Crystals and pharmaceuticals containing them

Abstract

The invention relates to novel crystals of the compound (S)-N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamin maleate (hereinafter referred to as “compound A”). The I-form crystals of compound A exhibit diffraction peaks in its X-ray powder diffraction spectrum at least at the following diffraction angles 2θ: 6.9°, 9.4°, 12.5°, 15.1°, 16.4°, 18.3°, 19.0°, 24.9°, 25.4°, 27.3°, and 27.7°, wherein the X-ray powder diffraction spectrum is obtained by using a Cu Kα irradiation source (λ=1.54Å). The second-form crystal of compound A exhibits diffraction peaks in its X-ray powder diffraction spectrum at least at the following diffraction angles 2θ: 6.9°, 9.2°, 12.4°, 14.8°, 16.5°, 18.1°, 18.5°, 19.8°, 23.6°, 24.9°, and 27.7°, wherein the X-ray powder diffraction spectrum was obtained using a Cu Kα irradiation source (λ=1.54Å). The invention also relates to a pharmaceutical containing this crystal.

Description

crystal

[0001] The present invention relates to (S)-N ２ -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N ６ The present invention relates to a novel crystal of 2,6-(pyrazin-2-yl)pyridine-2,6-diamine maleate (hereinafter referred to as "Compound A").

[0002] Pharmaceuticals must maintain their quality over long periods of time, even under various distribution and storage conditions. Therefore, active ingredients require high physicochemical stability. For this reason, crystalline forms, which are expected to be highly stable, are typically used as active pharmaceutical ingredients. Screening for crystalline forms of pharmaceutical active ingredients not only poses challenges in finding optimal conditions for crystallization, but also often poses problems due to the existence of polymorphs, even when crystals are obtained. This problem stems from differences in physicochemical stability depending on the crystalline form. Furthermore, if the wrong crystalline form is selected for an active pharmaceutical ingredient, the external environment during storage can cause a decrease in purity and crystalline form transition, making it difficult to maintain a consistent compound quality. Depending on the crystalline form, this can lead to unexpected consequences, such as reduced efficacy and side effects. Therefore, once crystals of a pharmaceutical active ingredient are successfully obtained, rigorous evaluation and study of the physicochemical stability of the crystalline polymorphs is essential.

[0003] However, it is impossible to predict the presence or absence of crystalline polymorphism or stable crystalline forms from the structure of a compound, and there may be compounds that cannot form crystals. Therefore, it is necessary to consider various conditions for forming crystals for each compound.

[0004] On the other hand, Compound A has an excellent JAK2 tyrosine kinase inhibitory activity, and is therefore expected to be effective in treating various diseases (see, for example, Patent Documents 1 and 2). However, the existence of crystalline polymorphism, and even the possibility of forming crystals, is not known at present. Therefore, obtaining optimal crystals has been an important challenge in developing it as a pharmaceutical.

[0005] WO2010 / 090290A1WO2012 / 020787A1

[0006] L.Richeldi,et al.,2006,Leukemia,20,2210-2211Peter J.Campbell,et al.,2006,New England Journal of Medicine,355,2452-2466A Tefferi ,et al.,2009,Leukemia,23,905-911A Tefferi ,et al.,2010,Leukemia,24,1302-1309Robert Kralovics, et al.,2005,New England Journal of Medicine,352,1779-1790Yana Pikman,et al.,2006,PLoS Medicine,3,1140-1151Animesh D,et al.,2006,Blood,108,3472-3476Lyne Valentino,et al.,2006,Biochemical Pharmacology,71,713-721MM Ceesay,et al.,2006,Leukemia,20,2260-2261C.Mullighan,et al.,2009,Proceedings of the National Academy of Science U.S.A,106,9414-9418A.Gaikwad,et al.,2008,British Journal of Haematology,144,930-932Ajoy K.Samanta,et al.,2006,Cancer Research,66,6468-6472Cecile Meier, et al.,2009,Modern Pathology,22,476-487Anja Mottok, et al.,2007,Blood,110,3387-3390Anja Mottok, et al.,2009,Blood,114,4503-4506Ingo Melzner, et al.,2005,Blood,105,2535-2542Anas Young, et al.,2009,51st ASH ANNUAL MEETING AND EXPOSITIONStefan Hert, et al.,2009,51st ASH ANNUAL MEETING AND EXPOSITIONL. Neilson, et al. , 2007, Molecular Endocrinology, 21, 2218-2232H. Yu, et al. , 2009, Nature Reviews Cancer, 9, 798-809H. Ogura, et al. , 2008, Immunity, 29, 628-636R. Catlett-Falcone, et al. , 1999, Immunity, 10, 105-115M. Narazaki, et al. , 1994, Proceedings of the National Academy of Science U. S. A, 91, 2285-2289P. Heinrich, et al. , 2003, Biochemical Journal, 374, 1-20M. Steiner, et al. , 2009, Circulation Research, 104, 236-244H. Alexander, et al. , 2009, Biochemical Pharmacology, 78, 539-552,

[0007] An object of the present invention is to provide a crystal of Compound A having excellent physicochemical stability, and to provide a pharmaceutical composition containing said crystal as an active ingredient.

[0008] As a result of extensive research aimed at solving the above problems, the present inventors have succeeded in forming crystals of Compound A, discovered that there exist crystal polymorphs of Form I and Form II, and have completed the present invention.

[0009] Examples of the present invention include the following (1) to (5): (1) A type I crystal of Compound B (hereinafter referred to as "the type I crystal of the present invention"), which exhibits diffraction peaks at diffraction angles (2θ) of 6.9 degrees, 9.4 degrees, 12.5 degrees, 15.1 degrees, 16.4 degrees, 18.3 degrees, 19.0 degrees, 24.9 degrees, 25.4 degrees, 27.3 degrees, and 27.7 degrees in a powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ=1.54 Å), (2) A type I crystal of the present invention, which exhibits an endothermic peak at 203±3°C in differential scanning calorimetry, (3) Cu (3) A type II crystal of Compound B (hereinafter referred to as "the type II crystal of the present invention"), which exhibits diffraction peaks at diffraction angles (2θ) of 6.9 degrees, 9.2 degrees, 12.4 degrees, 14.8 degrees, 16.5 degrees, 18.1 degrees, 18.5 degrees, 19.8 degrees, 23.6 degrees, 24.9 degrees, and 27.7 degrees in a powder X-ray diffraction spectrum obtained using Kα radiation (λ=1.54 Å). (4) A type II crystal of the present invention, which has an endothermic peak at 200±3°C in differential scanning calorimetry. (5) A pharmaceutical composition containing the crystal according to any one of (1) to (4) as an active ingredient (hereinafter referred to as "the pharmaceutical composition of the present invention").

[0010] When specifying the diffraction angle 2θ of a diffraction peak in the examples and claims of the present invention, the obtained value should be understood to be within the range of said value ±0.2 degrees, preferably within the range of said value ±0.1 degrees. Also, when specifying an absorption peak of an infrared absorption spectrum (hereinafter referred to as "IR spectrum") in the examples and claims of the present invention, the obtained value should be understood to be within the range of said value ±2 cm. －１ Within the range of ±1 cm －１ Furthermore, when specifying an endothermic peak of a differential scanning calorimeter (hereinafter referred to as "DSC") in the examples and claims of the present invention, the obtained value should be understood to be within the range of that value ±3°C, preferably within the range of that value ±2°C.

[0011] 1 shows a powder X-ray diffraction spectrum chart of the type I crystal of the present invention. The vertical axis represents peak intensity (cps), and the horizontal axis represents diffraction angle (2θ [°]). 1 shows a powder X-ray diffraction spectrum chart of the type II crystal of the present invention. The vertical axis represents peak intensity (cps), and the horizontal axis represents diffraction angle (2θ [°]). 1 shows a DSC measurement chart when the temperature of the type I crystal of the present invention was increased by 10°C per minute. The vertical axis represents the amount of heat generated (mW) per second (a negative number represents endotherm), and the horizontal axis represents temperature (°C). 1 shows a DSC measurement chart when the temperature of the type II crystal of the present invention was increased by 10°C per minute. The vertical axis of the figure represents the amount of heat generated (mW) (a negative number represents endotherm), and the horizontal axis represents temperature (°C). 1 shows an IR spectrum chart of the type I crystal of the present invention. The vertical axis represents transmittance (%), and the horizontal axis represents wave number (cm －１ ) represents the IR spectrum chart of the type II crystal of the present invention. The vertical axis represents transmittance (%), and the horizontal axis represents wave number (cm －１ ) represents

[0012] A. Form I Crystal of the Present Invention The form I crystal of the present invention is characterized by exhibiting diffraction peaks at diffraction angles (2θ) of 6.9 degrees, 9.4 degrees, 12.5 degrees, 15.1 degrees, 16.4 degrees, 18.3 degrees, 19.0 degrees, 24.9 degrees, 25.4 degrees, 27.3 degrees, and 27.7 degrees in a powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ=1.54 Å). Preferably, in addition to the above diffraction peaks, the form I crystal of the present invention is characterized by exhibiting diffraction peaks at 19.6 degrees, 21.8 degrees, and 23.5 degrees. Furthermore, in an infrared absorption spectrum (KBr method), the form I crystal of the present invention exhibits a wavenumber of 1617 cm －１ , 1509 cm －１ , 1351 cm －１ , 1224 cm －１ and 866 cm －１ The type II crystal of the present invention is characterized by having an endothermic peak at 203° C. in differential scanning calorimetry. The type I crystal of the present invention can be obtained, for example, by the method described in Example 1 below.

[0013] B. Form II Crystal of the Present Invention The form II crystal of the present invention is characterized by exhibiting diffraction peaks at diffraction angles (2θ) of 6.9 degrees, 9.2 degrees, 12.4 degrees, 14.8 degrees, 16.5 degrees, 18.1 degrees, 18.5 degrees, 19.8 degrees, 23.6 degrees, 24.9 degrees, and 27.7 degrees in a powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ=1.54 Å). Preferably, in addition to the above diffraction peaks, the form II crystal of the present invention is characterized by exhibiting diffraction peaks at 20.5 degrees, 21.2 degrees, and 21.9 degrees. Furthermore, in an infrared absorption spectrum (KBr method), the form II crystal of the present invention exhibits a wave number of 1617 cm －１ , 1507 cm －１ , 1350 cm －１ , 1224 cm －１ and 865 cm －１ The type II crystal of the present invention is characterized by having an absorption peak at 200° C. in differential scanning calorimetry. The type II crystal of the present invention can be obtained, for example, by the method described in Example 2 below.

[0014] C. Pharmaceutical Uses and Pharmaceutical Compositions of the Present Invention Compound A of the present invention has excellent JAK2 tyrosine kinase inhibitory activity (see, for example, Patent Document 1). Therefore, the type I crystal of the present invention and the type II crystal of the present invention (hereinafter collectively referred to as the "crystals of the present invention") or the pharmaceutical composition of the present invention can be used to treat, for example, cancer [e.g., blood cancer {e.g., myeloproliferative tumors (chronic myeloproliferative disorders) such as polycythemia vera (see, for example, Non-Patent Document 1), essential thrombocythemia, idiopathic myelofibrosis (see, for example, Non-Patent Document 2), and secondary myelofibrosis (see, for example, Non-Patent Documents 3 and 4) (see, for example, Non-Patent Documents 5, 6, 7, and 8), myelodysplastic syndrome (see, for example, Non-Patent Document 9), acute lymphocytic leukemia (see, for example, Non-Patent Documents 10 and 11), acute myeloid leukemia (see, for example, Non-Patent Document 8), secondary myelofibrosis (see, for example, Non-Patent Document 9), and the like. The compound can be used as a preventive or therapeutic agent for acute myeloid leukemia (e.g., see Non-Patent Documents 3 and 4), chronic myeloid leukemia (e.g., see Non-Patent Document 12), multiple myeloma} (e.g., see Non-Patent Document 8), malignant lymphoma (e.g., Non-Patent Documents 13-18), solid cancers {e.g., prostate cancer, breast cancer (e.g., Non-Patent Document 19)}, and diseases in which IL-6 transmitted via JAK2 tyrosine kinase is involved in the pathology {e.g., inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis), vascular disorders (e.g., pulmonary hypertension, arteriosclerosis, aneurysm, varicose vein)} (e.g., see Non-Patent Documents 20-26).

[0015] "Malignant lymphoma" is not particularly limited as long as it is a lymphoma in which JAK2 tyrosine kinase is involved, and examples thereof include Hodgkin's lymphoma and non-Hodgkin's lymphoma, including relapsed and refractory lymphomas. "Non-Hodgkin's lymphoma" includes, for example, B-cell lymphoma and NK / T-cell lymphoma. "Hodgkin's lymphoma" includes, for example, nodular lymphocyte-predominant Hodgkin's lymphoma and classical Hodgkin's lymphoma. Examples of "B-cell lymphoma" include precursor B-lymphoblastic leukemia / lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma / chronic lymphocytic leukemia, marginal zone B-cell lymphoma, extranodal marginal zone lymphoma, splenic marginal zone lymphoma, nodal marginal zone lymphoma, lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, and Burkitt's lymphoma. Examples of "NK / T-cell lymphomas" include precursor T-cell lymphoblastic leukemia / lymphoma, T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia / lymphoma, mycosis fungoides, Sézary syndrome, primary cutaneous CD30-positive T-cell proliferative disorder, extranodal NK / T-cell lymphoma, nasal type, enteropathic T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, angioimmunoblastic lymphoma, peripheral T-cell lymphoma, nonspecific type, and anaplastic large cell lymphoma. Examples of "secondary myelofibrosis" include secondary myelofibrosis secondary to polycythemia vera and secondary myelofibrosis secondary to essential thrombocythemia. Examples of "secondary acute myeloid leukemia" include secondary acute myeloid leukemia arising from polycythemia vera, secondary acute myeloid leukemia arising from essential thrombocythemia, and secondary acute myeloid leukemia arising from myelofibrosis.

[0016] When administered as a pharmaceutical, the crystals of the present invention may be used as is or may be contained in a pharmaceutically acceptable, non-toxic, inert carrier, for example, in a range of 0.1% to 99.5%, preferably 0.5% to 90%. Examples of the carrier include solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliaries. These may be used singly or in combination.

[0017] The pharmaceutical composition of the present invention can be in the form of a solid or liquid dosage unit, such as oral preparations (e.g., powders, capsules, tablets, sugar-coated tablets, granules, powders, suspensions, liquids, syrups, elixirs, and lozenges), or parenteral preparations (e.g., injections and suppositories). It may also be a sustained-release formulation. Among these, oral preparations (e.g., tablets) are particularly preferred. Powders can be prepared by grinding the crystals of the present invention to a suitable fine size. Powders can be prepared by grinding the crystals of the present invention to a suitable fine size and then mixing them with a similarly ground pharmaceutical carrier, e.g., an edible carbohydrate such as starch or mannitol. Optionally, flavors, preservatives, dispersants, colorants, fragrances, etc. can be added. Capsules can be prepared by first filling the powders or powders prepared as described above or granulated as described in the tablet section into capsule shells such as gelatin capsules. Alternatively, lubricants or glidants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be mixed with the powdered or powdered formulation, followed by a filling operation. Adding disintegrants or solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, or sodium carbonate can improve the efficacy of the pharmaceutical when the capsule is ingested. Alternatively, a fine powder of the present crystals can be suspended in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and then wrapped in a gelatin sheet to form a soft capsule. Tablets can be prepared by adding an excipient to the powdered crystals of the present invention to prepare a powder mixture, granulating or slugging the mixture, adding a disintegrant or lubricant, and then compressing the mixture into tablets. The powder mixture can be prepared by mixing the appropriately powdered crystals of the present invention with a diluent or base.If desired, binders (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), dissolution retarders (e.g., paraffin), resorbents (e.g., quaternary salts), adsorbents (e.g., bentonite, kaolin), etc. may be added. Granules can be prepared by first wetting a powder mixture with a binder, such as syrup, starch paste, gum arabica, cellulose solution, or polymer solution, stirring, mixing, and then drying and milling. Instead of granulating the powder in this manner, it is also possible to first run the mixture through a tablet press, and then mill the resulting imperfectly formed slugs to form granules. The addition of lubricants such as stearic acid, stearates, talc, or mineral oil to the resulting granules can prevent them from sticking together. Alternatively, tablets can be prepared by directly compressing the crystals of the present invention into a mixture with a free-flowing inert carrier, without the granulation or slugging steps described above. These tablets can then be film-coated or sugar-coated. Transparent or translucent protective coatings such as a sealing coating of shellac, coatings of sugar or polymeric materials, and polishing coatings made of wax can also be used. Other oral preparations, such as liquids, syrups, lozenges, and elixirs, can also be prepared in dosage unit forms, with a fixed amount containing a predetermined amount of the crystals of the present invention. Syrups can be prepared by dissolving the crystals of the present invention in a suitable flavored aqueous solution. Elixirs can be prepared using a non-toxic alcoholic carrier. Suspensions can be prepared by dispersing the crystals of the present invention in a non-toxic carrier. If necessary, solubilizers, emulsifiers (e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (e.g., peppermint oil, saccharin), etc. can be added. If necessary, dosage unit formulations for oral administration can be microencapsulated. The formulations can also be coated or embedded in polymers, wax, etc. to extend the duration of action or provide sustained release.Parenteral preparations can be in the form of liquid dosage units, such as solutions or suspensions, for subcutaneous, intramuscular, or intravenous injection. Such parenteral preparations can be prepared by suspending or dissolving a predetermined amount of the crystals of the present invention in a non-toxic liquid carrier suitable for injection, such as an aqueous or oily medium, and then sterilizing the suspension or solution. Stabilizers, preservatives, emulsifiers, etc. can also be added. Suppositories can be prepared by dissolving or suspending the crystals of the present invention in a low-melting, water-soluble or insoluble solid, such as polyethylene glycol, cocoa butter, semi-synthetic oils and fats (e.g., Witepsol®), higher esters (e.g., myristyl palmitate), or mixtures thereof.

[0018] The dosage will vary depending on the patient's condition, such as body weight and age, the route of administration, the nature and severity of the disease, and other factors. Generally, for an adult, the amount of the crystals of the present invention is in the range of 0.001 mg to 100 mg per day, preferably 0.01 mg to 10 mg. In some cases, a smaller dose may be sufficient, while in other cases a larger dose may be required. The crystals can be administered once or several times a day, or at intervals of one day to several days.

[0019] D. Production of Compound A Compound A can be produced, for example, by the method described in Patent Document 1, but can also be produced by the production method described below.

[0020]

[0021] Step 1: Preparation of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine. 2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine can be produced by reacting 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine with 4-iodo-1-methyl-1H-pyrazole in the presence of a palladium catalyst and a base. This reaction can be carried out by a known method for a coupling reaction using a palladium catalyst. Examples of the reaction solvent used include a mixed solvent of an organic solvent (e.g., aromatic hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, and tetrahydropyran, or a mixed solvent thereof) and water. Examples of the palladium catalyst used include, for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (hereinafter referred to as "PdCl ２ (pdf)-CH ２ Cl ２ "), tetrakis(triphenylphosphine)palladium (hereinafter referred to as "Pd(PPh ３ ) ４"). Examples of the base used include potassium carbonate, sodium carbonate, potassium phosphate, and sodium phosphate. The amount of 4-iodo-1-methyl-1H-pyrazole used is, for example, suitably 1 to 3 times by mole, and preferably 1 to 2 times by mole, relative to 2,6-dichloro-4-(4,4,5,5)tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The amount of palladium catalyst used is, for example, suitably 0.02 to 1 time by mole, and preferably 0.02 to 0.03 times by mole, relative to 2,6-dichloro-4-(4,4,5,5)tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The amount of base used is, for example, suitably 2 to 10 times the molar amount, and preferably 3 to 4 times the molar amount, of 2,6-dichloro-4-(4,4,5,5)tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The reaction temperature varies depending on the types of raw materials and reagents used, but is usually carried out within a range of 80 to 100°C. The reaction time varies depending on the types of raw materials, reagents, and solvent used, and the reaction temperature, but is usually suitably within a range of 1 to 5 hours.

[0022] Step 2: Preparation of Compound A. Compound A can be prepared by reacting 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine with (S)-1-(4-fluorophenyl)ethylamine in the presence of a palladium catalyst, a ligand, and a base, further reacting with 2-aminopyrimidine, and then converting the resulting compound into a maleate. The reaction of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine, (S)-1-(4-fluorophenyl)ethylamine, and 2-aminopyrimidine can be carried out by a known method for a coupling reaction using a palladium catalyst, a ligand, and a base. Examples of the reaction solvent include aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, and tetrahydropyran, and mixed solvents thereof. Examples of the palladium catalyst used include palladium acetate (hereinafter referred to as "Pd(OAc)"). ２ "), tris(dibenzylideneacetone)dipalladium (Pd ２ (dba) ３ ), bis(acetylacetonato)palladium (Pd(acac) ２ ), PdCl ２ (pdf)-CH ２ Cl ２ , Pd(PPh ３ ) ４Examples of the ligand used include (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (hereinafter referred to as "BINAP"), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos). Examples of the base used include t-butoxypotassium, methoxypotassium, ethoxypotassium, t-butoxysodium, and a mixed base thereof. The amount of (S)-1-(4-fluorophenyl)ethylamine used is, for example, suitably 1 to 3 times the molar amount, and preferably 1 to 2 times the molar amount, of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine. The amount of the palladium catalyst used is, for example, suitably 0.02 to 1 molar amount relative to 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine, preferably 0.02 to 0.03 molar amount. The amount of the ligand used is, for example, suitably 0.02 to 1 molar amount relative to 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine, preferably 0.02 to 0.03 molar amount. The amount of the base used is, for example, suitably 1 to 3 molar amount relative to 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine, preferably 1 to 1.5 molar amount. The temperature when reacting with (S)-1-(4-fluorophenyl)ethylamine varies depending on the types of raw materials and reagents used, but is usually within the range of 55 to 65°C. The reaction time varies depending on the types of raw materials, reagents, and solvent used, and the reaction temperature, but is usually within the range of 1 to 5 hours. The amount of 2-aminopyrimidine used is, for example, suitably 1 to 3 times the molar amount, and preferably 1 to 2 times the molar amount, of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine. When adding 2-aminopyridine to the reaction solution, a base may also be added.The amount of base used is, for example, 1 to 3 times the molar amount relative to 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine, preferably within the range of 1 to 1.5 times the molar amount. The temperature when reacting with 2-aminopyridine varies depending on the types of raw materials and reagents used, but is usually within the range of 80 to 110°C. The reaction time varies depending on the types of raw materials, reagents, and solvent used, and the reaction temperature, but is usually within the range of 1 to 24 hours. The amount of maleic acid used is, for example, 1 to 5 times the molar amount relative to 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine, preferably within the range of 1 to 3 times the molar amount. The reaction temperature is usually within the range of 50 to 60°C. The reaction time varies depending on the reaction temperature, but is usually within the range of 1 to 24 hours.

[0023] Each compound used as a starting material in the above-mentioned method for producing Compound A is a known compound or can be produced according to a known method.

[0024] The present invention will be explained in more detail below with reference to examples and test examples, but the present invention is not limited to these examples at all.

[0025] Powder X-ray diffraction spectra were measured using a SmartLab (Rigaku Corporation) (optics: focusing method, voltage: 45 kV, current: 200 mA, wavelength: Cu Kα, solar slit: 5.0 degrees, scanning range: 4 to 40 degrees, scanning speed: 47.3 degrees / min, sample rotation: 60 degrees / min). IR spectra were measured using an IR Affinity-1 (Shimadzu Corporation) (measurement mode: % Transmittance, number of integrations: 32, resolution: 2.0, wavenumber range: 400 to 4000 cm). －１ The DSC was measured using a DSC-50 (manufactured by Shimadzu Corporation) (cell: alumina (open), gas: nitrogen (20.0 mL / min), heating rate: 10.0°C / min, hold temperature: 300°C, hold time: 0 min).

[0026] Example 1 Preparation of Compound A To a suspension of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine (35.6 kg) in tetrahydrofuran (213 L) and toluene (106 L) was added (S)-1-(4-fluorophenyl)ethylamine (23.9 kg), Pd(OAc), ２ (1.75 kg) and (±)-BINAP (6.3 kg) were added and stirred at 60°C for 1 hour. Further, t-butoxypotassium (21.0 kg) was added and stirred at 60°C for 1 hour. After cooling to room temperature, 2-aminopyrimidine (17.8 kg) and t-butoxypotassium (19.3 kg) were added and stirred at 90°C for 5 hours. After cooling to 60°C, the organic layer was washed with an aqueous ethylenediamine solution, and the solvent was distilled off under reduced pressure. Ethyl acetate (356 L) was added to the concentrated residue, and maleic acid solution (maleic acid (21.7 kg) dissolved in 2-propanol (71 L)) was added at 55°C, followed by stirring at 55°C for 30 minutes. After cooling to below 10°C, stirring was continued for 1 hour. The resulting precipitate was filtered and washed with ethyl acetate (107 L). The precipitate was dried under reduced pressure at 50°C to obtain the target compound (35.9 kg).

[0027] Example 2: Preparation of Form I Crystal of the Present Invention Compound A (35.9 kg) prepared in Example 1, Si-Thiol (Biotage Japan) (1.76 kg), and activated carbon (1.84 kg) were dissolved in N,N-dimethylformamide (107 L) at 60°C and stirred at the same temperature for 30 minutes. This solution was filtered and washed with N,N-dimethylformamide (72 L), and the resulting filtrate was concentrated under reduced pressure. Ethyl acetate (539 L) was added to the concentrate at 50°C, gradually cooled, and stirred at 10°C or below for 1 hour. The precipitated crystals were collected by filtration and washed with ethyl acetate (108 L). The mixture was dried under reduced pressure at 80°C to obtain Form I Crystal of the present invention (31.6 kg). The results of powder X-ray diffraction, DSC, and IR measurements of the Form I crystal of the present invention are shown in Figures 1, 3, and 5, respectively. Diffraction angle 2θ: 6.9 degrees, 9.4 degrees, 12.5 degrees, 15.1 degrees, 16.4 degrees, 18.3 degrees, 19.0 degrees, 19.6 degrees, 21.8 degrees, 23.5 degrees, 24.9 degrees, 25.4 degrees, 27.3 degrees and 27.7 degrees IR absorption peak: 1617 cm －１ , 1509 cm－１ , 1351 cm －１ , 1224 cm －１ and 866 cm －１ DSC endothermic peak: 203°C

[0028] Example 3: Preparation of Form II Crystal of the Present Invention Compound A (0.5 g) prepared in Example 1 was suspended in 80% aqueous acetone (4 mL) and stirred at room temperature for 1 hour. The suspension was filtered and washed with a small amount of 80% aqueous acetone. Water (40 mL) was added to the filtrate and stirred at room temperature for 1 day. The mixture was further filtered and washed with a small amount of water, and the filtrate was concentrated under reduced pressure to remove acetone. After concentration, the concentrate was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration and washed with water. The concentrate was dried under reduced pressure at 60°C to obtain Form II Crystal of the Present Invention (0.13 g). The results of powder X-ray diffraction, DSC, and IR measurements of the Form II Crystal of the present invention are shown in Figures 2, 4, and 6, respectively. Diffraction angle 2θ: 6.9 degrees, 9.2 degrees, 12.4 degrees, 14.8 degrees, 16.5 degrees, 18.1 degrees, 18.5 degrees, 19.8 degrees, 20.5 degrees, 21.2 degrees, 21.9 degrees, 23.6 degrees, 24.9 degrees and 27.7 degrees IR absorption peak: 1617 cm －１ , 1507 cm －１ , 1350 cm －１ , 1224 cm －１ and 865 cm －１ DSC endothermic peak: 200°C

[0029] Test Example 1: Results of crystallization experiments in various solvents Various solvents were added to the type I crystal of the present invention (several mg), and crystals of Compound A were precipitated by the following procedures, and the crystal forms of the precipitated crystals were confirmed. The results of procedures 1 to 4 are shown in Tables 1 and 2, and the results of procedure 4 are shown in Table 3. The symbol "-" in Tables 1 to 3 means that no precipitate was obtained.

[0030] Procedure 1: Various solvents (50 μL) were added to the type I crystals of the present invention to form a suspension, and the suspension was stirred for two days while repeatedly cooling and heating between 4 and 40°C. Procedure 2: Various solvents (50 μL) were added to the type I crystals of the present invention to dissolve them at 40°C. If they did not dissolve, the insoluble matter was filtered to give a solution. The solution was cooled to 4°C and stirred for three days. Procedure 3: Various solvents (50 μL) were added to the type I crystals of the present invention to dissolve them at 40°C. If they did not dissolve, the insoluble matter was filtered to give a solution. The solvent was slowly distilled off at room temperature. Procedure 4: Various dissolving solvents (minimum volume) were added to the type I crystals of the present invention to prepare saturated solutions. Various antisolvents were added.

[0031]

[0032]

[0033] As described above, in crystallization from various solvents, the type I crystal of the present invention was preferentially crystallized, and the type II crystal of the present invention was crystallized only in aqueous systems that are not used in the production of active pharmaceutical ingredients, such as aqueous acetone, aqueous ethanol, and aqueous tetrahydrofuran.

[0034] Test Example 2: Stability Test: Form II crystals of Compound A were placed in a glass bottle, sealed, and stored at 90°C. After 1, 3, and 7 days, samples were taken out and dissolved in methanol at a concentration of 1 mg / mL to measure the amount of related substances by HPLC, and the crystal form of the crystals after 7 days was confirmed. The results are shown in Table 4.

[0035] The above results demonstrate that all crystalline forms have extremely high chemical and physical stability.

[0036] Test Example 3: Solvent-Mediated Transition Test: Each solvent was added to Form I crystals of Compound A and stirred at room temperature for 24 hours, and then insoluble matter was filtered to prepare saturated solutions. A 1:1 mixed crystal of Form I and Form II (approximately 10 mg) was added to each solution and stirred at room temperature for 5 days. The formed crystals were filtered and the crystal form was confirmed. The results are shown in Table 5.

[0037] As described above, the mixtures of various crystalline forms all transformed into the type I crystal of the present invention after 5 days in acetonitrile, ethyl acetate, and aqueous acetone at room temperature. This result demonstrated that the type I crystal of the present invention is thermodynamically stable in each solvent.

Claims

1. (S)-N, which exhibits diffraction peaks at diffraction angles (2θ) of 6.9 degrees, 9.4 degrees, 12.5 degrees, 15.1 degrees, 16.4 degrees, 18.3 degrees, 19.0 degrees, 24.9 degrees, 25.4 degrees, 27.3 degrees, and 27.7 degrees in a powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ=1.54 Å). ２ -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N ６ Form I crystal of -(pyrazin-2-yl)pyridine-2,6-diamine maleate.

2. (S)-N having an endothermic peak at 203±3°C in differential scanning calorimetry ２ -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N ６ Form I crystal of -(pyrazin-2-yl)pyridine-2,6-diamine maleate.

3. (S)-N, which exhibits diffraction peaks at diffraction angles (2θ) of 6.9 degrees, 9.2 degrees, 12.4 degrees, 14.8 degrees, 16.5 degrees, 18.1 degrees, 18.5 degrees, 23.6 degrees, 24.9 degrees, and 27.7 degrees in a powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ=1.54 Å). ２ -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N ６ -(pyrazin-2-yl)pyridine-2,6-diamine maleate crystal form II.

4. (S)-N having an endothermic peak at 200±3°C in differential scanning calorimetry ２ -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N ６ -(pyrazin-2-yl)pyridine-2,6-diamine maleate crystal form II.

5. A pharmaceutical composition containing the crystal according to any one of claims 1 to 4 as an active ingredient.

6. A JAK2 tyrosine kinase inhibitor containing the crystal according to any one of claims 1 to 4 as an active ingredient.

7. A therapeutic agent for polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, secondary myelofibrosis, acute myeloid leukemia, and secondary acute myeloid leukemia, comprising the crystal according to any one of claims 1 to 4 as an active ingredient.