Crystalline RET inhibitors

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] Serpercatinib (LOXO-292 or RETEVMO®) is used to treat metastatic RET Patients with fusion-positive NSCLC, RET-mutated medullary thyroid carcinoma, and RET-fusion-positive thyroid cancer. It is a RET inhibitor approved in the United States for use in the treatment of [condition]. Serpercatinib, Or 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methylpropoxy Cypyridine-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3 -yl)pyridine-3-yl)pyrazolo[1,5-a]pyridine-3-carbonilicate is It has the following chemical structure. [ka]

[0002] U.S. Patent No. 10,584,124 describes a cerupon containing a crystalline form called "Form A". While several crystalline forms of lukatinib are described, a new, thermodynamically more stable crystal is described. The form and method for producing this crystalline form are disclosed herein. The form can be incorporated into formulations such as tablets, capsules, and suspensions, providing benefits to the patient. . [Overview of the Initiative]

[0003] This disclosure describes a new crystalline form of serpercatinib, referred to as "Form B" throughout. This disclosure relates to a method for producing this thermodynamically stable polymorph. In a general sense, this disclosure is a means of producing this thermodynamically stable polymorph. The present invention provides methods for the preparation, isolation, and characterization of [the substance].

[0004] As will be explained in more detail below, the compound of formula I (serpercatinib) has polymorphic forms ( It can be provided in forms A and B), and surprisingly, serpercatinib is the most hot To provide a mechanically stable polymorph B, specific processes and methods are effective. As demonstrated by the exemplary examples described below, serpercatinib is used in specific cases. Processes and methods for generating and preparing polymorphic forms, for generating form B or other polymorphic forms Under crystalline conditions that are effective in converting (i.e., form A) to form B, one or more polymorphs To transform (i.e., react, contact, and) the compound of formula I provided in form This may include (scalding / processing). In other embodiments, it may include generating form B of serpercatinib. The process and method for producing serpercatinib form B is under conditions that are effective in generating serpercatinib form B. , a synthetic route that involves reacting one or more intermediate or precursor compounds (i.e., directly (May include synthetic pathways.)

[0005] Form B is measured at (a) 21.1° when using an X-ray wavelength of 1.5418A. The peak and one or more peaks at 17.1°, 17.7°, and 19.8°±0.2°²θ X-ray powder diffraction (XRPD) patterns including (b) 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (each ±0.2 ppm) ) includes a peak based on the high magnetic resonance of adamantane (δ=29.5 ppm). nothing 13 Characterized by at least one of the following: 13C solid-state NMR spectrum.

[0006] Form B and its pharmaceutical composition can be used to treat cancers with abnormal RET expression (e.g., thyroid cancer). We also offer treatment methods for cancers such as medullary carcinoma or RET-associated cancers (RET-fusion lung cancer, etc.). It is carried out. This method includes administering a therapeutically effective amount of Form B to a patient who requires it.

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

[0008] For treating cancer, in particular, the use of Form B in the manufacture of a medicament for use in the treatment of cancers associated with abnormal RET expression (such as medullary thyroid cancer or RET fusion lung cancer, such as RET-related cancers) is also provided herein. .

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

[0010] A method for converting selpercatinib Form A to selpercatinib Form B, comprising combining selpercatinib Form A with a C1-C5 alcohol to form a slurry, and isolating selpercatinib Form B from the slurry, is also detailed herein. . .

[0011] A method for converting selpercatinib Form A to selpercatinib Form B, this method being a. Dissolving selpercatinib Form A in a solvent containing DMSO to form a solution, and , b. Adding water to the solution to thereby form a slurry, and c. Isolating selpercatinib Form B, is also described.

[0012] Furthermore, a method for converting serpercatinib morph A to morph b, wherein the method is serpercatinib Combining tinib form A with methanol to form a slurry, and form A >9 The method also includes stirring the pre-slurry until 9% by weight is converted to form B. It will be done.

[0013] Another method described herein is a method for converting serpercatinib form A to form B. Then, dissolve serpercatinib form A in DMSO at approximately 60-80°C, and prepare 1 gram of form A. Form a solution with a DMSO concentration of approximately 10-15 mL / g per unit, and then dissolve the solution in approximately 40-60 ml. Cool to 0°C, add water, and optionally sow seed crystals of form B into the resulting mixture. Stir the mixture, add water, heat the mixture to approximately 60-80°C, and then cool the mixture. Form B is isolated.

[0014] Serpercatinib as polymorph B of formula I, [ka] or a process for preparing the pharmaceutically acceptable salt thereof, This process involves compounds with the following structure: [ka] Or a salt thereof, an acid used to prepare serpercatinib form B or a pharmaceutically acceptable salt thereof, and This involves reacting in a solvent containing 6-methoxynicotinaldehyde in the presence of a reducing agent. The process is also described.

[0015] 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyri [zyl]-6-(2-methyl-2-trimethylsilyloxy-propoxy)pyrazolo[1, 5-a] A compound that is pyridine-3-carbonitride, with structure [3], [ka] Compounds having a pharmaceutically acceptable salt thereof are described herein. [Brief explanation of the drawing]

[0016] [Figure 1] This is an overlay of XRPD data for morphology A and morphology B with a maximum of approximately 26° 2-theta (2θ). [Figure 2] This includes 13C solid-state NMR data for morphology A and morphology B, and an overlay of approximately 25–60 ppm comparing morphology A to morphology B. [Modes for carrying out the invention]

[0017] Serpercatinib form B is described herein. This crystal of serpercatinib The form is a disorder associated with abnormal RET activity, such as IBS or cancer, in particular, excessive RE It can be used to treat cancers caused by T signaling (i.e., RET-associated cancers). More specifically, this crystalline form of serpercatinib is used in lung cancer (e.g., small cell lung cancer). (or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma, etc.) Differential thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine cancer Adenoma, lung adenocarcinoma, bronchiololung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (each, MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer (breast cancer) Ancer, breast cancer, breast cancer Arcinoma, breast tumors, colorectal cancer (e.g., metastatic colorectal cancer), papillary Renal cell carcinoma, gangliomatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer, etc. It may be used to treat RET-related cancers.

[0018] When morphology B is measured using an X-ray wavelength of 1.5418A, the peak at 21.1° is observed. And one or more peaks at 17.1°, 17.7°, and 19.8°±0.2°²θ Characterized by having an X-ray powder diffraction (XRPD) pattern that includes, State B also has values ​​of 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 At ppm (each ±0.2 ppm), the high magnetic resonance (δ=29) of adamantane was observed. Includes a peak relative to 5 ppm. 13 The solid-state NMR spectrum of 13C is shown.

[0019] When morphology B is measured using an X-ray wavelength of 1.5418A, the peak at 21.1° is observed. And, 7.5°, 12.0°, 13.2°, 17.1°, 17.7°, and 19.8°± The X-ray powder diffraction (XRPD) pattern includes one or more peaks at 0.2°2θ. It can be further characterized by doing so.

[0020] Additionally, if morphology B is measured using an X-ray wavelength of 1.5418A, then 21.1 Peaks at °, and at 7.5°, 10.9°, 12.0°, 13.2°, 17.1°, and 17. 1 Having an X-ray powder diffraction (XRPD) pattern that includes one or more peaks is a distinctive feature. It can be marked.

[0021] Form B is 26.4, 28.0, 42.0, 43.9, 48.0, 56.3, 69.5 80.4, 102.3, 106.8, 115.2, 120.8, 130.2, 134. 9, 140.6, 149.5, 152.5, and 163.5 ppm (each ±0.2) In ppm, the P-value is based on the high magnetic resonance (δ=29.5 ppm) of adamantane. Includes 13 It can be further characterized by 13C solid-state NMR spectroscopy.

[0022] Furthermore, for form B, the values ​​are 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), One or more peaks including damantan's high magnetic resonance (δ=29.5 ppm) as reference. It can be further characterized by 3C solid-state NMR spectroscopy.

[0023] A pharmaceutical comprising form B and one or more pharmaceutically acceptable carriers, diluents, or excipients. Compositions are also described herein.

[0024] Pharmaceutical compositions containing form B are less than other crystalline forms of serpercatinib. 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% It contains form B in amounts of 95%, 96%, 97%, 98%, 99% by weight or 100% by weight. Alternatively, the pharmaceutical compositions described herein consist of at least 80% form B and less than 20% of other forms. The pharmaceutical composition comprises celpercatinib in crystalline form. More preferably, the pharmaceutical composition comprises at least 9 It contains 0% morphology B and less than 10% of other crystalline forms of serpercatinib. More preferably Alternatively, the pharmaceutical composition contains at least 95% of form B and less than 5% of other crystalline forms of cerup. It contains lucatinib. More preferably, the pharmaceutical composition contains at least 97% form B. The pharmaceutical composition comprises less than 3% of celpercatinib in other crystalline forms. More preferably, the pharmaceutical composition , with at least 98% or 99% of morphology B and less than 2% or 1% of other crystalline forms, respectively. Contains serpercatinib.

[0025] Form B involves treating cancer by administering an effective dose of Form B to patients who need it. It may be used in methods for doing so. It may be treated using the methods described herein. The types of cancer include blood cancers or solid tumor cancers. They can be treated using morphology B. Examples of cancer types 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 (and These include MEN2A or MEN2B, pheochromocytoma, parathyroid hyperplasia, breast cancer, and colorectal cancer. Examples include papillary renal cell carcinoma, ganglioneuroma of the gastrointestinal mucosa, and cervical cancer. Specifically, the type of cancer could be lung cancer or thyroid cancer. More specifically, cancer is non It could be small cell lung cancer or medullary thyroid carcinoma.

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

[0027] Form B is for the manufacture of pharmaceuticals for the treatment of RET-related diseases or disorders such as IBS or cancer. It may be used for cancers that can be treated with such drugs, as described herein above It is stated that the use of form B in the manufacture of pharmaceuticals also involves biological samples from patients. Perform an in vitro assay using the RET gene, RET kinase, or related products. Determine the presence of dysregulation in the expression, activity, or level of any of the RET genes. Dysregulation of the expression, activity, or level of RET kinase, or any of them. If present, the step may include administering a therapeutically effective dose of form B to the patient. In use, the biological sample may be a tumor sample, and the tumor sample is a genome / DNA sequence. It can be analyzed using methods known to those skilled in the art, such as determination. Furthermore, these uses Therefore, samples can be obtained from patients before the first dose of form B. In use, as described herein, the therapy involves the patient having the RET gene, RETkiner At least one of the following: dysregulation of the expression, activity, or level of ze, It may be based on the fact that it is selected for treatment. Also, the use of these Form B can be administered to patients at doses of approximately 1 mg / kg to 200 mg / kg (effective). The sub-ranges of the doses are described above in this specification.

[0028] In this specification, a patient is a patient who has been diagnosed with RET fusion or RET mutation. Therefore, the term "determine RET fusion or RET mutation" means RET fusion or This means determining whether a RET mutation exists. RET fusion or RET Methods for determining whether a mutation exists are known to those skilled in the art, for example, Wan g,Yucong et al.,Medicine2019;98(3):e1412 Please refer to 0.

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

[0030] "Pharmacologically acceptable carriers, diluents, or excipients" are biologically acceptable to mammals, such as humans. A medium that is generally accepted in the art for the delivery of scientifically active drugs. .

[0031] Terms such as "treatment," "to treat," and "the act of treating" imply that the progression of the disability will be slowed. This includes stopping or reversing. These terms also mean, Even if the fault or condition is not actually eliminated, and the progression of the fault or condition itself is delayed or reversed Even if not cured, one or more symptoms of the disorder or condition may be alleviated, remission, reduction, or elimination. or reduce.

[0032] "Effective dose" is determined by the treating clinician based on the patient's biological or medical response or the patient's condition. This refers to the amount of crystalline form of serpercatinib that induces the desired therapeutic effect. Furthermore, the crystalline form of serpercatinib can be determined by in vitro or ex vivo RET enzyme assay. It inhibits natural RET signaling. In another example, cerpercatinib crystals The morphology is that of the natural RET signal in whole blood of mice treated with different doses of the compound. It inhibits transmission.

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

[0034] The effective dose can be determined by a physician as skilled in the art, using known techniques, and similar methods. The effective dose for the patient can be easily determined by observing the results obtained under the given conditions. When making a decision, the diagnosing physician considers numerous factors, including the patient's... Race; patient's size, age, and overall health status; specific disease or disorder involved; disease or the degree or involvement or severity of the disability; the response of individual patients; the specific compounds administered; Mode of administration; characteristics of the bioavailability of the administered preparation; selected administration regimen; accompanying information. This includes, but is not limited to, the use of drugs; as well as other related circumstances.

[0035] Form B preferably involves the biological transmission of the compound via an oral, intravenous, and transdermal route. It is formulated as a pharmaceutical composition to be administered via any route that makes it readily available. Preferably, such compositions are for oral administration. Such pharmaceutical compositions and they The process for preparing is well known in the art. (For example, Remin gton:The Science and Practice of Pharmac y(DBTroy,Editor,21st Edition,Lippincott See t. Williams & Wilkins, 2006.

[0036] As used herein, “granular composition” means a composition in granular form, which is In the pharmaceutical manufacturing process, it is a composition that serves as a precursor to pharmaceutical compositions.

[0037] As used herein, "manufacturing container" is used in the manufacture of pharmaceuticals, but is not used in the pharmaceutical manufacturing process. This refers to containers not used in academic laboratories. An example of a manufacturing container is a hopper collector. , beds, dryer beds, granulator beds, dryer trays, granulator buckets, and mixing Examples include, but are not limited to, bowls for general use.

[0038] In some embodiments, the material of form B is prepared from the material of form A. So, the method for converting morphology A to morphology B is to use serpercatinib to convert morphology A to C1-C5 alcohol The process involves combining it with other ingredients to generate a slurry, and extracting selpercatinib morph B from the slurry. This includes separating. In some embodiments, the method involves about 10-80°C and about 10-30°C. It is executed at a temperature of approximately 15-25°C, or approximately 20°C.

[0039] In some embodiments, the C1-C5 alcohols include methanol. Preferred C1 ~C5 alcohols include methanol, and in some embodiments, methanol is present in small amounts. Each is approximately 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 involves combining serpercatinib form A with water to produce a slurry. This includes making the necessary steps and isolating serpercatinib form B from the slurry. In this embodiment, the method is performed at approximately 10-80°C, approximately 10-30°C, approximately 15-25°C, or It runs at a temperature of approximately 20°C.

[0041] In some embodiments, the method is performed for a period of time starting from at least about 5 minutes (for example) If so, at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, or at least 60 (minutes), including stirring, mixing, or agitating the slurry. Several implementations In this state, the certain period can be about 8 to 12 hours. In some further embodiments, The duration is at least 10 minutes.

[0042] In some embodiments, the method involves the serpercatinib form B produced by the method. This may further include isolation. In some embodiments, isolation may include vacuum filtration. In some embodiments, isolation may involve centrifugation.

[0043] In some further embodiments, the method involves drying the generated selpercatinib form B. This may further include drying. Drying can be achieved using vacuum and / or thermal means.

[0044] In other embodiments, the method involves dissolving cerpercatinib form A in a solvent containing DMSO. Forming a solution, adding an amount of water to the solution to form a slurry, and the slurry This includes isolating serpercatinib morph B, which is generated within the substance.

[0045] In some embodiments, the method involves adding about 1 gram of serpercatinib form A to about 10-1 This includes adding it to 5 mL / g of DMSO. In some further embodiments, the method is Adding approximately 1 equivalent of serpercatinib to approximately 12-13 mL / g of DMSO Therefore, the concentration of form A dissolved in DMSO is approximately 12-13 mL of DMSO. The internal volume of Form A is approximately 12-13 mL / g or 1 g.

[0046] In some embodiments of this method, a solution comprising DMSO and serpercatinib form A is used. Formation is achieved by heating a solvent containing cerpercatinib form A and DMSO at approximately 50°C to 70°C. This includes heating to about 70°C and about 2 The method includes cooling the solution to a temperature above 0°C. In a further embodiment, the method involves cooling the solution to about 50°C. This includes cooling to a temperature of °C.

[0047] In some embodiments of this method, adding water is approximately 0 per gram of form A. This includes adding 0.1 to approximately 1 mL / g of water to the solution. In some further embodiments, Adding water means adding approximately 0.3 mL / g of water per gram of form A to the solution. Includes.

[0048] In some embodiments of this method, the addition of water is in the form of about 1 to about 15% by weight. The further embodiment may include adding seed crystals of B to the slurry. Approximately 1 to 10 wt% of seed crystals of form B may be added to the slurry. Further implementation In terms of morphology, approximately 5 wt% of seed crystals of morphology B may be added to the slurry.

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

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

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

[0052] In some embodiments, isolation of cerpercatinib form B includes filtration. In the embodiment, isolated cerpercatinib form B is treated with methanol, ACN, MTBE, Alternatively, it may be washed with a solvent containing water. In some further embodiments, isolated cerupes Lucatinib form B is washed with a solvent containing methanol. In further embodiments, isolation The serpercatinib form B was isolated until it contained less than 0.5% by weight of DMSO. Wash the prepared serpercatinib form B with methanol.

[0053] In some of the above aspects and embodiments, the Disclosure relates to serpercatinib form A as form B A method for converting to , which involves combining serpercatinib type A and methanol. Forming a rally and stirring the slurry until >99% by weight of morph A is converted to morph B. The present invention provides a method that includes mixing. In some embodiments of the method, the slurry is approximately Stir for 18-24 hours. In further embodiments, the cerpercatinib form in methanol is used. The concentration of state A is approximately 8 mL / g.

[0054] In some of the above aspects and embodiments, the Disclosure relates to serpercatinib form A as form B A method for converting serpercatinib form A to DMSO at approximately 60-80°C. When dissolved, it produces a form A with a DMSO concentration of approximately 10-15 mL / g per gram of form A. Prepare a solution, cool the solution to approximately 40-60°C, add a first amount of water, and optionally select Next, seed crystals of form B are planted in the resulting mixture, the mixture is stirred, and a second amount of water is added. The method involves heating the mixture to approximately 60-80°C, cooling the mixture, and isolating form B. Provided. In some embodiments of the method, 5% by weight of seed crystals of form B is added to the mixture. In further embodiments, the first addition of water is approximately 0.1 mL / g of form A to form A is approximately 0.5 mL / g. In further embodiments, the addition of a second water is approximately A The concentration is 1.0 to 1.5 mL / g.

[0055] In another aspect, the present disclosure relates to serpercatinib as polymorph B of formula I, [ka] or a process for preparing a pharmaceutically acceptable salt thereof, wherein the process is as follows: Compounds of structure, [ka] Alternatively, react the salt thereof with 6-methoxynicotinaldehyde in a solvent in the presence of an acid and a reducing agent. The process involves preparing serpercatinib form B or a pharmaceutically acceptable salt thereof. Provide. A stoichiometric amount of acid may be used, but non-stoichiometric amounts are also acceptable. Structure [3] Therefore, oxygen has a TMS group. Although not explicitly stated, other alcohol protecting groups may be used. It is understood that it may be used. In addition to TMS as described herein. Other silyl groups can be used.

[0056] In some embodiments of this model, the process involves a compound of structure [3], or a salt thereof. Further comprising preparing a compound having the following structure: [ka] Alternatively, a salt thereof (wherein R1 is an amine protecting group) can be reacted with a deprotecting agent to obtain structure [3] It forms a compound or a salt thereof.

[0057] In some applications, the deprotecting agent is trifluoroacetic acid, hydrochloric acid, hydrobromic acid, or iodide. Hydrogen acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, tri Selected from the group consisting of aluminum chloride and boron trifluoride. Several further practical applications In terms of application methods, the deprotecting agent is a group consisting of sulfuric acid, p-toluenesulfonic acid, and acetyl chloride. Selected from.

[0058] In some embodiments, the reducing agent is alkali metal borohydride, hydrazine compounds, Citric acid, citrate, succinic acid, succinate, ascorbic acid, and ascorbate Selected from the group consisting of. In some further embodiments, the reducing agent is triacetoxy Sodium borohydride (STAB), sodium borohydride, and boro cyanohydride It is selected from the group consisting of sodium particles.

[0059] In some applications, R1 is formyl, acetyl, trifluoroacetyl, ben Zyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzyl Rubonyl, tert-butyloxycarbonyl (Boc), trimethylsilyl, 2-tri Methylsilyl-ethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl Lu, 9-Fluorenylmethyloxycarbonyl, Nitroveratryloxycarbonyl, p -Selected from the group consisting of methoxybenzyl and tosyl. In some embodiments, R1 is tert-butyloxycarbonyl (Boc).

[0060] In some embodiments, the acid is selected from the group consisting of pivalic acid and acetic acid. In a further embodiment, the acid is pivalic acid. In a further embodiment, a catalytic amount is used. 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 relates to the compound 4-[6-(3,6-diazabicyclo[ 3.1.1]Heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethicone) Lucilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile, [ka] Or provide a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, this disclosure is constructed according to the aspects and embodiments described herein. The present invention provides a method for preparing the compound [3].

[0064] In some embodiments of the above-described model, the method involves using a free amine as the cellulite. This includes preparing catinib form B.

[0065] Serpercatinib morph A (morph A) is a thermodynamically more stable polymorph of serpercatinib. It may contain a portion of state B (form B). Both polymorphic forms are crystalline, high melting point, anhydrous, and stable. While these polymorphs do not interconvert under normal storage or preparation conditions, they are different. It has characteristics and features that allow us to distinguish form A from form B. Form B is thermal Since it is mechanically more stable, we need to understand how to transform morphology A into morphology B.

[0066] definition Unless otherwise defined, all technical and scientific terms used herein are defined in accordance with the present invention. It has the meaning generally understood by those skilled in the art to which it belongs. In addition, unless otherwise specified, the following terms shall have the same meaning as the following terms.

[0067] As used herein, the term “polymorph” refers to the result of molecular order within a crystal lattice. This refers to crystals of the same compound that have different physical properties. A single compound (i.e., formula Different polymorphs of compound I are one or more different chemical, physical, mechanical, and electrical It has physical, thermodynamic, and / or biological properties. The physical properties shown by the polymorph The differences lie in 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 properties This affects pharmaceutical parameters such as physical stability, powder flowability, moisture adsorption, compressibility, and particle morphology. It is possible. The difference in stability is due to chemical reactivity (for example, when composed of one polymorph rather than another). When composed of polymorphs, the dosage form undergoes a more rapid change in color due to different oxidation (or mechanical change). Transformation (for example, when a kinetically favorable polymorph is transformed into a thermodynamically more stable polymorph) Changes in crystal structure during storage), or both (for example, one polymorph being more hygroscopic than the others) (i) This may be due to changes in solubility / decomposition. As a result of differences in solubility / decomposition, several changes may occur. The transfer affects the potency and toxicity. Furthermore, the physical properties of the crystal can be important in the process, for example. For example, one polymorph is likely to form a solvate, or impurities are filtered and washed away. It can be difficult to avoid including them (i.e., the shape and size distribution of the particles are different from others). (Compared to one polymorph, there may be differences between the two polymorphs.) Used in this specification In this context, "polymorph" does not include the amorphous form of the compound. In some specific embodiments, , polymorphs of the compound of formula I (i.e., serpercatinib form A and serpercatinib form B) includes the features described herein.

[0068] As used herein, "amorphous" means the solid state of a compound or the soluble state of a compound. This refers to the amorphous form of a compound that can exist in a chemical form. For example, "amorphous" means that the molecule or external plane is flat. This refers to compounds that lack a regular repeating arrangement of surfaces (for example, the solid form of a compound).

[0069] When used herein, the term "anhydrous" refers to the stoichiometric quantity related to the crystal lattice. This refers to the crystalline form of the compound of formula (I) that does not contain water. Typically, this includes anhydrous form A and anhydrous form B. It contains 1% by weight or less of water. For example, 0.5% by weight or less, 0.25% by weight or less, or It is water at a concentration of 0.1% by weight or less.

[0070] When used herein, the term "solvate" refers to a crystal lattice containing one or more solvents. This refers to the crystalline form of compounds containing formula (I).

[0071] The terms "hydrate" or "hydrated polymorph" refer to the polymorphic form of a compound in which the crystal lattice contains water. This refers to the crystalline form of compounds of formula (I), such as those shown above. Unless otherwise specified, the term "hydrate" is used. As used herein, the term refers to a “stoichiometric hydrate.” A stoichiometric hydrate is a… It contains water molecules as an essential part of the crystal lattice. In contrast, non-stoichiometric hydrates contain water. It contains water, but changes in water content do not cause significant changes in the crystal structure. Non-stoichiometric hydration During the drying process, a considerable amount of water can be removed without significantly disrupting the crystal network, Subsequently, the crystal can be rehydrated to yield the initial non-stoichiometric hydrated crystal form. Unlike stoichiometric hydrates, the dehydration and rehydration of non-stoichiometric hydrates do not involve a phase transition, therefore, non-stoichiometric hydrates All hydration states of stoichiometric hydrates represent the same crystal form.

[0072] When "purity" is used in reference to a composition containing polymorphs of the compound of formula (I), it refers to A particular polymorph or amorphous form of the compound of formula (I) in a composition This refers to the percentage of polymorphs. For example, a composition containing polymorph 1 with 90% purity. The substance consists of 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). Includes parts.

[0073] When used herein, if the compound or composition does not contain a significant amount of other components, The compound or composition “substantially does not contain” one or more such other components. The composition contains 5% by weight, 4% by weight, 3% by weight, 2% by weight, or less than 1% by weight of other components. It may contain. Such components include starting materials, residual solvents, or those provided herein. Other impurities may be present, which may result from the preparation and / or isolation of the compounds and compositions. In some embodiments, the polymorphic forms provided herein are substantially different from other polymorphic forms. Not included. In some embodiments, certain polymorphs of the compound of formula (I) are certain polymorphs If the compound of formula (I) in which the polymorph exists constitutes at least about 95% by weight, then other polymorphs "Substantially does not contain." In some embodiments, certain polymorphs of the compound of formula (I) are At least about 97% by weight, about 98% by weight, about If it constitutes 99% by weight, or approximately 99.5% by weight, it "substantially contains" other polymorphs. In certain embodiments, a particular polymorph of the compound of formula (I) is such that the amount of water is about 2 times the weight of the polymorph. If it constitutes %, approximately 1% by weight, or approximately 0.5% by weight or less, it is considered "substantially water-free."

[0074] As used herein, “substantially pure” means relating to the polymorphisms of the compound of formula (I). When used, based on the weight of the compound, 91%, 92%, 93%, 94% of the compound This includes percentages such as %, 95%, 96%, 97%, 98%, and 99%, as well as those equal to approximately 100%. This refers to a sample of polymorphic forms of a compound having a purity of over 90%, including more than 90%. The remaining material is derived from other forms of the compound, and / or reaction impurities and / or their preparation. It contains processed impurities. For example, polymorphs of the compound of formula (I) are currently known in the art. When measured by a known and generally accepted means, the combination of formula (I) The purity of the polymorphic form of the substance exceeds 90%, and the remaining less than 10% of the material is other components of the compound of formula (I). In that it contains form and / or reaction impurities and / or treatment impurities, it is substantially pure. It can be considered that the presence of reaction impurities and / or treatment impurities can be, for example, in chromatography. , analytical techniques known in the relevant field, such as nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy. It can be determined by the procedure.

[0075] To provide a more concise description, some of the quantitative expressions in this specification are approximate values ​​of X ~ approximate value The range of Y is listed. When a range is listed, the range is defined by its listed upper limit and It is not limited to the degree of approximation, but rather the entire range from approximation X to approximation Y, or any range within that range. include.

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

[0077] As used herein, the term “excipient” refers to an agent used to formulate a composition into a desired form. This refers to any necessary material. For example, suitable excipients include diluents or fillers, binders or compounding agents. Granules or adhesives, disintegrants, lubricants, anti-sticking agents, flow accelerators, dispersants or wetting agents, dissolution retarders The following are adsorbents or accelerators, buffers, chelating agents, preservatives, colorants, flavorings, and sweeteners. These are included, but not limited to.

[0078] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include biological Any solvent, co-solvent, complexing agent, or dispersion that is not academically or otherwise undesirable. This includes fertilizers, coatings, antibacterial and antifungal agents, isotonic agents and absorption retarders, etc. (Pharmaceutical) The use of such media and agents for active materials is well known in the art. Unless any conventional medium or agent is incompatible with the active ingredient, in therapeutic formulations Its use is intended. Auxiliary activators can also be incorporated into the formulation. In addition, various excipients commonly used in the relevant technical field may be included. For other such compounds, see the literature, e.g., Merck Index, Merck& The company, Rahway, NJ, states that various components are present in the pharmaceutical composition. For considerations regarding inclusion, see, for example, Gilman et al. (Eds.) (2010). ;Goodman and Gilman's: The Pharmacologica l Basis of Therapeutics,12th Ed.,The McG It is listed on raw-Hill Companies.

[0079] When used herein, the singular forms "a," "an," and "the" are also used in the context of the same meaning. Unless explicitly stated otherwise, it encompasses multiple targets.

[0080] When used herein, range and quantity may be expressed as "approximately" a specific value or range. The word "approximately" also includes the exact amount. Therefore, "approximately 5 grams" is not the same as "approximately 5 grams" or "5 grams". It also means "ram". Furthermore, the range expressed herein refers to integers and fractions within that range. It is understood that it includes numbers. For example, the range of 5 to 20 grams includes 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 grams, etc. Integer values, including but not limited to 5.25, 6.5, 8.75, and 11.95 grams. This includes fractions within an undefined range. The values ​​for DSC, TGA, TG, or DTA are... The preceding term "approximately" refers to the reported Celsius temperature with an acceptable variation of + / -5°C. .

[0081] When used herein, “as needed” or “as required” shall be followed by Whether or not the listed events or situations will occur, and whether the description of said events or situations will occur This means including examples of when it will happen and examples of when it will not happen. For example, "when necessary A reaction mixture that "contains a catalyst" means that the reaction mixture either contains a catalyst or does not contain a catalyst. It means...

[0082] As used herein, "strong base" refers to a base that deprotonates a weak acid in an acid-base reaction. This refers to basic compounds that can be converted into a base. Examples of strong bases include hydroxides, alkoxides, and This includes, but is not limited to, ammonia. A common example of a strong base is alkali gold. Hydroxides of the genus and alkaline earth metals, such as NaOH. Certain strong bases are insoluble in water. It can even deprotonate CH groups in very weakly acidic conditions. In the presence of a strong base, hydroxyl Sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, calcium hydroxide, This includes strontium hydroxide, lithium hydroxide, and rubidium hydroxide, but these Not limited to. In some embodiments, NaOH is used as a strong base. In this embodiment, potassium hydroxide is used as the strong base.

[0083] As used herein, the term "weak base" means only partially ionized in aqueous solution. This refers to inorganic and organic bases that are converted into weak bases. Weak bases typically have a pKa of about 6 to about 11. Many such weak bases are known, as described in the Handbook of Biochem. istry and Molecular Biology,Vol.1,3rd ed. ., GDFassman, CRC Press, 1976, pp. 305-347. Examples are provided by the enumerated items. Weak bases may 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 and other alkali metal carbonates; Primary amines; secondary amines; and tertiary amines such as trialkylamines, for example, methylamine, triethylamine, tripropylamine, and tributylamine, ben It contains dildiethylamine, pyridine, quinoline, N-methylmorpholine, aniline, etc. However, it is not limited to these.

[0084] As used herein, "non-nucleophilic base" refers to a base that does not act as a nucleophile, i.e., This refers to a base that does not donate electron pairs to electrophiles to form chemical bonds related to the reaction. Non-nucleophilic bases have protons that can bond to the basic center, but alkylation and Complexation is prevented by bulkiness and steric hindrance. Examples of non-nucleophilic bases include amines. and nitrogen heterocycles, for example, triethylamine and pyridine, amidine, lithium compounds, This also includes, but is not limited to, phosphazenes. Other examples of non-nucleophilic bases include: It contains sodium hydride and potassium hydride.

[0085] As used herein, the term “amine protecting group” means protecting an amine group This refers to any group known in the field 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). The following are included: Using any amine protecting group known in the art. It is possible. Examples of amine protecting groups include: (1) formyl, trifluoroacetyl, (2) phthalyl and acyl types such as p-toluenesulfonyl, (2) benzyloxycal Bonyl (Cbz) and substituted benzyloxycarbonyl, 1-(p-biphenyl)-1-methyl Thilethoxycarbonyl, and 9-Fluorenylmethyloxycarbonyl (Fmoc) Aromatic carbamate types such as (3) tert-butyloxycarbonyl (Boc) , ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl Aliphatic carbamate types such as (4) cyclopentyloxycarbonyl and Adamantine (5) Triphenylmethylcarbonyl and other cyclic alkylcarbamate types, Alkyl types such as (6) methylsilane and trialkyl types such as (6) trimethylsilane Lan, (7) phenylthiocarbonyl and dithiasuccinoyl thiol-containing types , and (8) alkyl types such as triphenylmethyl, methyl, and benzyl, and substituted aluminum such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl This includes kill type and trialkylsilane type such as trimethylsilane, These are not the only options.

[0086] As used herein, the term "deprotecting agent" refers to a reagent useful for removing a protecting group. Alternatively, it refers to a reagent system (reagent(s), and solvent). Deprotecting agents are acids, bases, or reducing agents. It is possible. For example, the removal of the benzyl (Bn) group can be achieved by reduction (hydrogen decomposition). To obtain the carbamate (e.g., Boc group), remove it by heating gently with an acid (e.g., For example, this can be achieved by using HCl, TFA, H2SO4, etc., and the removal of the silyl group is , weak acids or halides (e.g., tetra-n-butylammonium fluoride (TBAF)) By using fluorides (such as those provided by), optionally, gentle heating is required. It can be achieved.

[0087] As used herein, the term "reducing agent" generally means an agent that is itself oxidized. This refers to any species that can reduce another species while it is present. When used herein, "Oxidizing agent" or "oxidant" The term generally refers to any species that can oxidize another species while being reduced itself. It refers to.

[0088] As used herein, the term “triflate reagent” means that the triflate group This refers to compounds useful in reactions that bond to hydroxyl groups to form triflate esters. Triflate agents are sources of trifluoroacetyl groups. Triflate reagents include Trialkylsilyl triflate, trialkylstanyl triflate, triflic Anhydrous (trifluoromethanesulfonic acid anhydrous), N-phenyl-bis(trifluoromethanesulfonic acid anhydrous) Tansulfonimide (PhNTf2), N-(5-chloro-2-pyridyl)trifluid This includes, but is not limited to, mido and N-(2-pyridyl)trifluimide.

[0089] As used herein, "acrylonitrile derivatives" refers to a derivative in which one or more hydrogen atoms are located at the same time as another atom. Derived from acrylonitrile having the formula CH2CHCN, or substituted with a group It is a compound that can be used. An example of an acrylonitrile derivative is 2-chloroacrylonitrile. In acrylonitrile, one of the hydrogen atoms is replaced by a chlorine atom.

[0090] As used herein, the term “dilution” is used in reference to an acidic solution. This refers to a solution with an acid concentration of less than approximately 0.1 N.

[0091] The terms "hydrogen" and "H" are used interchangeably in this specification.

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

[0093] As used herein, the term "alkyl" means containing the indicated number of carbon atoms. This refers to hydrocarbon chains that can be straight-chain or branched. For example, C 1~6 The base is inside This indicates that a molecule can have 1 to 6 carbon atoms (including those at both ends). Examples include methyl and ester. It contains butyl, isopropyl, tert-butyl, and n-hexyl.

[0094] As used herein, the term "alkylamine" means one or more alkyl groups. This refers to amines containing [a certain substance]. Alkylamines are primary amines, secondary amines, or tertiary amines. It can be an amine. For example, a secondary alkylamine is an amine containing two alkyl groups. It is. Examples include diisopropylethylamine.

[0095] Salts can be formed from compounds in any manner well known to those skilled in the art. Therefore, the description "forms a compound or a salt thereof" implies that a compound is formed and its salt is This includes embodiments of which are subsequently formed from the compound in a manner well known to those skilled in the art.

[0096] Certain features of the present invention, described in relation to separate embodiments for clarity, are also: They may be provided in combination in a single embodiment. Conversely, for the sake of brevity, a single implementation The various features of the present invention described in relation to the state are also separately or any preferred partial It may be offered as a combination.

[0097] All combinations of embodiments relating to the aspects described herein are as if they were any combination Insofar as it includes possible combinations, it is as if each combination is explicitly listed individually. As described above, these are specifically encompassed by the present invention. Furthermore, embodiments described herein All partial combinations of the embodiments included herein, and all other embodiments described herein All partial combinations of the included embodiments are as if they were all embodiments The partial combinations described herein, as explicitly enumerated herein, are provided by the present invention. It is specifically included.

[0098] Crystallization method. A method for converting serpercatinib form A to serpercatinib form B is disclosed herein. It is possible to convert serpercatinib form A to form B using various different methods. However, a crystallization-based method to convert serpercatinib form A to serpercatinib form B. However, this is disclosed herein.

[0099] Appropriate methods for converting form A to form B include cooling crystallization, evaporation crystallization, vapor diffusion, and 1 This includes crystallization using one or more poor solvents (including the addition of reverse poor solvents), and slurry crystallization. These methods are discussed herein.

[0100] In one embodiment, a method for converting serpercatinib form A to serpercatinib form B is described in this This will be disclosed in the specification.

[0101] In another embodiment, a method for converting serpercatinib form A to serpercatinib form B is So, we combine serpercatinib form A with C1-C5 alcohols to produce a slurry. A method comprising the steps of: and the isolation of selpercatinib form B from the slurry, is described in this document. This will be disclosed in the specification.

[0102] In yet another embodiment, a method for converting serpercatinib form A to serpercatinib form B. And the method is a. Dissolve serpercatinib form A in a solvent containing DMSO to form a solution. and, b. Adding water to the solution to form a slurry, c. A method comprising isolating serpercatinib form B is disclosed herein. ru.

[0103] In another embodiment, a method for converting serpercatinib form A to form B, wherein the method is Combining lupercatinib form A with methanol to form a slurry, >99 A method comprising stirring a slurry until weight percent of form A is converted to form B is described below. This will be disclosed in the specification.

[0104] Morphology A has XRPD peaks specific to 4.9, 9.7, and 15.5°2θ, and morphology B has XRPD peaks specific to 7.5, 10.9 and 12.0°2θ. Other peaks The 2θ values ​​and / or peak intensity of the 'k' can also be seen between the two morphologies, as can be seen in Table 1 below. They differ. For clarity, all XRPD peaks disclosed herein are otherwise specified. Unless specifically identified, the value is ±0.2°2θ. [Table 1]

[0105] Table 1 does not include all peaks with a relative intensity of less than 1.00. .

[0106] The XRPD patterns of morphology A and morphology B are from a CuKα source (λ=1.54180A) and V Bruker D4 End with an Antec detector, operating at 35kV and 50mA. The results were obtained using an eavor X-ray powder diffractometer. The sample had a step size of 0.008 2θ°. And with a scanning speed of 0.5 seconds / step, a 1.0 mm divergent slit and a 6.6 mm fixed divergent slit are available. Scanning is performed at 2θ° from 4 to 40 using a randomization slit and an 11.3 mm detection slit. The dried powder is packed into a quartz sample holder, and a smooth surface is obtained using a glass slide. The crystalline morphology diffraction patterns are collected at ambient temperature and relative humidity. 8.853 and 26 Based on the internal NIST675 standard with a peak at 0.774 2θ°, the entire pattern After shifting, the crystal peak positions are determined in MDI-Jade. Furthermore, with respect to any given crystal form, favorable characteristics arise from factors such as crystal form and crystal habit. It is well known that the relative intensity of diffraction peaks can change due to orientation. If the effect exists, the peak intensity changes, but the characteristic peak position of the polymorph remains unchanged. For example, The United States Pharmacopeia #23, National Formulary#18,pages1843-1844,199 See 5. Furthermore, for any given crystal morphology, the angular peak position changes slightly. It is well known in the field of crystallography that peak positions can be variable. For example, peak positions can be affected by the analysis of the sample. Shifts due to temperature fluctuations, sample displacement, or the presence or absence of an internal standard. This is possible. In this case, the peak position variability of ±0.2 2θ° is clear from the exhibited crystal morphology. It is estimated that these potential variations should be taken into account without hindering identification. Crystal morphology This can be confirmed based on any unique combination of prominent peaks.

[0107] DSC-TGA analysis of anhydrous crystalline form A showed melting initiation at 207.6°C, with two absorptions. It exhibits heat, with the first being endothermic, followed by melting in form A, then exothermic recrystallization in form B, and then the subsequent form This corresponds to the melting of B. DSC-TGA analysis of anhydrous crystalline form B indicates melting at 213.3°C. It exhibited a single endothermic reaction accompanied by an initiation.

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

[0109] Forms A and B have similar solubility. Both are methyl ethyl ketone (MEK). Dissolution at 25°C in many organic solvents, including acetone and many alcohol-based solvents. The concentration is low, and it is present in dichloromethane (DCM), dimethyl sulfoxide (DMSO), and THF. It has moderate solubility (3-30 mg / ml). Form B is almost soluble in anisole. do not.

[0110] Form A and Form B 13 Figure 2 shows the solid-state NMR spectrum of 13C. Figure 2 also shows the spectrum Including a partial overlay, morphology A contains 30.9 ppm of particles not observed in morphology B. It has a peak of 48.0 ppm, which is not observed in morphology A. Both spectra are referenced to the high magnetic resonance (δ=29.5 ppm) of adamantane. .

[0111] operating at a carbon frequency of 100.62 MHz and a proton frequency of 400.13 MHz, Bruker Avance III equipped with a Bruker 4mm dual resonance probe using an HD400MHz wide-bore NMR spectrometer, 13 C cross polarization / magic angle rotation to obtain NMR (solid state NMR or ssNMR) spectra. TOSS sideband suppression is used with SPINAL64 decoupling and alternating cross polarization using a RAMP100 type H-nucleus CP pulse. The acquisition parameters are as follows: a 4.0 μs proton pulse, a 1 .5 ms contact time, a 5 kHz MAS frequency, a 30.2 kHz spectral width, and a 34 ms acquisition time. A 3 s recycle delay is used and the number of scans is 2655. Chemical shifts are referenced to adamantane (δ = 29.5 ppm) in a separate experiment. Representative CssNMR resonances for Form B are 13 26.44, 27.37, 28.00 , 41.98, 43.43, 43.91, 48.04, 53.92, 56.31, 58. 32, 69.48, 77.90, 80.38, 102.32, 106.77, 113.5 8, 115.24, 118.23, 120.76, 125.23, 130.23, 134 .86, 136.93, 140.59, 148.42, 149.50, 151.20, 1 52.45, 158.22, and 163.52 ppm.

[0112] The above data establish Forms A and B, which 1) have several different characteristics, 2) can be easily distinguished, and 3) Form A can be converted to Form B.

[0113] Various different solvents can be used to convert form A to form B. Solvents that can be used to convert to include C1-C5 alcohols (methanol or ethanol) (e.g., water, acetonitrile (ACN), methyl tert-butyl ether (MTBE)) ), heptane, n-butyl acetate (n-BuOAC), 81% ACN-MeOH (19m 81 mL of ACN combined with L of MeOH, wet ethyl acetate, cyclopentyl acetate 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 This includes, but is not limited to, DMSO / heptane mixtures or DMSO / water mixtures. No. In some embodiments, the solvent is C1-C5 alcohol, water, DMSO, MT The solvents include BE, ACN, and two or more mixtures thereof. In yet another embodiment, This includes methanol, ethanol, water, DMSO, MTBE, ACN, or two or more of these. It contains a mixture of the following.

[0114] As described above, serpercatinib can form a solvate and a metastable solid form. However, both of them are generally unstable when dry. The observed solvates include: Acetone solvate, chloroform solvate, 1,4-dioxane solvate, methyl ethyl Ketone (MEK) solvate, dichloromethane (DCM) solvate, 2-butanol solvate Substance, 1-butanol solvate, ethanol solvate, dimethyl sulfoxide (DMSO) -Includes aqueous solvate, DMSO solvate, and tetrahydrofuran (THF) solvate. The solvates and metastable forms usually revert to form A during isolation and / or drying, but the film Alternatively, amorphous materials may be formed. Chloroform and 1,4-dioxane solvate It was stable during separation / 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 about 25% by weight or less, or about The range is 0.5% by weight to approximately 17% by weight, or approximately 1% by weight to approximately 16% by weight.

[0116] Several non-restrictive methods for converting form A to form B are described below.

[0117] Conversion Method 1 In a preferred embodiment, the method involves using cerpercatinib form A as a C1-C5 alcohol. Which solvent is used to produce the slurry, and how is the serpercatinib derived from the slurry? This includes isolating B. When the slurry is stirred or otherwise agitated, Cellpercatinib form B is formed. In some embodiments, the alcohol is at ambient temperature It is maintained at this level. In other embodiments, the slurry is heated, thereby increasing the rate at which form B is formed. The degree increases. Except for the difference in temperature, these two embodiments are similar and are described below. It will be published.

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

[0119] Examples of C1-C5 alcohols include methanol, ethanol, isopropanol, propanol, butanol, 2-butanol, and 3-butanol. In certain embodiments, the alcohol comprises methanol and / or ethanol. In one embodiment, the alcohol comprises methanol.

[0120] An aqueous alcohol may also be used, and the amount of water present is from about 0.1 wt% to about 70 wt%, or from about 1 wt% to about 50 wt%, or from about 2 wt% to about 30 wt%. In another embodiment, the amount of water present is from about 0.5 wt% to about 20 wt%, or from about 1 wt% to about 15 wt%, or from about 2 wt% to about 12 wt%, or about 10 wt%, or less than about 10 wt%. In one embodiment, the alcohol comprises at least 90 wt% methanol. In another embodiment, the alcohol comprises about 90 wt% methanol and about 10 wt% water. In another embodiment, the alcohol comprises at

[0121] least 95 wt% methanol and about 5 wt% water. Other solvents may be present in the alcohol mixture. In some embodiments, up to about 3 wt% of one or more other solvents may be present. Temperature Temperature affects the rate at which Form A is converted to Form B,

[0122] and lower temperatures require longer times than higher temperatures. The temperature of an alcohol such as a C1-C5 alcohol is from about 10 The temperature is °C, or approximately 55°C. C1-C5 alcohols are added before the desired amount of substance A is added. The temperature may be the setting, or the temperature may be adjusted after substance A has been added.

[0123] In other embodiments, the temperature of alcohols such as C1-C5 alcohols is 10-30°C. Alternatively, it is approximately 15-25°C, or approximately 20°C. In other embodiments, the temperature is the ambient temperature. This is ambient temperature. Form A is converted to form B when stirred in a room-temperature solvent such as methanol. However, when a mixture of form A and the solvent is heated, the conversion becomes faster.

[0124] When the slurry is heated to the extent that all form A is dissolved, the resulting solution is filtered. All insoluble substances can be removed. After stirring, the solution is prepared as detailed 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 not stirred for more than 72 hours. or otherwise not stirred, but if necessary, the slurry may be stirred for longer than 72 hours. It may be mixed or otherwise stirred. In some embodiments, the slurry is It is stirred for approximately 1 to 12 hours.

[0126] cooling When heating the mixture of Form A and alcohol for the above time, stop heating and the slurry Then, let it cool for approximately 4 to 24 hours, or approximately 6 to 18 hours, or approximately 12 hours.

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

[0128] Ethanol, methanol, ACN, MTBE, water, or a combination of two or more of these. The morph B material can be washed using new solvents such as methanol, Wash the Form B material using ACN, MTBE, water, or a combination of two or more of these. To purify. More preferably, a solvent containing methanol is used. The new solvent is Before using it to clean Form B material, it should be cooled to a temperature of approximately 0°C to less than 20°C. That's good too.

[0129] The isolated serpercatinib form B was dried using methods known in the art. It may be dried. Typical methods include heating, passing an inert gas over the solid, and / or drying. This includes the use of pressures below atmospheric pressure.

[0130] In a further embodiment of this example, C1-C5 alcohols and serpercatinib form A are used. By combining these, the resulting slurry is stirred for a sufficient amount of time to convert form A to form B. Mix or otherwise agitate. Typical stirring time is at least about 10 minutes to a maximum of about 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, This is at least about 12 hours. Stir and / or agitate the mixture 24 hours if necessary. This can be done for more than a certain number of hours. Heating the mixture increases the rate of conversion from form A to form B. Add.

[0131] In another embodiment of this method, the method combines cerpercatinib form A with methanol. In addition, forming a slurry, >95% by weight, >96% by weight, >97% by weight, > Stir the slurry until 98% or >99% by weight of form A is converted to form B. This includes stirring the slurry for approximately 12-48 hours or approximately 18-24 hours. (Methanol) The concentration of serpercatinib form A inside is approximately 6-14 mL / g or approximately 8-12 mL / g. In some methods, it is approximately 8 mL / g.

[0132] Conversion Method 2 In another embodiment, the method includes mixing cerpercatinib form A with a solvent, Heat and stir the resulting mixture until state A dissolves in the solvent. Once a solution is formed, If any insoluble impurities are to be removed, the mixture may be filtered. Then the mixture Cool it down and add water. If a seed crystal is used, add the seed crystal at this point. Alternatively, after stirring, slowly add the additional water. Then, let the mixture cool to room temperature. After cooling to room temperature, the mixture is stirred, and then the morphological B material is isolated.

[0133] solvent Various different solvents may be used. Importantly, the solvent is cerpercatinib solvation. It must not form any substance, but rather give the desired form B. Examples of suitable solvents. These include DMSO, C1-C5 alcohols, ACN, MTBE, water, or two of these. The above combinations are examples, but are not limited to these. Preferred C1-C5 alcohols The liquid contains ethanol and / or methanol. In some embodiments, DMS O is a preferred solvent. In some embodiments, the solvent is 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 used in approximately 8... Use 20 mL, or approximately 10-15 mL, or approximately 11-14 mL, or approximately 12-13 mL. It dissolves in the solvent. In some embodiments, 1 gram of Form A is used in 10-15 mL Dissolve in DMSO at a concentration of / g, or in DMS with approximately 12-13 mL / g of Form A per gram. It dissolves in oxygen.

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

[0136] The mixture containing form A and the solvent is heated to a temperature of approximately 30°C to the boiling point of the solvent. The mixture is heated to a temperature of approximately 50-110°C or approximately 50-70°C. In one embodiment, the mixture is heated at approximately 50°C, approximately 60°C, approximately 70°C, approximately 80°C, approximately 90°C, and approximately 10°C. The mixture may be heated to 0°C or approximately 110°C. Heat the mixture to the desired temperature, and the material of form A After dissolving the agent, reduce the temperature of the solution by approximately 15-35°C. The temperature should be approximately 15°C, approximately 20°C. The temperature may be reduced to approximately 25°C, approximately 30°C, or approximately 35°C. In one embodiment, the solution is approximately It is cooled to a temperature below 70°C and above approximately 20°C.

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

[0138] In another embodiment, the solvent is not heated, i.e., it is stirred at ambient temperature. In this embodiment, the conversion from form A to form takes a longer time.

[0139] First portion of water When the first fraction of water (first stage water) is added to the solution, approximately 0.1-1.0 mL / Form A is added in g, or approximately 0.2-0.6 mL / g, or approximately 0.3 mL / g (form A (mL of water per g). In some embodiments, the first fraction 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 approximately 0.6 mL / g.

[0140] The first portion of water should be steeped for approximately 30 seconds to 15 minutes, or approximately 1 to 10 minutes, or approximately 4 to 6 minutes, or It is added over a period of approximately 5 minutes. A longer time can be used if necessary.

[0141] seed crystal When seed crystals of form B are added to the mixture, the amount is approximately 0.1 to 15% by weight, or approximately 1 to 10% by weight. A seed crystal of form B is used in weight percent, or approximately 5 weight percent.

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

[0143] Seed crystals can be prepared using the methods described herein.

[0144] time The mixture is heated to dissolve substance A, and the temperature of the mixture is reduced by 50-110°C, and If using seed crystals after adding them, the mixture should be steeped for approximately 1 to 96 hours, or approximately 6 to 72 hours. Stir the mixture for at least 8 hours, or approximately 8 to 24 hours. In some embodiments, stir the mixture for at least 8 hours. Hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours Between, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours Between, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours Between, at least 21 hours, at least 22 hours, at least 23 hours, or at least 2 Stir for 4 hours.

[0145] Second portion of water After stirring for 1 to 96 hours, slowly add the second portion of water (second stage water). The amount of water in the second divided portion is approximately 0.3-6 mL / g, 0.50-3.0 mL / g (Form A) (mL of water per gram), approximately 0.75-1.5 mL / g, or approximately 0.9-1.20 mL The value is L / g. In some embodiments, the second fraction of water is approximately 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 The values ​​are approximately 1.19 mL / g, 1.20 mL / g, and 1.20 mL / g.

[0146] The second portion of water is added slowly, that is, the entire second portion of water is added. This takes approximately 0.5 to 24 hours or approximately 1 to 12 hours. In some embodiments, the second minute It takes approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, and 5 hours to add the total amount of water. It takes 6 hours, approximately 7 hours, approximately 8 hours, approximately 9 hours, approximately 10 hours, approximately 11 hours, or approximately 12 hours. ru.

[0147] cooling After adding the second portion of water, the mixture is cooled to approximately 15-30°C, then to approximately 20-30°C. Bring to a temperature of approximately 15°C, approximately 16°C, approximately 17°C, approximately 18℃, approximately 19℃, approximately 20℃, approximately 21℃, approximately 22℃, approximately 23℃, approximately 24℃, approximately 25℃, approximately It is cooled to 26°C, approximately 27°C, approximately 28°C, approximately 29°C, or approximately 30°C. In one embodiment, The final temperature after cooling is room temperature. In other embodiments, the mixture is heated to a temperature of approximately 30-55°C. It is cooled. In these embodiments, the yield is slightly lower than when a lower temperature is used. The tendency is low.

[0148] After adding the second portion of water, heat the mixture until it reaches the desired temperature, approximately 1-20°C / Cooling is performed at a rate of approximately 3-17°C / hour or approximately 5-15°C / hour. One embodiment So, the cooling rates are approximately 1°C / hour, 2°C / hour, 3°C / hour, 4°C / hour, and 5°C / hour. / hour, approximately 6°C / hour, approximately 7°C / hour, approximately 8°C / hour, approximately 9°C / hour, approximately 10°C / hour, Approximately 11°C / hour, approximately 12°C / hour, approximately 13°C / hour, approximately 14°C / hour, approximately 15°C / hour, At approximately 16°C / hour, 17°C / hour, 18°C / hour, 19°C / hour, and 20°C / hour. be.

[0149] After reaching the desired temperature, stir the mixture for approximately 1 to 72 hours or approximately 2 to 48 hours. In some embodiments, the mixture is stirred for at least 2 hours. In other embodiments, the mixture is mixed. Stir the mixture for less than 72 hours.

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

[0151] Ethanol, methanol, ACN, MTBE, water, or a combination of two or more of these. The morph B material can be washed using new solvents such as methanol, Wash the Form B material using ACN, MTBE, water, or a combination of two or more of these. To purify. More preferably, a solvent containing methanol is used. The new solvent is Before using it to clean Form B material, it should be cooled to a temperature of approximately 0°C to less than 20°C. That's good too.

[0152] In embodiments where the solvent is DMSO, isolated serpercatinib form B is isolated The cerpercatinib form B was diluted with methanol until it contained less than 0.5% by weight of DMSO. It will be cleaned.

[0153] In a further example of this method, cerpercatinib form A is dissolved in a room-temperature solvent containing DMSO. A solution containing approximately 10-15 mL / g of DMSO per gram of form A, after dissolution. Form . Then add water. Then, let the mixture stand, during which time form B Formed. Then, form B can be isolated, or additional water can be added. And, after further stirring (as described above), morphology B can be isolated.

[0154] Another example of this method involves selpercatinib form A being DM at approximately 60-80°C or approximately 70°C. It dissolves in SO, resulting in a DMSO concentration of approximately 10-15 mL / g per gram of form A. Form a solution, cool the mixture to about 40-60°C or about 50°C, add water, and obtain Seed crystals of form B are planted in the mixture, the mixture is stirred, water is added, and the mixture is heated. Cool the mixture and isolate form B. The initial amount of water to add is approximately 0.1 m of form A. L / g is approximately 0.5 mL / g of form A, or approximately 0.3 mL / g of form A. The amount of seed crystals is in the range of approximately 1-10% by weight, or approximately 5% by weight, based on the amount of form A. Stir the seed crystal-containing mixture for approximately 8 to 24 hours or approximately 12 hours. Second addition amount / division The amount of water is approximately 1.0-1.5 mL / g of Form A, or approximately 1.10-1.15 mL / g, The amount is approximately 1.14 mL / g. Add the second amount of water / divided amount over approximately 3-8 hours or approximately 5 hours. Add over a period of time. After adding the second amount / divided amount of water, mix the slurry for about 20-30 minutes. Cool to 70°C or approximately 25°C. The rate at which the slurry is cooled from approximately 70°C to approximately 25°C is approximately 25°C. The temperature reaches approximately 10°C per hour. Stir the slurry at approximately 25°C for at least 2 hours. Then, heat to approximately 60-80°C, 70-75°C, or 73°C, and stir for approximately 1 hour. Next, the slurry is cooled again to approximately 20-30°C or approximately 25°C. Cool from approximately 73°C to approximately 25°C at a rate of approximately 10°C / hour. This takes at least approximately 30 minutes to approximately 8 After stirring for 1 hour, or about 1 to 8 hours, or about 2 hours, the cell percatinib form B is, for example, Then, isolate it by filtration.

[0155] A crystallization method effective for converting from form A to form B is described in the exemplary embodiment of the example. Further examples are given.

[0156] Direct synthesis of form B of compound I. In another embodiment, the present disclosure relates to a compound of formula I as form B (i.e., cerpercatinib ), [ka] Or relating to a process for preparing a pharmaceutically acceptable salt thereof.

[0157] In this embodiment, the process for preparing selpercatinib form B is disclosed elsewhere. and the methods described (for example, U.S. Patent No. 10,112,942, the whole of which is referenced) The synthesis of one or more precursor compounds by synthetic methods such as those incorporated herein. Includes. The following exemplary schemes 1 and 2 are derived from the precursor compound [2] into the serpercatinib form. This document describes general methods for preparing state B and important intermediate compounds [3]. [ka]

[0158] Precursor compound [2] (tert-butyl 3-(5-(3-cyano-6-(2-hydrox (C-2-methyl-propoxy))pyrazolo[1,5-a]pyridine-4-yl)pyridine -2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate A detailed description of a synthesis method that can provide ) is, for example, U.S. Patent No. 10,745,419 and Disclosed in Patent No. 10,112,942 and International Patent Publication No. 2018 / 071447 These are incorporated herein by reference in their entirety. In a brief overview of one embodiment, compound [2] is 4-(6-fluoropyrylene glycol) in DMSO. (quinolin-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 K2CO 3(s) (1:1:6.67 molar equivalents) by reaction, adjusted with stirring under heating (e.g., at 90 °C for 12 hours) to obtain. The resulting viscous slurry is diluted with additional DMSO and stirred under heating (e.g., at 90 °C for a further 12 hours). After the reaction, the mixture is cooled to ambient temperature and diluted with water, and the resulting aqueous mixture is washed with dichloromethane. The combined organic extracts are dried over anhydrous MgSO 4(s) and filtered, and concentrated in vacuo. The resulting residue is purified by silica chromatography —(EtOAc / hexane as a gradient eluent system) to provide compound [2] in high yield. Those skilled in the art will understand that compound [2] can be synthesized using other synthetic routes. Those skilled in the art will further understand that compound [2] may contain amine protecting groups other than Boc, including non-limiting examples of formyl, acetyl, trifluoro acetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-meth oxybenzylcarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl , trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxy carbonyl, nitroveratryloxycarbonyl, p-methoxybenzyl and tosyl. In some embodiments the protecting group is tert-butyloxycarbonyl (Boc).

[0159] Generally, a method for the direct synthesis of form B selpercatinib according to the present disclosure comprises (1) protecting To remove the protective group (e.g., Boc shown in [2]), and (2) 2-hydroxy-2- Silylation of hydroxyl groups on methyl-propoxy substituents (e.g., TMS shown in [3]) For this purpose, under effective conditions, compound [2](tert-butyl3-(5-(3-cyano -6-(2-hydroxy-2-methyl-propoxy))pyrazolo[1,5-a]pyridine -4-yl)pyridine-2-yl)-3,6-diazabicyclo[3.1.1]heptane- It contains 6-carboxylate. Then the silylated and deprotected compound [3] In any organic solvent (e.g., anisole), in the presence of a reducing agent and an acid, 6-methoxy-3- It is reacted with pyridinecarboxaldehyde.

[0160] The silyl portion (for example, TMS in some exemplary embodiments) is, for example, fu Decontamination by adding a chemical source (e.g., tetrabutylammonium fluoride (TBAF)) It is removed under conditions effective for protection. After the reaction and removal of the silyl protecting group, the pH of the reaction mixture is adjusted to the salt The mixture is prepared and cooled to enable the formation and isolation of crystalline form B cerpercatinib.

[0161] In some embodiments, the conditions effective for removing the protecting group and for silylation are: Alcohols (e.g., MeOH, EtOH), organic acids (e.g., p-toluenesulfonic acid) (such as aryl sulfonic acids), aprotic solvents (e.g., acetonitrile), Acyl halides in methanol that produce an HCl solution (for example, acetyl chloride in methanol) (e.g., ethyl acetate), ethers (e.g., anisole), and These may include a solvent selected from polar organic solvents such as combinations thereof. In this state, the reaction involves trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, Methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, aluminum trichloride, and It contains a deprotecting agent which may include boron trifluoride. In some embodiments, the deprotecting agent is sulfuric acid The conditions are acetyl chloride or p-toluenesulfonic acid. In some embodiments, the conditions are A period of time ranging from approximately 1 hour to approximately 8 hours or more (for example, overnight or approximately 12 hours), optional. Optionally, heating the reaction mixture may be required to reflux it.

[0162] In some embodiments, the silyl group used in the reaction is trimethylsilyl (TMS) , triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), i Isopropyldimethylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS) tert-butyldimethylsilyl (TBS / TBDMS), tetraisopropyl disyl Xane ilidene (TIPDS), di-t-butyl silylene (DTBS), or triisopropyl alcohol May contain ropylsilyl (TIPS). Silyl group (e.g., TMS group on compound [3]) In addition to acting as a protecting group, the presence of cerpercatinib form B, compound [2] , and anisole, a solvent that can be considered a poor solvent for non-silylated derivatives of compound [3]. It provides additional solubility for the compounds inside.

[0163] The silyl group can be added using methods known in the art.

[0164] In some embodiments, the compound [3] and 6-methoxy-3-pyridinecarboxyl The reaction with dehyde is such that compound [3] is the 2-hydroxy-2-methyl-propoxy form of [3]. Assuming that it exhibits higher solubility in anisole than in its natural state, anisole is used as the solvent. It is then executed. In some embodiments, the reducing agent is alkali metal borohydride, hi Drazine compounds, citric acid, citrates, succinic acid, succinates, ascorbic acid, and It may contain ascorbic acid. In some embodiments, the reducing agent is sodium boron hydride. Select from um, lithium borohydride, nickel borohydride, and potassium borohydride. Selected. In some embodiments, lithium borohydride is lithium borohydride and Selected from lithium triethylborohydride. In some embodiments, hydride Sodium borohydride is sodium triacetoxyborohydride (STAB), boron Selected from sodium and sodium borocyanohydride. 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 in such a way as an inorganic acid (e.g., HCl, H2SO4, etc.) or a water-soluble organic acid ( For example, it may include acetic acid, pivalic acid, etc. In some embodiments, the acid is pivalic acid. It contains acid.

[0165] The resulting compound is sufficient to remove the silyl group (e.g., TMS) and the reaction product Deprotection under conditions not harsh enough to cause decomposition by reacting with a substance (i.e., serpercatinib). In some embodiments, deprotection of the silyl group is effective for reacting with the silyl group. The amount of fluoride source used in the reaction (e.g., tetrabutylammonium fluoride (TBA)) F), pyridine (HF) x , trimethylamine hydrofluoric acid (Et3N·3HF), Hydrofluoric acid, tris(dimethylamino)sulfonium(T) difluorotrimethylsilicate This includes adding ASF, ammonium fluoride (H4NF), or a weak acid. The conditions for step may include a buffered fluoride source, and the conditions should be sufficiently mild to avoid decomposition reactions. It can be determined empirically while maintaining this.

[0166] After the reaction, adjust the pH of the reaction mixture with a base (e.g., K2CO3 slurry) and cool it down. This enables the formation and isolation of crystalline form B cerpercatinib. In some embodiments, Crystallization may further involve the addition of a small amount of seed crystal of serpercatinib morph B. In some further embodiments, crystallization is performed by reducing the remaining amount of cerpercatinib form B to form A This may include any of the crystallization techniques described herein that may be effective for conversion. Cut.

[0167] Specific starting materials and reagents are shown in the following scheme and related descriptions, but other By substituting the starting materials, reaction conditions, and reagents, the target compound (i.e., cell) can be prepared according to this disclosure. Percatinib morph B can be obtained.

[0168] In some embodiments of this model, the synthesis method is a general reaction shown in Scheme 1. Includes scheme. [ka]

[0169] In some embodiments of this model, the process is a general reaction as shown in Scheme 2. Includes scheme. [ka]

[0170] Cellpercatinib form B is synthesized by direct synthesis or cell percatinib according to the embodiments and aspects of this disclosure. Percatinib (i.e., amorphous cerpercatinib or another polymorphic form of cerpercatinib) Whether or not it is obtained by conversion from (b), it is further pharmaceutically acceptable. Salts thereof, or pharmaceutical compositions thereof, may be provided, along with other polyforms and / or amorphous forms thereof. Compared to lupercatinib, it can exhibit higher thermodynamic stability. Nib form B retains its activity as a RET inhibitor, for example, in PCT Publication No. 2. As described in Patent No. 018 / 071447 and U.S. Patent Application Publication No. 2018 / 0134702 The activity is evaluated by any assay known in the art, including the assay described above. And they can be assessed, and each of them is incorporated into the whole by reference.

[0171] The following examples are within the scope of the methods described herein and are included in the claims. This is provided solely for the purpose of illustrating and describing specific embodiments. [Examples]

[0172] Cellpercatinib (6-(2-hydroxy-) used in the crystallization procedure described herein 2-methylpropoxy)-4-(6-(6-((6-methoxypyridine-3-yl)methyl (Lu)-5 3,6-diazabicyclo[3.1.1]heptane-3)-yl)pyridine-3 -yl)pyrazolo[1,5-a]pyridine-3-carbonitride) is U.S. 10, It was manufactured using the techniques and methods described in Patent No. 112,942.

[0173] Example 1: Cooling crystallization Dissolve 264 mg of Form A in 20 mL of DCM, and (15) in an 8 mL vial, etc. The contents were then distributed to the desired portions. Next, these vials were placed in a 70°C vacuum oven and the solvent was removed. The solvent was removed. A birefringent white solid was observed in all vials. (Table 2) (See reference) was added at 50°C while shaking. The heat source was switched off and the sample was allowed to rest naturally. The sample was cooled to room temperature (RT). The sample was stirred overnight, and the resulting solid was isolated by vacuum filtration. Next, it was air-dried. The vials, which did not contain any solid matter, were placed in the refrigerator for 3 days and allowed to settle. If no moisture was found, it was removed and evaporated in a fume hood for one day. XRPD data is humid The solid was recovered (if possible). Approximately the experiment 2 / 3 (Approximately 66%), isolated and dried Sometimes metastable solvates were produced. These metastable solvates (chloroform solvates) (Except for) was converted to form A immediately after being removed from the mother liquor. Form B was obtained, while form A was obtained with Anisole. [Table 2]

[0174] Example 2: Evaporation and vapor diffusion crystallization Evaporation plates are prepared by dissolving 5 mg of Form A in 0.9-12 mL of solvent. 33) Prepared in vials. The evaporated solution was manually filtered with a syringe and then filtered into clean vials. Place it inside, cover with Parafilm with pinholes, and adjust the temperature inside the fume hood (RT) and ambient humidity. The solution was evaporated to dryness at [temperature]. The solution for vapor diffusion was placed in a 20 mL chamber containing 5 mL of poor solvent. Place it in the container and close the lid tightly.

[0175] Approximately half of the crystallization experiments produced either a solvate or a mixture of the solvate and form A. A very large number of solvates were converted to form A during desolvation. This is due to a template effect caused by structural similarity. It is possible that this may direct the nucleation of metastable forms. Form B is ACN and The result was obtained from only two crystallization experiments using a 5:1 MeOH-THF mixture. Morphic form / film is produced using five solvent systems (THF, 11:1 IPA:acetic acid, benzyl acetate). It was obtained from chloroform and alcohol, acetic acid and 10:1 EtOH:DMF. The 1,4-dioxane solvate was stable upon isolation, and solid-state property data was collected. PA is isopropyl alcohol, THF is tetrahydrofuran, and DMF is di It is methylformamide.

[0176] Vapor diffusion experiments yielded various solvates or amorphous materials. Five solvates were obtained. In other words, DCM, 1-BuOH, EtOH, THF, and DMSO are metastable and can be isolated. Sometimes form A was obtained. A mixture of form A and form B was obtained using a DMSO / heptane mixture. Obtained.

[0177] Example 3: Poor solvent crystallization (29) Various amounts (9-36 mg) of solvent in 1-15 mL of a 4 mL vial Poor solvent addition experiments were prepared by dissolving state A. Then, until a precipitate forms or the volume of the antisolvent is equal to or greater than the volume of the solvent, the mixture is turned over. The solvent was added dropwise to the filtered solution using a syringe. For the second set of 12 vials, The liquid was filtered using a syringe and placed in a clean vial containing 5 mL of the antisolvent. The solid was then processed. Isolation was performed by vacuum filtration and air drying. Vials in which no precipitate was observed were left for up to two weeks. The mixture was evaporated for a specified period. 71% of the additions of the poor solvent produced either form A or an unstable solvate leading to form A. It occurred. Morphology B appeared in 24% of the experiments (one result was amorphous). Reverse poor solvent addition. In addition, morph A or solvates were obtained in 83% of the experiments, and morph B was obtained in 17% of the experiments. .

[0178] Example 4: Slurry Crystallization A slurry of morph A vials was prepared using 10 mg of morph A in a 4 mL vial. A solvent was added according to the solubility of form A in those solvents to produce a certain slurry density. The slurry was shaken in a 500 rpm shaker block at 22°C for approximately 3 days. The material was analyzed as a wet cake by XRPD. The majority of the slurry screen. This yields a solid that matches form A, or a solvate that has been converted to form A during isolation / drying. did.

[0179] Another slurry plate containing 10 mg of Form A in a 4 mL vial was described in the previous paragraph. It was prepared in the same way as the betta. The slurry was shaken in a 500 rpm shaker block for 22 minutes. The mixture was shaken and stirred at °C for 24 hours. After 24 hours, the mother liquor in each vial was mixed with the respective new solvent. The mixture was replaced. Next, the slurry was stirred for 15 days. The solid material was wet by XRPD. The dry and ferrous compounds were analyzed. Approximately the experiment 2 / 3 Morphology B was observed in approximately 66% of cases. The rest of the experience 1 / 3 (Approximately 33%) consists of Form A and B or Form A and solvate (1 case) A mixture was obtained. These results suggest that equilibrium was not reached, which means 1) the solubility limit of form A in the tested solvent, or 2) the heat of phase transformation near the transition point. This may be due to the minimum mechanical driving force. In slurry crystallization experiments, In Nisole, morphology A was obtained again. [Table 3]

[0180] In Table 3 above, unless otherwise specified, the slurry was agitated for 15 days.

[0181] Example 5: Solvent-assisted grinding Two experiments were conducted using solvent-assisted mechanical grinding. 1 In one experiment, DMSO was used as the solvent. When used as the solvent, morphology B was observed. When water was used as the solvent, morphology changed. No transformation occurred; in other words, morphology A was not observed.

[0182] Example 6: Conversion from Form A to Form B Serpercatinib (2.0 g) is suspended in methanol (200 mL) and heated at 55°C and 75°C. Stir at 0 rpm. Stir the suspension at 55°C for 60 minutes. Stop heating and let the suspension cool in a cool, dry place. Allow to cool naturally to room temperature. The solid is recovered by filtration and dried under vacuum for 4 hours to form the title. A crystalline compound (1.72g, 86%) was obtained.

[0183] Example 7: Conversion from Form A to Form B Serpercatinib form A (152.0 g) was suspended in methanol (1.5 L) at room temperature. Stir at 750 rpm. Stir the suspension overnight at room temperature (approximately 20°C). Remove the solid from the vacuum. The solid is recovered by filtration below. The solid is dried at 45°C under full house vacuum with nitrogen purging. Then, crystals of the title compound (148.28 g, 97.6%) were obtained.

[0184] Example 8: Conversion from Form A to Form B Stir serpercatinib form A in methanol (8 mL / g) at room temperature for 18-24 hours. Filter and isolate the solids. Use a small amount of N2 purge under vacuum at 45°C. To dry solid objects.

[0185] Example 9: Conversion from Form A to Form B While stirring, dissolve Form A in DMSO (13 mL / g) at 70°C to obtain a clear solution. Obtain. Cool the solution to 50°C. Add water (0.3 mL / g), then form the solution. Seed crystals of form B (5% by weight, based on the amount of form A used) are planted. Stir for 12 hours, then Then, add water (1.14 mL / g) over 5 hours. Let the slurry steep at 10°C / h for 2 hours. Cool to 5°C. Stir for at least 2 hours. Heat the slurry to 73°C and stir for 1 hour. Mix. Cool the slurry to 25°C at 10°C / h. Stir for at least 2 hours. The solids are isolated by filtration. The wet cake is washed three times with MeOH (8 mL / g). The solid material is dried under vacuum at 45°C using a small amount of N2 purge.

[0186] Example 10: Synthesis of Form B [ka] This synthetic pathway to form B of the compound of formula I (i.e., serpercatinib) is for 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 Any synthetic route that produces cyclo[3.1.1]heptane-6-carboxylate[2] It can include...

[0187] A round-bottom flask (three-necked) equipped with an overhead stirrer, condenser, and thermocouple is filled with methanol. 100% acetyl chloride (200 mL, 100%) and 3.1 mL, 44 mmol, 100% Add ) to the mixture. Xy-2-methyl-propoxy)pyrazolo[1,5-a]pyridin-4-yl]-2-py Lysyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate[2 Allow the mixture to react before adding ], (9.9965g, 19.81 mmol, 100%). During addition, the reaction is heated to approximately 60°C (63°C). The temperature is measured by the amount of off-gas that can be observed. Adjustments were made to reduce the risk and avoid the possibility of overdrive of the installed condenser. After assaying the reaction to determine the complete conversion (approximately 2 hours), the solvent was removed. The mixture Acetonitrile (ACN) (approximately 100 mL) was added to the material, and the sides of the reaction vessel were rinsed. The solvent mixture was removed again and the area was maintained under a nitrogen atmosphere.

[0188] Add ACN (300 mL, 100%) and hexamethyldisilazane (H) to the reaction vessel. Add 25 mL of MDS (119 mmol, 100%) to the reaction mixture. Before sampling, stir at ambient temperature for about 1 hour, and based on the amount of [2], about 1.6% The title compound was produced. The reaction was allowed to proceed overnight at ambient temperature. Sampling of the overnight reaction. Next, the mixture is heated to 40°C and sampled after 1 hour at that temperature. The heating will raise the temperature to 56°C. As the temperature rises, the mixture will reflux and foam, which is This is presumed to indicate the occurrence of nemonia. At that temperature, after about 1 to 1.25 hours, the reaction Sampling is performed, and continuous reflux is maintained for observation. The reaction is sustained at that temperature for another 3 hours. Then, take another sample. Remove the reaction solvent and use potassium carbonate aqueous solution (100 mL, 5 0.45 mmol, 5% by mass is slurryed in a reaction vessel. The resulting mixture is then mixed with water (2 Wash with 5 mL of water and dry to obtain 7.89 g of the title compound [3] (78% yield). (Mass spectrometry, m / z=477.20, 477.30(M+H). 1 1H 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 thermocouples, te rt-butyl3-[5-[3-cyano-6-(2-hydroxy-2-methyl-propoxy ) Pyrazolo[1,5-a]pyridin-4-yl]-2-pyridyl]-3,6-diazabic Kuro[3.1.1]heptane-6-carboxylate[2], (9.9965g, 19. 81 mmol, 100%, and p-toluenesulfonic acid (2.1 equivalents) in 10 volumes Add with an organic solvent. React the mixture for 1 hour, then add pyridine (2.1 equivalents) and hex Add methyldisilazane ("HMDS") 6 equivalents. Allow this reaction mixture to stand for approximately 1 hour. Stirring is performed to obtain the compound described in the title [3]. [ka]

[0190] In a reaction vessel equipped with a magnetic stirrer, 4-[6-(3,6-diazabicyclo[ 3.1.1]Heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethicone) Lucilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitriel[ 3] (0.9981g, 2.094 mmol, 100% by mass), 6-methoxy-3-pyriol Dincarboxaldehyde (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 Add 00% by mass and stir to form a slurry. Continue until a homogeneous solution mixture is obtained. Heat while stirring. Even after the solution has cooled to ambient temperature, it remains a homogeneous solution. Once cooled, add sodium triacetoxyborohydride (1.0840g, 5.11 Add 47 mmol (100% by mass) and allow the reaction to proceed. The analysis of the reaction after 2 hours is described below. The formation of a TMS-protected derivative of the compound was demonstrated.

[0191] After the reaction is complete, this method can be continued to remove the TMS protection and crystallize morphology B. Add water (1 mL, 55.5099 mmol, 100% by mass) and tetrafluoroethylene to the mixture. Rabutyruammonium trihydrate (0.6070g, 2.322 mmol, 100% by mass) And, optionally, a certain amount (approximately 10 mg) of the compound seed crystals in form B of the title, Add to the mixture. If no crystals are observed after a while, heat the mixture to 50°C. It is possible to maintain the elevated temperature overnight, then sample the reactants and confirm that the process is complete. No crystallization was observed. The pH of the mixture (slightly acidic) was adjusted, and the carbon as a slurry was used. The solution was adjusted by adding potassium acid (5% by mass in water), and the observed foaming stopped. The solution was added to 1 mL aliquots until the test solution became basic. The mixture was stirred overnight, and the sample was then sumpted. The compound was then ring-molded to obtain the title compound free of detectable impurities, with a total isolation yield of 54%. (Mass spectrometry, m / z = 526.30(M+H).) 1 1H NMR (400MHz, 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, 4-[6-(3,6-di Azabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl -2-trimethylsilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-ca Rubonitrile [3] (1.00 g, 2.10 mmol), 6-Methoxy-3-pyridine Ruboxyaldehyde (1.6 equivalents), pivalic acid (approximately 5 volume equivalents), triacetoxyhydrate Sodium borochloride (2.5 equivalents), anisole (10 mL, 91.8 mmol, 10 Add 0% by mass and react for about 1 hour. Add water (10 mL) to the reaction mixture. The mixture is filtered through Celite (diatomaceous earth, filter aid). Saturated sodium chloride is added to the organic layer. Add 10 mL of solution and separate the layers. Separate the layers. Add 5N HCl to the organic layer. Add 1 mL. Heat the mixture at 95°C for 3 hours. After the reaction, the pH of the mixture is acidic. The pH is adjusted to 9 by adding potassium carbonate. The mixture is then cooled and allowed to crystallize. The resulting cerpercatinib form B crystals were filtered and methyl tert-butyl ether ( Wash with MTBE and dry to obtain the pure title compound.

[0193] Example 11 The physical and chemical stability of form B is solely for ensuring solubility and solubility. Furthermore, it is not only useful for API and dosage form drug development and manufacturing operations (drying, storage, delivery, etc.). This is an important attribute. All crystal forms possess the stability necessary to enable drug development. It is not a matter of temperature and humidity. A crystalline form that is stable against both temperature and humidity is desired. To evaluate the stability of the crystal morphology of B, an accelerated stability test will be conducted. Two samples of morphology B will be used. Weigh the contents into a 0 mL scintillation vial and ferment at the temperature and specified in Table 4. Place in a bell jar containing saturated salt solution in the oven for a specified time (open dish). State B was analyzed before and after the accelerated stability test, and the CuKα source (wavelength = 1.54056A) and It features a Linxeye detector, operates at 40kV and 40mA, and has a 0.2mm diverging slit. Each sample is collected using a Bruker D8 Advance XRPD equipped with the following features: Scanning 4° to 30°²θ in 0.02° steps at a speed of 0.2 seconds per step. The assay for the starting material and impurities is performed using an Agil diode array detector. The evaluation will be performed using the ent1260 HPLC system. The sample will be prepared in 50 / 50 0.0 ohms of water. Prepared at an appropriate concentration with 0.1% TFA in 1% TFA / ACN, and the following HPL C condition: Column Zorbax Bonus-RP, 75x4.6mm id 3.5 microns, mobile phase A is 0.1% TFA in water, mobile phase B is 0.1% in ACN The TFA gradient is 95% A at time 0 and 23% at time 9.5-12.1 minutes. A, 5% A at a flow rate of 1.5 mL / min at 13-16 minutes, time 16.1-20 minutes. Using 95% A, a column temperature of 30°C, a UV detection wavelength of 210nm, and an injection volume of 3μL, It is evaluated using [method]. The stability of form B is characterized by chemical and physical [conditions] under test conditions. It can be seen that it is relatively stable (Table 4). [Table 4]

[0194] Example 12: Solubility Solubility tests were completed for the crystalline forms of serpercatinib described herein. These tests used aqueous media covering the physiological pH range and three simulated fluids. A sufficient amount of solid compound to saturate the solvent volume was weighed into a container containing approximately 1 mL of the specified solvent. The samples were mixed at 37°C in an incubator shaker set to 100 rpm. After equilibration, the samples were transferred to a centrifugal filter (Durapore PVDF, pore size 0.22 μm) and centrifuged at 10,000 rpm for 3 minutes while maintaining 37°C. Then, 100 μL aliquots were taken from each sample and diluted with 900 μL of 50:50 acetonitrile:water. The pH of the filtrate was recorded using a calibrated chemical pH instrument. The solution concentration of the compound was determined by HPLC using an Agilent Zorbax Bonus-RP 4.6x75mm, 3.5μm column under the following conditions: temperature 30°C, injection volume 4μL, UV detection at 238nm, flow rate 1.5mL / min, autosampler temperature 25°C, mobile phase A being 0.1% trifluoroacetic acid in water, and mobile phase B being 0.1% trifluoroacetic acid in acetonitrile. The HPLC gradient was as follows: 0 min - 95% A, 5% B; 9.5 min - 23% A, 77% B; 12.1 min - 23% A, 77% B; 13 min - 5% A, 95% B; 16 min - 5% A, 95% B; 16.1 min - 95% A, 5% B; 20 min - 95% A, 5% B. The table below (Table 3) details the equilibrium solubility data and equilibrium pH reported as the average of two sample preparations. As shown in Table 5, the solid morphology of the residual solid from the centrifuged sample is verified by XRPD. [Table 5] The invention described in the original claims of this application is listed below. [1] A crystalline form of serpercatinib, (a) When measured using an X-ray wavelength of 1.5418A, an X-ray powder diffraction (XRPD) pattern including a peak at 21.1° and one or more peaks at 17.1°, 17.7°, and 19.8°±0.2°²θ, or (b) Peaks at 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (each ±0.2 ppm) include a peak referenced to the high magnetic resonance of adamantane (δ=29.5 ppm). 13 C solid-state NMR spectrum, A crystalline form of serpercatinib characterized by at least one of the following. [2] The crystal morphology of celpercatinib according to [1], characterized in that when measured using an X-ray wavelength of 1.5418 A, the crystal morphology has an X-ray powder diffraction (XRPD) pattern including a peak at 21.1° and one or more peaks at 7.5°, 12.0°, 13.2°, 17.1°, 17.7° and 19.8°±0.2°²θ. [3] The crystal morphology of selpercatinib according to [1], characterized in that the crystal morphology 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. [4] The crystalline form includes peaks at 26.4, 28.0, 42.0, 43.9, 48.0, 56.3, 69.5, 80.4, 102.3, 106.8, 115.2, 120.8, 130.2, 134.9, 140.6, 149.5, 152.5 and 163.5 ppm (each ±0.2 ppm) with respect to the high magnetic resonance of adamantane (δ=29.5 ppm). 13 The crystalline form of cerpercatinib described in [1], characterized by its 13C solid-state NMR spectrum. [5] The crystalline form includes peaks at 26.4, 27.4, 28.0, 42.0, 43.4, 43.9, 48.0, 53.9, 56.3, 58.3, 69.5, 77.9, 80.4, 102.3, 106.8, 113.6, 115.2, 118.2, 120.8, 125.2, 130.2, 134.9, 136.9, 140.6, 148.4, 149.5, 151.2, 152.5, 158.2 and 163.5 ppm (each ±0.2 ppm) with reference to the high magnetic resonance of adamantane (δ=29.5 ppm). 13 The crystalline form of cerpercatinib described in [1], characterized by its 13C solid-state NMR spectrum. A pharmaceutical composition comprising the crystalline form of serpercatinib described in any of [1] to [5] [6] and a pharmaceutically acceptable carrier, diluent, or excipient. [7] The pharmaceutical composition according to [6], wherein the composition contains less than about 20% by weight of another crystalline form of serpercatinib. [8] The pharmaceutical composition according to [6], wherein the composition contains less than about 10% by weight of another crystalline form of serpercatinib. [9] The pharmaceutical composition according to [6], wherein the composition contains less than about 5% by weight of another crystalline form of serpercatinib.

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

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

[12] A pharmaceutical composition according to any one of [6] to [9] for use in the treatment of cancer.

[13] The pharmaceutical composition for use according to

[12] , wherein the cancer is selected from the group consisting of lung cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuroma of the gastrointestinal mucosa, and cervical cancer.

[14] The pharmaceutical composition for use according to

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

[15] The pharmaceutical composition for use according to

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

[16] The pharmaceutical composition for use according to

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

[17] A process for producing the crystalline form of serpercatinib described in [1], (a) Suspending serpercatinib in a solvent, (b) Heat the suspension to 50°C to 60°C while stirring for 30 to 90 minutes, (c) Remove heat and cool the suspension to room temperature to form solid crystals, (d) recovering the solid crystals A process that includes this.

[18] The process according to

[17] , wherein the solvent comprises methanol.

[19] The process according to

[17] or

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

[20] The process according to any one of

[17] to

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

[21] The process according to any one of

[17] to

[20] , wherein the solid crystal is recovered by vacuum filtration.

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

[23] The method described above involves selpercatinib morph A to C 1 ~C 5 The method according to

[22] , comprising: combining with an alcohol to produce a slurry; and isolating serpercatinib form B from the slurry.

[24] Said C 1 ~C5 The method according to

[22] or

[23] , wherein the alcohol is at a temperature of approximately 10°C to approximately 30°C.

[25] Said C 1 ~C 5 The method described in any of

[22] to

[24] , wherein the alcohol is at approximately 15-25°C.

[26] Said C 1 ~C 5 The method described in any of

[22] to

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

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

[22] or

[23] , wherein the alcohol is at a temperature of approximately 10°C to approximately 80°C.

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

[22] to

[27] , wherein the alcohol comprises methanol.

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

[22] to

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

[30] The method according to any one of

[22] to

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

[31] The method of any of

[22] to

[30] , wherein the isolation of form B is performed by vacuum filtration.

[32] The method of any of

[22] to

[31] , comprising centrifugation, to isolate morph B.

[33] The method according to any one of

[22] to

[32] , further comprising drying of serpercatinib form B.

[34] The above method, a. Dissolving the serpercatinib form A in a solvent containing DMSO to form a solution, b. Adding water to the above solution to form a slurry, c. The method according to

[22] , comprising isolating selpercatinib form B.

[35] The method according to

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

[36] The method according to

[34] or

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

[37] The method according to any one of

[34] to

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

[38] The method according to any one of

[34] to

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

[39] The method according to

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

[40] The method according to any one of

[34] to

[39] , wherein step b is to add about 0.1 to about 1 mL of water per gram of form A to the solution.

[41] The method according to any one of

[34] to

[40] , wherein step b is to add about 0.3 mL of water per gram of form A to the solution.

[42] The method according to any one of

[34] to

[41] , further comprising step b adding about 1 to about 15% by weight of a seed crystal of form B.

[43] The method according to any one of

[34] to

[42] , further comprising step b adding about 1 to about 10% by weight of a seed crystal of form B.

[44] The method according to

[42] or

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

[45] The method according to any one of

[34] to

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

[46] The method according to any one of

[34] to

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

[47] The method according to any one of

[34] to

[46] , further comprising step b being the addition of a second fraction of a volume of water to the slurry.

[48] ​​The method according to

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

[49] The method according to any one of

[34] to

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

[50] The method according to any of

[34] to

[49] , wherein step c is filtration.

[51] The method according to any one of

[34] to

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

[52] The method according to

[51] , wherein the isolated cerpercatinib form B is washed with a methanol-containing solvent.

[53] The method according to

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

[54] The method according to

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

[55] The method according to

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

[56] The method according to

[54] or

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

[57] The method according to

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

[58] The method according to

[57] , wherein 5% by weight of a seed crystal of form B is added to the mixture.

[59] The method according to

[57] or

[58] , wherein the first addition of water is approximately 0.1 mL / g to approximately 0.5 mL / g of form A.

[60] The method according to any of

[57] to

[59] , wherein the addition of a second amount of water is approximately 1.0 to 1.5 mL / g of form A.

[61] Serpercatinib as polymorph B of formula I,

change

change

[62] Further comprising preparing a compound of structure [3] or a salt thereof, wherein the process is such that the compound has the following structure:

change

[61] , comprising reacting a (which is an amine protecting group) with a deprotecting agent to form a compound of structure [3] or a salt thereof.

[63] The process according to

[61] or

[62] , wherein the deprotecting agent is selected from the group consisting of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride, aluminum trichloride, and boron trifluoride.

[64] The process according to

[62] or

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

[65] The process according to any one of

[61] to

[64] , wherein the reducing agent is selected from the group consisting of alkali metal borohydrides, hydrazine compounds, citric acid, citrates, succinic acid, succinates, ascorbic acid, and ascorbic acid salts.

[66] The process according to any one of

[61] to

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

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

[61] to

[66] , wherein the group consists of formyl, acetyl, trifluoroacetyl, benzyl, benzoyl, carbamate, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butyloxycarbonyl (Boc), trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, nitroberatryloxycarbonyl, p-methoxybenzyl, and tosyl.

[68] R 1 The process described in any of

[61] to

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

[69] The process according to any one of

[61] to

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

[70] The process according to any one of

[61] to

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

[71] Compounds having structure [3], which are 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-methyl-2-trimethylsilyloxy-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitride,

change

Claims

1. A crystal of celpercatinib morph B, characterized by having an X-ray powder diffraction (XRPD) pattern with characteristic peaks occurring at 7.5°, 10.9°, 12.0°, 13.2°, 17.1°, 17.7°, 18.2°, 19.8°, 21.1°, and 24.5°±0.2°²θ when measured using an X-ray wavelength of 1.5418A.

2. A pharmaceutical composition comprising crystals of celpercatinib form B as described in claim 1, and a pharmaceutically acceptable carrier, diluent, or excipient.

3. The pharmaceutical composition according to claim 2, wherein the composition contains less than 20% by weight of crystals of another form of serpercatinib.

4. The pharmaceutical composition according to claim 2, wherein the composition contains less than 10% by weight of crystals of another form of serpercatinib.

5. The pharmaceutical composition according to claim 2, wherein the composition contains less than 5% by weight of crystals of another form of serpercatinib.

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

7. The pharmaceutical composition according to claim 6, wherein the cancer is selected from the group consisting of lung cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuroma of the gastrointestinal mucosa, and cervical cancer.

8. The pharmaceutical composition according to claim 7, wherein the cancer is medullary thyroid carcinoma.

9. The pharmaceutical composition according to claim 7, wherein the cancer is lung cancer, and the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiolocellular lung cancer, RET fusion lung cancer, or lung adenocarcinoma.

10. The pharmaceutical composition according to claim 9, wherein the cancer is RET-fusion lung cancer.

11. A process for producing crystals of cerpercatinib morph B as described in claim 1, (a) Suspending serpercatinib in a methanol-containing solvent, (b) Heat the suspension to 50°C to 60°C while stirring for 30 to 90 minutes, (c) Remove heat and cool the suspension to room temperature to form solid crystals, (d) Recovering the solid crystals A process that includes this.

12. A method for converting crystals of serpercatinib form A to crystals of serpercatinib form B as described in claim 1, wherein the crystals of serpercatinib form A are C １ ~C ５ This includes generating a slurry by combining it with an alcohol, and isolating crystals of serpercatinib form B from the slurry. The crystalline form A of the cell percatinib exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.9, 9.7, and 15.5°±0.2°²θ when measured using an X-ray wavelength of 1.5418 Å. method.

13. Said C １ ~C ５ The alcohol is at a temperature of 10°C to 30°C, and the above C １ ~C ５ The method according to claim 12, wherein the alcohol comprises methanol.

14. Said C １ ~C ５ The method according to claim 12 or 13, wherein the alcohol comprises at least 90% by weight of methanol.

15. A method for converting serpercatinib form A crystals to serpercatinib form B crystals, a. Dissolving the cerpercatinib form A crystals in a solvent containing DMSO to form a solution, b. Adding water to the solution to form a slurry, c. To isolate the crystals of serpercatinib form B. Includes, The crystalline form A of the cell percatinib, when measured using an X-ray wavelength of 1.5418 Å, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.9, 9.7, and 15.5°±0.2°²θ. The crystalline form B of the cell percatinib, when measured using an X-ray wavelength of 1.5418 Å, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks 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. method.

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

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

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

19. The method according to any one of claims 15 to 18, wherein the solution is cooled to a temperature of less than 70°C and greater than 20°C.

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

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

22. The method according to any one of claims 15 to 21, further comprising step b adding 1 to 15% by weight of a seed crystal of form B.

23. The method according to any one of claims 15 to 22, wherein the slurry is stirred for 6 to 72 hours after the water is added in step b.

24. The method according to any one of claims 15 to 23, further comprising step b adding a second fraction of water to the slurry.

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

26. The method according to any one of claims 15 to 25, wherein the slurry in step b is cooled to 20 to 30°C.

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

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

29. A method for converting serpercatinib form A crystals to serpercatinib form B crystals, The process involves combining cerpercatinib form A crystals with methanol to form a slurry, The slurry is stirred until >99% by weight of the crystals of form A are converted to crystals of form B. Includes, The concentration of the cerpercatinib form A crystals in the methanol is 8 mL / g. The crystalline form A of the cell percatinib, when measured using an X-ray wavelength of 1.5418 Å, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.9, 9.7, and 15.5°±0.2°²θ. The crystalline form B of the cell percatinib, when measured using an X-ray wavelength of 1.5418 Å, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks 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. method.

30. A method for converting serpercatinib form A crystals to serpercatinib form B crystals, The method comprises: dissolving crystals of celpercatinib form A in DMSO at 60-80°C to form a solution having a DMSO concentration of 10-15 mL / g per gram of crystals of form A; cooling the solution to 40-60°C and adding water; optionally sowing seed crystals of form B into the resulting mixture; stirring the mixture; adding more water; heating the mixture to 60-80°C; cooling the mixture; and isolating the crystals of form B. The crystalline form A of the cell percatinib, when measured using an X-ray wavelength of 1.5418 Å, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.9, 9.7, and 15.5°±0.2°²θ. The crystalline form B of the cell percatinib, when measured using an X-ray wavelength of 1.5418 Å, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks 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. method.

31. The method according to claim 30, wherein 5% by weight of seed crystals of form B is added to the mixture.

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

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

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