TW202202501A - Crystalline ret inhibitor - Google Patents

Abstract

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

Description

Crystalline RET inhibitors

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

(Formula I).

Although US Pat. No. 10,584,124 describes several crystalline forms of selpatinib, including a crystalline form designated "Form A," a new thermodynamically more stable crystalline form, and methods for preparing this crystalline form, are disclosed herein. This new crystalline form can be incorporated into formulations such as lozenges, capsules and suspensions, which will benefit patients.

The present invention relates to a new crystalline form of serpatinib, and a method for preparing this thermodynamically stable polymorph, which is referred to throughout as "Form B". In a general sense, the present invention provides methods for their preparation, isolation and characterization.

As described in more detail below, the compound of Formula I (Selpatinib) can be provided in polymorphic forms (Form A and Form B) and, surprisingly, certain processes and methods are effective in most of their thermodynamically stable polymorphs. Form B provides serpatinib. As described below and demonstrated by illustrative working examples, processes and methods for producing and preparing selpatinib in a particular polymorphic form can be included in the efficient production or conversion of other polymorphic forms (i.e., forms A compound of formula I provided in one or more polymorphic forms is converted (ie, reacted, contacted and/or treated) to form B under the crystallization conditions of A). In other aspects, the processes and methods for producing serpatinib Form B can comprise a synthetic route comprising subjecting one or more intermediates or precursors to conditions effective to produce serpatinib Form B Compound reactions (ie, direct synthetic routes).

Form B is characterized by at least one of: (a) x-ray powder diffraction comprising a peak at 21.1° and one or more peaks at 17.1°, 17.7°, and 19.8° ± 0.2° 2θ ( XRPD) pattern, as measured using an x-ray wavelength of 1.5418 Å, or (b) ^a13C solid-state NMR spectrum containing peaks referenced to the high-field resonance of adamantane (δ = 29.5 ppm) at: 28.0, 48.0, 80.4, 106.8, 130.2 and 134.9 ppm (± 0.2 ppm respectively).

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

Form B for use in therapy is also provided herein. Further provided herein is Form B for use in the treatment of cancer, in particular for the treatment of cancers with aberrant RET performance (eg, RET-related cancers such as medullary thyroid cancer or RET fusion lung cancer).

Also provided is the use of Form B in the manufacture of a medicament for the treatment of cancer, in particular for the treatment of cancers with aberrant RET expression (eg, RET-related cancers such as medullary thyroid cancer or RET fusion lung cancer).

Methods of converting Serpatinib Form A to Serpatinib Form B are also disclosed.

Also detailed herein is a method for converting Serpatinib Form A to Serpatinib Form B, the method comprising: combining Serpatinib Form A with a _C1 - _C5 alcohol to produce a slurry and isolation of Serpatinib Form B from the slurry.

Also described is a method for converting Serpatinib Form A to Serpatinib Form B, the method comprising: a. Dissolving the Serpatinib Form A in a solvent comprising DMSO to form a solution; b. adding water to the solution and thereby forming a slurry; c. Isolate the Serpatinib Form B.

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

Another method described herein is a method for converting Serpatinib Form A to Form B, wherein the Serpatinib Form A is dissolved in DMSO at about 60-80°C to form a concentration A solution of about 10-15 mL/g of DMSO per gram of Form A; cool the solution to about 40-60°C, add water; seed the resulting mixture with Form B as appropriate; stir the mixture; add more water; heat the mixture to about 60-80°C; cool the mixture and isolate the Form B.

(式I) 或其醫藥學上可接受之鹽的方法， 其中該方法包含使以下結構之化合物：

或其鹽，在酸及還原劑之存在下在溶劑中與含有6-甲氧基菸鹼醛反應以製備塞爾帕替尼形式B或其醫藥學上可接受之鹽。Also described is a serpatinib for the preparation of formula I in polymorph Form B:

(Formula I) or a method of a pharmaceutically acceptable salt thereof, wherein the method comprises making a compound of the following structure:

or a salt thereof, reacted with 6-methoxynicotinaldehyde containing 6-methoxynicotinic aldehyde in a solvent in the presence of an acid and a reducing agent to prepare Serpatinib Form B or a pharmaceutically acceptable salt thereof.

或其醫藥學上可接受之鹽。Described herein is 4-[6-(3,6-diazabicyclo[3.1.1]hept-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyl Oxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile compound having structure [3]

or its pharmaceutically acceptable salt.

Serpatinib Form B is described herein. This crystalline form of serpatinib is useful in the treatment of disorders associated with aberrant RET activity, such as IBS or cancer, especially cancers derived from over-activated RET signaling (ie, RET-related cancers). More specifically, this crystalline form of serpatinib is useful in the treatment of RET-related cancers, such as lung cancer (eg, small cell lung cancer or non-small cell lung cancer), thyroid cancer (eg, papillary thyroid cancer, medullary thyroid cancer) , differentiated thyroid cancer, relapsed thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine neoplasia, lung adenocarcinoma, bronchiolopulmonary cell carcinoma, multiple endocrine tumors type 2A or 2B (respectively MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, breast neoplasia, colorectal cancer (eg, metastatic colorectal cancer), nipple renal cell carcinoma, gangliomatosis of the gastrointestinal mucosa, inflamed myofibroblastic tumor, or cervical cancer.

Form B is characterized by an x-ray powder diffraction (XRPD) pattern comprising a peak at 21.1° and one or more peaks at 17.1°, 17.7°, and 19.8° ± 0.2° 2θ, as using the 1.5418 Å measured at x-ray wavelengths. Form B also exhibits ^a13C solid-state NMR spectrum containing peaks referenced to the upfield resonance of adamantane (δ=29.5 ppm) at 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (± 0.2 ppm, respectively).

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

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

Form B can be further characterized by ^a13C solid state NMR spectrum comprising peaks referenced to the high field resonance of adamantane (δ = 29.5 ppm) at: 26.4, 28.0, 42.0, 43.9, 48.0, 56.3, 69.5, 80.4 , 102.3, 106.8, 115.2, 120.8, 130.2, 134.9, 140.6, 149.5, 152.5 and 163.5 ppm (± 0.2 ppm respectively).

Additionally, Form B can be characterized as comprising a 13C solid state NMR spectrum comprising one or more peaks referenced to the upfield resonance of adamantane (δ = 29.5 ppm) at: 26.4, 27.4, 28.0, 42.0, 43.4, 43.9 ( + 0.2 ppm respectively).

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

Compared with other crystalline forms of Serpatinib, the pharmaceutical composition containing Form B includes at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% by weight %, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% by weight of Form B. Preferably, the pharmaceutical compositions described herein comprise at least 80% Form B and less than 20% other crystalline forms of Serpatinib. More preferably, the pharmaceutical composition comprises at least 90% Form B and less than 10% other crystalline forms of selpatinib. Even more preferably, the pharmaceutical composition comprises at least 95% Form B and less than 5% other crystalline forms of Serpatinib. Still more preferably, the pharmaceutical composition comprises at least 97% Form B and less than 3% other crystalline forms of selpatinib. More preferably, the pharmaceutical composition comprises at least 98% or 99% Form B and less than 2% or 1%, respectively, of other crystalline forms of selpatinib.

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 cancers that can be treated using the methods described herein include blood cancers or solid tumor cancers. Examples of cancer types that can be treated using Form B include lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, relapsed thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine tumors type 2A or 2B (respectively). MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gangliomatosis of gastrointestinal mucosa and cervical cancer. In particular, the type of cancer may be lung cancer or thyroid cancer. More specifically, the cancer may be non-small cell lung cancer or medullary thyroid cancer.

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 RET-related diseases or disorders, such as IBS or cancer. Cancers that can be treated using such agents are described above. The use of Form B in the manufacture of a medicament may also include the steps of performing an in vitro assay using a biological sample from a patient to determine the presence of a dysregulation in the expression or activity or level of the RET gene, RET kinase, or any of them, and if present Dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them, a therapeutically effective amount of Form B is administered to the patient. In such uses, the biological sample can be a tumor sample and the tumor sample can be analyzed using methods known to those skilled in the art, such as genome/DNA sequencing. Additionally, in these uses, the sample can be obtained from the patient prior to the first administration of Form B. In these uses of Form B as described herein, a patient may be selected for treatment in therapy based on having at least one disorder in the expression or activity or content of the RET gene, RET kinase, or any of them. Furthermore, in these uses, Form B can be administered to the patient at a dose of about 1 mg/kg to 200 mg/kg (effective dose subranges are mentioned above).

Herein, a patient is a patient with an established RET fusion or RET mutation. Thus, the term "determining a RET fusion or RET mutation" means determining the presence or absence of a RET fusion or RET mutation. Methods for determining the presence of RET fusions or RET mutations are known to those of ordinary skill in the art, eg, see Wang, Yucong et al., Medicine 2019; 98(3) : e14120.

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

A "pharmaceutically acceptable carrier, diluent or excipient" is a medium generally accepted in the art for delivering biologically active agents to mammals (eg, humans).

The terms "treatment/treat/treating" and the like are meant to include slowing, halting or reversing the progression of a disorder. These terms also include alleviating, ameliorating, alleviating, eliminating or reducing one or more symptoms of a disorder or condition (even if the disorder or condition is not actually eliminated and even if the progression of the disorder or condition itself is not slowed, stopped or reversed).

"Effective amount" means the amount of crystalline form of serpatinib that will elicit a biological or medical response in a patient or a desired therapeutic effect in a patient by the treating clinician. In one example, the crystalline form of serpatinib inhibits native RET signaling in an in vitro or ex vivo RET enzyme assay. In another example, the crystalline form of serpatinib 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 being.

An effective amount can be readily determined by the attending diagnosing physician, such as one skilled in the art, by using known techniques and by observing the results obtained under similar circumstances. In determining an effective amount for a patient, the attending diagnosing physician considers a number of factors, including (but not limited to): the species of the patient; its size, age, and general health; the particular disease or condition involved; the extent or disease or condition involved individual patient response; particular compound administered; mode of administration; bioavailability characteristics of the formulation administered; dosing regimen selected; use of concomitant medications; and other relevant circumstances.

Form B is preferably formulated for administration to the pharmaceutical composition by any route that renders the compound bioavailable, including oral, intravenous, and transdermal routes. Optimally, such compositions are for oral administration. Such pharmaceutical compositions and methods of making them are well known in the art. (See, eg, Remington: The Science and Practice of Pharmacy (ed. D.B. Troy, 21st ed., Lippincott, Williams & Wilkins, 2006)).

As used herein, a "particulate composition" refers to a composition in the form of particles that is a precursor composition to a pharmaceutical composition in a pharmaceutical manufacturing process.

As used herein, "manufacturing container" refers to containers employed in pharmaceutical manufacturing, rather than in medicinal chemistry laboratories. Examples of manufacturing vessels include, but are not limited to, hopper collectors, beds, dryer beds, granulator machines, dryer trays, granulator buckets, and mixing bowls.

In some embodiments, the Form B material is prepared from the Form A material. In one embodiment, the method of converting Form A to Form B comprises: combining Serpatinib Form A with a _C1 - _C5 alcohol to produce a slurry and isolating Serpatinib Form B from the slurry. In some embodiments, the method is performed at a temperature of about 10 to 80°C, about 10 to 30°C, about 15 to 25°C, or about 20°C.

In some embodiments, the _C1 - _C5 alcohol comprises methanol. Preferred _C1 - _C5 alcohols comprise methanol, and in some embodiments, methanol is at least about 90 wt%, or 92 wt%, or 94 wt%, or 96 wt%, or 98 wt%, or 99 wt% methanol.

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

In some embodiments, the method comprises stirring, mixing, or agitating the slurry for a range of at least about 5 minutes (eg, 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 to 12 hours. In some other embodiments, the period of time is at least 10 minutes.

In some embodiments, the method can further comprise isolating the serpatinib Form B produced by the method. In some embodiments, separating can include vacuum filtration. In some embodiments, the separation can comprise centrifugation.

In some other embodiments, the method may further comprise drying the serpatinib Form B produced. Drying can be accomplished using vacuum and/or heat.

In other embodiments, the method comprises dissolving Serpatinib Form A in a solvent comprising DMSO to form a solution; adding water to the solution in an amount to form a slurry; and separating the resulting plug in the slurry Ilpatinib Form B.

In some embodiments, the method comprises adding about 1 gram of Serpatinib Form A to about 10 to 15 mL/g of DMSO. In some other embodiments, the method comprises adding about 1 equivalent of the serpatinib form to about 12 to 13 mL/g of DMSO, and thus, the concentration of Form A dissolved in DMSO is about 12 to 13 mL /g or 1 g Form A in about 12-13 mL of DMSO.

In some embodiments of the method, forming a solution comprising DMSO and serpatinib Form A comprises heating serpatinib Form A and a solvent comprising DMSO to about 50°C to about 70°C. In some other embodiments, the method includes cooling the solution to a temperature below about 70°C and above about 20°C. In yet other embodiments, the method includes cooling the solution to a temperature of about 50°C.

In some embodiments of the method, adding water comprises adding about 0.1 to about 1 mL/g of water per gram of the Form A solution. In some other 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, adding water may further comprise adding about 1 to about 15 wt % of Form B seeds to the slurry. In some other embodiments, about 1 to about 10 wt % of Form B seeds may be added to the slurry. In yet other embodiments, about 5 wt% of Form B seeds may be added to the slurry.

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

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

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

In some embodiments, isolating serpatinib Form B comprises filtration. In some embodiments, the isolated serpatinib Form B can be washed with a solvent comprising methanol, ACN, MTBE, or water. In some other embodiments, the isolated serpatinib Form B is washed with a solvent comprising methanol. In yet other embodiments, the isolated Serpatinib Form B is washed with methanol until the isolated Serpatinib Form B contains less than 0.5 wt% DMSO.

In some of the above aspects and embodiments, the present invention provides a method for converting Serpatinib Form A to Form B, comprising: combining Serpatinib Form A with methanol to form a slurry feed, and agitate the slurry until >99 wt% of Form A is converted to Form B. In some embodiments of the method, the slurry is stirred for about 18 to 24 hours. In yet other embodiments, the concentration of Serpatinib Form A in methanol is about 8 mL/g.

In some of the above aspects and embodiments, the present invention provides a method for converting Serpatinib Form A to Form B, wherein Serpatinib Form A is dissolved at about 60 to 80°C in DMSO to form a solution of about 10 to 15 mL/g of DMSO per gram of Form A; cool the solution to about 40 to 60°C, add a first amount of water; seed the resulting mixture with Form B as appropriate ; Stir the mixture; add a second amount of water; heat the mixture to about 60 to 80° C.; cool the mixture and isolate Form B. In some embodiments of the method, 5 wt % of Form B seeds are added to the mixture. In yet other embodiments, the first addition of water is about 0.1 mL/g of Form A to about 0.5 mL/g of Form A. In yet other embodiments, the second addition of water is about 1.0 to 1.5 mL/g of Form A.

(式I) 或其醫藥學上可接受之鹽的方法，其中方法包含使以下結構之化合物：

或其鹽，在酸及還原劑之存在下在溶劑中與含有6-甲氧基菸鹼醛反應以製備塞爾帕替尼形式B或其醫藥學上可接受之鹽。雖然可使用化學計算量之酸，但非化學計算量亦可接受。在結構[3]中，氧在其上具有TMS基團。雖然未明確展示，但應理解可使用其他醇保護基。除TMS以外，可使用其他矽基，如本文所描述。In another aspect, the present invention provides a serpatinib for use in the preparation of polymorph Form B of Formula I:

(Formula I) or a method of a pharmaceutically acceptable salt thereof, wherein the method comprises making a compound of the following structure:

or a salt thereof, reacted with 6-methoxynicotinaldehyde containing 6-methoxynicotinic aldehyde in a solvent in the presence of an acid and a reducing agent to prepare Serpatinib Form B or a pharmaceutically acceptable salt thereof. While stoichiometric amounts of acid can be used, non-stoichiometric amounts are also acceptable. In structure [3], the oxygen has a TMS group on it. Although not explicitly shown, it is understood that other alcohol protecting groups may be used. In addition to TMS, other silicon bases can be used, as described herein.

或其鹽，其中R₁ 為胺保護基，與去保護劑反應以形成結構[3]之化合物或其鹽。In some embodiments of this aspect, the method further comprises preparing a compound of structure [3], or a salt thereof, comprising making a compound of structure

or a salt thereof, wherein R ₁ is an amine protecting group, reacts 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-toluenesulfonic acid, acetyl chloride, trichloride Aluminum and boron trifluoride. In some other embodiments, the deprotecting agent is selected from the group consisting of sulfuric acid, p-toluenesulfonic acid, and acetyl chloride.

In some embodiments, the reducing agent is selected from the group consisting of alkali metal borohydrides, hydrazine compounds, citric acid, citrate, succinic acid, succinate, ascorbic acid, and ascorbate. In some other 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 selected from the group consisting of carboxyl, acetyl, trifluoroacetyl, benzyl, benzyl, carbamate, benzyloxycarbonyl , p-methoxybenzylcarbonyl, tertiary butoxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted triphenyl Methyl, allyloxycarbonyl, 9-intenylmethoxycarbonyl, nitroveratrolyloxycarbonyl, p-methoxybenzyl and tosyl. In some other embodiments, R ₁ is tertiary butoxycarbonyl (Boc).

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

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

或其醫藥學上可接受之鹽。In another aspect, the present invention provides a compound of structure [3] 4-[6-(3,6-diazabicyclo[3.1.1]hept-3-yl)-3-pyridyl]-6 -(2-Methyl-2-trimethylsiloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile:

or its pharmaceutically acceptable salt.

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

In some embodiments of any of the above aspects, the method comprises preparing serpatinib Form B in the free amine form.

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

definition

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

As used herein, the term "polymorph" refers to crystals of the same compound that have different physical properties due to the order of the molecules in the crystal lattice. 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 can affect pharmaceutical parameters such as storage stability, compressibility, density (important in composition and product manufacture), dissolution rate (important in determining bioavailability) factors), solubility, melting point, chemical stability, physical stability, powder flow, water absorption, compactness and particle morphology. Differences in stability can result from changes in chemical reactivity (eg, differential oxidation such that the dosage form changes color faster when one polymorph is contained than when another polymorph is contained) or mechanical changes (eg, with kinetics The most favorable polymorph is converted to a thermodynamically more stable polymorph, the crystals changing on storage) or both (eg, one polymorph is more hygroscopic than the other). Some transformations affect efficacy and/or toxicity due to solubility/dissolution differences. In addition, the physical properties of the crystals can be important in processing; for example, a polymorph is more likely to form solvates or may be difficult to filter and wash away from impurities (ie, particle shape and size distribution within a polymorph may be different with respect to the other). As used herein, "polymorph" does not include amorphous forms of a compound. In some specific embodiments, the polymorphic forms of the compound of Formula I (ie, Serpatinib Form A and Serpatinib Form B) comprise features as described herein.

As used herein, "amorphous" refers to a non-crystalline form of a compound, which may be a solid state form of the compound or a dissolved form of the compound. For example, "amorphous" refers to a compound that has no molecules or a regularly repeating arrangement of outer surface planes (eg, a solid form of the compound).

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

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

The term "hydrate" or "hydrated polymorphic form" refers to a crystalline form of a compound of formula (I), such as a polymorphic form of the compound, wherein the crystal lattice includes water. As used herein, the term "hydrate" refers to "stoichiometric hydrate" unless otherwise specified. Stoichiometric hydrates contain water molecules as an integral part of the crystal lattice. In contrast, non-stoichiometric hydrates contain water, but changes in water content do not cause significant changes in crystal structure. During drying of the non-stoichiometric hydrate, a substantial portion of the water can be removed without significantly disturbing the crystal network, and the crystals can then be rehydrated to give the initial non-stoichiometric hydrated crystalline form. Unlike stoichiometric hydrates, dehydration and rehydration of non-stoichiometric hydrates are not accompanied by phase transitions, and thus all hydration states of non-stoichiometric hydrates represent the same crystal form.

When used with reference to a composition (including a polymorph of a compound of formula (I)), "purity" refers to the concentration of one particular polymorph with respect to another polymorph of a compound of formula (I) in the referenced composition Form or percentage of amorphous form. For example, a composition comprising polymorphic Form 1 at 90% purity would comprise 90 parts by weight of Form 1 and 10 parts by weight of another polymorph and/or amorphous form of the compound of formula (I).

As used herein, a compound or composition is "substantially free" of one or more other components if the compound or composition does not contain substantial amounts of such other components. For example, the composition may contain less than 5%, 4%, 3%, 2%, or 1% by weight of other components. Such components may include 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, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorph of a compound of formula (I) is "substantially free" of other polymorphs if the particular polymorph comprises at least about 95% by weight of the compound of formula (I) present thing. In some embodiments, if a particular polymorph comprises at least about 97%, about 98%, about 99%, or about 99.5% by weight of the compound of formula (I) present, then the compound of formula (I) A particular polymorph is "substantially free" of other polymorphs. In certain embodiments, a particular polymorph of a compound of formula (I) is "substantially free of "water.

As used herein, when used with reference to a polymorphic form of a compound of formula (I), "substantially pure" means greater than 90% (including greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99%, and also includes samples equal to about 100%) of polymorphic forms of the compound. The remaining material includes other forms of the compound, and/or reaction impurities and/or processing impurities resulting from its preparation. For example, a polymorphic form of a compound of formula (I) may be considered substantially pure because it is greater than 90% purer than a polymorphic form of a compound of formula (I), as is known in the art at this time and The remaining less than 10% of the material comprises other forms of the compound of formula (I) and/or reactive impurities and/or processing impurities, as measured by accepted means. 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.

In order to provide a more concise description, some quantitative expressions herein are recited in a range from about an amount X to about an amount Y. It should be understood that when a range is recited, the range is not limited to the upper and lower limits, but 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 usually about 25°C.

As used herein, the term "excipient" refers to any substance required to formulate a composition in a desired form. By way of example, suitable excipients include, but are not limited to, diluents or fillers, binders or granulating or sticking agents, disintegrating agents, lubricants, anti-sticking agents, gliding agents, dispersing agents or wetting agents , dissolution blockers or enhancers, adsorbents, buffers, chelating agents, preservatives, colors, flavors and sweeteners.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, co-solvents, complexes, dispersion media, Coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional medium or agent is incompatible with the active ingredient, it is contemplated for use in therapeutic formulations. Supplementary active ingredients can also be incorporated into the formulations. In addition, various excipients may be included, such as those commonly used in the art. These and other such compounds are described in the literature, eg, in the Merck Index, Merck & Company, Rahway, N.J. Considerations for incorporating various components into pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Edition, The McGraw-Hill Companies.

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

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

As used herein, "optional" or "optionally" means that the subsequently described event or circumstance occurs or does not occur and that the description includes both instances in which the event or circumstance occurs and instances in which the event or circumstance occurs situation that does not happen. For example, a reaction mixture that "optionally includes a catalyst" means that the reaction mixture contains a catalyst or it does not contain a catalyst.

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

As used herein, the term "weak base" refers to inorganic and organic bases that are only partially ionized in aqueous solution. The pKa of weak bases is usually between about 6 and about 11. A large number of such weak bases are known and exemplified by those listed in Handbook of Biochemistry and Molecular Biology, Vol. 1, 3rd Edition, G. D. Fassman, CRC Press, 1976, pp. 305-347. Weak bases are soluble or insoluble in water. Suitable weak bases include, but are not limited to, alkali metal carbonates and bicarbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate; ammonia; primary amines, such as methylamine; secondary amines; and Tertiary amines, such as trialkylamines such as trimethylamine, triethylamine, tripropylamine and tributylamine, benzyldiethylamine, pyridine, quinoline, N-methylpyridine, aniline and the like.

As used herein, a "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 associated with a reaction. Typically, non-nucleophilic bases are bulky and sterically hindered, allowing protons to attach to basic centers, but preventing alkylation and complexation. Examples of non-nucleophilic bases include, but are not limited to, amines and nitrogen heterocycles such as triethylamine and pyridine, amidines, lithium compounds, and phosphazenes. Other examples of non-nucleophilic bases include sodium hydride and potassium hydride.

As used herein, the term "amine protecting group" means any group known in the art of organic synthesis for protecting amine groups. Such amine protecting groups include Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3", Academic Press, New York (1981) Such amine protecting groups are listed in . Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: (1) carboxyl types such as carboxyl, trifluoroacetate, phthalo and p-toluenesulfonyl; (2) aromatic carbamic acids Esters such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1-(p-biphenyl)-1-methylethoxycarbonyl and 9-inylmethoxycarbonyl (Fmoc); (3 ) aliphatic carbamate types such as tertiary butoxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; (4) cyclic carbamates Ester type, such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl type, such as trityl and benzyl; (6) trialkylsilane, such as trimethylsilane; (7) Thiol-containing forms, such as thiophenylcarbonyl and dithiabutanediyl; and (8) alkyl forms, such as trityl, methyl, and benzyl; and substituted alkyl forms, such as 2 , 2,2-trichloroethyl, 2-phenylethyl and tertiary butyl; and trialkylsilane types, such as trimethylsilane.

As used herein, the term "deprotecting agent" refers to a reagent or reagent system (one or more reagents and solvents) suitable for removing protecting groups. The deprotecting agent can be an acid, a base or a reducing agent. For example, removal of benzyl (Bn) groups can be achieved by reduction (hydrogenolysis), while removal of carbamates (eg, Boc groups) can be achieved by using acids (eg, HCl, TFA) , H ₂ SO ₄ , etc.), and simultaneous removal of the silicon group can be accomplished by using a weak acid or a halide (eg, a fluoride such as provided by tetra-n-butylammonium fluoride (TBAF)), as appropriate by moderate heating to realise.

As used herein, the phrase "reducing agent" generally refers to any species capable of reducing another species while oxidizing itself. As used herein, the phrase "oxidizing agent/oxidant" generally refers to any species that is capable of oxidizing another species while reducing itself.

As used herein, the term "triflate" refers to a compound suitable for use in a reaction in which a triflate group is attached to a hydroxyl group to form a triflate. The trifluoromethanesulfonating agent is the source of the trifluoroacetate group. Trifluoromethanesulfonate reagents include, but are not limited to, trialkylsilyl trifluoromethanesulfonate, trialkylstannyl trifluoromethanesulfonate, triflic anhydride (trifluoromethanesulfonic anhydride) (trifluoromethanesulfonic anhydride), N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf ₂ ), N-(5-chloro-2-pyridyl)trifluoroimide, and N-(2-pyridyl) ) trifluoroamide.

As used herein, an "acrylonitrile derivative" is a compound derived from acrylonitrile having the _formula CH2CHCN wherein one or more of the hydrogen atoms have been replaced with another atom or group. An example of an acrylonitrile derivative is 2-chloroacrylonitrile in which one of the hydrogen atoms of acrylonitrile has been replaced with a chlorine atom.

As used herein, the term "diluted" when used relative 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, which may be straight or branched, containing the specified number of carbon atoms. For example, a _C1-6 indicated group may have from 1 to 6, inclusive, carbon atoms therein. Examples include methyl, ethyl, isopropyl, tertiary butyl and n-hexyl.

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

Salts can be formed from the compounds in any manner familiar to those skilled in the art. Thus, the recitation "to form a compound or a salt thereof" includes embodiments in which the compound is formed and then a salt is formed from the compound in a manner familiar to those skilled in the art.

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

The invention specifically covers all combinations of embodiments pertaining to the aspects described herein, just as each and every combination was expressly recited individually, and in this regard, such combinations cover the possible aspects. In addition, the invention specifically also covers all sub-combinations of embodiments contained within aspects described herein and all sub-combinations of embodiments contained within all other aspects described herein, just as all sub-combinations of embodiments are and each sub-combination is expressly recited herein. Crystallization method .

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

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

In one aspect, disclosed herein is a method of converting Serpatinib Form A to Serpatinib Form B.

In another aspect, disclosed herein is a method of converting Serpatinib Form A to Serpatinib Form B, the method comprising: combining Serpatinib Form A with a _C1 - _C5 alcohol To produce a slurry and isolate Serpatinib Form B from the slurry.

In yet another aspect, disclosed herein is a method for converting Serpatinib Form A to Serpatinib Form B, the method comprising: a. Serpatinib Form A is dissolved in a solvent comprising DMSO to form a solution; b. adding water to the solution and thereby forming a slurry; c. Isolation of Serpatinib Form B.

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

Form A has unique XRPD peaks at 4.9, 9.7 and 15.5° 2Θ, while Form B has unique XRPD peaks at 7.5, 10.9 and 12.0° 2Θ. The 2Θ values and/or peak intensities of other peaks also differ between the two forms, as can be seen in Table 1 below. For clarity, all XRPD peaks disclosed herein are ±0.2° 2Θ unless explicitly identified otherwise.surface 1. X Rays Powder Diffraction Peak Analysis, Form A and form B Form A Form B Peak position Relative Strength Peak position Relative Strength 4.9 100.0% 7.5 18.2% 8.1 6.2% 9.2 3.8% 9.7 41.6% 10.9 4.6% 12.7 2.2% 12.0 20.3% 13.8 1.4% 13.2 21.9% 14.8 16.0% 14.3 2.7% 15.5 15.5% 15.0 1.3% 16.5 18.0% 16.2 5.3% 16.8 16.5% 17.1 44.4% 18.0 23.9% 17.7 19.4% 18.5 17.2% 18.1 6.5% 18.8 24.3% 18.6 1.8% 20.2 4.0% 19.6 13.5% 21.0 5.7% 19.8 18.8% 21.9 6.4% 20.1 6.4% 22.6 8.1% 21.1 100.0% 23.6 9.1% 22.5 7.6% 25.1 7.7% 24.3 3.1% 25.5 14.4% 24.6 5.8% 26.0 8.9% 25.0 6.1% 26.4 6.3% 26.5 2.0% 27.2 4.6% 26.7 3.1% 28.2 5.6% 27.7 2.0% 28.8 3.1% 28.0 2.1% 29.3 1.6% 28.4 3.2% 31.5 1.5% 28.9 4.1% 32.2 1.4% 29.2 7.5% 33.2 1.0% 30.0 7.7% 33.7 1.4% 30.3 3.3% 32.6 1.4% 33.2 2.7% 34.1 1.3% 34.3 1.3% 35.3 1.0%

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

XRPD patterns of Form A and Form B (above) were obtained on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKα source (λ = 1.54180 Å) and a Vantec detector operating at 35 kV and 50 mA. The sample was scanned between 4 and 40 2θ° with a step size of 0.008 2θ° and a scan rate of 0.5 sec/step and using a 1.0 mm divergence, a fixed anti-scatter of 6.6 mm, and a detector slit of 11.3 mm. The dry powder was loaded on a quartz sample holder and a glass slide was used to obtain a smooth surface. Crystalline diffraction patterns were collected at ambient temperature and relative humidity. Crystalline peak positions were determined in MDI-Jade after all patterns were transformed based on the intrinsic 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 intensities of diffraction peaks can vary due to preferred orientation resulting from factors such as crystal morphology and habit. In the presence of the effect of better orientation, the peak intensities changed, but the characteristic peak positions of the polymorphs did not change. See, eg, The United States Pharmacopeia 23rd Edition, National Formulary 18th Edition, pp. 1843-1844, 1995. In addition, it is well known in crystallography that for any given crystal form, the angular peak positions can vary slightly. For example, peak positions may be shifted due to temperature changes when the sample is analyzed, sample shift, or the presence or absence of internal standards. In the context of the present invention, peak position variations of ±0.2 2Θ° are assumed to account for these potential variations without preventing unambiguous identification of a given crystal form. Confirmation of crystal form can be performed based on any unique combination of distinct peaks.

DSC-TGA analysis of anhydrous crystalline Form A confirmed a melting onset of 207.6°C and exhibited two endotherms, the first of which corresponds to the melting of Form A, followed by the exothermic recrystallization of Form B and then the melting of Form B. DSC-TGA analysis of anhydrous crystalline Form B confirmed a single endotherm of melting onset at 213.3°C.

Although 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 alcohol-based solvents, while in dichloromethane (DCM), dimethylsulfite (DMSO), and Moderate solubility in THF (3-30 mg/ml) Form B has little solubility in anisole.

The ¹³ C solid state NMR spectra of Forms A and B are presented in FIG. 2 . Figure 2 also contains an overlay of a portion of the spectrum showing that Form A has a peak not observable in Form B at 30.9 ppm, while Form B has a peak not observable in Form A at 48.0 ppm. Both spectra are referenced to the upfield resonance of adamantane (δ = 29.5 ppm).

The above-mentioned13C cross-polarization/variable angle was obtained using a Bruker Avance III HD 400 MHz wide aperture NMR spectrometer operating at a carbon frequency of 100.62 MHz and a proton frequency of ^400.13 MHz and equipped with a Bruker 4mm dual resonance probe Spin NMR (solid state NMR or ssNMR) spectroscopy. TOSS sideband suppression was used with cross-polarized and RAMP 100-shaped H-core CP pulses with SPINAL64 decoupling. The 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 recycle delay was used and the number of scans was 2655. In a separate experiment, chemical shifts were referenced to adamantane (δ = 29.5 ppm). Representative13C ^ssNMR resonances for Form B include: 26.44, 27.37, 28.00, 41.98, 43.43, 43.91, 48.04, 53.92, 56.31, 58.32, 69.48, 77.90, 80.38, 102.32, 106.77, 113.58, 115.24, 118.24 , 130.23, 134.86, 136.93, 140.59, 148.42, 149.50, 151.20, 152.45, 158.22 and 163.52 ppm.

The above data establishes that Forms A and B: 1) have some different properties, 2) are easily identifiable, 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, but are not limited to, _C1 - _C5 alcohols such as methanol or ethanol, water, acetonitrile (ACN, methyl tertiary butyl ether (MTBE), heptane, n-Butyl acetate (n-BuOAC), 81% ACN-MeOH (81 mL ACN mixed with 19 mL MeOH), wet ethyl acetate, cyclopentyl methyl ether (CPME), 1,2-dimethoxyethyl Alkane, 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/water mixture. In some embodiments, the solvent includes _{a C1} - _C5 alcohol, water, DMSO, MTBE, ACN, and a mixture of two or more thereof In yet other embodiments, the solvent comprises methanol, ethanol, water, DMSO, MTBE, ACN, or a mixture of two or more thereof.

As mentioned above, serpatinib can form solvates; and it can also form metastable solid forms, both of which are generally unstable on drying. The observed solvates include acetone solvate, chloroform solvate, 1,4-dioxane solvate, methyl ethyl ketone (MEK) solvate, dichloromethane (DCM) solvate , 2-butanol solvate, 1-butanol solvate, ethanol solvate, dimethylsulfoxide (DMSO)-water solvate, DMSO solvate and tetrahydrofuran (THF) solvate. Solvate and metastable forms usually revert to Form A during isolation and/or drying, although films or amorphous materials occasionally form. Chloroform and 1,4-dioxane solvates are 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 wt% to no more than about 25 wt%, or from about 0.5 wt% to about 17 wt%, or from about 1 wt% to about 16 wt%.

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 Serpatinib Form A with a solvent, such as _{a C1} - _C5 alcohol, to produce a slurry, and isolating Serpatinib Form B from the slurry. As the slurry is stirred or otherwise agitated, Serpatinib Form B is formed. In some embodiments, the alcohol is maintained at ambient temperature. In other embodiments, the slurry is heated, which increases the rate at which Form B is formed. Except for the temperature difference, these two embodiments are similar and are described below.

solvent

Examples of _C1 - _C5 alcohols include methanol, ethanol, isopropanol, propanol, butanol, 2-butanol, 3-butanol, and 1-pentanol. In some embodiments, methanol is the preferred _C1 - _C5 alcohol.

Examples of _C1 - _C5 alcohols include methanol, ethanol, isopropanol, propanol, butanol, 2-butanol, and 3-butanol. In certain embodiments, the alcohol comprises methanol and/or ethanol. In one embodiment, the alcohol comprises methanol.

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

temperature

Temperature affects the rate at which Form A is converted to Form B, with lower temperatures taking longer than higher temperatures. While it is possible to agitate the Form A and solvent slurries at sub-ambient temperatures, this will prolong the conversion of Form A to Form B and is therefore generally avoided.

The temperature of the alcohol, such as _{a C1} - _C5 alcohol, is about 10 to 80°C, or about 20 to 60°C, or about 55°C. The _C1 - _C5 alcohol can be at the desired temperature before adding the Form A material, or the temperature can be adjusted after adding the Form A material.

In other embodiments, the temperature of the alcohol, such as _{a C1} - _C5 alcohol, is 10 to 30°C, or about 15 to 25°C, or about 20°C. In other embodiments, the temperature is the ambient temperature, which is the outside temperature. While Form A will convert to Form B upon stirring in a room temperature solvent such as methanol, the conversion is faster if the Form A and solvent mixture is heated.

If the slurry is heated to such an extent that all Form A dissolves, the resulting solution can be filtered to remove any insoluble material. 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 agitated or otherwise agitated for more than 72 hours, although the slurry can be agitated or otherwise agitated for more than 72 hours, if desired. In some embodiments, the slurry is stirred for about 1 to 12 hours.

cool down

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

Separate form B

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

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

The isolated Serpatinib Form B can be dried using methods known in the art. Typical methods include heating, passing an inert gas through the solid, and/or using less than atmospheric pressure.

In another embodiment of this example, the _C1 - _C5 alcohol is combined with Serpatinib Form A and the resulting slurry is stirred or otherwise agitated for a length of time sufficient to convert Form A to Form B. Typical stirring times are at least about 10 minutes to about 36 hours, or about 24 hours, but usually 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 necessary, stirring and/or agitating the mixture may be longer than 24 hours. Heating the mixture will increase the rate at which Form A is converted to Form B.

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

Conversion method 2

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

solvent

A variety of different solvents can be used. Importantly, the solvent should not form a selpatinib solvate; in fact, it should give the desired Form B. Examples of suitable solvents include, but are not limited to, DMSO, _C1 - _C5 alcohols, ACN, MTBE, water, or a combination of two or more thereof. Preferred _C1 - _C5 alcohols include ethanol and/or methanol. In some embodiments, DMSO is the preferred solvent. In some embodiments, the solvent contains at least 2 wt% water.

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

temperature

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

The mixture comprising Form A and the solvent is heated to any temperature from about 30°C 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 heating the mixture to the desired temperature and dissolving the Form A material, the temperature of the solution decreased by about 15 to 35°C. The temperature may be lowered 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 below about 70°C and above about 20°C.

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

In an alternative embodiment, the solvent is not heated, ie, it is allowed to stir at ambient temperature. In these examples, the conversion of Form A to Form B took a long time.

first batch of water

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

The first batch of water is added within about 30 seconds to about 15 minutes or about 1 to 10 minutes or about 4 to 6 minutes or about 5 minutes. If necessary, a longer time can be used.

seed crystal

If Form B seeds are added to the mixture, about 0.1 to 15 wt % or about 1 to about 10 wt % or about 5 wt % of Form B seeds are used.

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

Seed crystals can be prepared using the methods described herein.

time

After heating the mixture and dissolving the Form A material and reducing the temperature of the mixture by 50 to 110°C, and adding seed crystals (if using seed crystals), the mixture is stirred for about 1 to 96 hours, or about 6 to 72 hours, or about 8 to 24 hours. In some embodiments, the mixture is stirred for at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, or at least 24 hours.

second batch of water

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

Slowly adding the second batch of water, ie adding the entire second batch of water, took about 0.5 to 24 hours or about 1 to 12 hours. In some embodiments, the addition of the entire second batch of water takes about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours.

cool down

After the second batch of water was added, the mixture was allowed to cool to a temperature of about 15 to 30°C to about 20 to 30°C. In some embodiments, the mixture is cooled to about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, About 25°C, about 26°C, about 27°C, about 28°C, about 29°C, or about 30°C. In one embodiment, the final temperature after cooling is room temperature. In other embodiments, the mixture is cooled to a temperature of about 30-55°C. In these examples, yields tended to be slightly lower than when lower temperatures were used.

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

After the desired temperature is reached, 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 two hours. In other embodiments, the mixture is stirred for less than 72 hours.

Separate form B

Form B was isolated as described above.

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

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

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

In another example of this method, serpatinib Form A is dissolved in DMSO at about 60-80°C or about 70°C to form a concentration of about 10 to 15 mL/g of DMSO per gram of Form A. solution; cool the mixture to about 40-60°C or about 50°C; add water; seed the resulting mixture with Form B, stir the mixture, add more water, heat the mixture; cool the mixture and isolate Form B. The initial amount of water added is from about 0.1 mL/g of Form A to about 0.5 mL/g of Form A, or about 0.3 mL/g of Form A. Seed crystals can be used in amounts ranging from about 1 to 10 wt % or about 5 wt % based on the amount of Form A. The seed crystals containing the mixture are stirred for about 8 to 24 hours or about 12 hours. The second addition/batch of water was about 1.0 to 1.5 mL/g of Form A, or about 1.10 to 1.15 mL/g, or about 1.14 mL/g. A second addition/batch of water is added over about 3 to 8 or about 5 hours. After adding the second addition/batch of water, the slurry was cooled to about 20 to 30°C or about 25°C. The slurry was cooled from about 70°C to about 25°C at a rate of about 10°C/hour until about 25°C was reached. The about 25°C slurry is stirred for at least about 2 hours, and then heated to about 60 to 80°C or 70 to 75°C or about 73°C and stirred for about one hour. The slurry is then cooled again to about 20 to 30°C or about 25°C. The slurry was cooled from about 73°C to about 25°C at a rate of about 10°C/hour. After stirring for at least about 30 minutes to about 8 hours, or about 1 to 8 hours or about 2 hours, serpatinib Form B is isolated, eg, by filtration.

Crystallization methods effective to convert Form A to Form B are further exemplified in the illustrative examples described in the Examples. Direct synthesis of compounds of formula I Form B.

(式I) 或其醫藥學上可接受之鹽的方法。In another aspect, the present invention relates to a method for preparing a compound of formula I in Form B (ie, selpatinib)

The method of (Formula I) or a pharmaceutically acceptable salt thereof.

In embodiments, methods for preparing serpatinib Form B comprise synthesis via synthetic methods such as those disclosed and described elsewhere (eg, US Pat. No. 10,112,942, herein incorporated by reference in its entirety) One or more precursor compounds. The following illustrative Schemes 1 and 2 show a general method for the preparation of serpatinib Form B from precursor compound [2] , as well as key intermediate compounds [3] :

Precursor compound [2] (3-(5-(3-cyano-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridine-4- yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate tertiary butyl ester) is described in detail in, for example, US Pat. Nos. 10,745,419 and 10,112,942 and International Patents In publication WO 2018/071447, each of which is incorporated herein by reference in its entirety. In a brief overview of a non-limiting example, compound [2] can be treated with 4-(6-fluoropyridin-3-yl)- 6-(2-Hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile; 3,6-diaza-bicyclo[3.1.1]heptane-6 - Prepared by the reaction of tertiary butyl formate and K2CO3 _(s) ( ₁ :1:6.67 molar equivalents) in DMSO. The resulting viscous slurry was diluted with additional DMSO and stirred with heating (eg, at 90°C for an additional 12 hours). After the reaction, the mixture was cooled to ambient temperature and diluted with water, and the resulting aqueous mixture was washed with dichloromethane. The combined organic extracts were dried over anhydrous MgSO4 _(s) , filtered and concentrated in vacuo. The resulting residue was purified by silica chromatography (EtOAc/hexane as gradient eluent system) to provide compound [2] in high yield. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize compounds [2] . Those skilled in the art will further appreciate that compound [2] may contain amine protecting groups other than Boc, including carboxyl, acetyl, trifluoroacetyl, benzyl, benzyl, amidomethyl ester group, benzyloxycarbonyl, p-methoxybenzylcarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl, Non-limiting examples of allyloxycarbonyl, 9-intenylmethoxycarbonyl, nitroveratryloxycarbonyl, p-methoxybenzyl and tosyl. In some embodiments, the protecting group is tertiary butoxycarbonyl (Boc).

In general, the method for the direct synthesis of Form B selpatinib according to the present invention comprises compounding [2] (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-carboxylic acid tertiary butyl esters) in effective (1) removal of protecting groups (eg, Boc, as shown in [2] ) and (2) for hydroxyl groups on 2-hydroxy-2-methyl-propoxy substituents (eg, TMS , as shown in [3] ) under silylation conditions. The silylated and deprotected compound [3] is then reacted with 6-methoxy-3-pyridinecarbaldehyde in an organic solvent (eg, anisole) in the presence of a reducing agent and an acid.

The silicon-based moiety (eg, TMS in some illustrative embodiments) is removed under conditions effective for deprotection, such as, for example, adding a fluorine source (eg, tetrabutylammonium fluoride (TBAF)). After the reaction and removal of the silicon-based protecting group, the pH of the reaction mixture was adjusted with base and cooled to allow the formation and isolation of crystalline Form B selpatinib.

In some embodiments, conditions effective to remove protecting groups and for silylation may include solvents selected from polar organic solvents, such as alcohols (eg, MeOH, EtOH), organic acids (eg, arylsulfonic acids, such as p-toluenesulfonic acid), aprotic solvents (eg, acetonitrile), alcohols containing acyl halides (eg, acetyl chloride in methanol to yield HCl solutions), esters (eg, ethyl acetate), ethers (eg, anisole) and combinations thereof. In some embodiments, the reactant includes a deprotecting agent, which may include trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, Aluminum trichloride and boron trifluoride. In some embodiments, the deprotecting agent is sulfuric acid, acetyl chloride, or p-toluenesulfonic acid. In some embodiments, conditions can include heating the reaction mixture, optionally refluxing for a period ranging from about 1 hour to about 8 hours or longer (eg, overnight, or about 12 hours).

In some embodiments, the silicon group used in the reaction may include trimethylsilyl (TMS), triethylsilyl (TES), tertiary butyldiphenylsilyl (TBDPS), isopropyldiphenylsilyl Methylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), Tertiary Butyldimethylsilyl (TBS/TBDMS), Tetraisopropyldisiloxane (TIPDS), Diethylsilyl - Tertiary butylsilylidene (DTBS) or triisopropylsilyl (TIPS). In addition to acting as a protecting group, the presence of a silicon group (eg, the TMS group on compound [3] ) provides additional solubility of the compound in the solvent anisole, which can be considered for the selpatinib form B. Antisolvent of compound [2] and non-silylated derivatives of compound [3] .

Silicon bases can be added using methods known in the art.

In some embodiments, given that compound [3] proves to be more soluble in anisole than the 2-hydroxy-2-methyl-propoxy form of [3], compound [3] and 6-methoxy- The reaction of 3-pyridinecarbaldehyde is carried out using anisole as a solvent. In some embodiments, the reducing agent in the reaction may include alkali metal borohydrides, hydrazine compounds, citric acid, citrate, succinic acid, succinate, ascorbic acid, and ascorbate. In some embodiments, the reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, nickel borohydride, and potassium borohydride. In some embodiments, the lithium borohydride is selected from lithium borohydride and lithium triethylborohydride. In some embodiments, the sodium borohydride is selected from sodium triacetoxyborohydride (STAB), sodium borohydride, and sodium cyanoborohydride. In some embodiments, the reducing agent is STAB. In some embodiments, the acid in the reaction acts as a catalyst for the reaction and may comprise an inorganic acid (eg, HCl, _H2SO4 , etc.) or a water _- soluble organic acid (eg, acetic acid, pivalic acid, etc.). In some embodiments, the acid comprises pivalic acid.

The resulting compound is deprotected under conditions sufficient to remove the silicon group (eg, TMS), but not so severe, to react with and decompose the reaction product (ie, serpatinib). In some embodiments, deprotection of the silicon group comprises adding a fluorine source (eg, tetrabutylammonium fluoride (TBAF), pyridine (HF) _x , trimethylamine trihydrofluoric acid (Et ) in an amount effective to react with the silicon group ₃ N·3HF), hydrofluoric acid, gins(dimethylamino) periliodifluorotrimethyl silicate (TASF), ammonium fluoride (H ₄ NF)) or weak acid were added to the reactants. Conditions for the deprotection step can include a buffered fluorine source and can be determined empirically, where conditions are kept mild enough to avoid decomposition reactions.

After the reaction, the pH of the reaction mixture is adjusted with a base (eg, K2CO3 slurry ₎ and cooled to allow the formation and isolation of crystalline Form B _selpatinib . In some embodiments, the crystallization may further comprise adding a small amount of seed crystals of Serpatinib Form B. In some other embodiments, the crystallization can comprise any of the crystallization techniques described herein that are effective to convert any remaining amount of serpatinib Form A to Form B.

While specific starting materials and reagents are depicted in the schemes and associated descriptions below, other starting materials, reaction conditions, and reagents can be substituted to provide the target compound (ie, serpatinib Form B) according to the present invention.

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

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

Regardless of whether serpatinib Form B is produced by direct synthetic methods or from serpatinib (ie, amorphous serpatinib or in another polymorphic form, according to aspects and embodiments as in the present invention) It can be further provided in the form of its pharmaceutically acceptable salt or its pharmaceutical composition, and relative to its other polymorphic and/or amorphous forms of serpatinib Nicole exhibits greater thermodynamic stability. Serpatinib Form B retains its activity as a RET inhibitor and can be analyzed by any assay known in the art (including those described in, eg, PCT Publication No. WO2018/071447 and US Patent Application Publication No. US 20180134702, each of which is incorporated herein by reference in its entirety) to assess and assess activity.

The following examples are provided for purposes of illustration and description only of certain embodiments that fall within the scope of the methods described herein and are covered by the scope of the claims. EXAMPLES Serpatinib (6-(2-hydroxy-2-methylpropoxy)-4-( 6-(6-((6-Methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo [1,5-a]pyridine-3-carbonitrile.

example 1 : Crystallization by cooling

264 mg of Form A were dissolved in 20 mL DCM and aliquoted into (15) 8 mL vials. The vials were then placed in a vacuum oven at 70°C to remove solvent. A birefringent white solid was observed in all vials. The respective solvents were added with shaking at 50°C (see Table 2.). The heat source was turned off and the samples were allowed to cool naturally 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 vials were placed in the freezer for 3 days and allowed to evaporate in the fume hood for 1 day if no precipitation occurred. XRPD data were collected on wet solids (where possible). About 2/3 (about 66%) of the experiments yielded a solvate that was metastable when isolated and dried. These metastable solvates (with the exception of the chloroform solvate) were converted to Form A upon withdrawal from the mother liquor. 81% ACN-MeOH gave Form B and anisole gave Form A. Table 2. Summary of Cooling Crystallization Experiments solvent antisolvent temperature ℃ product DMSO MTBE RT Form B 4:1 Toluene-DMF MTBE 50 Form B acetone Heptane 50 Form B THF Heptane 50 Form B MeOH MTBE 50 Form B + Form A (trace) DCM n-BuOAc 50 Form A //Form B

example 2 :evaporation & Vapor Diffusion Crystallization

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

About half of the crystallization experiments yielded solvates or mixtures of solvates and Form A. Most of the solvate was converted to Form A upon desolvation. Template effects due to structural similarity are suspected to direct the metastable form of nucleation. Form B was obtained from only two crystallization experiments using ACN and 5:1 MeOH-THF. X-ray diffraction amorphous forms/films were obtained from 5 solvent systems (THF, 11:1 IPA:acetic acid, benzyl alcohol, acetic acid and 10:1 EtOH:DMF). Chloroform and 1,4-dioxane solvates were stable upon isolation and solid state characterization data was collected. IPA is isopropanol, THF is tetrahydrofuran and DMF is dimethylformamide.

Vapor diffusion experiments yielded various solvates or amorphous materials. Five solvates (ie, DCM, 1-BuOH, EtOH, THF, and DMSO) were metastable and gave Form A when isolated. The DMSO/heptane mixture gave a mixture of Form A and Form B.

Example 3 : Anti-solvent crystallization

Antisolvent addition experiments were prepared by dissolving various amounts (9-36 mg) of Form A in 1-15 mL of solvent in (29) 4 mL vials. For the first 17 vials, the antisolvent was added dropwise to the syringe filtered solution until precipitation occurred or the volume of antisolvent was equal to or greater than the volume of solvent. For the next 12 vials, the solution was syringe filtered into clean vials containing 5 mL of anti-solvent. The solid was isolated by vacuum filtration and air drying. Evaporation of vials where no precipitation was observed continued for a period of up to 2 weeks. 71% of the antisolvent addition yielded Form A or resulted in an unstable solvate of Form A. Form B was present in 24% of experiments (one result was amorphous). For reverse antisolvent addition, 83% of the experiments resulted in Form A or a solvate and 17% of the experiments resulted in Form B.

example 4 : Slurry crystal

Form A vials were slurried with 10 mg of Form A in 4 mL vials. Solvents are added according to the solubility of Form A in these solvents to produce the slurry density. The slurry was shaken on a shaking block at 500 rpm for approximately 3 days at 22°C. The solids as wet cake were analyzed by XRPD. Most slurry screening yields solids consistent with Form A or solvates that convert 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 shaken on a shaking block at 500 rpm for 24 hours at 22°C. After 24 hours, the stock solution in each vial was replaced with freshly prepared individual solvent. The slurry was then stirred for 15 days. Wet and dry solids were analyzed by XRPD. Form B was observed in about 2/3 (about 66%) of the experiments. In the remaining 1/3 (about 33%) of the experiments, a mixture of Forms A and B or Form A and a solvate (1 example) was obtained. These results suggest that an equilibrium has not been reached, which may be due to: 1) the solubility limitation of Form A in the test solvent or 2) the minimal thermodynamic driving force for the phase transition near the transition point. In slurry crystallization experiments, anisole again gave Form A. Table 3. Summary of slurry conditions and results solvent temperature (℃) Final wet form (XRPD) Final dry form (XRPD) MeOH RT Form B Form B EtOH RT Form B Form B ACN RT Form B Form B Wet EtOAc RT Form B Form B nBuOAc RT Form A+B Form A + B CPME RT Form B Form B 1,2-Dimethoxyethane RT Form B Form B EtOAc RT Form B Form B Ethyl formate RT Form B Form B Heptane RT Form A + B Form A + B MIBK RT Form B Form B Nitromethane RT Amorphous Form B + A (trace) NPA RT Amorphous Form A + B (trace) 1-Pentanol RT Amorphous Form A + B Toluene RT Form A + B Form A + B 1:1 MeOH-water RT Form B Form B 1:1 EtOH-water RT Form B Form B DMSO RT Amorphous Form B water RT Amorphous Form A + B methanol RT (2 hours) Form B Form B Methanol: Water (any weight = 0.5) RT (1 day) Form B Form B Acetonitrile: Water (arbitrary weight = 0.8) RT (1 day) Form B Form B water RT (5 days) Form A+ B (trace) Form A+ B (trace) water RT (7 days) Form A+ B (trace) Form A+ B (trace)

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

example 5 : Solvent-assisted grinding

Two experiments using solvent-assisted mechanical milling were performed ¹ . In one experiment, Form B was observed when DMSO was used as the solvent. When water was used as the solvent, no form change was observed, ie Form A.

example 6 : will form A transform into form B

Serpatinib (2.0 g) was suspended in methanol (200 mL) and stirred at 750 rpm at 55°C. The suspension was stirred at 55°C for 60 minutes. Heating was 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 provide the title compound as crystals (1.72 g, 86%).

example 7 : will form A transform into form B

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

example 8 : will form A transform into form B

Serpatinib Form A was stirred in methanol (8 mL/g) for 18-24 hours at room temperature. Filter to isolate solids. Dry the solid under vacuum at 45 °C with a slight N _purge .

example 9 : will form A transform into form B

Form A was dissolved in DMSO (13 mL/g) at 70°C with stirring to obtain a clear solution. The solution was cooled to 50°C. Water (0.3 mL/g) was charged and the solution was then seeded with Form B seeds (5 wt% based on the amount of Form A used). Stir for 12 hours, then charge water (1.14 mL/g) 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 solids were isolated by filtration. The wet cake was washed 3x with MeOH (8 mL/g). Dry the solid under vacuum at 45 °C with a slight N _purge .

4-[6-(3,6-二氮雜雙環[3.1.1]庚-3-基)-3-吡啶基]-6-(2-甲基-2-三甲基矽氧基-丙氧基)吡唑并[1,5-a]吡啶-3-甲腈[3] example 10 : synthetic form B

4-[6-(3,6-Diazabicyclo[3.1.1]hept-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsiloxy-propane oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile[3]

The synthetic route to Form B of the compound of formula I (ie, serpatinib) can comprise the production of the compound 3-[5-[3-cyano-6-(2-hydroxy-2-methylpropoxy)pyridine Any of azolo[1,5-a]pyridin-4-yl]-2-pyridinyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester [2] synthetic route.

To a round bottom flask (3 neck) equipped with overhead stirring, condenser and thermocouple was added methanol (200 mL, 100%) and acetyl chloride (3.1 mL, 44 mmol, 100%). The mixture was allowed to react, followed by the addition of 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-carboxylic acid tert-butyl ester [2] (9.9965 g, 19.81 mmol, 100%). After the addition, the reaction was heated to about 60°C (63°C). The temperature is adjusted to reduce the amount of observable exhaust gas and avoid potential overdrive of the attached condenser. After the reaction was analyzed to determine complete conversion (about 2 hours), the solvent was stripped. To this mixture was added acetonitrile (ACN) (about 100 mL), rinsing the sides of the reaction vessel. The solvent mixture was stripped again and kept under nitrogen atmosphere.

Additional ACN (300 mL, 100%) and hexamethyldisilazane ("HMDS", 25 mL, 119 mmol, 100%) were added to the reaction vessel. The reaction was stirred at ambient temperature for about 1 hour. Before initial sampling of the reaction mixture, about 1.6% of the title compound was formed based on [2] . The reaction was allowed to proceed overnight at ambient temperature. After sampling the overnight reaction, the mixture was heated to 40°C and sampled after one hour at that temperature. The heat of reaction was raised to 56°C. During the temperature increase, the mixture refluxed and foamed, presumably indicating the evolution of ammonia. After about 1-1.25 hours, the reaction was sampled at temperature with continued observable reflux. The reaction was held at temperature for an additional 3 hours and resampled. The reaction solvent was stripped and an aqueous potassium carbonate solution (100 mL, 50.45 mmol, 5 mass %) was slurried into the reaction vessel. The resulting mixture was washed with water (25 mL) and dried to provide 7.89 g of the title compound [3] (78% yield). (Mass 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).

6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈( 形式 B) Alternative method . Add 3-[5-[3-cyano-6-(2-hydroxy-2-methyl-propoxy)pyrazolo to reaction vessel equipped with overhead stirring, condenser and thermocouple [1,5-a]Pyridin-4-yl]-2-pyridyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester [2] (9.9965 g, 19.81 mmol, 100%) and p-toluenesulfonic acid (2.1 equiv) in 10 vol of organic solvent. The mixture was allowed to react for 1 hour, after which pyridine (2.1 equiv) and hexamethyldisilazane ("HMDS", 6 equiv) were added. The reaction mixture was stirred for about an additional hour to provide the title compound [3] .

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

To a reaction vessel equipped with a magnetic stirrer was added 4-[6-(3,6-diazabicyclo[3.1.1]hept-3-yl)-3-pyridinyl]-6-(2-methyl -2-Trimethylsiloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile [3] (0.9981 g, 2.094 mmol, 100 mass %), 6-methoxy -3-Pyridinecarbaldehyde (ie, 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 %), and stirred to form a slurry. Heat was applied with stirring until a homogeneous solution mixture was obtained. The solution was cooled to ambient temperature and maintained as a homogeneous solution. Once cooled, sodium triacetoxyborohydride (1.0840 g, 5.1147 mmol, 100 mass %) was added and allowed to react. Analysis of the reaction after 2 hours indicated the formation of a TMS protected derivative of the title compound.

After the reaction is complete, the method can continue to remove the TMS protection and crystallize Form B. To the mixture were added water (1 mL, 55.5099 mmol, 100 mass %) and tetrabutylammonium fluoride trihydrate (0.6070 g, 2.322 mmol, 100 mass %) and optionally an amount (about 10 mg) of Form B Seed crystals of the title compound were added to the mixture. If no crystals are observed after a period of time, the mixture can be warmed to 50°C. After holding the high temperature overnight, the reaction was sampled and confirmed to be complete, but no crystallization was observed. The pH of the mixture (weak acid) was adjusted by adding potassium carbonate (5 mass % in water) as a slurry, added in 1 mL aliquots until any observed bubbling ceased and the pH tested basic. The mixture was stirred overnight and sampled to provide the title compound without detectable impurities; obtained in 54% overall isolated yield. (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 method . To a reaction vessel equipped with a magnetic stirrer was added 4-[6-(3,6-diazabicyclo[3.1.1]hept-3-yl)-3-pyridinyl]-6-( 2-Methyl-2-trimethylsiloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile [3] (1.00 g, 2.10 mmol), 6-methoxy -3-pyridinecarbaldehyde (1.6 equiv), pivalic acid (about 5 vol equiv), sodium triacetoxyborohydride (2.5 equiv), and anisole (10 mL, 91.8 mmol, 100 mass %), and react 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. Separate the layers. 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 of the mixture (acidic) was adjusted to pH 9 by adding potassium carbonate. The mixture was cooled to allow crystallization. The resulting crystals of serpatinib Form B were filtered, washed with methyl tertiary butyl ether (MTBE) and dried to obtain the pure title compound. Example 11

Physical and chemical stability of Form B is an important attribute not only for ensuring solubility and solubility, but also for API and dosage form drug development and manufacturing operations (drying, storage, transport transfer, etc.). Not all crystalline forms have the stability required to achieve drug development. A crystal form that is stable to both temperature and humidity is required. To assess the stability of the crystalline form of serpatinib, an accelerated stability study was performed. Samples of Form B were weighed into 20 mL scintillation vials and placed (open pan) in a bell jar containing saturated saline solution in an oven at the temperatures and times indicated in Table 4. Form B was analyzed before and after accelerated stability studies and collected on a Bruker D8 Advance XRPD equipped with a CuKα source (wavelength = 1.54056 Å) and Linxeye detector, operating at 40 kV and 40 mA, with a 0.2 mm divergence slit . Each sample was scanned from 4° to 30° 2Θ at a rate of 0.2 seconds per step in 0.02° steps. Analysis and impurities relative to starting material were assessed using an Agilent 1260 HPLC system with a diode array detector. Samples were prepared in 50/50 0.1% TFA/water/0.1% TFA/ACN at appropriate concentrations and evaluated using the following HPLC conditions: Column Zorbax Bonus-RP, 75 x 4.6 mm id, 3.5 microns, mobile phase A was 0.1% TFA/water, mobile phase B was 0.1% TFA/ACN, gradient was 95% A at time 0, 23% A at time 9.5-12.1 minutes, 5% A at time 13-16 minutes, at 95% A at times 16.1-20 min with a flow rate of 1.5 mL/min, a column temperature of 30°C, a UV detection wavelength of 210 nm and an injection volume of 3 µL. The stability of Form B was characterized and found to be chemically and physically stable under the conditions tested (Table 4). Table 4 : Stability of Crystal Forms of Serpatinib time ( days) Temperature ( °C) RH (%) Form ¹ Analysis (%) ² Impurities (%) 0 — — form — 0.09 7 40 11 NC 99.2 0.10 14 40 11 NC 99.9 0.09 7 40 75 NC 99.4 0.11 14 40 75 NC 99.9 0.10 7 50 30 NC 99.4 0.09 14 50 30 NC 100.5 0.09 7 50 50 NC 99.2 0.10 14 50 50 NC 100.4 0.11 7 70 11 NC 100.7 0.09 14 70 11 NC 99.3 0.10 7 70 75 NC 100.3 0.10 14 70 75 NC 100.9 0.11 ¹ It should be noted that the form was compared to the XRPD of the unstressed (time 0) sample; NC = no change. ² It should be noted that the analytical values were determined in comparison to unstressed (time 0) samples. Example 12 : Solubility

A solubility study was performed on the crystalline form of serpatinib described herein. Aqueous media covering the physiological pH range and three simulated fluids were used in these studies. An amount of solid compound sufficient to saturate the solvent volume is weighed into a vessel containing approximately 1 mL of the indicated solvent. The samples were mixed at 37°C in an incubator shaker set at 100 rpm. After equilibration, samples were transferred to centrifugal filters (Durapore PVDF, 0.22 μm pore size) and centrifuged at 10,000 rpm for 3 min while maintaining 37°C. A 100 µL aliquot was then taken 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 device. 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: temperature 30°C; injection volume 4 µL; UV detection at 238 nm; flow rate The autosampler temperature was 25°C; mobile phase A was 0.1% trifluoroacetic acid/water; and mobile phase B was 0.1% trifluoroacetic acid/acetonitrile. HPLC gradient 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 following table (Table 3) details the equilibrium solubility data and equilibrium pH, reported as the average of replicate sample preparations. The solid form of residual solids from centrifuged samples was verified by XRPD as indicated in Table 5. Table 5 : Solpatinib at 37°C after 24 hour equilibration of crystalline forms of serpatinib. Solvent ¹ Solubility (mg/mL) Equilibrate pH water 0.0036 7.146 0.1N HCl ² ≥ 10 1.297 0.01N HCl 4.7700 3.634 pH 4.0 Citrate/Phosphate 0.7116 4.134 pH 4.5 Acetate (USP) 0.1694 4.496 pH 6.0 Phosphate (USP) 0.0086 6.027 pH 7.5 Phosphate (USP) 0.0022 7.526 0.01N NaOH 0.0011 9.985 SGF ³ 1.440 ⁴ 2.644 FaSSIF ⁵ 0.0096 6.445 FeSSIF ⁶ 0.2277 4.928 ^1Description is consistent with USP, European Pharmacopoeia and Japanese Pharmacopoeia. ² Measure the solubility of 0.1 N HCl at 21.5°C (ambient). ³ SGF: simulated gastric fluid (0.01N HCl/sodium lauryl sulfate 0.05%/NaCl 0.2%). ⁴ XRPD of the remaining solid revealed amorphous material. ⁵ FaSSIF: Fasting state simulated intestinal fluid ( _NaH2PO4 28.66 mM, sodium taurocholate ₃ mM, lecithin 0.75 nM, NaCl 105.8 mM, pH 6.5). ⁶ FeSSIF: Intestinal fluid simulated in fed state (acetic acid 144.04 mM, sodium 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 are consistent with weak free bases with low intrinsic solubility. The results indicated that the inherent solubility of this serpatinib crystalline form was low (approximately 0.001 mg/mL).

Figure 1 is an overlay of Form A and Form B XRPD data up to about 26° 2θ (2 ϴ).

Figure 2 contains13C solid state NMR data for Form A, Form B, and an overlay of about ²⁵ to 60 ppm comparing Form A to Form B.

Claims (71)

A crystalline form of selpercatinib characterized by at least one of the following: (a) comprising a peak at 21.1° and one of 17.1°, 17.7° and 19.8° ± 0.2° 2θ or an x-ray powder diffraction (XRPD) pattern of multiple peaks, as measured using an x-ray wavelength of 1.5418 Å; or (b) including an upfield resonance of adamantane (δ = 29.5 ppm) referenced throughout ¹³ C solid state NMR spectra of the peaks of: 28.0, 48.0, 80.4, 106.8, 130.2 and 134.9 ppm (± 0.2 ppm, respectively). The crystalline form of Serpatinib as claimed in claim 1, wherein the crystalline form is characterized by having a peak comprised at 21.1° and at 7.5°, 12.0°, 13.2°, 17.1°, 17.7° and 19.8°±0.2 An x-ray powder diffraction (XRPD) pattern of one or more peaks at °2Θ, as measured using an x-ray wavelength of 1.5418 Å. The crystalline form of Serpatinib as claimed in claim 1, wherein the crystalline form is characterized by having an x-ray powder diffraction (XRPD) pattern having at 7.5°, 10.9°, 12.0°, Characteristic peaks appearing at 13.2°, 17.1°, 17.7°, 18.2°, 19.8°, 21.1° and 24.5° ± 0.2° 2θ. A crystalline form of serpatinib as claimed in claim 1, wherein the crystalline form is characterized by ^a13C solid state NMR spectrum comprising peaks referenced to the high field resonance of adamantane (δ = 29.5 ppm) at: 26.4 , 28.0, 42.0, 43.9, 48.0, 56.3, 69.5, 80.4, 102.3, 106.8, 115.2, 120.8, 130.2, 134.9, 140.6, 149.5, 152.5, and 163.5 ppm (± 0.2 ppm, respectively). A crystalline form of serpatinib as claimed in claim 1, wherein the crystalline form is characterized by ^a13C solid state NMR spectrum comprising peaks referenced to the high field resonance of adamantane (δ = 29.5 ppm) at: 26.4 ,27.4,28.0,42.0,43.4,43.9,48.0,53.9,56.3,58.3,69.5,77.9,80.4,102.3,106.8,113.6,115.2,118.2,120.8,125.2,130.2,134.9,146.9,495.4 , 151.2, 152.5, 158.2, and 163.5 ppm (± 0.2 ppm, respectively). A pharmaceutical composition comprising the crystalline form of serpatinib as claimed in any one of claims 1 to 5, and a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical composition of claim 6, wherein the composition contains less than about 20% by weight of other crystalline forms of selpatinib. The pharmaceutical composition of claim 6, wherein the composition contains less than about 10% by weight of other crystalline forms of selpatinib. The pharmaceutical composition of claim 6, wherein the composition contains less than about 5% by weight of other crystalline forms of selpatinib. A use of a crystalline form of serpatinib as claimed in any one of claims 1 to 5 for the manufacture of a medicament for the treatment of cancer. A pharmaceutical composition according to any one of claims 6 to 9 for use in therapy. A pharmaceutical composition according to any one of claims 6 to 9 for the treatment of cancer. The pharmaceutical composition of claim 12, wherein the cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, 2A Or type 2B multiple endocrine tumors (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gangliomatosis of gastrointestinal mucosa, and cervical cancer. The pharmaceutical composition of claim 13, wherein the cancer is medullary thyroid cancer. The pharmaceutical composition of claim 13, wherein the cancer is lung cancer and the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiopulmonary cell carcinoma, RET fusion lung cancer, or lung adenocarcinoma. The pharmaceutical composition of claim 15, wherein the cancer is RET fusion lung cancer. A method for preparing the crystalline form of Serpatinib as claimed in item 1, comprising the steps of: (a) Suspend Serpatinib in a solvent; (b) heating the suspension to between 50°C and 60°C while stirring for 30 to 90 minutes; (c) removing heat and allowing the suspension to cool to room temperature to form solid crystals; and (d) Collect such solid crystals. The method of claim 17, wherein the solvent comprises methanol. A method as claimed in claim 17 or 18, wherein the suspension is heated to 55°C. A method as claimed in claim 17 or 18, wherein the suspension is stirred for 60 minutes. The method of claim 17 or 18, wherein the solid crystal systems are collected by vacuum filtration. A method that converts Serpatinib Form A to Serpatinib Form B. The method of claim 22, the method comprising: combining serpatinib Form A with a _C1 - _C5 alcohol to produce a slurry; and isolating serpatinib Form B from the slurry. The method of claim 23, wherein the _C1 - _C5 alcohol is from about 10°C to about 30°C. The method of claim 24, wherein the _C1 - _C5 alcohol is about 15 to 25°C. The method of claim 25, wherein the _C1 - _C5 alcohol is about 20°C. The method of claim 23, wherein the _C1 - _C5 alcohol is from about 10°C to about 80°C. The method of any one of claims 22 to 27, wherein the _C1 - _C5 alcohol comprises methanol. The method of claim 28, wherein the _C1 - _C5 alcohol comprises at least 90 wt% methanol. The method of any one of claims 22 to 27, wherein the slurry is agitated or otherwise agitated for at least about 10 minutes. The method of any one of claims 22 to 27, wherein the separation form B comprises vacuum filtration. The method of any one of claims 22 to 27, wherein the separation form B comprises centrifugation. The method of any one of claims 22 to 27, further comprising drying the serpatinib Form B. As in the method of claim 22, the method includes: a. Dissolving the Serpatinib Form A in a solvent comprising DMSO to form a solution; b. adding water to the solution and thereby forming a slurry; c. Isolate the Serpatinib Form B. The method of claim 34, wherein the concentration of Form A dissolved in DMSO is about 10 to 15 mL/g. The method of claim 35, wherein the concentration of Form A dissolved in DMSO is about 12 to 13 mL/g. The method of any one of claims 34 to 36, wherein forming the solution of step a comprises heating the serpatinib Form A and the solvent comprising DMSO to about 50°C to about 70°C. The method of any one of claims 34 to 36, wherein the solution is cooled to a temperature below about 70°C and above about 20°C. The method of claim 37, wherein the solution is cooled to a temperature of about 50°C. The method of any one of claims 34 to 36, wherein step b comprises adding to the solution about 0.1 to about 1 mL of water per gram of Form A. The method of claim 40, wherein step b comprises adding to the solution about 0.3 mL of water per gram of Form A. The method of any one of claims 34 to 36, wherein step b further comprises adding about 1 to about 15 wt % of Form B seeds. The method of claim 42, wherein step b further comprises adding about 1 to about 10 wt % of Form B seeds. The method of claim 43, wherein about 5 wt % of Form B seeds are added. The method of any one of claims 34 to 36, wherein the slurry is stirred for about 6 to about 72 hours after the addition of water in step b. The method of claim 45, wherein the slurry is stirred for at least 12 hours. The method of any one of claims 34 to 36, wherein step b further comprises adding a second batch of water to the slurry. The method of claim 47, wherein about 0.5 to about 3 mL of water per gram of Form A is added to the slurry. The method of any one of claims 34 to 36, wherein the slurry of step b is cooled to about 20-30°C. A method as in any of claims 34 to 36, wherein step c comprises filtering. The method of any one of claims 34 to 36, wherein the isolated serpatinib Form B from step c is washed with a solvent comprising methanol, ACN, MTBE or water. The method of claim 51, wherein the isolated serpatinib Form B is washed with a solvent comprising methanol. The method of claim 52, wherein the isolated Serpatinib Form B is washed with methanol until the isolated Serpatinib Form B contains less than 0.5 wt% DMSO. The method of claim 22, comprising: combining serpatinib Form A with methanol to form a slurry, and stirring the slurry until >99 wt% of the Form A is converted to Form B. The method of claim 54, wherein the slurry is stirred for about 18 to 24 hours. The method of claim 54 or 55, wherein the concentration of the serpatinib Form A in the methanol is about 8 mL/g. The method of claim 22, comprising dissolving Serpatinib Form A in DMSO at about 60 to 80°C to form a solution of DMSO having a concentration of about 10 to 15 mL/g per gram of Form A; Cool the solution to about 40-60°C, add water; seed the resulting mixture with Form B crystals as appropriate; stir the mixture; add more water; heat the mixture to about 60-80°C; cool the mixture and separate The Form B. The method of claim 57, wherein 5 wt % of Form B seeds are added to the mixture. The method of claim 57 or 58, wherein the first addition of water is from about 0.1 mL/g of Form A to about 0.5 mL/g of Form A. The method of claim 57 or 58, wherein the second addition of water is about 1.0 to 1.5 mL/g of Form A. A serpatinib for the preparation of formula I in polymorph Form B:

(Formula I) or a method of a pharmaceutically acceptable salt thereof, wherein the method comprises making a compound of the following structure:

or a salt thereof, reacted with 6-methoxynicotinaldehyde in a solvent in the presence of an acid and a reducing agent to prepare Serpatinib 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, the method comprising making a compound of the following structure

or a salt thereof, wherein R ₁ is an amine protecting group, reacts with a deprotecting agent to form a compound of structure [3] or a salt thereof. The method of claim 62, wherein the deprotecting agent is selected from the group consisting of: trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride , aluminum trichloride and boron trifluoride. The method of claim 63, wherein the deprotecting agent is selected from the group consisting of sulfuric acid, p-toluenesulfonic acid, and acetyl chloride. The method of any one of claims 61 to 64, wherein the reducing agent is selected from the group consisting of alkali metal borohydrides, hydrazine compounds, citric acid, citrate, succinic acid, succinate, Ascorbic acid and ascorbate. The method of any one of claims 61 to 64, wherein the reducing agent is selected from the group consisting of sodium triacetoxyborohydride (STAB), sodium borohydride, and sodium cyanoborohydride. The method of any one of claims 61 to 64, wherein R ₁ is selected from the group consisting of carboxyl, acetyl, trifluoroacetyl, benzyl, benzyl, aminomethyl Ester, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tertiary butoxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, triphenyl Methyl and substituted trityl, allyloxycarbonyl, 9-intenylmethoxycarbonyl, nitroveratrolyloxycarbonyl, p-methoxybenzyl and tosyl. The method _of claim 67, wherein R1 is tertiary butoxycarbonyl (Boc). The method of any one of claims 61 to 64, wherein the acid is selected from the group consisting of pivalic acid and acetic acid. The method of any one of claims 61 to 64, wherein the reaction is carried out in a solvent, and the solvent comprises anisole. One is 4-[6-(3,6-diazabicyclo[3.1.1]hept-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsiloxy -Propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile compound having structure [3]

or its pharmaceutically acceptable salt.

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