KR20230002706A - Crystalline RET inhibitors - Google Patents

Abstract

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

Description

Crystalline RET inhibitors

background art

Celpercatinib (LOXO-292 or RETEVMO™) is a RET inhibitor approved in the US for use in the treatment of patients with metastatic RET fusion-positive NSCLC, RET-mutant medullary thyroid carcinoma and RET fusion-positive thyroid carcinoma. selpercatinib, or 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabi Cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile has the following chemical structure:

.

.

Although U.S. Patent No. 10,584,124 describes several crystalline forms for selpercatinib, including a crystalline form referred to as "Form A", disclosed herein are novel thermodynamically more stable crystalline forms, and preparation of such crystalline forms. way. These novel crystalline forms can be incorporated into formulations that will benefit the patient, such as tablets, capsules and suspensions.

summary

The present disclosure relates to novel crystalline forms of selpercatinib, and methods of making this thermodynamically stable polymorph, referred to throughout as "Form B". In a general sense, the present disclosure provides methods for their preparation, isolation, and characterization.

As described in more detail below, the compound of Formula I (selpercatinib) can be provided in polymorphic forms (Form A and Form B), and surprisingly, certain processes and methods are used to obtain selpercatinib in its most thermodynamic form. is effective in providing stable polymorphic form B. As described below and demonstrated by the illustrative working examples, processes and methods for generating and preparing specific polymorphic forms of selpercatinib can provide compounds of Formula I, provided as one or more polymorphic forms, in other polymorphic forms. transforming (ie, reacting, contacting and/or treating) under crystallization conditions effective to produce form (ie, Form A) or convert to Form B. In another aspect, processes and methods for producing selpercatinib Form B are synthetic pathways comprising reacting one or more intermediate or precursor compounds under conditions effective to produce selpercatinib Form B (i.e., direct synthesis). path) may be included.

Form B is (a) X-ray powder diffraction (XRPD) comprising a peak at 21.1° and at least one peak at 17.1°, 17.7° and 19.8° ± 0.2° 2θ as measured using an X-ray wavelength of 1.5418 Å. ) pattern, or (b) a ¹³ C solid comprising peaks at 28.0, 48.0, 80.4, 106.8, 130.2 and 134.9 ppm (each ± 0.2 ppm) based on the high field resonance of adamantane (δ = 29.5 ppm). characterized by at least one of the state NMR spectra.

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

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

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

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

Conversion of selpercatinib Form A to selpercatinib Form B comprising combining selpercatinib Form A with a C ₁ -C ₅ alcohol to form a slurry and isolating selpercatinib Form B from the slurry Methods of doing so are also detailed herein.

Also described is a method for converting selpercatinib Form A to selpercatinib Form B comprising the following steps:

a. dissolving selpercatinib Form A in a solvent comprising DMSO to form a solution;

b. adding water to the solution to form a slurry;

c. isolating selpercatinib Form B.

Conversion of selpercatinib Form A to Form B comprising combining selpercatinib Form A and methanol to form a slurry and agitating the slurry until >99% by weight of Form A has been converted to Form B Methods are further described.

Another method described herein is a method of converting selpercatinib Form A to Form B, wherein selpercatinib Form A is dissolved in DMSO at about 60-80° C. to about 10-15 mL per gram of Form A. /g of DMSO; Cool the solution to about 40-60° C. and add water; optionally, seeding Form B seed crystals into the resulting mixture; Stir the mixture; add more water; Heat the mixture to about 60-80°C; The mixture is cooled and Form B is isolated.

A process for the preparation of selpercatinib, or a pharmaceutically acceptable salt thereof, as polymorph Form B, of Formula I,

A compound of the structure

Also described are methods comprising reacting the salt or a salt thereof with 6-methoxynicotinaldehyde in a solvent in the presence of an acid and a reducing agent to prepare selpercatinib Form B or a pharmaceutically acceptable salt thereof.

Compound having structure [3] 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy -propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

or pharmaceutically acceptable salts thereof are described herein.

1 is an overlay of Form A and Form B XRPD data up to about 26° 2 theta (2θ).
2 contains ¹³ C solid state NMR data for Form A, Form B, and an overlay of about 25 to 60 ppm comparing Forms A and B.

Celpercatinib form B is described herein. This crystalline form of selpercatinib can be used to treat disorders associated with abnormal RET activity, such as IBS or cancer, particularly cancers resulting from hyperactive RET signaling (ie, RET-associated cancers). More specifically, these crystalline forms of selpercatinib are RET-associated cancers such as lung cancer (eg small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (eg papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated Thyroid cancer, recurrent thyroid cancer or refractory differentiated thyroid cancer), thyroid adenoma, endocrine neoplasia, lung adenocarcinoma, bronchiopulmonary cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer , breast cancer, breast carcinoma, breast neoplasia, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, inflammatory myofibroblastoma, or cervical cancer. .

Form B has an X-ray powder diffraction (XRPD) pattern comprising a peak at 21.1° and at least one peak at 17.1°, 17.7° and 19.8° ± 0.2° 2θ when measured using an X-ray wavelength of 1.5418 Å. characterized by having Form B also contains peaks ^at 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (each ± 0.2 ppm) based on the high field resonance of adamantane (δ = 29.5 ppm). represents the spectrum.

Form B contains a peak at 21.1° and one or more peaks occurring at 7.5°, 12.0°, 13.2°, 17.1°, 17.7° and 19.8° ± 0.2° 2θ when measured using an X-ray wavelength of 1.5418 Å. It can be further characterized as having an X-ray powder diffraction (XRPD) pattern that

Additionally, Form B has a peak at 21.1° and a peak at 7.5°, 10.9°, 12.0°, 13.2°, 17.1°, 17.7°, 18.2°, 19.8°, 21.1° and It can be characterized as having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks occurring at 24.5° ± 0.2° 2θ.

Form B is based on the high field resonance of adamantane (δ = 29.5 ppm): , 152.5, and ^163.5 ppm (each ± 0.2 ppm).

Form B also has 26.4, 27.4, 28.0, 42.0, 43.4, 43.9, 48.0, 53.9, 56.3, 58.3, 69.5, 77.9, 80.4, 102.3, 106.8 based on the high field resonance of adamantane (δ = 29.5 ppm). , 113.6, 115.2, 118.2, 120.8, 125.2, 130.2, 134.9, 136.9, 140.6, 148.4, 149.5, 151.2, 152.5, 158.2, 163.5 ppm (+ 0.2 ppm each) at least one solid-state peak containing at least one ³ C NMR spectra can be characterized.

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

A pharmaceutical composition containing Form B can contain at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% by weight of the other crystalline forms of selpercatinib. %, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% Form B, by weight. Preferably, the pharmaceutical compositions described herein include at least 80% Form B and less than 20% of selpercatinib in other crystalline forms. More preferably the pharmaceutical composition comprises at least 90% of Form B and less than 10% of selpercatinib in other crystalline forms. Even more preferably the pharmaceutical composition comprises at least 95% Form B and less than 5% of selpercatinib in other crystalline forms. Even more preferably, the pharmaceutical composition comprises at least 97% Form B and less than 3% of selpercatinib in other crystalline forms. More preferably, the pharmaceutical composition comprises at least 98% or 99% Form B and less than 2% or 1%, respectively, of selpercatinib in other crystalline forms.

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

Form B for use in therapy is also described herein.

Form B can be used in the manufacture of a medicament for the treatment of a RET-associated disease or disorder, such as IBS or cancer. Cancers that can be treated using these medicaments are described herein above. Use of Form B in the manufacture of a medicament may also include performing an in vitro assay using a biological sample from a patient, determining the presence of dysregulation of the RET gene, RET kinase, or expression or activity or level of any of these. and administering to the patient a therapeutically effective amount of Form B if dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of these is present. In these applications, the biological sample may be a tumor sample, and the tumor sample may be analyzed using methods known to those skilled in the art, such as genome/DNA sequencing. Additionally, for these uses a sample may be obtained from the patient prior to the first administration of Form B. In the use of these forms B, the therapy as described herein may be based on a patient selected for treatment as having dysregulation of at least one expression or activity or level of the RET gene, RET kinase, or any of these. can Additionally, for these uses Form B may be administered to a patient at a dose of about 1 mg/kg to 200 mg/kg (effective dosage sub-ranges are noted herein above).

Herein, a patient is a patient for whom a RET fusion or RET mutation has been determined. Thus, the term “determining a RET fusion or RET mutation” means determining whether a RET fusion or RET mutation is present. Methods for determining whether a RET fusion or RET mutation is present are known to those skilled in the art and are described, for example, in Wang, Yucong et al., Medicine 2019; 98 (3): e14120.

As used above and throughout the description of the present invention, the following terms will be understood to have the following meanings unless otherwise indicated:

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

The terms "treatment", "treat", "treating" and the like are intended to include slowing, arresting or reversing the progression of a disorder. These terms also refer to alleviating, ameliorating, attenuating, eliminating or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and the progression of the disorder or condition itself is not slowed, stopped, or reversed. includes doing

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

As used herein, the term “patient” refers to a human.

An effective amount can be readily determined by the attending diagnostician as a person skilled in the art by use of known techniques and by observing results obtained under similar circumstances. In determining an effective amount for a patient, the patient's species; his size, age, and overall health; the specific disease or disorder involved; the extent or severity of the disease or disorder; individual patient response; the specific compound administered; mode of administration; bioavailability characteristics of the administered agent; selected dose regimen; use of concomitant medications; A number of factors are taken into account by the attending diagnostician, including but not limited to, and other relevant circumstances.

Form B is preferably formulated as a pharmaceutical composition to be administered by any route that renders the compound bioavailable, such as 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, eg, Remington: The Science and Practice of Pharmacy (D.B. Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006)).

As used herein, “granular composition” refers to a composition in granular form that is a precursor to a pharmaceutical composition in the pharmaceutical manufacturing process.

As used herein, “manufacturing vessel” refers to a vessel used in the manufacture of pharmaceuticals and not in medicinal chemistry laboratories. Examples of manufacturing vessels include, but are not limited to, hopper collectors, beds, dryer beds, granulator beds, dryer trays, granulator buckets, and mixing bowls.

In some embodiments, Form B material is prepared from Form A material. In one embodiment, the method of converting Form A to Form B comprises combining selpercatinib Form A with a C ₁ -C ₅ alcohol to form a slurry and isolating selpercatinib Form B from the slurry. In some embodiments, the method is performed at a temperature of about 10-80°C, about 10-30°C, about 15-25°C, or about 20°C.

In some embodiments, the C ₁ -C ₅ alcohol includes methanol. Preferred C ₁ -C ₅ alcohols include methanol, and in some embodiments, methanol is at least about 90%, or 92%, or 94%, or 96%, or 98%, or 99% by weight. of methanol.

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

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

In some embodiments, the method may further comprise isolating selpercatinib Form B produced by the method. In some embodiments, isolation may include vacuum filtration. In some embodiments, isolation may include centrifugation.

In some further embodiments, the method may further comprise drying the resulting selpercatinib Form B. Drying can be accomplished using vacuum and/or thermal means.

In another embodiment, the method comprises dissolving selpercatinib Form A in a solvent comprising DMSO to form a solution; adding water to the solution in an amount to form a slurry; and isolating selpercatinib Form B produced in the slurry.

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

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

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

In some embodiments of the method, the addition of water may further comprise adding from about 1 to about 15 weight percent of the Form B seed crystals to the slurry. In some further embodiments, from about 1 to about 10 weight percent of the Form B seed crystals may be added to the slurry. In a further embodiment, about 5% by weight of the Form B seed crystals may be added to the slurry.

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

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

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

In some embodiments, isolation of selpercatinib Form B comprises filtration. In some embodiments, isolated selpercatinib Form B can be washed with a solvent comprising methanol, ACN, MTBE or water. In some further embodiments, the isolated selpercatinib Form B is washed with a solvent comprising methanol. In a further embodiment, isolated selpercatinib Form B is washed with methanol until the isolated selpercatinib Form B contains less than 0.5% DMSO by weight.

In some of the above aspects and embodiments, the present disclosure includes combining selpercatinib Form A and methanol to form a slurry and stirring the slurry until >99% by weight of Form A has converted to Form B A method for converting selpercatinib Form A to Form B is provided. In some embodiments of the method, the slurry is stirred for about 18-24 hours. In a further embodiment, the concentration of selpercatinib Form A in methanol is about 8 mL/g.

In some of the above aspects and embodiments, the present disclosure provides a method of converting selpercatinib Form A to Form B, wherein Form A is dissolved in DMSO at about 60-80° C. forming a solution having a concentration of about 10-15 mL/g of DMSO per gram of; Cool the solution to about 40-60° C. and add a first amount of water; optionally, seeding Form B seed crystals into the resulting mixture; Stir the mixture; adding a second amount of water; Heat the mixture to about 60-80°C; The mixture is cooled and Form B is isolated. In some embodiments of the method, 5% by weight of Form B seed crystals are added to the mixture. In a further embodiment, the first addition of water is from about 0.1 mL/g Form A to about 0.5 mL/g Form A. In a further embodiment, the second addition of water is about 1.0-1.5 mL/g Form A.

In another aspect, the present disclosure provides a process for the preparation of selpercatinib, or a pharmaceutically acceptable salt thereof, as polymorph Form B, of formula (I):

Here, the method is a compound having the structure

or a salt thereof with 6-methoxynicotinaldehyde in the presence of an acid and a reducing agent in a solvent to prepare selpercatinib Form B or a pharmaceutically acceptable salt thereof. Stoichiometric amounts of acid may be used, but non-stoichiometric amounts are also acceptable. In structure [3], oxygen has a TMS group thereon. Although not explicitly indicated, it is understood that other alcohol protecting groups may be used. In addition to TMS, other silyl groups may be used as described herein.

In some embodiments of this aspect, the method further comprises preparing a compound of structure [3] or a salt thereof, which has the structure

or a salt thereof (where R ₁ is an amine protecting group) with a deprotecting agent to form a compound of structure [3] or a salt thereof.

In some embodiments, the deprotecting agent is selected from the group consisting of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluene sulfonic acid, acetyl chloride, aluminum trichloride, and boron trifluoride. is chosen In some further embodiments, the deprotecting agent is selected from the group consisting of sulfuric acid, p-toluene sulfonic acid and acetyl chloride.

In some embodiments, the reducing agent is selected from the group consisting of alkali metal borohydride, hydrazine compound, citric acid, citric acid salts, succinic acid, succinic acid salts, ascorbic acid and ascorbic acid salts. In some further embodiments, the reducing agent is selected from the group consisting of sodium triacetoxyborohydride (STAB), sodium borohydride and sodium cyanoborohydride.

In some embodiments, R ₁ is formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzyl carbonyl, tert-butyloxycarbonyl (Boc), trimethyl Silyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitroveratryloxycarbonyl, p-methoxybenzyl and tosyllo selected from the group consisting of In some further embodiments, R ₁ is tert-butyloxycarbonyl (Boc).

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

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

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

In some embodiments, the present disclosure provides methods of making compounds of structure [3] according to aspects and embodiments described herein.

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

Celpercatinib Form A (Form A) may contain some of its thermodynamically more stable polymorph, selpercatinib Form B (Form B). Although both polymorphic forms are crystalline, have high melting points, are anhydrous, stable, and do not interconvert under typical storage or purification conditions, the polymorphs have different properties and characteristics that distinguish Form A from Form B. do. Since Form B is thermodynamically more stable, it is necessary to understand how to convert Form A to Form B.

Justice

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

As used herein, the term “polymorph” refers to crystals of the same compound that have different physical properties as a result of the arrangement of the molecules in the crystal lattice. The different polymorphs of a single compound (ie, a compound of Formula I) have one or more different chemical, physical, mechanical, electrical, thermodynamic and/or biological properties from each other. Differences in physical properties exhibited by polymorphs include pharmaceutical parameters such as storage stability, compressibility, density (important in the manufacture of compositions and products), rate of dissolution (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability. , powder flowability, water sorption, compaction and particle morphology can be affected. Differences in stability may be due to changes in chemical reactivity (e.g., differential oxidation that causes a more rapid discoloration when a dosage form is composed of one polymorph than when composed of another polymorph) or mechanical changes (e.g., , crystal change on storage as a kinetically favored polymorph converts to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than the other). there is. As a result of solubility/dissolution differences, some transition affects potency and/or toxicity. Additionally, the physical properties of crystals can be important in processing; For example, one polymorph may be more likely to form solvates or may be difficult to filter and wash free of impurities (i.e., particle shape and size distribution may differ between one polymorph and another). ). As used herein, “polymorph” does not include amorphous forms of a compound. In some specific embodiments, the polymorphs of the compound of Formula I (ie, selpercatinib Form A and selpercatinib Form B) include features as described herein.

As used herein, "amorphous form" refers to an amorphous form of a compound, which can be either a solid state form of the compound or a solubilized form of the compound. For example, “amorphous” refers to a compound without regularly repeating arrangements of molecules or external faces (eg, a solid form of the compound).

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

As used herein, the term "solvate" refers to a crystalline form of a compound of Formula I wherein the crystal lattice comprises one or more solvents.

The term "hydrate" or "hydrated polymorphic form" refers to a crystalline form of a compound of formula (I) in which the crystal lattice contains water, such as a polymorphic form of the compound. Unless otherwise specified, the term "hydrate" as used herein refers to "stoichiometric hydrate". Stoichiometric hydrates contain water molecules as an integral part of the crystal lattice. In comparison, non-stoichiometric hydrates contain water, but changes in water content do not cause significant changes in crystal structure. During drying of the non-stoichiometric hydrate, a significant proportion of the water can be removed without significantly disturbing the crystal network, and the crystal can subsequently be rehydrated to give the initial non-stoichiometric hydrated crystalline form. . Unlike stoichiometric hydrates, dehydration and rehydration of non-stoichiometric hydrates do not involve phase transitions, and thus all hydration states of non-stoichiometric hydrates exhibit the same crystal form.

"Purity", when used in reference to a composition comprising a polymorph of a compound of formula (I), means one particular polymorphic form, another polymorphic form, of a compound of formula (I) in the stated composition. or percentage relative to the amorphous form. For example, a composition comprising polymorph Form 1 having a purity of 90% will contain 90 parts by weight of Form 1 and 10 parts by weight of other polymorphs and/or amorphous forms of the compound of formula (I).

As used herein, a compound or composition is “substantially free” of one or more other ingredients if the compound or composition does not contain significant amounts of such other ingredients. For example, the composition may contain less than 5%, 4%, 3%, 2% or 1% by weight of other components. Such components may include starting materials, residual solvents, or 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 provided 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 of formula (I) present. ". In some embodiments, a particular polymorph of a compound of Formula (I) comprises at least about 97%, about 98%, about 99%, or about 99.5% by weight of the compound of Formula (I) in which the particular polymorph is present. % "substantially free" of other polymorphs. In certain embodiments, a particular polymorph of a compound of Formula (I) is “substantially free of water if the amount of water constitutes no greater than about 2%, about 1%, or about 0.5% by weight of the polymorph. ".

As used herein, "substantially pure" when used in reference to a polymorphic form of a compound of formula (I) is greater than 90% of the compound by weight, such as 90%, 91%, 92%, 93 %, 94%, 95%, 96%, 97%, 98%, and greater than 99% purity, and also about 100%. The remaining material includes the other form(s) of the compound, and/or reaction impurities and/or processing impurities resulting from its preparation. For example, the polymorphic form of the compound of formula (I) is greater than 90% pure of the polymorphic form of the compound of formula (I), as determined by means currently known and generally accepted in the art. wherein the remaining less than 10% of the material contains other form(s) of the compound of formula (I) and/or reaction impurities and/or processing impurities. The presence of reaction impurities and/or processing impurities can be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy, and the like.

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

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

As used herein, the term "excipient" refers to any substance necessary to formulate a composition into a desired form. For example, suitable excipients are diluents or fillers, binders or granulating agents or adhesives, disintegrants, lubricants, antiadherents, glidants, dispersants or wetting agents, dissolution retarders or enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweetening agents, but are not limited thereto.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents that are not biologically or otherwise undesirable. topical and absorption delaying agents; and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except where any conventional medium or agent is incompatible with the active ingredient, its use in therapeutic formulations is contemplated. Supplementary active ingredients may also be incorporated into the formulations. In addition, various excipients such as those commonly used in the related art may be included. These and other such compounds are described, for example, in Merck Index, Merck & Company, Rahway, N.J. Considerations for the inclusion of various components in pharmaceutical compositions], eg Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

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

As used herein, ranges and amounts can be expressed as "about" a particular value or range. Medicines also include exact amounts. Thus, “about 5 grams” means “about 5 grams” and also “5 grams”. Ranges expressed herein are also understood to include whole numbers and fractions thereof within the range. For example, a range of 5 grams to 20 grams includes integer values such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 grams, and fractions within the range including, but not limited to, 5.25, 6.5, 8.75 and 11.95 grams. The term "about" preceding a value for DSC, TGA, TG or DTA reported in degrees Celsius has an acceptable variability of +/-5 degrees Celsius.

As used herein, "optional" or "optionally" means that the subsequently described event or circumstance does or does not occur, and that such description includes instances where said event or circumstance occurs and instances in which it does not. For example, a reaction mixture "optionally comprising a catalyst" means that the reaction mixture either contains a catalyst or is free of a catalyst.

As used herein, “strong base” refers to a basic chemical compound capable of deprotonating a weak acid in an acid-base reaction. Examples of strong bases include, but are not limited to, hydroxides, alkoxides, and ammonia. Typical examples of strong bases are the hydroxides of alkali and alkaline earth metals, for example NaOH. Certain strong bases can deprotonate very weakly acidic C——H groups even in the absence of water. Strong bases include, but are not limited to, sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide, lithium hydroxide, and rubidium hydroxide. In some embodiments, NaOH is used as a strong base. In some embodiments, potassium hydroxide is used as a 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 of about 6 to about 11. A number of such weak bases are known and are described in Handbook of Biochemistry and Molecular Biology, Vol. 1, 3rd ed., G. D. Fassman, CRC Press, 1976, pp. 305-347]. Weak bases may be soluble or insoluble in water. Suitable weak bases include 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 such as trimethylamine, triethylamine, tripropylamine and tributylamine, benzyldiethylamine, pyridine, quinoline, N-methylmorpholine, aniline, and the like. It doesn't work.

As used herein, “non-nucleophilic base” refers to a base that will not act as a nucleophile, that is, a base that will not donate an electron pair to an electrophile to form a chemical bond in connection with a reaction. Typically, non-nucleophilic bases are bulky and sterically hindered, allowing a proton to attach to the basic center, but preventing alkylation and complexation. Examples of non-nucleophilic bases include, but are not limited to, amines and nitrogen heterocycles such as triethylamine and pyridines, 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" means any group known in the art of organic synthesis for the protection of amine groups. Such amine protecting groups are described in Greene, "Protective Groups in Organic Synthesis," John Wiley & Sons, New York (1981) and in "The Peptides: Analysis, Synthesis, Biology, Vol. 3," Academic Press, New York ( 1981)]. Any amine protecting group known in the art may be used. Examples of amine protecting groups include, but are not limited to: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) Aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl bornyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanes such as trimethylsilane; (7) thiol-containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilane types such as trimethylsilane.

As used herein, the term "deprotecting agent" refers to a reagent or reagent system (reagent(s) and solvent) useful for removing a protecting group. The deprotecting agent may be an acid, base or reducing agent. For example, removal of the benzyl (Bn) group can be achieved by reduction (hydrogenolysis), while removal of the carbamate (e.g. Boc group) can be achieved with an acid (e.g. HCl, TFA, H ₂ SO ₄ , etc.), and removal of the silyl group can be accomplished with the use of a weak acid or halide (eg, a fluoride as provided by tetra-n-butylammonium fluoride (TBAF)). , optionally with mild heating.

As used herein, the phrase "reducing agent" generally refers to any species capable of reducing another species while being oxidized itself. As used herein, the phrase "oxidizing agent" or "oxidizing agent" generally refers to any species capable of oxidizing another species while itself being reduced.

As used herein, the term "triflation reagent" refers to a compound useful in a reaction in which a triflate group is attached to a hydroxy group to form a triflate ester. Triflatifying agents are a source of trifluoroacetyl groups. The triflating reagent is trialkylsilyl triflate, trialkylstannyl triflate, triflic acid anhydride (trifluoromethanesulfonic acid anhydride), N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf ₂ ), N -(5-chloro-2-pyridyl)tripleimide and N-(2-pyridyl)tripleimide.

As used herein, an “acrylonitrile derivative” is a compound derived from acrylonitrile having the formula CH ₂ CHCN, wherein one or more of the hydrogen atoms have been replaced by another atom or group. An example of an acrylonitrile derivative is 2-chloroacrylonitrile in which one of the hydrogen atoms of acrylonitrile 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 herein.

The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

As used herein, the term “alkyl” refers to a hydrocarbon chain that may be straight or branched containing the indicated number of carbon atoms. For example, C _1-6 represents a group which may have 1 to 6 (upper and lower limits inclusive) carbon atoms therein. Examples include methyl, ethyl, iso-propyl, tert-butyl and n-hexyl.

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

Salts may be formed from compounds in any manner familiar to those skilled in the art. Thus, reference to “to form a compound or a salt thereof” includes embodiments in which the compound is formed and a salt is subsequently formed from the compound in a manner familiar to those skilled in the art.

It is recognized that certain features of the invention that, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, the various features of the invention that, for brevity, are described in the context of a single embodiment can also be provided individually or in any suitable sub-combination.

All combinations of embodiments relating to aspects described herein are specifically encompassed by the present invention, as if each and every combination were individually and expressly recited, to the extent such combinations encompass possible aspects. Also, every sub-combination of embodiments contained within an aspect described herein, as well as every sub-combination of embodiments contained within every other aspect described herein, also includes each and every sub-combination of every embodiment. As if expressly recited herein, it is specifically covered by the present invention.

crystallization method.

Methods for converting selpercatinib Form A to selpercatinib Form B are disclosed herein. Although a variety of different methods can be used to convert selpercatinib Form A to Form B, a crystallization-based method for converting selpercatinib Form A to selpercatinib Form B is disclosed herein.

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

In one aspect, disclosed herein are methods for converting selpercatinib Form A to selpercatinib Form B.

In another aspect, selpercatinib Form A is prepared by combining selpercatinib Form A with a C ₁ -C ₅ alcohol to form a slurry and isolating selpercatinib Form B from the slurry. Methods for converting to nip Form B are disclosed herein.

In another aspect, disclosed herein is a method of converting selpercatinib Form A to selpercatinib Form B comprising:

a. dissolving selpercatinib Form A in a solvent comprising DMSO to form a solution;

b. adding water to the solution to form a slurry;

c. isolating selpercatinib Form B.

In another aspect, selpercatinib Form A is prepared comprising combining selpercatinib Form A and methanol to form a slurry and agitating the slurry until >99% by weight of Form A has been converted to Form B. Methods for converting to Form B are disclosed herein.

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

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

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

The XRPD patterns of Form A and Form B (above) were obtained using a Bruker D4 Endeavor X-ray powder diffraction equipped with a CuKα source (λ = 1.54180 Å) and a Vantec detector operating at 35 kV and 50 mA. Obtained on the system. Samples were scanned from 4 to 40 2θ° using a 1.0 mm divergence, 6.6 mm fixed antiscatter and 11.3 mm detector slit, with a step size of 0.008 2θ° and a scan rate of 0.5 sec/step. The dry powder was packed on a quartz sample holder and a smooth surface was obtained using a glass slide. Crystal form diffraction patterns were collected at ambient temperature and relative humidity. Determination peak positions were determined in MDI-Jade after full pattern transfer based on the internal NIST 675 standard with peaks at 8.853 and 26.774 2θ°. It is well known in the art of crystallography that for any given crystal form, the relative intensity of the diffraction peaks can vary due to the preferred orientation resulting from factors such as crystal form and habit. When the effect of preferred orientation is present, the peak intensities change, but the characteristic peak positions of the polymorphs do not. See, eg, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Moreover, it is also well known in the art of crystallography that the angular peak positions may vary slightly for any given crystal form. For example, the peak position may shift due to fluctuations in the temperature at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In this case, peak position variability of ±0.2 2θ° is assumed to account for these potential variations without precluding unambiguous identification of the indicated crystal form. Identification of crystal form can be made based on any unique combination of characteristic peaks.

DSC-TGA analysis of anhydrous crystalline Form A showed a melting onset of 207.6 °C and showed two endotherms, where the first endotherm corresponds to the melting of Form A, followed by exothermic recrystallization of Form B followed by Form B corresponded to the melting of DSC-TGA analysis of anhydrous crystalline Form B showed a single endotherm with an onset of melting of 213.3 °C.

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

Forms A and B have similar solubility. Both exhibit poor 25° C. solubility in many organic solvents including methyl ethyl ketone (MEK), acetone and many alcoholic solvents, and moderate solubility in dichloromethane (DCM), dimethylsulfoxide (DMSO) and THF (3 -30 mg/ml). Form B has little solubility in anisole.

¹³ C solid state NMR spectra of Forms A and B are shown in FIG. 2 . 2 also includes an overlay of a portion of the spectrum, where Form A has a peak at 30.9 ppm that is not observable for Form B, while Form B has a peak at 48.0 ppm that is not observable for Form A. indicates that Both spectra were referenced to the high field resonance of adamantane (δ = 29.5 ppm).

The aforementioned ¹³ C cross-polarization/magic angle spinning NMR (solid-state NMR or ssNMR) spectrum was analyzed using a Bruker Avance equipped with a Bruker 4 mm double resonance probe operating at a carbon frequency of 100.62 MHz and a proton frequency of 400.13 MHz. (Bruker Avance) III HD 400 MHz wide aperture NMR spectrometer. TOSS sideband suppression was used with cross polarization using SPINAL64 decoupling and RAMP 100 shaped H-nuclear CP pulses. Acquisition parameters were as follows: 4.0 μs proton pulse, 1.5 ms contact time, 5 kHz MAS frequency, 30.2 kHz spectral width, and 34 ms acquisition time. A 3 second recirculation delay was used, and the number of scans was 2655. Chemical shifts are relative to adamantane (δ = 29.5 ppm) in a separate experiment. Representative ¹³ C SSNMR resonance for form B is 26.44, 27.37, 28.00, 41.98, 43.43, 43.91, 48.04, 53.92, 56.31, 58.32, 69.48, 77.90, 80.38, 102.32, 106.77, 113.58 130.23, 134.86, 136.93, 140.59, 148.42, 149.50, 151.20, 152.45, 158.22, and 163.52 ppm.

The data establishes that Forms A and B 1) have some different properties, 2) can be readily identified, and 3) Form A can be converted to Form B.

A variety of different solvents can be used to convert Form A to Form B. Solvents that can be used to convert Form A to Form B include C ₁ -C ₅ alcohols (such as methanol or ethanol), water, acetonitrile (ACN, methyl tert-butyl ether (MTBE), heptane, n-butyl acetate ( n-BuOAC), 81% ACN-MeOH (81 mL ACN combined with 19 mL MeOH), wet ethyl acetate, cyclopentyl methyl ether (CPME), 1,2-dimethoxyethane, ethyl acetate, ethyl formate, methyl Isobutyl ketone (MIBK), nitromethane, n-propyl acetate (NPA), 1-pentanol, toluene, 1:1 MeOH:water, 1:1 EtOH:water, ACN:water, DMSO/heptane mixture, or DMSO In some embodiments, the solvent includes a C ₁ -C ₅ alcohol, water, DMSO, MTBE, ACN, and mixtures of two or more thereof. In other embodiments, the solvent includes methanol, ethanol, water, DMSO, MTBE, ACN or a mixture of two or more thereof.

As mentioned above, selpercatinib can form solvates; It can also form metastable solid forms, both of which are generally not stable upon drying. Observed solvates are acetone solvate, chloroform solvate, 1,4-dioxane solvate, methyl ethyl ketone (MEK) solvate, dichloromethane (DCM) solvate, 2-butanol solvate, 1-butanol solvate , ethanol solvate, dimethylsulfoxide (DMSO)-water solvate, DMSO solvate and tetrahydrofuran (THF) solvate. Solvates and metastable forms usually revert to Form A during isolation and/or drying, but films or amorphous materials are occasionally formed. The chloroform and 1,4-dioxane solvates were stable upon isolation/drying.

Form A used in the methods described herein may contain some Form B. The amount of Form B, if present, ranges from at least about 0.1% to about 25% by weight, or from about 0.5% to about 17% by weight, or from about 1% to about 16% by weight.

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

Conversion Method 1

In a preferred embodiment, the method comprises combining selpercatinib Form A with a solvent such as a C ₁ -C ₅ alcohol to form a slurry, and isolating selpercatinib Form B from the slurry. As the slurry is stirred or otherwise agitated, selpercatinib Form B is formed. In some embodiments, the alcohol is maintained at ambient temperature. In another embodiment, the slurry is heated, which increases the rate of Form B formation. Other than the temperature difference, these two embodiments are similar and are described below.

menstruum

Examples of C ₁ -C ₅ alcohols include methanol, ethanol, isopropanol, propanol, butanol, 2-butanol, 3-butanol and 1-pentanol. In some embodiments, methanol is the preferred C ₁ -C ₅ alcohol.

Examples of C ₁ -C ₅ alcohols include methanol, ethanol, isopropanol, propanol, butanol, 2-butanol and 3-butanol. In certain embodiments, the alcohol includes methanol and/or ethanol. In one embodiment, the alcohol includes methanol.

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

Temperature

Temperature affects the rate at which Form A converts to Form B, with lower temperatures taking longer than higher temperatures. It is possible to stir Form A and the solvent slurry at a temperature below ambient, but this will prolong the conversion of Form A to Form B and is therefore generally avoided.

The alcohol, such as a C ₁ -C ₅ alcohol, has a temperature of about 10-80°C, or about 20-60°C, or about 55°C. The C ₁ -C ₅ alcohol can be at a desired temperature before the Form A material is added, or the temperature can be adjusted after the Form A material is added.

In another embodiment, the temperature of the alcohol, such as a C ₁ -C ₅ alcohol, is 10-30°C, or about 15-25°C, or about 20°C. In other embodiments, the temperature is ambient temperature, which is the outside temperature. Form A will convert to Form B upon stirring in a room temperature solvent such as methanol, but conversion is faster when the Form A and solvent mixture is heated.

When the slurry is heated to such an extent that all Form A is dissolved, the resulting solution can be filtered to remove any insoluble matter. After stirring, the solution will be stirred and cooled as detailed below.

time

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

Cooling

When the Form A and alcohol mixture has been heated for the time indicated above, the heating is discontinued and the slurry is allowed to cool for about 4 to 24 hours or about 6 to 18 hours or about 12 hours.

Isolation Form B

Form B material may be isolated using any method known in the art. In one embodiment, separation comprises gravity filtration. In another embodiment, separation includes vacuum filtration. In another embodiment, separating comprises the use of centrifugation.

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

Isolated selpercatinib Form B can be dried using methods known in the art. Typical methods include heating, passing an inert gas over the solid phase and/or the use of sub-atmospheric pressure.

In a further embodiment of this example, the C ₁ -C ₅ alcohol and selpercatinib Form A are combined and the resulting slurry is stirred or otherwise agitated for a length of time sufficient to convert Form A to Form B. Typical stirring times are at least about 10 minutes to about 36 hours, or about 24 hours, but typically at least about 30 minutes, or at least about 1 hour, or at least about 4 hours, or at least about 6 hours, or at least about 8 hours, or at least about 12 hours. If desired, stirring and/or churning of the mixture can proceed beyond 24 hours. Heating the mixture will increase the rate of conversion of Form A to Form B.

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

Conversion Method 2

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

menstruum

A variety of different solvents may be used. Importantly, the solvent must not form a selpercatinib solvate; Rather, it should give the desired Form B. Examples of suitable solvents include, but are not limited to, DMSO, C ₁ -C ₅ alcohols, ACN, MTBE, water or combinations of two or more thereof. Preferred C ₁ -C ₅ alcohols include ethanol and/or methanol. In some embodiments, DMSO is a preferred solvent. In some embodiments, the solvent contains at least 2% water by weight.

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

Temperature

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

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

In some embodiments, the solvent comprises DMSO, which is heated to about 50 °C to about 70 °C. In a further embodiment, the DMSO is then cooled to about 50°C.

In an alternative embodiment, the solvent is not heated, i.e., allowed to stir at ambient temperature. In these embodiments, conversion of Form A to the form takes longer.

1st quantity of water

When the first portion of water is added to the solution, about 0.1-1.0 mL/g, or about 0.2-0.6 mL/g, or about 0.3 mL/g Form A is added (mL of water to g of Form A). In some embodiments, the first portion of water is about 0.1 mL/g or about 0.2 mL/g, about 0.3 mL/g, about 0.4 mL/g, about 0.5 mL/g or about 0.6 mL/g.

The first portion of water is added over about 30 seconds to about 15 minutes or about 1-10 minutes or about 4-6 minutes or about 5 minutes. If desired, longer times may be used.

seed determination

When Form B seed crystals are added to the mixture, about 0.1-15 weight percent or about 1 to about 10 weight percent or about 5 weight percent of Form B seed crystals are used.

In some embodiments, about 1%, 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14% or about 15% by weight of seed crystals are added.

Seed crystals can be prepared using the methods described herein.

time

After heating the mixture, dissolving the Form A material, reducing the mixture temperature to 50-110° C., adding the seed crystals—if seed crystals were used, the mixture was stirred for about 1-96 hours, or about 6-72 hours. hour, or about 8-24 hours. In some embodiments, the mixture is 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 portion of water

After stirring for 1-96 hours, the second portion of water is slowly added. The amount of water in the second portion is about 0.3-6 mL/g, 0.50-3.0 mL/g (mL of water per gram of Form A), about 0.75-1.5 mL/g, or about 0.9-1.20 mL/g. In some embodiments, the second 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, about 1.14 mL/g, about 1.15 mL/g, about 1.16 mL/g, about 1.17 mL/g, about 1.18 mL/g, about 1.19 mL/g, about 1.20 mL/g Form A.

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

Cooling

After the second portion of water is added, the mixture is cooled to a temperature of about 20-30°C by about 15-30°C. In some embodiments, the mixture is 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 another embodiment, the mixture is cooled to a temperature of about 30-55 °C. In these embodiments, yields tend to be slightly lower than when lower temperatures are used.

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

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

Isolation Form B

Form B is isolated as described above.

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

In embodiments wherein the solvent comprises DMSO, isolated selpercatinib Form B is washed with methanol until the isolated selpercatinib Form B contains less than 0.5% DMSO by weight.

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

In another example of this method, selpercatinib Form A is dissolved in DMSO at about 60-80°C or about 70°C to form a solution having a concentration of about 10-15 mL/g of DMSO per gram of Form A. do; Cool the mixture to about 40-60 °C or about 50 °C; add water; Form B seed crystals were seeded into the resulting mixture, the mixture was stirred, additional water was added, and the mixture was heated; The mixture is cooled and Form B is isolated. The initial amount of water added is about 0.1 mL/g Form A to about 0.5 mL/g Form A, or about 0.3 mL/g Form A. The amount of seed crystals that can be used ranges from about 1-10 weight percent, or about 5 weight percent, based on the amount of Form A. The seed crystal containing mixture is stirred for about 8-24 hours or about 12 hours. The second addition/amount of water is about 1.0-1.5 mL/g Form A, or about 1.10-1.15 mL/g or about 1.14 mL/g. The second addition/quantity of water is added over about 3-8 or about 5 hours. After the second addition/quantity of water is added, the slurry is cooled to about 20-30°C or about 25°C. The rate of cooling the slurry from about 70°C to about 25°C is about 10°C/hour until it reaches about 25°C. The about 25°C slurry is stirred for at least about 2 hours, then it is heated to about 60-80°C or 70-75°C or about 73°C and stirred for about 1 hour. The slurry is then cooled back to about 20-30°C or about 25°C. Cool the slurry from about 73°C to about 25°C at a rate of about 10°C/hour. After stirring for at least about 30 minutes to about 8 hours, or about 1-8 hours or about 2 hours, selpercatinib Form B is isolated, eg, by filtration.

Crystallization methods effective for conversion of Form A to Form B are further illustrated in the illustrative embodiments described in the Examples.

Direct Synthesis of Form B of Compound of Formula I.

In another aspect, the present disclosure relates to a method for preparing a compound of Formula I as Form B (ie, selpercatinib) or a pharmaceutically acceptable salt thereof.

In an embodiment, the process for preparing selpercatinib Form B is the preparation of one or more precursor compounds via synthetic methods as disclosed and described elsewhere (eg, US Pat. No. 10,112,942, incorporated herein by reference in its entirety). including synthesis. Exemplary Schemes 1 and 2 below show general methods for preparing selpercatinib Form B from precursor compound [2], as well as key intermediate compound [3]:

Precursor compound [2] (tert-butyl 3-(5-(3-cyano-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridin-4-yl) A detailed description of synthetic methods that can give pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate) can be found in, for example, U.S. Patents 10,745,419 and 10,112,942, and International Disclosed in patent publication WO 2018/071447, each of which is incorporated herein by reference in its entirety. In a brief overview of one non-limiting embodiment, compound [2] is 4-(6-fluoropyridin-3-yl)-6-(2 -hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3carbonitrile; can be prepared by reaction of 3,6-diaza-bicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester and K ₂ CO _3(s) (1:1:6.67 molar equivalents). . The resulting thick slurry was diluted with additional DMSO and stirred under heating (e.g., at 90° C. for an additional 12 hours). 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 MgSO _4(s) , filtered and concentrated under vacuum. The resulting residue was purified by silica chromatography (EtOAc/hexane as gradient eluent system) to give compound [2] in high yield. A person skilled in the art will recognize that other synthetic routes may be used to synthesize compound [2]. A person skilled in the art knows that compound [2] is formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzyl carbonyl, trimethylsilyl, 2-trimethyl Silyl-ethanesulfonyl, trityl and substituted trityl groups, including but not limited to examples of allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitroveratryloxycarbonyl, p-methoxybenzyl and tosyl. , amine protecting groups other than Boc. In some embodiments, the protecting group is tert-butyloxycarbonyl (Boc).

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

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

In some embodiments, conditions effective for silylation and removal of protecting groups are polar organic solvents such as alcohols (eg, MeOH, EtOH), organic acids (eg, aryl sulfonic acids such as p-toluenesulfonic acid), aprotic Magnetic solvents (e.g. acetonitrile), acyl halides in alcohols (e.g. acetyl chloride in methanol to produce HCl solutions), esters (e.g. ethyl acetate), ethers (e.g. anisole ) and combinations thereof. In some embodiments, the reaction may include trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluene sulfonic acid, acetyl chloride, aluminum trichloride, and boron trifluoride. Contains a deprotecting agent. In some embodiments, the deprotecting agent is sulfuric acid, acetyl chloride or p-toluene sulfonic acid. In some embodiments, the conditions may include heating the reaction mixture, optionally under reflux, for a period ranging from about 1 hour to about 8 hours or more (eg, overnight, or about 12 hours).

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

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

In some embodiments, the reaction of compound [3] with 6-methoxy-3-pyridinecarboxaldehyde is carried out using anisole as a solvent, provided that compound [3] is 2-hydroxy-2 of [3]. -shows greater solubility in anisole than the methyl-propoxy form. In some embodiments, reducing agents in the reaction may include alkali metal borohydride, hydrazine compounds, citric acid, citric acid salts, succinic acid, succinic acid salts, ascorbic acid and ascorbic acid salts. In some embodiments, the reducing agent is selected from sodium borohydride, lithium borohydride, nickel borohydride and potassium borohydride. In some embodiments, the lithium borohydride is selected from lithium borohydride and lithium triethylborohydride. In some embodiments, the sodium borohydride is selected from sodium triacetoxy borohydride (STAB), sodium borohydride and sodium cyanoborohydride. In some embodiments, the reducing agent is STAB. In some embodiments, an acid in the reaction serves as a catalyst for the reaction, and is an inorganic acid (eg, HCl, H ₂ SO ₄ , etc.), or an organic acid that has solubility in water (eg, acetic acid, pivalic acid, etc.) ) may be included. In some embodiments, the acid comprises pivalic acid.

The resulting compound is deprotected under conditions sufficient to remove the silyl group (eg TMS) but not severe enough to react with and degrade the reaction product (ie selpercatinib). In some embodiments, deprotection of the silyl group is performed using a fluoride source (eg, tetrabutylammonium fluoride (TBAF), pyridine.(HF) _x , trimethylamine trihydrofluoride (Et ₃ N.3HF), fluoro and adding hydrofluoric acid, tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), ammonium fluoride (H4NF)) or a weak acid to the reaction in an amount effective to react with the silyl group. Conditions for the deprotection step can include a buffered fluoride source and can be determined empirically, wherein conditions are kept mild enough to avoid degradation reactions.

After the reaction, the pH of the reaction mixture is adjusted with a base (eg, K ₂ CO ₃ slurry) and cooled to allow formation and isolation of crystalline Form B selpercatinib. In some embodiments, crystallization may further comprise the addition of a small amount of seed crystals of selpercatinib Form B. In some further embodiments, crystallization can include any crystallization technique described herein that can be effective to convert any residual amount of selpercatinib Form A to Form B.

Although specific starting materials and reagents are shown in the schemes below and related descriptions, other starting materials, reaction conditions and reagents may be substituted to provide the desired compound (ie, selpercatinib Form B) according to the present disclosure.

In some embodiments of this aspect, synthetic methods include the general scheme shown in Scheme 1.

Scheme 1

In some embodiments of this aspect, the method comprises the general reaction scheme shown in Scheme 2.

Scheme 2

selpercatinib Form B by direct synthetic methods according to aspects and embodiments according to the present disclosure or by conversion from selpercatinib (i.e., amorphous selpercatinib or another polymorphic form of selpercatinib) Regardless of whether is obtained, it may further 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 polymorphs and/or amorphous forms. there is. Celpercatinib Form B retains its activity as a RET inhibitor and is associated with related assays including, for example, those described in PCT Publication No. WO2018/071447 and US Patent Application Publication No. US 20180134702, each of which is incorporated by reference in its entirety. Activity can be assessed by any assay known in the art.

The following examples are provided solely for the purpose of illustrating and describing specific embodiments falling within the scope of the methods described herein, and are encompassed by the claims.

Example

selpercatinib (6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl) used in the crystallization procedure described herein -5 3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile) is described in U.S. Patent No. 10,112,942 and method.

Example 1: Cooling Crystallization

264 mg of Form A was dissolved in 20 mL DCM and (15) divided in equal portions into 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. Each solvent (see Table 2) was added with shaking at 50°C. The heat source was turned off and the sample was naturally cooled to room temperature (RT). The sample was stirred overnight and the resulting solid was isolated by vacuum filtration and then air dried. The solid-free vial was placed in the refrigerator for 3 days, and if precipitation did not occur, it was then allowed to evaporate in a fume hood for 1 day. XRPD data were collected on wet solids (when available). Approximately 2/3 of the experiments (˜66%) produced solvates that were metastable upon isolation and drying. These metastable solvates (except for the chloroform solvates) converted to Form A upon withdrawal from the mother liquor. 81% ACN-MeOH gave form B, while anisole gave form A.

Table 2. Summary of cold crystallization experiments.

Example 2: Evaporation and Vapor Diffusion Crystallization

An evaporation plate was prepared by dissolving 5 mg of Form A in 0.9-12 mL solvent in a (33) vial. The evaporated solution was manually syringe filtered into clean vials, covered with pinhole parafilm, and evaporated to dryness at room temperature (RT) and ambient humidity in a fume hood. The solution for vapor diffusion was placed in a 20 mL chamber containing 5 mL of anti-solvent and tightly capped.

A solvate or a mixture of solvate and Form A was obtained in approximately half of the crystallization experiments. A predominant number of solvates were converted to Form A upon desolvation. It is speculated that the templating effect due to structural similarity may lead to the nucleation of metastable forms. Form B was only obtained from two crystallization experiments using ACN and 5:1 MeOH-THF. X-ray diffraction amorphous forms/films were obtained from five solvent systems (THF, 11:1 IPA:acetic acid, benzyl alcohol, acetic acid and 10:1 EtOH:DMF). The chloroform and 1,4-dioxane solvates were stable upon isolation and solid state characterization data were collected. IPA is isopropyl alcohol, THF is tetrahydrofuran, and DMF is dimethylformamide.

Vapor diffusion experiments gave various solvates or amorphous materials. Five solvates, namely DCM, 1-BuOH, EtOH, THF and DMSO, were metastable and yielded Form A upon isolation. The DMSO/heptane mixture provided a mixture of Form A and Form B.

Example 3: Antisolvent Crystallization

(29) Anti-solvent addition experiments were prepared by dissolving various amounts (9-36 mg) of Form A in 1-15 mL solvent in 4 mL vials. For the first 17 vials, the anti-solvent was added dropwise into the syringe-filtered solution until either precipitation occurred or the volume of the anti-solvent equaled or exceeded the volume of the solvent. For the second 12 vials, the solution was syringe filtered into a clean vial containing 5 mL of anti-solvent. The solid was isolated by vacuum filtration and air drying. Vials in which no precipitation was observed were evaporated over a period of up to 2 weeks. 71% of the antisolvent additions resulted in Form A or an unstable solvate leading to Form A. Form B appeared in 24% of the trials (one result was amorphous). For the reverse antisolvent addition, 83% of the runs produced Form A or the solvate and 17% of the runs produced Form B.

Example 4: Slurry Crystallization

A slurry of the Form A vial was prepared with 10 mg of Form A in a 4 mL vial. Solvents were added depending on the solubility of Form A in these solvents to create a slurry density. The slurry was shaken at 22° C. on a 500 rpm shaker block for about 3 days. The solid was analyzed by XRPD as a wet cake. Most slurry screens produced solids consistent with Form A or solvates that converted to Form A during isolation/drying.

Another slurry plate containing 10 mg of Form A in a 4 mL vial was prepared in a similar manner as mentioned in the previous paragraph. The slurry was agitated at 22° C. on a 500 rpm shaker block for 24 hours. After 24 hours, the mother liquor in each vial was replaced with fresh respective solvent. The slurry was then stirred for 15 days. The solid was analyzed wet as well as dry by XRPD. In about 2/3 of the experiments (~66%), form B was observed. In the remaining third of the experiments (˜33%), Forms A and B or mixtures of Form A and solvates (in one case) were obtained. These results suggest that equilibrium has not been reached, which may be due to 1) limited solubility of Form A in the solvents tested or 2) minimal thermodynamic driving force for phase transformation near the transition point. In slurry crystallization experiments, anisole again provided Form A.

Table 3. Summary of slurry conditions and results.

In Table 3 above, the slurry was stirred for 15 days unless a different time period was noted.

Example 5: Solvent-Assisted Grinding

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

Example 6: Conversion of Form A to Form B

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

Example 7: Conversion of Form A to Form B

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

Example 8: Conversion of Form A to Form B

At room temperature, selpercatinib Form A was stirred in methanol (8 mL/g) for 18-24 hours. The solid was isolated by filtration. The solid was dried under vacuum at 45° C. with a slight N ₂ purge.

Example 9: Conversion of Form A to Form B

While stirring, Form A was dissolved in DMSO (13 mL/g) at 70° C. to give a clear solution. The solution was cooled to 50 °C. After charging with water (0.3 mL/g), the solution was seeded with Form B seed crystals (5% by weight based on the amount of Form A used). After stirring for 12 hours, water (1.14 mL/g) was charged over 5 hours. The slurry was cooled to 25 °C at 10 °C/h. Stir for at least 2 hours. The slurry was heated to 73 °C and stirred for 1 hour. The slurry was cooled to 25 °C at 10 °C/h. Stir for at least 2 hours. The solid was isolated by filtration. The wet cake was washed 3x with MeOH (8 mL/g). The solid was dried under vacuum at 45° C. with a slight N ₂ purge.

Example 10: Synthesis of Form B

4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy-propoxy)pyrazolo[ 1,5-a]pyridine-3-carbonitrile [3]

This synthetic route to Form B of the compound of Formula I (i.e., selpercatinib) is the compound tert-butyl-3-[5-[3-cyano-6-(2-hydroxy-2-methylpropoxy) Any synthesis resulting in pyrazolo[1,5-a]pyridin-4-yl]-2-pyridyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [2] path may be included.

To a round bottom flask (3 neck) equipped with an overhead stirrer, condenser and thermocouple was added methanol (200 mL, 100%) and acetyl chloride (3.1 mL, 44 mmol, 100%). After reacting the mixture, tert-butyl 3-[5-[3-cyano-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridin-4-yl] -2-pyridyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [2] (9.9965 g, 19.81 mmol, 100%) was added. Upon addition, the reaction was heated to about 60° C. (63° C.). The temperature was adjusted to reduce the amount of observable off-gas and avoid potential overdrive of the attached condenser. After assaying the reaction to determine complete conversion (approximately 2 hours), the solvent was stripped. To the mixture, acetonitrile (ACN) was added (approximately 100 mL) while rinsing the sides of the reaction vessel. The solvent mixture was stripped again and maintained under a nitrogen atmosphere.

To the reaction vessel was added additional ACN (300 mL, 100%) and hexamethyldisilazane ("HMDS" 25 mL, 119 mmol, 100%). After stirring the reaction at ambient temperature for about 1 hour, an initial sampling of the reaction mixture yielded about 1.6% of the title compound, based on the amount in [2]. The reaction was allowed to proceed overnight at ambient temperature. After sampling the reaction overnight, the mixture was heated to 40° C. and sampled at temperature after 1 hour. The heat of reaction was raised to 56 °C. During the temperature increase, the mixture was refluxed and foamed, presumably indicating evolution of ammonia. After about 1-1.25 hours at temperature, the reaction was sampled while observable reflux was continued. The reaction was held at temperature for an additional 3 hours and sampled again. The reaction solvent was stripped off and an aqueous potassium carbonate solution (100 mL, 50.45 mmol, 5% by mass) was slurried into the reaction vessel. The resulting mixture was washed with water (25 mL) and dried to give 7.89 g (78% yield) of the title compound [3]. (Mass spectrum, m/z = 477.20, 477.30 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ ) d: 8.55 (s, 1H), 8.06 (d, 1H), 7.82 (dd, 1H ), 7.66 (dd, 1H).

alternative way. tert-butyl 3-[5-[3-cyano-6-(2-hydroxy-2-methyl-propoxy)pyrazol in 10 volumes of organic solvent in a reaction vessel equipped with an overhead stirrer, condenser and thermocouple. [1,5-a]pyridin-4-yl]-2-pyridyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [2], (9.9965 g, 19.81 mmol, 100%) and p-toluenesulfonic acid (2.1 eq) were added. After allowing the mixture to react for 1 hour, pyridine (2.1 equiv.) and hexamethyldisilazane (6 equiv. "HMDS") were added. The reaction mixture was stirred for about an additional 1 hour to give the title compound [3].

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

4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyl Oxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile [3] (0.9981 g, 2.094 mmol, 100 mass%), 6-methoxy-3-pyridinecarboxaldehyde (i.e. 6 -Methoxynicotinaldehyde, 0.4909 mg, 0.003401 mmol, 95 mass %), pivalic acid (0.5328 mg, 0.005217 mmol, 100 mass %), and anisole (10 mL, 91.8 mmol, 100 mass %) were added and stirred. to form a slurry. Heat was applied while stirring until a homogeneous solution mixture was obtained. The solution was cooled to ambient temperature and maintained as a homogeneous solution. Upon cooling, sodium triacetoxyborohydride (1.0840 g, 5.1147 mmol, 100 mass%) was added and allowed to react. Analysis of the reaction after 2 hours indicated the formation of a TMS-protected derivative of the title compound.

After completion of the reaction, the process may continue to remove the TMS protection and crystallize Form B. Amount of water (1 mL, 55.5099 mmol, 100 mass %) and tetrabutylammonium fluoride trihydrate (0.6070 g, 2.322 mmol, 100 mass %) and seed crystals of the title compound optionally as Form B (˜10 mg) in the mixture. was added to the mixture. If no crystals are observable after a period of time, the mixture can be warmed to 50°C. After holding the elevated temperature overnight, the reaction was sampled and confirmed complete, but no crystallization was observed. The pH (slightly acidic) of the mixture was adjusted by adding potassium carbonate (5% by mass in water) as a slurry and added in 1 mL aliquots until any observed bubbling ceased and the pH tested basic. The mixture was stirred overnight and sampled to give the title compound with no detectable impurities; A total isolated yield of 54% was obtained. (Mass spectrum, m/z = 526.30 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ ) d: 8.55 (s, 1H), 8.06 (d, 1H), 7.82 (dd, 1H), 7.66 (dd, 1H)

alternative way. 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-trimethylsilyl Oxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile [3] (1.00 g, 2.10 mmol), 6-methoxy-3-pyridinecarboxaldehyde (1.6 eq), pivalic acid ( ~ 5 vol equivalents), sodium triacetoxyborohydride (2.5 equiv) and anisole (10 mL, 91.8 mmol, 100 mass%) were added and allowed to react for about 1 hour. Water (10 mL) was added to the reaction mixture. The mixture was filtered through celite (diatomaceous earth, filter aid). The layers were separated and saturated sodium chloride solution (10 mL) was added to the organic layer. The layers were separated. To the organic layer was added 5N HCl (1 mL). The mixture was heated to 95 °C for 3 hours. After the reaction, the pH (acidic) of the mixture was adjusted to pH 9 by adding potassium carbonate. The mixture was allowed to crystallize by cooling. The resulting crystals of selpercatinib Form B were filtered, washed with methyl tert-butyl ether (MTBE) and dried to give the pure title compound.

Example 11

The physical and chemical stability of Form B is an important attribute in relation to API and dosage form drug development and manufacturing operations (drying, storage, transport movement, etc.), as well as ensuring dissolution and solubility. Not all crystalline forms have the necessary stability to enable drug development. Crystal forms that are stable to both temperature and humidity are preferred. To evaluate the stability of the crystalline form of selpercatinib, an accelerated stability study was performed. A sample of Form B was weighed into a 20 mL scintillation vial and placed in a bell jar with saturated salt solution in an oven at the specified temperature for the time specified in Table 4 (open dish). Form B was analyzed before and after accelerated stability studies and collected on a Bruker D8 Advanced XRPD equipped with a CuKα source (wavelength = 1.54056 Å) and a Linxeye detector, operating at 40 kV and 40 mA, with a 0.2 mm divergence slit. . Each sample was scanned from 4° to 30° 2θ with 0.02° steps at a rate of 0.2 seconds per step. Assays for starting materials and impurities were evaluated using an Agilent 1260 HPLC system equipped with a diode array detector. Samples were prepared at appropriate concentrations in 50/50 0.1% TFA in water/0.1% TFA in ACN and evaluated using the following HPLC conditions: Column Zorbax Bonus-RP, 75 x 4.6 mm i.d., 3.5 micron, Mobile phase A is 0.1% TFA in water, mobile phase B is 0.1% TFA in ACN, and the gradient is time with a flow rate of 1.5 mL/min, column temperature of 30°C, UV detection wavelength of 210 nm, and injection volume of 3 μL. 95% A at 0, 23% A at time 9.5-12.1 minutes, 5% A at time 13-16 minutes, 95% A at time 16.1-20 minutes. The stability of Form B was characterized and found to be chemically and physically stable under the conditions tested (Table 4).

Table 4: Stability of crystalline forms of selpercatinib

¹ week, compare morphology to XRPD of unstressed (time 0) sample; NC = no change.

² weeks, assay values are determined by comparison to unstressed (time 0) samples.

Example 12: Solubility

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

Table 5: Solubility of crystalline forms of selpercatinib at 37°C after 24 hours equilibration.

¹ Description is consistent with USP, European Pharmacopoeia and Japanese Pharmacopoeia.

Solubility in ² 0.1 N HCl was measured at 21.5°C (ambient temperature).

³ SGF: simulated gastric fluid (0.01 N HCl/Na lauryl sulfate 0.05%/NaCl 0.2%).

XRPD of the ⁴ retained solids showed non-crystalline material.

⁵ FaSSIF: Fasting-state artificial intestinal fluid (NaH ₂ PO ₄ 28.66 mM, Na taurocholate 3 mM, lecithin 0.75 nM, NaCl 105.8 mM, pH 6.5).

⁶ FeSSIF: fed-state simulated intestinal fluid (acetic acid 144.04 mM, Na taurocholate 15 mM, lecithin 3.75 mM, NaCl 203.17 mM, pH 5.0).

Low solubility at higher pH and moderate to high solubility in acidic media is consistent with a weak free base having low intrinsic solubility. The results indicate that the intrinsic solubility of this crystalline form of selpercatinib is low (approximately 0.001 mg/mL).

Claims (71)

A crystalline form of selpercatinib characterized by at least one of:
(a) an X-ray powder diffraction (XRPD) pattern comprising a peak at 21.1° and at least one peak at 17.1°, 17.7° and 19.8° ± 0.2° 2θ as measured using an X-ray wavelength of 1.5418 Å; or
(b) ¹³ C solid state NMR spectrum containing peaks at 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (each ± 0.2 ppm) based on the high field resonance of adamantane (δ = 29.5 ppm). . The method of claim 1 , wherein the peak is measured at 21.1° and at least one peak at 7.5°, 12.0°, 13.2°, 17.1°, 17.7° and 19.8° ± 0.2° 2θ when measured using an X-ray wavelength of 1.5418 Å. A crystalline form of selpercatinib characterized by having an X-ray powder diffraction (XRPD) pattern comprising The X-ray powder according to claim 1, having characteristic peaks occurring at 7.5°, 10.9°, 12.0°, 13.2°, 17.1°, 17.7°, 18.2°, 19.8°, 21.1° and 24.5° ± 0.2° 2θ. A crystalline form of selpercatinib characterized by having a diffraction (XRPD) pattern. 26.4, 28.0, 42.0, 43.9, 48.0, 56.3, 69.5, 80.4, 102.3, 106.8, 115.2, 120.8, 130.2, 134.9, A crystalline form of selpercatinib characterized by a ¹³ C solid state NMR spectrum comprising peaks at 140.6, 149.5, 152.5, and 163.5 ppm (±0.2 ppm each). 26.4, 27.4, 28.0, 42.0, 43.4, 43.9, 48.0, 53.9, 56.3, 58.3, 69.5, 77.9, 80.4, 102.3, Peaks at 106.8, 113.6, 115.2, 118.2, 120.8, 125.2, 130.2, 134.9, 136.9, 140.6, 148.4, 149.5, 151.2, 152.5, 158.2, and 163.5 ppm ( ^NMR13 C containing ± 0.2 ppm each) solid state A crystalline form of selpercatinib characterized by a spectrum. A pharmaceutical composition comprising the crystalline form of selpercatinib according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, diluent or excipient. 7. The pharmaceutical composition of claim 6, which contains less than about 20% by weight of selpercatinib in other crystalline forms. 7. The pharmaceutical composition of claim 6, which contains less than about 10% by weight of selpercatinib in other crystalline forms. 7. The pharmaceutical composition of claim 6, which contains less than about 5% by weight of selpercatinib in other crystalline forms. 10. A method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of selpercatinib according to any one of claims 1 to 9. 10. A pharmaceutical composition according to any one of claims 6 to 9 for use in therapy. 10. A pharmaceutical composition according to any one of claims 6 to 9 for use in the treatment of cancer. 13. The method of claim 12, wherein the cancer is lung cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid carcinoma, recurrent thyroid carcinoma, refractory differentiated thyroid carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid gland A pharmaceutical composition selected from the group consisting of hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer. 14. The pharmaceutical composition according to claim 13, wherein the cancer is medullary thyroid cancer. 14. The pharmaceutical composition according to claim 13, wherein the cancer is lung cancer, and the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronchiolar pneumocarcinoma, RET fusion lung cancer or lung adenocarcinoma. 16. The pharmaceutical composition according to claim 15, wherein the cancer is RET fusion lung cancer. A process for preparing the crystalline form of selpercatinib of claim 1 comprising the following steps:
(a) suspending selpercatinib in a solvent;
(b) heating the suspension to 50° C. to 60° C. while stirring for 30 to 90 minutes;
(c) removing heat and cooling the suspension to room temperature to form solid crystals; and
(d) collecting solid crystals. 18. The method of claim 17, wherein the solvent comprises methanol. 19. The method of claim 17 or 18, wherein the suspension is heated to 55°C. 20. The method according to any one of claims 17 to 19, wherein the suspension is stirred for 60 minutes. 21. The method according to any one of claims 17 to 20, wherein the solid crystals are collected by vacuum filtration. A method of converting selpercatinib form A to selpercatinib form B. 23. The method of claim 22, wherein selpercatinib Form A is combined with a C ₁ -C ₅ alcohol to form a slurry; A method comprising isolating selpercatinib Form B from the slurry. 24. The method of claim 22 or 23, wherein the C ₁ -C ₅ alcohol is from about 10° C. to about 30° C. 25. The method of any one of claims 22-24, wherein the C ₁ -C ₅ alcohol is about 15-25°C. 26. The method of any one of claims 22-25, wherein the C ₁ -C ₅ alcohol is about 20°C. 24. The method of claim 22 or 23, wherein the C ₁ -C ₅ alcohol is from about 10° C. to about 80° C. 28. The method of any one of claims 22-27, wherein the C ₁ -C ₅ alcohol comprises methanol. 29. The process of any one of claims 22-28, wherein the C ₁ -C ₅ alcohol comprises at least 90% methanol by weight. 30. The method of any one of claims 22-29, wherein the slurry is stirred or otherwise agitated for at least about 10 minutes. 31. The method of any one of claims 22-30, wherein isolation of Form B comprises vacuum filtration. 32. The method of any one of claims 22-31, wherein isolation of Form B comprises centrifugation. 33. The method of any one of claims 22-32, further comprising drying the selpercatinib Form B. 23. The method of claim 22 comprising:
a. dissolving selpercatinib Form A in a solvent comprising DMSO to form a solution;
b. adding water to the solution to form a slurry;
c. isolating selpercatinib Form B. 35. The method of claim 34, wherein the concentration of Form A dissolved in DMSO is about 10-15 mL/g. 36. The method of claim 34 or 35, wherein the concentration of Form A dissolved in DMSO is about 12-13 mL/g. 37. The method of any one of claims 34-36, wherein forming the solution of step a comprises heating a solvent comprising selpercatinib Form A and DMSO to about 50°C to about 70°C. method. 38. The method of any one of claims 34-37, wherein the solution is cooled to a temperature less than about 70°C and greater than about 20°C. 38. The method of claim 37, wherein the solution is cooled to a temperature of about 50°C. 40. The method of any one of claims 34-39, wherein step b comprises adding from about 0.1 to about 1 mL of water per gram of Form A to the solution. 41. The method of any one of claims 34-40, wherein step b comprises adding about 0.3 mL of water per gram of Form A to the solution. 42. The method of any one of claims 34-41, wherein step b further comprises adding about 1 to about 15 weight percent of Form B seed crystals. 43. The method of any one of claims 34-42, wherein step b further comprises adding about 1 to about 10 weight percent of Form B seed crystals. 44. The method of claim 42 or 43, wherein about 5% by weight of the Form B seed crystals are added. 45. The method of any one of claims 34-44, wherein after adding the water in step b, the slurry is stirred for about 6 to about 72 hours. 46. The method of any one of claims 34-45, wherein the slurry is stirred for at least 12 hours. 47. The method of any one of claims 34-46, wherein step b further comprises adding a second portion of water to the slurry. 48. The method of claim 47, wherein about 0.5 to about 3 mL of water is added to the slurry per gram of Form A. 49. The process of any one of claims 34-48, wherein the slurry of step b is cooled to about 20-30°C. 50. The method of any one of claims 34-49, wherein step c comprises filtration. 51. The method of any one of claims 34-50, wherein the isolated selpercatinib Form B from step c is washed with a solvent comprising methanol, ACN, MTBE or water. 52. The method of claim 51, wherein the isolated selpercatinib Form B is washed with a solvent comprising methanol. 53. The method of claim 52, wherein the isolated selpercatinib Form B is washed with methanol until the isolated selpercatinib Form B contains less than 0.5% DMSO by weight. 23. The method of claim 22 comprising combining selpercatinib Form A and methanol to form a slurry and stirring the slurry until >99% by weight of Form A has been converted to Form B. 55. The method of claim 54, wherein the slurry is stirred for about 18-24 hours. 56. The method of claim 54 or 55, wherein the concentration of selpercatinib Form A in methanol is about 8 mL/g. 23. The method of claim 22, wherein selpercatinib Form A is dissolved in DMSO at about 60-80°C to form a solution having a concentration of about 10-15 mL/g of DMSO per gram of Form A; Cool the solution to about 40-60° C. and add water; optionally, seeding Form B seed crystals into the resulting mixture; Stir the mixture; add more water; Heat the mixture to about 60-80 °C; cooling the mixture and isolating Form B. 58. The method of claim 57, wherein 5% by weight of Form B seed crystals are added to the mixture. 59. The method of claim 57 or 58, wherein the first addition of water is from about 0.1 mL/g Form A to about 0.5 mL/g Form A. 60. The method of any one of claims 57-59, wherein the second addition of water is about 1.0-1.5 mL/g Form A. A process for the preparation of selpercatinib, or a pharmaceutically acceptable salt thereof, as polymorph Form B, of Formula I,

A compound of the structure

or a salt thereof with 6-methoxynicotinaldehyde in the presence of an acid and a reducing agent in a solvent to prepare selpercatinib Form B or a pharmaceutically acceptable salt thereof. The method of claim 61, further comprising preparing a compound of structure [3] or a salt thereof, a compound of the structure

or a salt thereof, wherein R ₁ is an amine protecting group, with a deprotecting agent to form a compound of structure [3] or a salt thereof. 63. The method of claim 61 or 62, wherein the deprotecting agent is trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluene sulfonic acid, acetyl chloride, aluminum trichloride and trifluorinated acid. and selected from the group consisting of boron. 64. The method of claim 62 or 63, wherein the deprotecting agent is selected from the group consisting of sulfuric acid, p-toluene sulfonic acid and acetyl chloride. 65. The method of any one of claims 61-64, wherein the reducing agent is selected from the group consisting of alkali metal borohydride, hydrazine compound, citric acid, citric acid salts, succinic acid, succinic acid salts, ascorbic acid and ascorbic acid salts. . 66. The method of any one of claims 61-65, wherein the reducing agent is selected from the group consisting of sodium triacetoxyborohydride (STAB), sodium borohydride and sodium cyanoborohydride. 67. The compound of any one of claims 61-66, wherein R ₁ is formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzyl carbonyl, tert- Butyloxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitroveratryloxycarbonyl , p-methoxybenzyl and tosyl. 68. The method of any one of claims 61-67, wherein R ₁ is tert-butyloxycarbonyl (Boc). 69. The method of any one of claims 61-68, wherein the acid is selected from the group consisting of pivalic acid and acetic acid. 70. The method of any one of claims 61 to 69, wherein the reaction is conducted in a solvent and the solvent comprises anisole. Compound having structure [3] 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy -propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

or a pharmaceutically acceptable salt thereof.

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