated sodium chloride solution (10 ml) was added to the organic layer. The layers were separated. 5 N HCl (1 ml) was added to the organic layer. The mixture was heated to 95 °C for 3 h. After the reaction was complete, the pH of the mixture (acidic) was adjusted to pH 9 by adding potassium carbonate.

The mixture was cooled to allow crystallization. The resulting crystals

Selpercatinib Form B was filtered, washed with methyl tert-butyl ether (MTBE), dried, and the pure title compound was obtained.

Example 11

The physical and chemical stability of Form B is an important characteristic not only for ensuring dissolution and solubility, but also for the development and manufacturing operations of APIs and dosage forms (drying, storage, transportation, etc.). Not all crystalline forms have the stability required for drug formulation. A crystalline form that is stable with respect to temperature and humidity is desirable. An accelerated stability study was performed to evaluate the stability of the crystalline form of selpercatinib. Samples of Form B were weighed into 20 mL scintillation vials and placed (open cup) in glass jars with saturated salt solutions in an oven at the indicated temperatures and for the times indicated in Table 4. Form B was analyzed before and after the accelerated stability study and collected for powder X-ray diffraction using a powder X-ray diffractometer.

Vgikeg 08 Aduapse, equipped with a SiKa source (X-1.54056 A-0.154056 nm) and a detector

The MPHE operates at 40 kV and 40 mA with a 0.2 mm separation. Each sample was scanned within 47-30" 29 with a step size of 0.027 at a scan rate of 0.2 s/step.

The result of the study of the substance and the impurity relative to the starting material was evaluated using the Adiipe 1260 NRI C system with a diode detector. The samples were prepared at the appropriate concentrations of 50/50 0.195 TEA in water/0.1 95 TEA in AFM, and evaluated under the following conditions

NRIS: 7ograch Vopy5-KR column, 75x4.5mm (inner diameter), 33.5mm, mobile phase A was 0.1 95 TEA in water, mobile phase B was 0.1 95 TEA in AFM, gradient was 95 95

A at time point 0, 23 95 A after 9.5-12.1 min., 5 95 A after 13-16 min., 95 95 A after 16.1-20 min. with a flow rate of 1.5 ml/min. at a column temperature of 30 "C, a UV detection wavelength of 210 nm and an injection volume of 3 μl. The stability of Form B was characterized and found to be chemically and physically stable under the test conditions (Table 4).

Table 4

Stability of the crystalline form of selpercatinib

Time point, Temperature Relative Crystalline Result . (days) (s) humidity (95) form! study |Impurities (95) substances (95)2 07771117 -111117117111111- 111111 | Form | - - | 009 714.11 40771777171711111 1711 me | 77119969 ..юЮюююююююю..7 009 714.40 1771111175. | ms | 9859 6 щ З оо 271 Ї1111150..1717171717130 | ms | 9954 2 щ 009 714.50 25Южюк ЮЛщ

Example 12: Solubility

Solubility studies have been completed for the crystalline form of selpercatinib disclosed herein. These studies utilized aqueous media spanning the physiological pH range and three simulated liquids. A sufficient amount of solid compound was weighed into a vessel containing approximately 1 mL of the solvent indicated to saturate the volume of the solvent.

The samples were mixed at 37°C in an incubator shaker set at 100 rpm. After equilibration, the samples were transferred to centrifugal filters (Yogaro PMOE, 0.22 µm pore size) and centrifuged for 3 min at 10,000 rpm, maintaining the temperature at 37°C. A 100 µl aliquot was then taken from each sample and diluted with 900 µl of a mixture (50:50) of acetonitrile:water. The pH of the filtrate was recorded using calibrated scientific pH equipment. The concentration of the compound in the solution was determined using

HRIS using an Adipie Ograh Vopy5-KR column 4.6x75 mm, 3.5 μm, under the following conditions: temperature 30 °C; injection volume 4 μl; ultraviolet detection at 238 nm; flow rate 1.5 ml/min; autosampler temperature 25 °C; mobile phase A - 0.1 95 trifluoroacetic acid in water; and mobile phase B - 0.1 95 trifluoroacetic acid in acetonitrile. The HRIS gradient is as follows: 0 min. -9595 A, 595 V; 9.5 min. - 2395 A, 77 95 V; 12.1 min. - 2395 A, 77 95 V; 13 min. - 5 95 A, 95 95 V; 16 min. - 5 95 A, 95 95 V; 16.1 min. - 9595 A, 5 95 V; 20 min. - 95 95 A, 5 95 V. The table below (Table 5) provides detailed data on equilibrium solubility and equilibrium pH, given as an average for duplicate preparative samples. The solid form of the residual solid from the centrifuge sample was checked using X-ray powder diffraction as indicated in Table 5.

Table 5

Solubility at 37°C after 24-hour equilibration of the crystalline form of selpercatinib "Descriptions are in accordance with the United States Pharmacopeia, the European Pharmacopoeia, and the Japanese Pharmacopoeia. 2Solubility in 0.1 N HCl was determined at 21.5°C (ambient temperature).

ZORE: simulated gastric juice (0.01 N HCl/Ma lauryl sulfate 0.05 U5/Ma 0.2 90).

Powder X-ray diffraction of the residual solids shows non-crystalline material. » gasviE: simulated fasting interstitial fluid (ManNgPoOx 28.66 mm, Ma taurocholate C

MM, lecithin 0.75 NM, Massi 105.8 mM, pH 6.5). bre55IE: simulated interstitial fluid in a state of satiety (acetic acid 144.04 mM, Ma taurocholate 15 mM, lecithin 3.75 mM, Massi 203.17 mM, pH 5.0).

The low solubility at higher pH and moderate to high solubility in acidic media were consistent with a weak free base with low intrinsic solubility.

The results showed that the inherent solubility of this crystalline form of selpercatinib is low (approximately 0.001 mg/mL).

Claims (8)

FORMULA OF THE INVENTION 1. A crystalline form of selpercatinib characterized by an X-ray powder diffraction (XPD) pattern containing a peak at 21.17 and one or more peaks at 17.1", 17.77 and 19.8750.27 28, as determined using X-ray radiation at a wavelength of 1.5418 Å (0.15418 nm). 2. The crystalline form of selpercatinib according to claim 1, characterized by an X-ray powder diffraction pattern (XRD) containing a peak at 21.17 and one or more peaks at 7.57, 12.0", 13.27, 17.17, 17.77 and 19.870.27 28, as determined using X-ray radiation with a wavelength of 1.5418 Å (0.15418 nm). 3. The crystalline form of selpercatinib according to claim 1, characterized by an X-ray powder diffraction pattern (XRD) having characteristic peaks at 7.57, 10.97, 12.07, 13.27, 17.17, 17.77, 18.27, 19.87, 21.17 and 24.570.27 29. 4. A pharmaceutical composition comprising a crystalline form of selpercatinib according to any one of claims 1-3 and a pharmaceutically acceptable carrier, diluent or excipient. 5. The pharmaceutical composition of claim 4, characterized in that it contains less than about 20% by weight of other crystalline forms of selpercatinib. 6. The pharmaceutical composition of claim 4, characterized in that it contains less than about 10 95 (w/w) of other crystalline forms of selpercatinib. 7. The pharmaceutical composition of claim 4, characterized in that it contains less than about 5% (w/w) of other crystalline forms of selpercatinib. 8. A method for preparing a crystalline form of selpercatinib according to claim 1, comprising the following steps: (a) suspending selpercatinib in a solvent containing methanol; (b) heating the suspension to 50-60°C with stirring for 30-90 min, stopping heating and cooling the suspension to room temperature to form solid crystals; and