Crystalline RET inhibitor

Abstract

To provide 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.SOLUTION: The present invention provides a crystalline form of selpercatinib, which is characterized by at least one of: a) an x-ray powder diffraction (XRPD) pattern comprising a peak at 21.1° and one or more peaks at 17.1°, 17.7°, and 19.8°±0.2° 2θ, as measured using an x ray wavelength of 1.5418A; and (b) a 13C solid state NMR spectrum which comprises 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).SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] Selpercatinib (LOXO-292 or RETEVMO™) is an anti-cancer drug that targets metastatic RET Patients with fusion-positive NSCLC, RET-mutated medullary thyroid cancer, and RET fusion-positive thyroid cancer Selpercatinib is a RET inhibitor approved in the United States for use in the treatment of or 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxy (Cypridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3 -yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile , which has the following chemical structure: [ka]

[0002] U.S. Patent No. 10,584,124 describes a crystalline form of Serpepilepsy that includes a crystalline form called "Form A." Several crystalline forms of lucatinib have been described, but a new, thermodynamically more stable crystalline form has been Disclosed herein is a novel crystalline form, and a method for making this crystalline form. The forms can be incorporated into formulations such as tablets, capsules, and suspensions to provide benefits to patients. . Summary of the Invention

[0003] The present disclosure relates to a new crystalline form of selpercatinib, referred to throughout as "Form B," In general terms, the present disclosure relates to a method for producing a thermodynamically stable polymorph thereof. The present invention provides methods for the preparation, isolation, and characterization of

[0004] As described in more detail below, the compound of formula I (selpercatinib) may exist in polymorphic forms ( Surprisingly, selpercatinib can be provided in its most potent form, Form A and Form B. To provide the mechanically stable polymorphic form B, certain processes and methods are available. As described below and demonstrated by the illustrative examples, selpercatinib can be administered in a specific The processes and methods for producing and preparing the polymorphic forms are intended to produce Form B or other polymorphs. (i.e., Form A) under crystallization conditions effective to convert the form into Form B. Converting (i.e., reacting, contacting, and In another embodiment, the method for producing Form B of selpercatinib may include the steps of: The process and method for producing Form B of selpercatinib are provided under conditions effective to produce Form B of selpercatinib. , a synthetic route that involves reacting one or more intermediate or precursor compounds (i.e., directly Synthetic routes).

[0005] Form B is (a) at 21.1° when measured using an x-ray wavelength of 1.5418 A; and one or more peaks at 17.1°, 17.7°, and 19.8° ± 0.2° 2θ. or (b) an x-ray powder diffraction (XRPD) pattern comprising 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (respectively, ±0.2 ppm) ) contains a peak based on the high magnetic resonance of adamantane (δ=29.5 ppm). nothing 13 C solid-state NMR spectrum.

[0006] Form B and pharmaceutical compositions thereof can be used to treat cancers associated with aberrant RET expression (e.g., thyroid The present invention also provides a method for treating cancers such as medullary carcinoma or RET-associated cancers such as RET fusion lung cancer. The method includes administering a therapeutically effective amount of Form B to a patient in need thereof.

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

[0008] For treating cancer, particularly cancers with abnormal RET expression (e.g., medullary thyroid cancer). or RET-associated cancers, such as RET fusion lung cancers The use of Form B in the preparation of pharmaceutical compositions is also provided herein.

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

[0010] A method for converting serpercatinib form A to serpercatinib form B, comprising the steps of: combining Catinib Form A with a C1-C5 alcohol to form a slurry; and isolating percatinib form B from the slurry. can be.

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

[0012] Further, there is provided a method for converting selpercatinib form A to form b, the method comprising the steps of: combining tinib form A with methanol to form a slurry; and stirring the pre-slurry until 9 wt. % is converted to Form B. will be done.

[0013] Another method described herein is a method for converting selpercatinib form A to form B. Then, selpercatinib form A was dissolved in DMSO at about 60-80° C. to obtain 1 gram of form A. Form a solution having a concentration of about 10-15 mL / g of DMSO per 10 mL of solution, and dilute the solution to about 40-60 mL / g. Cool to 0° C., add water, and optionally seed the resulting mixture with seed crystals of Form B. The mixture is stirred, more water is added, the mixture is heated to about 60-80°C, the mixture is cooled, and Form B is isolated.

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

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

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

[0017] Selpercatinib Form B is described herein. This crystal of selpercatinib The morphology is related to disorders associated with abnormal RET activity, such as IBS or cancer, particularly excessive RET activity. Can be used to treat cancers caused by T signaling (i.e., RET-associated cancers) More specifically, this crystalline form of selpercatinib is a potent anti-cancer agent for lung cancer (e.g., small cell lung cancer). or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine Adenocarcinoma of the lung, adenocarcinoma of the lung, bronchiolopulmonary cell carcinoma, multiple endocrine neoplasia type 2A or 2B (respectively, MEN2A or MEN2B, pheochromocytoma, parathyroid hyperplasia, breast cancer ancer, breast cancer, mammary cancer arcinoma), breast tumors, colorectal cancer (e.g., metastatic colorectal cancer), papillary Renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer It may be used to treat RET-associated cancers.

[0018] Form B has a peak at 21.1° when measured using an x-ray wavelength of 1.5418A. and one or more peaks at 17.1°, 17.7°, and 19.8°±0.2° 2θ. The compound is characterized by having an x-ray powder diffraction (XRPD) pattern comprising: State B also has values ​​of 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9. ppm (respectively ±0.2 ppm), the high magnetic resonance of adamantane (δ=29. Includes peaks based on 5 ppm 13 C solid-state NMR spectrum is shown.

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

[0020] Additionally, Form B has a molecular weight of 21.1 when measured using an x-ray wavelength of 1.5418A. 1°, and 7.5°, 10.9°, 12.0°, 13.2°, 17.1°, and 17. 1 occurring at 7°, 18.2°, 19.8°, 21.1°, and 24.5°±0.2° 2θ and having an x-ray powder diffraction (XRPD) pattern including at least one peak. It can be marked.

[0021] Form B: 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 (respectively, ±0.2 ppm), the peak is based on the high magnetic resonance of adamantane (δ=29.5 ppm). Including 13 It can be further characterized by C solid-state NMR spectroscopy.

[0022] Furthermore, form B has the following characteristics: 26.4, 27.4, 28.0, 42.0, 43.4, 43.9, 4 8.0, 53.9, 56.3, 58.3, 69.5, 77.9, 80.4, 102.3, 106.8, 113.6, 115.2, 118.2, 120.8, 125.2, 130. 2, 134.9, 136.9, 140.6, 148.4, 149.5, 151.2, 15 At 2.5, 158.2, and 163.5 ppm (each ±0.2 ppm), 1 containing one or more peaks based on the high magnetic resonance of damantane (δ = 29.5 ppm) It may be further characterized by 3C solid state NMR spectroscopy.

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

[0024] The pharmaceutical composition containing Form B has less crystalline selpercatinib compared to other crystalline forms of selpercatinib. All are 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% , 95%, 96%, 97%, 98%, 99% or 100% by weight of Form B. Alternatively, the pharmaceutical compositions described herein contain at least 80% form B and less than 20% of other forms. More preferably, the pharmaceutical composition comprises at least 9 More preferably, the compound contains selpercatinib in an amount of 0% to 10% of Form B and less than 10% of other crystalline forms of selpercatinib. Alternatively, the pharmaceutical composition may contain at least 95% form B and less than 5% of other crystalline forms of ceramide. Even more preferably, the pharmaceutical composition comprises at least 97% of Form B and lucatinib. More preferably, the pharmaceutical composition contains less than 3% of other crystalline forms of selpercatinib. , at least 98% or 99% of Form B and less than 2% or 1%, respectively, of other crystalline forms. and selpercatinib.

[0025] Form B is a compound that is useful in treating cancer, comprising administering to a patient in need thereof an effective amount of Form B. The methods described herein may be used in methods for treating The types of cancer that can be treated using form B include blood cancers or solid tumor cancers. Examples of types of cancer include lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, Recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (or MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, and colorectal cancer. These include cancer of the cervix, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer. Specifically, the type of cancer may be lung cancer or thyroid cancer. More specifically, the cancer may be non- It may be small cell lung cancer or medullary thyroid cancer.

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

[0027] Form B is for the manufacture of a pharmaceutical agent for the treatment of a RET-related disease or disorder, such as IBS or cancer. Cancers that may be treated using such agents are described herein above. The use of Form B in the manufacture of pharmaceutical products also involves the collection of biological samples from patients. The RET gene, RET kinase, or their related proteins were identified using in vitro assays. determining the presence of dysregulation of the expression or activity or level of any of the RET genes; , RET kinase, or dysregulation of the expression or activity or levels of any of them. These may include administering to the patient a therapeutically effective amount of Form B when In use, the biological sample may be a tumor sample, the tumor sample being subjected to genomic / DNA sequencing. These uses may be analyzed using methods known to those skilled in the art, such as by determining the For these uses, samples can be obtained from patients prior to the first administration of Form B. In one embodiment, the therapy includes determining whether a patient has a RET gene, a RET kinase, or a combination thereof, as described herein. or dysregulation of their expression, activity or level. In addition, these uses may be based on the selection of a subject for treatment based on the subject's In this case, Form B may be administered to a patient at a dose of about 1 mg / kg to 200 mg / kg (effective Suitable dosage subranges are described herein above.

[0028] As used herein, the patient is one in which a RET fusion or RET mutation has been determined. Thus, the term "determining a RET fusion or RET mutation" refers to a RET fusion or means to determine whether a RET mutation is present. Methods for determining whether a mutation is present are known to those of skill in the art and can be found, for example, in Wan et al. g,Yucong et al.,Medicine2019;98(3):e1412 Please refer to 0.

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

[0030] A "pharmaceutical acceptable carrier, diluent, or excipient" is a substance that is administered to a mammal, e.g., a human, is a vehicle generally accepted in the art for the delivery of biologically active agents. .

[0031] The terms "treatment," "treat," "treating" and similar terms refer to the treatment or prophylaxis of a disorder. These terms are also meant to include: Even if the disability or condition is not actually eliminated and the progression of the disability or condition itself is delayed or reversed, alleviate, ameliorate, attenuate, eliminate, or eliminate one or more symptoms of a disorder or condition, even if the disorder or condition is not converted to a This includes reducing or mitigating the effects of

[0032] An "effective amount" is defined as the biological or medical response of a patient or the amount of In one embodiment, the crystalline form of selpercatinib is an amount that induces a desired therapeutic effect on the The crystalline form of selpercatinib is characterized by in vitro or ex vivo RET enzyme assays. In another example, the crystals of selpercatinib inhibit native RET signaling in Morphology of native RET signals in mouse whole blood from animals treated with different doses of the compound Inhibits transmission.

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

[0034] An effective amount can be determined by the attending diagnostician, such as one of ordinary skill in the art, using known techniques and under similar circumstances. The effective amount for a patient can be readily determined by observing the results obtained under certain conditions. A number of factors are considered by the treating physician in making the decision, including the patient's Race; size, age, and overall health of the patient; the specific disease or disorder involved; or the extent or involvement or severity of the disorder; the response of an individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing regimen; as well as other related conditions.

[0035] Form B is preferably administered via biological routes, including oral, intravenous, and transdermal routes of administration of the compound. The compound may be formulated as a pharmaceutical composition to be administered by any route that makes it effectively available. Preferably, such compositions are for oral administration. Such pharmaceutical compositions and their Processes for preparing are well known in the art (see, for example, Remin gton:The Science and Practice of Pharmac y(DBTroy,Editor,21st Edition,Lippincott (see Williams & Wilkins, 2006).

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

[0037] As used herein, a "manufacturing vessel" refers to a vessel used in the manufacture of a pharmaceutical product, This refers to a container that is not used in a scientific laboratory. Examples of production containers include hopper collectors. , beds, dryer beds, granulator beds, dryer trays, granulator buckets, and mixers. These include, but are not limited to, bowls.

[0038] In some embodiments, Form B material is prepared from Form A material. So, the method to convert form A to form B is to convert selpercatinib form A to C1-C5 alcohol. and isolating selpercatinib Form B from the slurry. In some embodiments, the method comprises: °C, about 15-25 °C, or about 20 °C.

[0039] In some embodiments, the C1-C5 alcohol comprises methanol. The C to C alcohol comprises methanol, and in some embodiments, the methanol comprises at least About 90% by weight, or 92% by weight, or 94% by weight, or 96% by weight, or 98% by weight , or 99% by weight methanol.

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

[0041] In some embodiments, the method comprises administering the compound to a patient for at least about 5 minutes or for a period of time (e.g., At least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, or at least 60 The method includes stirring, mixing, or agitating the slurry for a period of time of about 10 minutes (minutes). In some further embodiments, the period of time can be about 8 to 12 hours. The duration is at least 10 minutes.

[0042] In some embodiments, the method comprises the steps of: It may further comprise isolating, hi some embodiments, isolating may comprise vacuum filtration. In some embodiments, the isolating may comprise centrifugation.

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

[0044] In another embodiment, the method comprises dissolving selpercatinib Form A in a solvent comprising DMSO. forming a solution; adding water to the solution in an amount to form a slurry; and and isolating the selpercatinib form B produced in the

[0045] In some embodiments, the method comprises administering about 1 gram of selpercatinib form A to about 10-1 In some further embodiments, the method comprises adding to 5 mL / g of DMSO. Approximately 1 equivalent of selpercatinib form is added in approximately 12-13 mL / g of DMSO. Therefore, the concentration of Form A dissolved in DMSO is about 12-13 mL of DMSO. Form A in the amount of about 12-13 mL / g or 1 g.

[0046] In some embodiments of the method, a solution comprising DMSO and selpercatinib Form A is The forming comprises heating selpercatinib form A and a solvent comprising DMSO at about 50° C. to about 70° C. In some further embodiments, the method comprises heating to less than about 70° C. and to about 2 In a further embodiment, the method further comprises cooling the solution to a temperature above about 50° C. The method includes cooling the mixture to a temperature of 0.5 °C.

[0047] In some embodiments of this method, adding water comprises about 0.05 g of Form A per gram of Form A. In some further embodiments, the method further comprises adding 0.1 to about 1 mL / g of water to the solution. Adding water means adding about 0.3 mL / g of water per gram of Form A to the solution. Includes.

[0048] In some embodiments of this method, the adding of water is in the form of about 1 to about 15% by weight. In some further embodiments, the method may further include adding seed crystals of B to the slurry. Alternatively, about 1 to about 10 wt % of seed crystals of Form B may be added to the slurry. In one embodiment, about 5 wt % of Form B seed crystals may be added to the slurry.

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

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

[0051] In some embodiments of the method, the slurry formed by the addition of water is stirred for about 20 to 30 minutes. Cool to °C.

[0052] In some embodiments, isolating selpercatinib form B comprises filtration. In an embodiment, isolated selpercatinib form B is obtained by dissolving in methanol, ACN, MTBE, In some further embodiments, the isolated cerpeptides may be washed with a solvent containing water. Lucatinib form B is washed with a solvent comprising methanol. The resulting selpercatinib form B was isolated until it contained less than 0.5% DMSO by weight. The precipitated selpercatinib form B is washed with methanol.

[0053] In some of the above aspects and embodiments, the present disclosure provides a method for converting selpercatinib Form A to Form B. The method comprises combining selpercatinib Form A with methanol to obtain forming a slurry and stirring the slurry until >99 wt. % of Form A is converted to Form B. In some embodiments of the method, the slurry is stirred at about The mixture is stirred for 18 to 24 hours. In yet a further embodiment, the selpercatinib form in methanol is The concentration of form A is approximately 8 mL / g.

[0054] In some of the above aspects and embodiments, the present disclosure provides a method for converting selpercatinib Form A to Form B. The method comprises the steps of: Form A was dissolved in DMSO at a concentration of about 10-15 mL / g of DMSO per gram of Form A. cooling the solution to about 40-60° C. and adding a first amount of water, optionally Optionally, the resulting mixture is seeded with seed crystals of Form B, the mixture is stirred, and a second amount of water is added. heating the mixture to about 60-80° C., cooling the mixture, and isolating Form B. In some embodiments of the method, 5% by weight of seed crystals of Form B are added to the mixture. In yet a further embodiment, the first water addition is from about 0.1 mL / g of Form A to Form B. In yet further embodiments, the second water addition is about 0.5 mL / g of Form A. 1.0~1.5mL / g.

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

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

[0057] In some embodiments, the deprotecting agent is trifluoroacetic acid, hydrochloric acid, hydrobromic acid, iodine Hydrogen acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, trisodium citrate Aluminum chloride, and boron trifluoride. In an embodiment, the deprotecting agent is selected from the group consisting of sulfuric acid, p-toluenesulfonic acid, and acetyl chloride. is selected from.

[0058] In some embodiments, the reducing agent is an alkali metal borohydride, a hydrazine compound, Citric acid, citrate, succinic acid, succinate, ascorbic acid, and ascorbate In some further embodiments, the reducing agent is selected from the group consisting of triacetoxy Sodium borohydride (STAB), sodium borohydride, and cyanoborohydride sodium hydroxide.

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

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

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

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

[0063] In some embodiments, the present disclosure provides a method for constructing a method for treating a cancer cell according to aspects and embodiments described herein. The present invention provides a method for preparing a compound of the structure [3].

[0064]

[0013] In some embodiments of any of the above aspects, the method further comprises the step of: The method includes preparing Catinib Form B.

[0065] Selpercatinib Form A (Form A) is a thermodynamically more stable polymorphic form of selpercatinib Both polymorphic forms are crystalline, high melting, anhydrous, stable and While they do not interconvert under normal storage or processing conditions, these polymorphic forms have different Form A has properties and characteristics that distinguish it from Form B. Form B has thermal There is a need to understand how to convert form A to form B, as it is mechanically more stable.

[0066] definition Unless otherwise defined, all technical and scientific terms used herein are intended to be understood as meaning the principles of the present invention. As used herein, the terms "terminology" and "terminology" have the meaning commonly understood by those of ordinary skill in the art to which they pertain. In this document, the following terms have the meanings ascribed to them unless otherwise specified.

[0067] As used herein, the term "polymorph" refers to a result of the ordering of molecules within a crystal lattice. refers to crystals of the same compound that have different physical properties as a single compound (i.e., Different polymorphs of compound I) have one or more distinct chemical, physical, mechanical, or electrical properties. The physical properties exhibited by polymorphs have chemical, thermodynamic, and / or biological properties. The differences are storage stability, compressibility, density (important in the manufacture of compositions and products), and dissolution rate. (important factors in determining bioavailability), solubility, melting point, chemical stability, physical Affects drug parameters such as chemical stability, powder flowability, moisture sorption, compaction, and particle morphology. Differences in stability may be due to chemical reactivity (e.g., the ability of a compound to be composed of one polymorph rather than another). When comprised of polymorphs, the dosage form may experience different oxidative or mechanical changes that may cause it to discolor more rapidly. conversion (e.g., when a kinetically favored polymorph is converted to a thermodynamically more stable polymorph) changes in crystallography during storage), or both (e.g., one polymorph is more hygroscopic than the other) As a result of differences in solubility / degradation, some transitions may occur. In addition, the physical properties of the crystals can be important in processing, e.g. For example, one polymorph is more likely to form a solvate, or it may be necessary to filter and wash away impurities. It can be difficult to exclude particles from the rest of the sample (i.e., the particle shape and size distribution may differ from other (The term "polymorphic form" may vary between one polymorphic form as compared to the other polymorphic form). In some particular embodiments, "polymorphs" do not include amorphous forms of the compound. Polymorphs of the compound of formula I (i.e., selpercatinib form A and selpercatinib form B) B) includes the features described herein.

[0068] As used herein, "amorphous" refers to a solid state form of a compound or a soluble form of a compound. For example, "amorphous" refers to a compound that is not crystalline, and may be in a crystallized form. It refers to a compound (eg, a solid form of a compound) that does not have a regular repeating arrangement of faces.

[0069] The term "anhydrous" as used herein refers to an anhydrous substance that is free of the stoichiometric amounts associated with the crystal lattice. It refers to the crystalline form of the compound of formula (I) that does not contain water. Usually, it is anhydrous form A and anhydrous form B. has 1% or less water by weight. For example, 0.5% or less, 0.25% or less by weight, or It contains less than 0.1% water by weight.

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

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

[0072] "Purity" when used in reference to a composition containing a polymorph of the compound of formula (I) refers to In a composition comprising one particular polymorphic or amorphous form of the compound of formula (I), Refers to the percentage of a polymorphic form. For example, a composition containing polymorphic form 1 with a purity of 90% The product contains 90 parts by weight of Form 1 and 10 parts by weight of other polymorphs and / or amorphous forms of the compound of formula (I). The present invention also includes a quantity portion.

[0073] As used herein, a compound or composition does not contain significant amounts of other components. A compound or composition is "substantially free" of one or more such other components. For example, The composition may contain less than 5%, 4%, 3%, 2%, or 1% by weight of other ingredients. Such components may include starting materials, residual solvents, or the components provided herein. These compounds and compositions may contain other impurities that may result from the preparation and / or isolation of the compounds and compositions. In some embodiments, the polymorphic forms provided herein are substantially similar to other polymorphic forms. In some embodiments, a particular polymorph of a compound of formula (I) is not included in the particular polymorph When the polymorph comprises at least about 95% by weight of the compound of formula (I) present, other polymorphs may be present. "Substantially free." In some embodiments, a particular polymorph of the compound of formula (I) is At least about 97%, about 98%, about "Substantially free" of other polymorphs if they constitute 99% or about 99.5% by weight In certain embodiments, a particular polymorph of the compound of formula (I) may have an amount of water that is about 2% by weight of the polymorph. %, about 1% by weight, or about 0.5% by weight or less of water.

[0074] As used herein, "substantially pure" refers to a compound of formula (I) that is free of polymorphic forms. When used as a syrup, it is 91%, 92%, 93%, 94%, or 100% based on the weight of the compound. %, 95%, 96%, 97%, 98%, and 99%, as well as those equal to approximately 100%. "Polymorphic" means a sample of a polymorphic form of a compound having a purity of greater than 90%, including greater than 90%. The remaining material may be other forms of the compound and / or reaction impurities and / or resulting from its preparation. For example, polymorphic forms of the compound of formula (I) are known to those skilled in the art. When measured by known and generally accepted means, the compound of formula (I) The purity of the polymorphic form of the product is greater than 90%, with less than 10% of the remaining material being other than the compound of formula (I). Substantially pure in terms of morphology and / or reaction and / or processing impurities The presence of reaction and / or processing impurities can be seen, for example, by chromatographic Analytical techniques known in the art, such as spectroscopy, nuclear magnetic resonance spectroscopy, mass spectroscopy, or infrared spectroscopy, may be used. It can be determined by surgery.

[0075] In order to provide a more concise description, some of the quantitative expressions herein may be expressed as from about X to about A range of Y is recited. When a range is recited, the range includes the recited upper and lower limits. Rather than being limited to the amount and the degree of difference, the entire range from approximation X to approximation Y, or any range therein, include.

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

[0077] As used herein, the term "excipient" refers to an agent that is used to formulate a composition into a desired form. For example, suitable excipients include diluents or fillers, binders or building blocks. Granules or adhesives, disintegrants, lubricants, anti-adhesives, glidants, dispersants or wetting agents, dissolution retardants Sustaining or enhancing agents, adsorbents, buffers, chelating agents, preservatives, colorants, flavorings, and sweeteners. Includes, but is not limited to:

[0078] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any Any and all solvents, co-solvents, complexing agents, dispersing agents, etc. that are not chemically or otherwise undesirable. These include media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. The use of such media and agents for actively active materials is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, it may be used in therapeutic formulations. The use thereof is contemplated. Supplementary active agents can also be incorporated into the formulation. In addition, various excipients may be included as commonly used in the art. and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Co. Company, Rahway, NJ. Considerations for including ;Goodman and Gilman's:The Pharmacologica l Basis of Therapeutics,12th Ed.,The McG Listed in raw-Hill Companies.

[0079] As used herein, the singular forms "a," "an," and "the" are used interchangeably throughout the context. Unless explicitly stated otherwise, includes multiple referents.

[0080] As used herein, ranges and amounts may be expressed as "about" a particular value or range. About also includes exact amounts. Therefore, "about 5 grams" can be used interchangeably with "about 5 grams" and "5 grams." In addition, ranges expressed in this specification include integers and fractions within the range. For example, the range of 5 to 20 grams includes the numbers 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 grams, etc. Including but not limited to whole numbers, as well as 5.25, 6.5, 8.75, and 11.95 grams. Fractions within the range not specified are included. Values ​​for DSC, TGA, TG, or DTA are The term "about" precedes temperatures reported as degrees Celsius and has an acceptable variation of + / - 5°C. .

[0081] As used herein, "as needed" or "as needed" refers to any statements made herein may not be accurate, complete or implied, and you agree that the information contained herein may not be accurate, complete or implied. This is meant to include examples of when it will happen and examples of when it will not happen. The term "reaction mixture optionally containing a catalyst" refers to the reaction mixture containing or not containing a catalyst. means.

[0082] As used herein, a "strong base" refers to a base that deprotonates a weak acid in an acid-base reaction. Examples of strong bases include hydroxides, alkoxides, and Common examples of strong bases include, but are not limited to, alkali metal bases and ammonia. Certain strong bases are the hydroxides of metals and alkaline earth metals, e.g., NaOH. In the presence of a strong base, it can even deprotonate very weakly acidic CH groups. Sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, calcium hydroxide, These include strontium hydroxide, lithium hydroxide, and rubidium hydroxide. Not limited thereto. In some embodiments, NaOH is used as the strong base. In this embodiment, potassium hydroxide is used as the strong base.

[0083] As used herein, the term "weak base" refers to a base that is only partially ionic in aqueous solution. Weak bases typically have a pKa of about 6 to about 11. Many such weak bases are known and are listed in the Handbook of Biochem istry and Molecular Biology,Vol.1,3rd ed. ., GDFassman, CRC Press, 1976, pp. 305-347. Examples are listed below. Weak bases can be water-soluble or water-insoluble. Weak bases include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and bicarbonate. Alkali metal carbonates and bicarbonates such as sodium; ammonia; methylamine; Primary amines; secondary amines; and tertiary amines, such as trialkylamines, e.g. Trimethylamine, triethylamine, tripropylamine, and tributylamine, These include diethylamine, pyridine, quinoline, N-methylmorpholine, and aniline. Examples include, but are not limited to:

[0084] As used herein, a "non-nucleophilic base" refers to a base that does not act as a nucleophile, i.e., A base that does not donate an electron pair to an electrophile to form a chemical bond involved in a reaction. Typically In the case of non-nucleophilic bases, a proton can be attached to the basic center, but alkylation and They are bulky and sterically hindered so that complexation is prevented. Examples of non-nucleophilic bases include amines. and nitrogen heterocycles, e.g., triethylamine and pyridine, amidines, lithium compounds, Other examples of non-nucleophilic bases include, but are not limited to, Includes sodium hydride and potassium hydride.

[0085] As used herein, the term "amine protecting group" refers to a group for the protection of an amine group. means any group known in the art of organic synthesis. Such amine protecting groups include: Greene, “Protective Groups in Organic Syn thesis,”John Wiley&Sons,New York(1981)an d “The Peptides:Analysis,Synthesis Biolo gy, Vol. 3,” Academic Press, New York (1981). Any amine protecting group known in the art can be used. Examples of amine protecting groups include: (1) formyl, trifluoroacetyl, (2) acyl types such as phthalyl and p-toluenesulfonyl; benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1-(p-biphenyl)-1-methyl 9-Fluorenylmethyloxycarbonyl (Fmoc) Aromatic carbamate type such as (3) tert-butyloxycarbonyl (Boc) , ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl (4) Aliphatic carbamate type such as cyclopentyloxycarbonyl and adamantyl (5) Cyclic alkyl carbamate type such as triphenyloxycarbonyl, (6) Alkyl types such as ethyl and benzyl; and (7) trialkylsilane such as trimethylsilane. Ran, (7) thiol-containing types such as phenylthiocarbonyl and dithiasuccinoyl and (8) alkyl types such as triphenylmethyl, methyl, and benzyl, and Substituted aryl groups such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl are added to the These include silane types such as trialkylsilane and trialkylsilane types such as trimethylsilane. The present invention is not limited to these.

[0086] As used herein, the term "deprotecting agent" refers to a reagent useful for removing a protecting group. Deprotection agents are acids, bases, or reducing agents. For example, removal of a benzyl (Bn) group can be accomplished by reduction (hydrogenolysis). The carbamate (e.g., Boc group) can be removed by the addition of an acid (e.g., Removal of the silyl group can be achieved by the use of a suitable solvent (e.g., HCl, TFA, H2SO4, etc.). , weak acids or halides (e.g., tetra-n-butylammonium fluoride (TBAF) Fluorides such as those provided by This can be achieved.

[0087] As used herein, the term "reducing agent" generally refers to a compound that is itself oxidized. As used herein, "reducing" refers to any species that is capable of reducing another species while in use. "Oxidizing agent" or "oxidant" The term generally refers to any species that is capable of oxidizing another species while being itself reduced. Refers to...

[0088] As used herein, the term "triflating agent" refers to a compound in which a triflate group is Refers to compounds useful in reactions that combine with hydroxy groups to form triflate esters. Triflating agents are a source of trifluoroacetyl groups. , trialkylsilyl triflate, trialkylstannyl triflate, triflic Anhydride (trifluoromethanesulfonic anhydride), N-phenyl-bis(trifluoromethane Tansulfonimide) (PhNTf2), N-(5-chloro-2-pyridyl)trifluoride Examples of suitable aryl groups include, but are not limited to, N-(2-pyridyl)triflimide ... and N-(2-pyridyl)triflimide.

[0089] As used herein, an "acrylonitrile derivative" refers to an acrylonitrile derivative in which one or more of the hydrogen atoms have been replaced with another atom. or a group derived from acrylonitrile having the formula CH2CHCN. An example of an acrylonitrile derivative is 2-chloroacrylonitrile. , one of the hydrogen atoms of acrylonitrile is replaced by a chlorine atom.

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

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

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

[0093] As used herein, the term "alkyl" refers to any alkyl group containing the indicated number of carbon atoms. It refers to a hydrocarbon chain that can be linear or branched, e.g., C 1~6 The base is in it. It can have 1 to 6 (inclusive) carbon atoms. Examples include methyl, ethyl, and ethyl. Examples of aryl groups include ethyl, isopropyl, tert-butyl, and n-hexyl.

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

[0095] Salts can be formed from compounds in any manner well known to those skilled in the art. Thus, the phrase "form a compound or a salt thereof" includes the meaning that a compound is formed and the salt is Included are embodiments that are subsequently formed from compounds in a manner well known to those of skill in the art.

[0096] Certain features of the invention, which are, for clarity, described in the context of separate embodiments, also Conversely, for the sake of brevity, the following may be provided in combination in a single embodiment: The various features of the invention described in relation to the embodiments may also be used separately or in any suitable subcomponent. It may be provided in combination.

[0097] All combinations of embodiments of aspects described herein are intended to be illustrative and not restrictive. As long as the combination includes possible combinations, it is as if each combination was explicitly listed separately. Specifically encompassed by the present invention as if set forth above. All subcombinations of the embodiments included herein, and all other aspects described herein. All subcombinations of the included embodiments are also included as if each and every embodiment were included. Each such subcombination is hereby incorporated by reference as if it were expressly recited herein. Specifically included.

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

[0099] Suitable methods for converting form A to form B include cooling crystallization, evaporative crystallization, vapor diffusion, 1 These include crystallization using one or more antisolvents (including reverse antisolvent addition), and slurry crystallization. These methods are discussed herein.

[0100] In one embodiment, the method for converting selpercatinib form A to selpercatinib form B comprises the steps of: Disclosed in the specification.

[0101] In another embodiment, a method for converting serpercatinib form A to serpercatinib form B. Selpercatinib Form A is then combined with a C1-C5 alcohol to form a slurry. and isolating selpercatinib form B from the slurry. Disclosed in the specification.

[0102] In yet another embodiment, a method for converting selpercatinib form A to selpercatinib form B. 40. The method comprising: a. Dissolving selpercatinib form A in a solvent comprising DMSO to form a solution. and, b. adding water to the solution, thereby forming a slurry; and c. isolating selpercatinib form B. do.

[0103] In another embodiment, there is provided a method for converting selpercatinib form A to form B, the method comprising: combining lupercatinib form A with methanol to form a slurry; and agitating the slurry until % by weight of Form A is converted to Form B. Disclosed in the specification.

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

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

[0106] The XRPD patterns of Forms A and B were measured using a CuKα source (λ=1.54180A) and V A Bruker D4 Endoscope with an antec detector operated at 35 kV and 50 mA The samples were obtained on an Eavor X-ray powder diffractometer with a step size of 0.008 2θ°. and a scanning speed of 0.5 sec / step, with a divergence slit of 1.0 mm and a fixed divergence of 6.6 mm. The measurement was performed from 4 to 40 2θ° using a disturbance prevention slit and an 11.3 mm detection slit. The dry powder was packed into a quartz sample holder and a glass slide was used to obtain a smooth surface. The crystalline form diffraction patterns are collected at ambient temperature and relative humidity. The entire pattern was based on an internal NIST 675 standard with a peak at .774 2θ°. After shifting, the crystal peak position is determined in MDI-Jade. For any given crystalline form, preferred crystal forms may result from factors such as crystalline form and habit. It is well known that the relative intensities of diffraction peaks can change due to orientation. If an effect is present, the peak intensities will change but the characteristic peak positions of the polymorph will not. For example, The United States Pharmacopeia #23, National Formulary#18,pages1843-1844,199 5. Furthermore, for any given crystalline form, the angular peak positions may vary slightly. It is also well known in the crystallography art that peak positions can vary depending on the sample being analyzed. Shifts due to variations in temperature, sample displacement, or the presence or absence of an internal standard. In this case, the peak position variability of ±0.2 2θ° is consistent with the apparent crystal morphology shown. It is assumed that these potential variations will be taken into account without precluding accurate identification. Identification of can be based on any unique combination of prominent peaks.

[0107] DSC-TGA analysis of the anhydrous crystalline form A showed a melting onset of 207.6°C with two absorbances. The first endotherm is the melting of form A, followed by the exothermic recrystallization of form B, and then the DSC-TGA analysis of the anhydrous crystalline form B shows a melting point of 213.3 °C. It showed a single endotherm with an onset.

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

[0109] Forms A and B have similar solubilities. Both are dissolved in methyl ethyl ketone (MEK). Soluble at 25°C in many organic solvents, including acetone, and many alcohol-based solvents In low concentration, dichloromethane (DCM), dimethyl sulfoxide (DMSO) and THF Form B is almost completely soluble in anisole. do not.

[0110] Form A and Form B 13 The C solid-state NMR spectrum is shown in Figure 2. Form A contains a peak at 30.9 ppm that is not observable in Form B. and Form B has a peak at 48.0 ppm that is not observable in Form A. Both spectra were referenced to the high magnetic resonance of adamantane (δ = 29.5 ppm). .

[0111] It operates at a carbon frequency of 100.62 MHz and a proton frequency of 400.13 MHz. Bruker Avance III with Bruker 4mm dual resonance probe Using a HD 400MHz wide-bore NMR spectrometer, 13 C Cross Polarization / Magic Angle Spinning Obtain an NMR (solid-state NMR or ssNMR) spectrum. TOSS sideband suppression is performed. Cross-section using SPINAL64 decoupling and RAMP100 H-nucleus CP pulses Acquisition parameters are: 4.0 μs proton pulse, 1 .5 ms contact time, 5 kHz MAS frequency, 30.2 kHz spectral width, and 3 An acquisition time of 4 ms. A recycle delay of 3 seconds was used, and the number of scans was 2655. Chemical shifts are referenced to adamantane (δ = 29.5 ppm) in a separate experiment. Representative of form B 13 The Css NMR resonances are 26.44, 27.37, and 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, 113.5 8, 115.24, 118.23, 120.76, 125.23, 130.23, 134 .86, 136.93, 140.59, 148.42, 149.50, 151.20, 1 Includes 52.45, 158.22, and 163.52 ppm.

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

[0113] A variety of different solvents can be used to convert Form A to Form B. Solvents that can be used to convert to C1-C5 alcohols (methanol or ethanol) include water, acetonitrile (ACN, methyl tert-butyl ether (MTBE ), heptane, n-butyl acetate (n-BuOAC), 81% ACN-MeOH (19m 81 mL of ACN combined with 1 L of MeOH), wet ethyl acetate, cyclopentane methyl ether (CPME), 1,2-dimethoxyethane, ethyl acetate, ethyl formate, Methyl isobutyl ketone (MIBK), nitromethane, n-propyl acetate (NPA), 1 -Pentanol, Toluene, 1:1 MeOH:water, 1:1 EtOH:water, ACN:water DMSO / heptane mixtures, or DMSO / water mixtures. In some embodiments, the solvent includes C1-C5 alcohols, water, DMSO, MT In yet another embodiment, the solvent includes BE, ACN, and mixtures of two or more thereof. is methanol, ethanol, water, DMSO, MTBE, ACN, or two or more of them Contains a mixture of.

[0114] As mentioned above, selpercatinib can form solvates and metastable solid forms. Both of which are generally not stable when dry. Observed solvates include: Acetone solvate, chloroform solvate, 1,4-dioxane solvate, methyl ethyl Ketone (MEK) solvate, dichloromethane (DCM) solvate, 2-butanol solvate solvate, 1-butanol solvate, ethanol solvate, dimethyl sulfoxide (DMSO) - Water solvate, DMSO solvate, and tetrahydrofuran (THF) solvate. Solvates and metastable forms usually revert to Form A during isolation and / or drying, but in films Or amorphous material may be formed. Chloroform and 1,4-dioxane solvates was stable upon isolation / drying.

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

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

[0117] Conversion method 1 In a preferred embodiment, the method comprises: isolating selpercatinib Form A with an alcohol such as a C1-C5 alcohol. The method includes the steps of: combining the solvent to form a slurry; and extracting selpercatinib form from the slurry. and isolating B. When the slurry is stirred or otherwise agitated, Selpercatinib form B is formed. In some embodiments, the alcohol is added at ambient temperature. In another embodiment, the slurry is heated, which increases the rate of Form B formation. Except for the temperature difference, these two embodiments are similar and are described below. It will be published.

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

[0119] Examples of C1-C5 alcohols include methanol, ethanol, isopropanol, These include propanol, butanol, 2-butanol, and 3-butanol. In an embodiment, the alcohol comprises methanol and / or ethanol. The alcohol includes methanol.

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

[0121] temperature Temperature affects the rate at which form A is converted to form B, with lower temperatures converting more rapidly than higher temperatures. Stirring the Form A and solvent slurry at sub-ambient temperatures takes longer than this. is possible, but this is usually avoided because it prolongs the conversion of form A to form B. .

[0122] The temperature of the alcohol, such as C1 to C5 alcohol, is about 10 to 80°C, or about 20 to 60°C. C., or about 55.degree. C. The C1-C5 alcohol is added to the desired temperature before the Form A material is added. It may be the temperature, or the temperature may be adjusted after the Form A material is added.

[0123] In another embodiment, the temperature of the alcohol, such as a C1-C5 alcohol, is 10-30° C. Or about 15-25° C., or about 20° C. In other embodiments, the temperature is ambient temperature. Form A converts to form B upon stirring in a room temperature solvent such as methanol. However, when a mixture of Form A and solvent is heated, the conversion is more rapid.

[0124] When the slurry is heated to the point where all of Form A has dissolved, the resulting solution is filtered and After stirring, the solution is stirred at 37° C. for 1 hour, at which time any insoluble material may be removed. After stirring, the solution is stirred at 37° C. for 1 hour, at which time any insoluble material may be removed, as described in more detail below. Stir and cool.

[0125] time The slurry is stirred or otherwise agitated for at least about 5 minutes, or at least about 10 minutes. In some embodiments, the slurry is typically not stirred for longer than 72 hours. or otherwise not stirred, but if desired, the slurry may be stirred for longer than 72 hours. In some embodiments, the slurry may be stirred or otherwise agitated. The mixture is stirred for about 1 to 12 hours.

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

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

[0128] Ethanol, methanol, ACN, MTBE, water, or a combination of two or more of these Fresh solvents such as ethanol, ethyl acetate ... Wash the Form B material using ACN, MTBE, water, or a combination of two or more thereof. Even more preferably, a solvent containing methanol is used. The new solvent is is cooled to a temperature of about 0° C. to less than about 20° C. before being used to wash the Form B material. Good too.

[0129] The isolated selpercatinib form B can be dried using methods known in the art. Typical methods include heating, passing an inert gas over the solid, and / or centrifugation. This includes the use of subatmospheric pressures.

[0130] In a further embodiment of this example, a C1-C5 alcohol and selpercatinib form A are and stirring the resulting slurry for a period of time sufficient to convert Form A to Form B. Stir or otherwise agitate. Typical stirring times are at least about 10 minutes and up to about 20 minutes. 36 hours, or about 24 hours, but typically at least about 30 minutes, or at least about 1 hours, or at least about 4 hours, or at least about 6 hours, or at least about 8 hours, or The incubation time is at least about 12 hours. If necessary, the mixture may be stirred and / or rocked for up to 24 hours. Heating the mixture may be performed for a period of time or longer. The rate of conversion of Form A to Form B is increased by heating the mixture. Add.

[0131] In another embodiment of this method, the method comprises combining selpercatinib Form A with methanol. and forming a slurry of >95 wt.%, >96 wt.%, >97 wt.%, > The slurry is stirred until 98% or >99% by weight of Form A is converted to Form B. The slurry is stirred for about 12 to 48 hours or about 18 to 24 hours. The concentration of selpercatinib form A in the solution is about 6-14 mL / g or about 8-12 mL / g. In some methods, it is about 8 mL / g.

[0132] Conversion method 2 In another embodiment, the method comprises mixing selpercatinib Form A with a solvent, The resulting mixture is heated and stirred until Form A dissolves in the solvent. Once a solution is formed, The mixture may be filtered to remove any insoluble impurities. Cool and add water. If seed crystals are used, add seed crystals at this point. After stirring, additional water is slowly added and the mixture is then cooled to room temperature. After cooling to room temperature, the mixture is stirred and then the Form B material is isolated.

[0133] solvent A variety of different solvents may be used. Importantly, the solvent may be selected from the group consisting of selpercatinib solvates. The solvent should not form a product, but rather should give the desired form B. Examples of suitable solvents The solvent may be DMSO, C1-C5 alcohol, ACN, MTBE, water, or any combination of two of them. The above combinations are exemplary, but not limited to these. In some embodiments, the distillate may include ethanol and / or methanol. O is a preferred solvent. In some embodiments, the solvent contains at least 2% by weight of water. Contains.

[0134] The amount of solvent used depends on the solvent used. Typically, 1 g of Form A is dissolved in about 8 to 100 ml of water. Use 20mL, or about 10-15mL, or about 11-14mL, or about 12-13mL In some embodiments, 1 gram of Form A is dissolved in 10-15 mL of the solvent. / g DMSO, or 1 gram of Form A is dissolved in approximately 12-13 mL / g DMS It is dissolved in O.

[0135] temperature Temperature affects the rate at which form A is converted to form B, with lower temperatures converting more rapidly than higher temperatures. It takes a much longer time.

[0136] A mixture containing Form A and a solvent is heated to a temperature ranging from about 30° C. to the boiling point of the solvent. In some cases, the mixture is heated to a temperature of about 50 to 110° C. or about 50 to about 70° C. In embodiments, the mixture is heated to about 50° C., about 60° C., about 70° C., about 80° C., about 90° C., about 10° C., about 20° C., about 25° C., about 30° C., about 4 ...50° C., about 60° C., about 70° C., about 80° C. The mixture may be heated to a desired temperature and Form A material. After the ingredients are dissolved, the temperature of the solution is reduced by about 15 to 35°C. °C, about 25 °C, about 30 °C, or about 35 °C. In one embodiment, the solution is It is cooled to a temperature below 70°C and above about 20°C.

[0137] In some embodiments, the solvent comprises DMSO and is heated to about 50° C. to about 70° C. In a further embodiment, the DMSO is then cooled to about 50° C.

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

[0139] First Tranche of Water When the first aliquot of water (stage 1 water) is added to the solution, about 0.1-1.0 mL / g, or about 0.2-0.6 mL / g, or about 0.3 mL / g of Form A is added (Form In some embodiments, the first aliquot of water is about 0.1 ml L / g or about 0.2mL / g, about 0.3mL / g, about 0.4mL / g, about 0.5mL / g , or about 0.6 mL / g.

[0140] The first aliquot of water is stirred for about 30 seconds to about 15 minutes, or for about 1 to 10 minutes, or for about 4 to 6 minutes, or Add over about 5 minutes, longer times may be utilized if desired.

[0141] seed crystal When seed crystals of Form B are added to the mixture, they are present in an amount of about 0.1 to 15% by weight, or about 1 to about 10 %, or about 5% by weight, of Form B seed crystals are used.

[0142] In some embodiments, about 1%, 2%, about 3%, about 4%, about 5%, %, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, About 12%, about 13%, about 14%, or about 15% by weight of seed crystals are added.

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

[0144] time heating the mixture to dissolve the Form A material, reducing the temperature of the mixture by 50-110°C; and After the seed crystals are added, the mixture is stirred for about 1 to 96 hours, or for about 6 to 72 hours if seed crystals are used. In some embodiments, the mixture is stirred for at least 8 hours, or for about 8 to 24 hours. time, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 o'clock 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 2 Stir for 4 hours.

[0145] Second Tranche of Water After stirring for 1-96 hours, a second aliquot of water (stage 2 water) is added slowly. The amount of water in the second aliquot is about 0.3-6 mL / g, 0.50-3.0 mL / g (Form A mL of water per gram of water), about 0.75 to 1.5 mL / g, or about 0.9 to 1.20 mL In some embodiments, the second aliquot of water is about 0.90 mL of Form A. / g, approx. 0.91mL / g, approx. 0.92mL / g, approx. 0.93mL / g, approx. 0.94mL / g, approx. 0.95mL / g, approx. 0.96mL / g, approx. 0.97mL / g, approx. 0.98mL / g, approx. 0.99mL / g, approx. 1.00mL / g, approx. 1.01mL / g, approx. 1.02mL / g, approx. 1.03mL / g, approx. 1.04mL / g, approx. 1.05mL / g, approx. 1.06mL / g, approx. 1.07mL / g, approx. 1.08mL / g, approx. 1.09mL / g, approx. 1.10mL / g, approx. 1.11mL / g, approx. 1.12mL / g, approx. 1.13mL / g, approx. 1.14mL / g, approx. 1.15mL / g, approx. 1.16mL / g, approx. 1.17mL / g, approx. 1.18mL / g, approximately 1.19 mL / g, and approximately 1.20 mL / g.

[0146] The second aliquot of water is added slowly, i.e., the entire second aliquot of water is added. It takes about 0.5 to 24 hours or about 1 to 12 hours for the second fraction to be dissolved. It takes about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours do.

[0147] cooling After the second aliquot of water is added, the mixture is cooled to about 15-30° C. and then cooled to about 20-30° C. In some embodiments, the mixture is heated to a temperature of about 15° C., about 16° C., about 17° C., about 18℃, about 19℃, about 20℃, about 21℃, about 22℃, about 23℃, about 24℃, about 25℃, about The mixture is cooled to about 26° C., about 27° C., about 28° C., about 29° C., or about 30° C. In one embodiment, The final temperature after cooling is room temperature. In another embodiment, the mixture is cooled to a temperature of about 30-55° C. In these embodiments, the yield is slightly higher than when a lower temperature is used. The trend is for the

[0148] After the second aliquot of water is added, the mixture is heated at about 1-20°C / hour, or at a rate of about 3-17° C. / hour, or about 5-15° C. / hour. The cooling rate is about 1°C / hour, about 2°C / hour, about 3°C / hour, about 4°C / hour, about 5°C / hour. / hour, about 6°C / hour, about 7°C / hour, about 8°C / hour, about 9°C / hour, about 10°C / hour, About 11°C / hour, about 12°C / hour, about 13°C / hour, about 14°C / hour, about 15°C / hour, Approximately 16℃ / hour, approximately 17℃ / hour, approximately 18℃ / hour, approximately 19℃ / hour, approximately 20℃ / hour be.

[0149] After the desired temperature is reached, the mixture is stirred for about 1 to about 72 hours, or for about 2 to 48 hours. In some embodiments, the mixture is stirred for at least 2 hours. The material is stirred for less than 72 hours.

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

[0151] Ethanol, methanol, ACN, MTBE, water, or a combination of two or more of these Fresh solvents such as ethanol, ethyl acetate ... Wash the Form B material using ACN, MTBE, water, or a combination of two or more thereof. Even more preferably, a solvent containing methanol is used. The new solvent is is cooled to a temperature of about 0° C. to less than about 20° C. before being used to wash the Form B material. Good too.

[0152] In embodiments in which the solvent comprises DMSO, the isolated selpercatinib form B is with methanol until the resulting selpercatinib form B contained less than 0.5% DMSO by weight. It is washed.

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

[0154] In another example of this method, selpercatinib form A is DMSO-treated at about 60-80° C. or at about 70° C. and dissolving in DMSO to have a concentration of about 10-15 mL / g DMSO per gram of Form A. The mixture is cooled to about 40-60° C. or about 50° C., water is added, and the resulting solution is seeding the mixture with seed crystals of Form B, stirring the mixture, adding more water, and heating the mixture; The mixture is cooled and Form B is isolated. The initial amount of water added is about 0.1 m of Form A. L / g to about 0.5 mL / g of Form A, or about 0.3 mL / g of Form A. The amount of seed crystals to be added ranges from about 1 to 10% by weight, or about 5% by weight, based on the amount of Form A. The seed crystal-containing mixture is stirred for about 8 to 24 hours, or for about 12 hours. The amount of water is about 1.0 to 1.5 mL / g of Form A, or about 1.10 to 1.15 mL / g, or The second addition / aliquot of water is added for about 3-8 hours or for about 5 hours. After the second charge / portion of water is added, the slurry is stirred for about 20-30 minutes. The slurry is cooled from about 70° C. to about 25° C. at a rate of about 25° C. The temperature is increased by about 10° C. / hour until the slurry reaches about 25° C. The slurry is stirred for at least about 2 hours at about 25° C. Then, the mixture is heated to about 60 to 80°C, 70 to 75°C, or about 73°C, and stirred for about 1 hour. The slurry is then cooled again to about 20-30°C or about 25°C. Cool from about 73°C to about 25°C at a rate of about 10°C / hour. After stirring for about 1-8 hours, or for about 2 hours, selpercatinib Form B is added to, e.g. and isolated by filtration.

[0155] A crystallization method effective for the conversion of Form A to Form B is described in the exemplary embodiment in the Examples. This is further exemplified by:

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

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

[0158] Precursor compound [2] (tert-butyl 3-(5-(3-cyano-6-(2-hydroxy 2-methyl-propoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridine -2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate Detailed descriptions of synthetic methods that can provide and 10,112,942, as well as in International Patent Publication No. 2018 / 071447. each of which is incorporated herein by reference in its entirety. In a brief overview of one embodiment, compound [2] is prepared by reacting 4-(6-fluoropyridine) in DMSO. 1,5-diphenyl-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5- a] Pyridine-3 carbonitrile, 3,6-diaza-bicyclo[3.1.1]heptane- 6-Carboxylic acid tert-butyl ester and KCO 3(s) (1:1:6.67 mol (in equivalent amounts) under heating (e.g., 90°C for 12 hours) with stirring. The resulting viscous slurry is diluted with additional DMSO and heated (e.g., at 90° C.). After the reaction, the mixture was cooled to ambient temperature and diluted with water to give The combined aqueous mixture was washed with dichloromethane. The combined organic extracts were washed with anhydrous MgSO 4(s) The resulting residue is purified by silica gel chromatography. (EtOAc / hexanes as gradient eluent system) to give compound [2]. The compound [2] can be synthesized in high yields by those skilled in the art. Those skilled in the art will further appreciate that compound [2] may be a formyl, acetyl, trifluoro Acetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-meth Benzylcarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl , trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxy dicarbonyl, nitroveratryloxycarbonyl, p-methoxybenzyl and tosyl Amine protecting groups other than Boc, including non-limiting examples, may be included. is the protecting group, tert-butyloxycarbonyl (Boc).

[0159] Generally, a method for the Direct Synthesis of Form B selpercatinib in accordance with the present disclosure includes: (1) preparing a compound comprising: (2) to remove protecting groups (e.g., Boc shown in [2]), and (3) to remove 2-hydroxy-2- Silylation of the hydroxyl group on a methyl-propoxy substituent (e.g., TMS shown in [3]) ) under effective conditions, compound [2] (tert-butyl 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- The silylated and deprotected compound [3] is then reacted with In the presence of a reducing agent and an acid in an organic solvent (e.g., anisole), 6-methoxy-3- React with pyridinecarboxaldehyde.

[0160] The silyl moiety (e.g., TMS in some exemplary embodiments) can be, for example, a fluorine-containing Deprotection methods such as the addition of a chloride source (e.g., tetrabutylammonium fluoride (TBAF)) After reaction and removal of the silyl protecting group, the pH of the reaction mixture is adjusted to salt. The mixture is cooled and adjusted with water to allow for the formation and isolation of crystalline form B selpercatinib.

[0161] In some embodiments, conditions effective for removing protecting groups and for silylation include: Alcohols (e.g., MeOH, EtOH), organic acids (e.g., p-toluenesulfonic acid arylsulfonic acids, aprotic solvents (e.g., acetonitrile, etc.), Acyl halides in coal (e.g., acetyl chloride in methanol to give an HCl solution) esters (e.g., ethyl acetate), ethers (e.g., anisole), and The solvent may include a solvent selected from polar organic solvents, such as combinations of these. In the present state, the reaction is carried out with trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, Methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, aluminum trichloride, and In some embodiments, the deprotecting agent may include boron trifluoride. In some embodiments, the deprotecting agent may include sulfuric acid. , acetyl chloride, or p-toluenesulfonic acid. In some embodiments, the conditions are , for a period of time ranging from about 1 hour to about 8 hours or more (e.g., overnight, or about 12 hours), Optionally, this may include heating the reaction mixture to reflux.

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

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

[0164] In some embodiments, compound [3] and 6-methoxy-3-pyridinecarboxylate The reaction with aldehyde produces compound [3] in the 2-hydroxy-2-methyl-propoxy form of [3]. Based on the premise that benzophenone shows higher solubility in anisole than in the benzophenone phase, anisole was used as the solvent. In some embodiments, the reducing agent is an alkali metal borohydride, arsenic, tetracycline compounds, citric acid, citrates, succinic acid, succinates, ascorbic acid, and In some embodiments, the reducing agent may include sodium borohydride. selected from lithium, lithium borohydride, nickel borohydride, and potassium borohydride; In some embodiments, the lithium borohydride is selected from the group consisting of lithium borohydride and and lithium triethylborohydride. In some embodiments, the borohydride is Sodium borohydride is also known as sodium triacetoxyborohydride (STAB), In some embodiments, the cation is selected from sodium, sodium cyanoborohydride, 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. It acts as a phosphate buffer and can be used with inorganic acids (e.g., HCl, H2SO4, etc.) or water-soluble organic acids ( For example, acetic acid, pivalic acid, etc. In some embodiments, the acid may be pivalic acid. Contains acid.

[0165] The resulting compound has sufficient silyl group (e.g., TMS) removal and reaction product. Deprotection under conditions that are not so harsh as to react with and decompose the product (i.e., selpercatinib). In some embodiments, deprotection of the silyl group provides a compound effective to react with the silyl group. A fluoride source (e.g., tetrabutylammonium fluoride (TBA F), pyridine (HF) x , trimethylamine trihydrofluoride (Et3N·3HF), Hydrofluoric acid, tris(dimethylamino)sulfonium difluorotrimethylsilicate (T This involves adding ammonium fluoride (ASF), ammonium fluoride (H4NF) or a weak acid. The conditions of this step may include a buffered fluoride source and the conditions may be sufficiently mild to avoid decomposition reactions. can be empirically determined while maintaining

[0166] After the reaction, the pH of the reaction mixture is adjusted with a base (e.g., K2CO3 slurry) and cooled. This allows for the formation and isolation of crystalline form B selpercatinib. Alternatively, the crystallization may further comprise the addition of a small amount of seed crystals of selpercatinib form B. In some further embodiments, the crystallization further comprises converting the remaining amount of selpercatinib Form B to Form A. This can include any of the crystallization techniques described herein that can be effective to convert Cut.

[0167] Certain starting materials and reagents are set forth in the following schemes and related discussion, but other Starting materials, reaction conditions, and reagents may be substituted to produce target compounds (i.e., Percatinib form B can be obtained.

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

[0169] In some embodiments of this aspect, the process can be carried out by the general reaction shown in Scheme 2: Includes scheme. [ka]

[0170] Selpercatinib Form B can be prepared by direct synthesis or cell synthesis according to aspects and embodiments of the present disclosure. Selpercatinib (i.e., amorphous selpercatinib or another polymorphic form of selpercatinib) It is further intended to provide a method for the preparation of a compound which is soluble in water, whether or not it is obtained by conversion from a compound selected from the group consisting of phenylalanine, ... or pharmaceutical compositions thereof, other polymorphs and / or amorphous forms thereof. It can show higher thermodynamic stability compared to lupercatinib. Nib Form B retains its activity as a RET inhibitor, see, e.g., PCT Publication No. 2003 / 013363. No. 2018 / 071447 and U.S. Patent Application Publication No. 2018 / 0134702. Activity is assessed by any assay known in the art, including assays that have been and can be assessed, each of which is incorporated by reference in its entirety.

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

[0172] The crystallization procedure described herein uses selpercatinib (6-(2-hydroxy- 2-Methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl 3,6-Diazabicyclo[3.1.1]heptan-3)-yl)pyridine-3 -yl)pyrazolo[1,5-a]pyridine-3-carbonitrile) is disclosed in U.S. Pat. The antibodies were prepared using the techniques and methods described in US Pat. No. 112,942.

[0173] Example 1: Cooling Crystallization 264 mg of Form A was dissolved in 20 mL of DCM (15) in an 8 mL vial. These vials were then placed in a vacuum oven at 70°C to separate the solvent. The birefringent white solid was observed in all vials. ) was added at 50° C. with shaking. The heat source was switched off and the sample was allowed to cool naturally. Cool to room temperature (RT). Stir the sample overnight and isolate the resulting solid by vacuum filtration. The vials without solids were placed in a refrigerator for 3 days and allowed to settle. If no changes occurred, the sample was removed and allowed to evaporate in a fume hood for 1 day. XRPD data were The solids were collected (if possible). 2 / 3 (about 66%), isolated and dried Sometimes metastable solvates were produced. These metastable solvates (chloroform solvates) All except for Form A were converted to Form A immediately upon removal from the mother liquor. With anisole, form B was obtained, and with anisole, form A was obtained. [Table 2]

[0174] Example 2: Evaporation and Vapor Diffusion Crystallization Evaporation plates were prepared by dissolving 5 mg of Form A in 0.9–12 mL of solvent ( 33) Prepare a vial. Manually syringe filter the evaporated solution into a clean vial. The container was then placed 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 antisolvent. and tightly covered.

[0175] Approximately half of the crystallization experiments produced solvates or mixtures of solvates and Form A. The vast majority of solvates were converted to form A upon desolvation. Templating effect due to structural similarity It is thought that the nucleation of the metastable form may be induced by ACN and The results were obtained from only two crystallization experiments using MeOH-THF in a ratio of 5:1 and 5:1. Amorphous forms / films were obtained in five solvent systems (THF, 11:1 IPA:acetic acid, benzene It was obtained from diethyl ether, acetic acid and 10:1 EtOH:DMF. The 1,4-dioxane solvate was stable upon isolation and solid state characterization data was collected. PA is isopropyl alcohol, THF is tetrahydrofuran, and DMF is dihydrofuran. Methylformamide.

[0176] Vapor diffusion experiments yielded a variety of solvates or amorphous materials. Five solvates, all DCM, 1-BuOH, EtOH, THF, and DMSO are metastable and may be isolated. Form A was obtained in DMSO / heptane mixtures. Obtained.

[0177] Example 3: Antisolvent crystallization (29) Various amounts (9–36 mg) of the form were added to 1–15 mL of solvent in 4 mL vials. Antisolvent addition experiments were prepared by dissolving form A in the first 17 vials. Reaction is continued until precipitation occurs or the volume of antisolvent is equal to or greater than the volume of solvent. The solvent was dropped into the filtered solution with a syringe. For the second 12 vials, the solvent was added dropwise. The liquid was syringe filtered into a clean vial containing 5 mL of antisolvent. The vials were isolated by vacuum filtration and air-dried. Vials in which no precipitate was observed were stored for up to 2 weeks. The mixture was allowed to evaporate for a period of time. 71% of the antisolvent additions yielded Form A or an unstable solvate leading to Form A. Form B appeared in 24% of the runs (one result was amorphous). In addition, 83% of the experiments yielded Form A or a solvate, and 17% of the experiments yielded Form B. .

[0178] Example 4: Slurry Crystallization A Form A vial slurry was prepared with 10 mg of Form A in a 4 mL vial. Solvents were added according to the solubility of Form A in these solvents to produce a certain slurry density. The slurry was shaken in a shaker block at 500 rpm at 22° C. for approximately 3 days. The material was analyzed as a wet cake by XRPD. yields a solid consistent with Form A or a solvate that is converted to Form A during isolation / drying. did.

[0179] Another slurry plate containing 10 mg of Form A in a 4 mL vial was prepared using the same method as described in the previous paragraph. The slurry was prepared in the same manner as described above. The slurry was shaken for 22 h on a shaker block at 500 rpm. After 24 hours, the mother liquor in each vial was mixed with fresh solvent and The slurry was then stirred for 15 days. The solids were identified by wet XRPD. The analysis was performed for both dry and wet samples. 2 / 3 Form B was observed in about 66% of the samples. The remainder of the experience 1 / 3 (approximately 33%), Forms A and B or Form A and a solvate (1 case) These results suggest that equilibrium was not reached, which is 1) the solubility limit of Form A in the solvent tested, or 2) the heat of phase transformation near the transition point. This may be due to the minimal mechanical driving force. Again, Form A was obtained with Nisole. [Table 3]

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

[0181] Example 5: Solvent-assisted milling Two experiments using solvent-assisted mechanical milling were carried out 1 In one experiment, DMSO was used as the solvent. When water was used as a solvent, form B was observed. No polymerization, i.e., Form A was not observed.

[0182] Example 6: Conversion of Form A to Form B Selpercatinib (2.0 g) was suspended in methanol (200 mL) and incubated at 55°C and 75°C. The suspension is stirred at 50 rpm for 60 minutes at 55°C. Heating is stopped and the suspension is cooled to room temperature. The solid was collected by filtration and dried under vacuum for 4 hours to give the title compound. The mixture was obtained as crystals (1.72 g, 86%).

[0183] Example 7: Conversion of Form A to Form B Selpercatinib form A (152.0 g) was suspended in methanol (1.5 L) and incubated at room temperature. The suspension is stirred at 750 rpm at room temperature (approximately 20° C.) overnight. The solid is vacuum The solids are dried under full house vacuum with a nitrogen purge at 45°C. The title compound is obtained as crystals (148.28 g, 97.6%).

[0184] Example 8: Conversion of Form A to Form B Stir selpercatinib form A in methanol (8 mL / g) at room temperature for 18–24 h. Filter and isolate the solids. Mix under vacuum at 45°C with a slight N2 purge. The solid is dried.

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

[0186] Example 10: Synthesis of Form B [ka] This synthetic route to Form B of the compound of formula I (i.e., selpercatinib) comprises the steps of compound t ert-Butyl-3-[5-[3-cyano-6-(2-hydroxy-2-methylpropoxy) C) Pyrazolo[1,5-a]pyridin-4-yl]-2-pyridyl]-3,6-diazabi Optional synthetic route to produce cyclo[3.1.1]heptane-6-carboxylate [2] may include.

[0187] Add methanol to a three-necked round-bottom flask equipped with an overhead stirrer, condenser, and thermocouple. ethanol (200 mL, 100%) and acetyl chloride (3.1 mL, 44 mmol, 100%) ) is added. The mixture is cooled to 0°C and cooled to 0°C. 2-methyl-2-propoxy)pyrazolo[1,5-a]pyridin-4-yl]-2-pyrazolo[1,5-a]pyridin-4-yl Lysyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [2 ], (9.9965 g, 19.81 mmol, 100%) was added and allowed to react. During the addition, the reaction is heated to about 60° C. (63° C.). The temperature is monitored to determine the amount of observable off-gassing. and adjusted to avoid possible overdrive of the attached condenser The reaction was assayed to determine complete conversion (approximately 2 hours) and then the solvent was removed. Acetonitrile (ACN) (approximately 100 mL) was added to rinse the sides of the reaction vessel. The solvent mixture was again removed and kept under a nitrogen atmosphere.

[0188] Add additional ACN (300 mL, 100%) and hexamethyldisilazane ("H Add 25 mL of MDS (119 mmol, 100%). Before sampling, stir at ambient temperature for about 1 hour and add about 1.6% of the mixture based on the amount of [2]. The title compound is produced. The reaction is allowed to proceed overnight at ambient temperature. Sampling of the overnight reaction The mixture is then heated to 40° C. and sampled after 1 hour at that temperature. Heating increases the temperature to 56°C. During the temperature increase, the mixture refluxes and bubbles, which indicates After about 1 to 1.25 hours at that temperature, the reaction Take samples and allow the reaction to continue to reflux observably. Hold the reaction at temperature for an additional 3 hours. The reaction solvent was removed and an aqueous potassium carbonate solution (100 mL, 5 0.45 mmol, 5% by weight was slurried in a reaction vessel. The resulting mixture was added to water (2 5 mL) and dried to give 7.89 g of the title compound [3] (78% yield). (Mass spectrometry, m / z=477.20, 477.30(M+H). 1 H NMR(400 MHz, (DMSO-d6)d:8.55(s,1H), 8.06(d,1H), 7.8 2(dd,1H), 7.66(dd,1H).

[0189] Alternative process. A reaction vessel equipped with an overhead stirrer, condenser, and thermocouple was rt-Butyl 3-[5-[3-cyano-6-(2-hydroxy-2-methyl-propoxy ) Pyrazolo[1,5-a]pyridin-4-yl]-2-pyridyl]-3,6-diazabicin Chloro[3.1.1]heptane-6-carboxylate [2] (9.9965 g, 19. 81 mmol, 100%), and p-toluenesulfonic acid (2.1 equiv.) in 10 volumes of The mixture was allowed to react for 1 hour, after which pyridine (2.1 equiv.) and hexane were added. 6 equivalents of dimethyldisilazane ("HMDS") are added. The reaction mixture is stirred for an additional hour. Stir to give the title compound [3]. [ka]

[0190] In a reaction vessel equipped with a magnetic stirrer, add 4-[6-(3,6-diazabicyclo[ 3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethyl (phenylsilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile[ 3] (0.9981 g, 2.094 mmol, 100% by mass), 6-methoxy-3-pyridyl Nicotinic acid aldehyde (i.e., 6-methoxynicotinaldehyde, 0.4909 mg, 0.003401 mmol, 95% by mass), pivalic acid (0.5328 mg, 0. 005217mmol, 100% by mass), anisole (10mL, 91.8mmol, 1 00% by weight) and stir to form a slurry. Heat with stirring until the solution cools to ambient temperature and remains homogeneous. Once cooled, add sodium triacetoxyborohydride (1.0840 g, 5.11 47 mmol, 100% by weight was added and reacted. After 2 hours, the reaction was analyzed as shown in the table. The formation of the TMS-protected derivative of the compound was demonstrated.

[0191] After completion of the reaction, the process can be continued to remove the TMS protection and crystallize Form B. The mixture was added with water (1 mL, 55.5099 mmol, 100% by weight) and tetrafluoroethylene. Tributylammonium trihydrate (0.6070 g, 2.322 mmol, 100% by weight) and optionally an amount (about 10 mg) of seed crystals of the title compound as Form B, Add to the mixture. If no crystals are observed after a while, warm the mixture to 50°C. The elevated temperature can be maintained overnight, after which the reaction is sampled and checked for completion. No crystallization was observed. The pH of the mixture (slightly acidic) was adjusted to 1.0. The pH was adjusted by the addition of potassium hydroxide (5% by weight in water) until the observed bubbling ceased and the pH test The mixture was stirred overnight and then diluted with water. Cyclization afforded the title compound free of detectable impurities in 54% overall isolated yield. (Mass spectrometry, m / z = 526.30 (M+H). 1 H NMR (400 MHz, D MSO-d6d:8.55(s,1H), 8.06(d,1H), 7.82(dd,1H ), 7.66(dd,1H)

[0192] Alternative process. In a reaction vessel equipped with a magnetic stirrer, add 4-[6-(3,6-diphenyl Azabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl -2-Trimethylsilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3- Carboxynitrile [3] (1.00 g, 2.10 mmol), 6-methoxy-3-pyridine Carboxyaldehyde (1.6 equivalents), pivalic acid (approximately 5 volume equivalents), triacetoxy water Sodium borohydride (2.5 equiv.), anisole (10 mL, 91.8 mmol, 10 0% by weight) and react for about 1 hour. Add water (10 mL) to the reaction mixture. The mixture was filtered through Celite (diatomaceous earth, filter aid). The organic layer was diluted with saturated sodium chloride. Add 5N HCl (10 mL) to the organic layer and separate the layers. 1 mL) is added. The mixture is heated at 95° C. for 3 hours. After the reaction, the pH of the mixture (acidic ) is adjusted to pH 9 by the addition of potassium carbonate. The mixture is cooled and allowed to crystallize. The resulting crystals of selpercatinib form B were filtered and purified by methyl tert-butyl ether ( MTBE) and dried to give the pure title compound.

[0193] Example 11 The physical and chemical stability of Form B is not only to ensure solubility and dissolution. Not only for API and dosage form drug development and manufacturing operations (drying, storage, distribution, etc.) This is an important attribute: all crystalline forms have the necessary stability to enable drug development. A crystal form that is stable to both temperature and humidity is desired. To evaluate the stability of the crystalline form of Form B, accelerated stability studies are performed. 0 mL scintillation vial and stored at the temperatures and temperatures specified in Table 4. Place in a bell jar (open dish) with a saturated salt solution in an oven for 1 hour. Form B was analyzed before and after the accelerated stability test, and a CuKα source (wavelength = 1.54056A) and Equipped with a Linxeye detector, operated at 40 kV and 40 mA, with a 0.2 mm divergence slit Each sample was collected on a Bruker D8 Advance XRPD equipped with Scans from 4° to 30° 2θ in 0.02° steps at a speed of 0.2 seconds per step Assays for starting materials and impurities were performed using an Agilent HPLC system equipped with a diode array detector. The samples were evaluated using an ent1260 HPLC system. Prepared at appropriate concentrations in 0.1% TFA in 1% TFA / ACN, the following HPLC C condition: Column Zorbax Bonus-RP, 75x4.6mm id , 3.5 microns, mobile phase A was 0.1% TFA in water, mobile phase B was 0.1% in ACN of TFA, gradient was 95% A at time 0, 23% A from time 9.5 to 12.1 min. A, 5% A at time 13–16 min, flow rate of 1.5 mL / min, time 16.1–20 min A column temperature of 30 °C, a UV detection wavelength of 210 nm, and an injection volume of 3 μL were used. The stability of Form B has been characterized and its chemical and physical properties have been evaluated under the test conditions. It can be seen that the results are generally stable (Table 4). [Table 4]

[0194] Example 12: Solubility Solubility studies have been completed on the crystalline forms of selpercatinib described herein. In their study, aqueous media covering the physiological pH range and three simulated fluids were used. A sufficient amount of solid compound was added to saturate the volume of the solvent, approximately 1 mL. The samples are weighed into a container containing the solvent. After equilibration, the samples were transferred to a centrifugal filter (Durapore The plate was transferred to a PVDF (pore size 0.22 μm) and rotated at 10,000 rpm while maintaining the temperature at 37°C. Centrifuge for 3 minutes. Then take an aliquot of 100 μL from each sample and mix it in 900 μL. Dilute with 50:50 acetonitrile:water. The pH of the filtrate was measured using a calibrated scientific pH apparatus. The compound solution concentrations are recorded using an Agilent Zorbax Bon Using a US-RP 4.6x75mm, 3.5μm column, the following conditions: temperature 30℃ , injection volume 4 μL, UV detection at 238 nm, flow rate 1.5 mL / min The autosampler temperature was 25°C, and mobile phase A was 0.1% trifluoroacetate in water. mobile phase B is 0.1% trifluoroacetic acid in acetonitrile; As determined by HPLC below, the HPLC gradient is as follows: 0 min - 95% of A, 5% of B; 9.5 min - 23% of A, 77% of B; 12.1 min - 23% of A, 77% B; 13 min - 5% A, 95% B; 16 min - 5% A, 95% B; 16.1 1 min - 95% A, 5% B; 20 min - 95% A, 5% B. The table below (Table 3) shows the results of two Table 5 details equilibrium solubility data and equilibrium pH reported as averages for sample preparation. The solid morphology of the residual solids from the centrifuged samples was verified by XRPD as shown in . [Table 5]

Claims

1. A crystal of selpercatinib, characterized in that it has an x-ray powder diffraction (XRPD) pattern having characteristic peaks occurring at 7.5°, 10.9°, 12.0°, 13.2°, 17.1°, 17.7°, 18.2°, 19.8°, 21.1° and 24.5°±0.2° 2θ when measured using an x-ray wavelength of 1.5418 A.

2. A pharmaceutical composition comprising the crystal of selpercatinib described in claim 1 and a pharma- ceutically acceptable carrier, diluent or excipient.

3. The pharmaceutical composition described in claim 2, wherein the composition contains less than 20% by weight of other crystal forms of selpercatinib.

4. The pharmaceutical composition described in claim 2, wherein the composition contains less than 10% by weight of other crystal forms of selpercatinib.

5. The pharmaceutical composition described in claim 2, wherein the composition contains less than 5% by weight of other crystal forms of selpercatinib.

6. A pharmaceutical composition described in any one of claims 2 to 5 for use in the treatment of cancer.

7. The pharmaceutical composition described in claim 6, wherein the cancer is selected from the group consisting of lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN 2A or MEN 2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer.

8. The pharmaceutical composition described in claim 7, wherein the cancer is medullary thyroid cancer.

9. The pharmaceutical composition described in claim 7, wherein the cancer is lung cancer, and the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiolocarcinoma, RET fusion lung cancer, or lung adenocarcinoma.

10. The pharmaceutical composition described in claim 9, wherein the cancer is RET fusion lung cancer.

11. A process for producing crystals of selpercatinib according to claim 1, comprising: (a) suspending selpercatinib in a solvent comprising methanol; (b) heating the suspension to 50° C. to 60° C. with stirring for 30 to 90 minutes; (c) removing heat and allowing the suspension to cool to room temperature to form solid crystals; (d) recovering the solid crystals. A process including.

12. A method for converting crystals of serpercatinib form A to crystals of serpercatinib form B as described in claim 1, comprising combining crystals of serpercatinib form A with a C1-C5 alcohol to produce a slurry; and isolating crystals of serpercatinib form B from the slurry.

13. The method of claim 12, wherein the C1-C5 alcohol is at 10° C. to 30° C., and the C1-C5 alcohol comprises methanol.

14. The method of claim 12 or 13, wherein the C1-C5 alcohol comprises at least 90% by weight of methanol.

15. A method for converting crystalline selpercatinib form A to crystalline selpercatinib form B, comprising: a. dissolving the crystals of selpercatinib form A in a solvent comprising DMSO to form a solution; b. adding water to the solution, thereby forming a slurry; c. isolating the crystals of selpercatinib form B; The method includes:

16. The method of claim 15, wherein the concentration of the crystals of Form A dissolved in DMSO is 10-15 mL / g.

17. The method of claim 15, wherein the concentration of the crystals of Form A dissolved in DMSO is 12-13 mL / g.

18. The method of any one of claims 15 to 17, wherein forming the solution in step a comprises heating the crystals of selpercatinib form A and a solvent containing DMSO to 50°C to 70°C.

19. The method of claim 15, wherein the solution is cooled to a temperature below 70°C and above 20°C.

20. The method of any one of claims 15 to 19, wherein step b comprises adding 0.1 to 1 mL of water per gram of form A crystals to the solution.

21. The method of any one of claims 15 to 20, wherein step b comprises adding 0.3 mL of water per gram of form A crystals to the solution.

22. The method of claim 15, wherein step b further comprises adding 1 to 15% by weight of seed crystals of form B.

23. The method of claim 15, wherein after the water is added in step b, the slurry is stirred for 6 hours to 72 hours.

24. The method of claim 15, wherein step b further comprises adding a second aliquot of water to the slurry.

25. The method of claim 24, wherein 0.5 to 3 mL of water per gram of form A crystals is added to the slurry.

26. The method of claim 15, wherein the slurry of step b is cooled to 20 to 30°C.

27. The method of any one of claims 15 to 26, wherein the isolated crystals of selpercatinib form B from step c are washed with a solvent comprising methanol, ACN, MTBE, or water.

28. The method of claim 27, wherein the isolated crystals of selpercatinib form B are washed with methanol until the isolated crystals of selpercatinib form B contain less than 0.5% by weight of DMSO.

29. A method for converting crystalline selpercatinib form A to crystalline selpercatinib form B, comprising: combining crystals of selpercatinib form A with methanol to form a slurry; agitating the slurry until >99 wt. % of the Form A crystals are converted to Form B crystals. Including, The concentration of the crystals of selpercatinib form A in the methanol is 8 mL / g. method.

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

31. The method of claim 30, wherein 5 wt. % seed crystals of form B are added to the mixture.

32. The method of claim 30 or 31, wherein the first water addition is from 0.1 mL / g of form A crystals to 0.5 mL / g of form A crystals.

33. The method of any one of claims 30 to 32, wherein the second water addition is 1.0 to 1.5 mL / g of crystals of form A.

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