Tartrate salt of 1-((3s,4r)-3-((2-((1-ethyl-1h-pyrazol-4-yl)amino)-7h-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, crystalline form thereof, and method for preparing same

Abstract

The present invention relates to a tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, a crystalline form thereof, and a method for preparing same. The tartrate salt and the crystalline form have lower hygroscopicity and improved stability and solubility compared to a free base, and thus are suitable for pharmaceutical use. In addition, the method for preparing the tartrate salt or crystalline form of the present invention has the advantage of enabling mass production and improving the safety of the preparation process by using safer substances than reactants used in conventional preparation methods.

Description

Tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-D]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, crystal form thereof and preparation method thereof

[0001] Cross-citation with related application(s)

[0002] This application claims the benefit of priority to Korean Patent Application No. 10-2023-0174736, filed December 5, 2023, Korean Patent Application No. 10-2023-0174737, filed December 5, 2023, Korean Patent Application No. 10-2024-0006933, filed January 16, 2024, and Korean Patent Application No. 10-2024-0164582, filed November 18, 2024, the entire contents of which are incorporated herein by reference.

[0003]

[0004] The present invention relates to a tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, a crystalline form thereof and a process for preparing the same.

[0005]

[0006] The selection of pharmaceutically acceptable salts and their polymorphs is a crucial step in the research and development of new drugs. This is because specific salt forms and their polymorphs can significantly impact the development of the drug substance manufacturing process, the design of the finished drug product, and its formulation.

[0007]

[0008] Specifically, the type of salt and its polymorph can influence the recrystallization yield, process speed, and purity during the final stages of raw pharmaceutical manufacturing, namely recrystallization and purification. In particular, crystal size and shape can affect the crystallization rate, making the selection of salt and polymorph crucial for both raw pharmaceutical productivity and manufacturing costs.

[0009]

[0010] Furthermore, adding a salt to a specific drug can alter its physicochemical and biological properties without altering its chemical structure. From a pharmaceutical perspective, physicochemical properties such as hygroscopicity, stability, solubility, particle flowability, and dissolution rate are influenced by the salt's form and its polymorphism. Accordingly, the salt's form and its polymorphism determine the finished drug product's production process, production and storage conditions, and shelf life.

[0011]

[0012] Therefore, continuous research is needed to select salts and polymorphs that can exhibit better stability and better bioavailability in the preparation of specific drugs.

[0013]

[0014] Meanwhile, the present inventors have identified 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one as a novel active pharmaceutical substance having excellent inhibitory activity as a kinase inhibitor for both JAK3 and BTK.

[0015]

[0016] Accordingly, the inventors of the present invention conducted research on the selection of a pharmaceutically acceptable salt and a crystal form thereof that can improve the solubility and stability of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, and as a result, confirmed that it is possible to obtain a crystalline structure when producing a tartrate salt, and that the solubility, crystallinity, and stability under harsh conditions can be improved, thereby completing the present invention.

[0017]

[0018] The present invention provides a tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0019]

[0020] In addition, the present invention provides a method for preparing a tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0021]

[0022] In addition, the present invention provides a crystalline form of tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0023]

[0024] In addition, the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, an autoimmune disease, a proliferative disease, a hyperproliferative disease, an immunologically mediated disease, a cancer, or a tumor, comprising at least one selected from the group consisting of a crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate and a crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate.

[0025]

[0026] In addition, the present invention provides a novel intermediate compound obtained during the process for preparing the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0027]

[0028] To solve the above problem, the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one is provided.

[0029]

[0030] In addition, the present invention provides a method for preparing a tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, which is a compound represented by the following chemical formula 1, and more specifically, the method comprises the following steps, but further comprises a crystallizing step in at least one of the following steps 1 to 4:

[0031] (Step 1) A step of preparing a compound represented by the following chemical formula 1-3 by reacting a compound represented by the following chemical formula 1-1 and a compound represented by the following chemical formula 1-2 in the presence of a base;

[0032] (Step 2) A step of producing a compound represented by the following chemical formula 1-5 by reacting a compound represented by the following chemical formula 1-3 and a compound represented by the following chemical formula 1-4 in the presence of a palladium catalyst and a base;

[0033] (Step 3) A step of reacting a compound represented by the following chemical formula 1-5 with an acid to produce a compound represented by the following chemical formula 1-6;

[0034] (Step 4) A step of preparing a compound represented by the following chemical formula 1 by reacting a compound represented by the following chemical formula 1-6 and a compound represented by the following chemical formula 1-7 in the presence of a base; and

[0035] (Step 5) A step of producing a tartrate salt of a compound represented by chemical formula 1 by reacting a compound represented by chemical formula 1 with tartaric acid.

[0036] [Chemical Formula 1]

[0037]

[0038] [Chemical Formula 1-1]

[0039]

[0040] [Chemical Formula 1-2]

[0041]

[0042] [Chemical Formula 1-3]

[0043]

[0044] [Chemical Formula 1-4]

[0045]

[0046] [Chemical Formula 1-5]

[0047]

[0048] [Chemical Formula 1-6]

[0049]

[0050] [Chemical Formula 1-7]

[0051]

[0052] In the above chemical formulas 1-1 to 1-7,

[0053] P1 stands for protector.

[0054]

[0055] The present invention also provides a crystalline form of tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0056]

[0057] In addition, the present invention provides a method for preparing a tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, which comprises a compound represented by the following chemical formula 1-5 as an intermediate:

[0058] [Chemical Formula 1-5]

[0059]

[0060] In the above chemical formula 1-5,

[0061] P1 stands for protector.

[0062]

[0063] In addition, the present invention provides a compound represented by the following chemical formula 1-5:

[0064] [Chemical Formula 1-5]

[0065]

[0066] In the above chemical formula 1-5,

[0067] P1 stands for protector.

[0068]

[0069] Preferably, in the present invention, the tartaric acid of the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one may be L-tartaric acid.

[0070]

[0071] Meanwhile, the novel active pharmaceutical ingredient 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one is represented by the following chemical formula 1:

[0072] [Chemical Formula 1]

[0073]

[0074]

[0075] The above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one and pharmaceutically acceptable salts thereof can be usefully used for the prevention or treatment of diseases in which kinase inhibition is beneficial. Therefore, the above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one and pharmaceutically acceptable salts thereof can be usefully applied to the prevention or treatment of inflammatory diseases, autoimmune diseases, proliferative diseases, hyperproliferative diseases, immunologically mediated diseases, cancer, or tumors.

[0076]

[0077] Here, the pharmaceutically acceptable salt of the above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one is a tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one. The above tartrate can be prepared by reacting the free base of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one with tartaric acid at a specific ratio.

[0078]

[0079] In addition, the tartrate salt of the above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one can exhibit a crystal form. The tartrate salt of the above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one can be prepared by various crystallization methods such as evaporative crystallization, melt crystallization, reaction crystallization, solvent-mediated polymorphic transition, and solid-state polymorphic transition, which are selected depending on the thermodynamic and dynamic properties of the salt. Accordingly, the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one can be produced in a crystalline form as such.

[0080]

[0081] At this time, the tartrate salt or the crystalline form of the tartrate salt of the 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one can be confirmed through X-ray powder diffraction analysis. Specifically, the tartrate salt or the crystalline form can be distinguished through the diffraction angle (2θ) showing a characteristic peak in the X-ray powder diffraction pattern and the intensity of the peak according to each diffraction angle (2θ). Here, the diffraction angle (2θ) may vary by ±0.2°, or preferably ±0.1°, depending on various factors such as the manufacturing technique of the measurement sample, the fixing procedure of the measurement sample, and the measurement device.

[0082]

[0083] In addition, the crystalline form of the tartrate or tartrate salt of the above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one can also be distinguished by the endothermic temperature indicating the endothermic onset temperature and the maximum endothermic peak in differential scanning calorimetry, respectively. Here, the temperature may vary by ±3°C, preferably ±2°C, or more preferably ±1°C, depending on various factors such as the manufacturing technique of the sample for measurement, the measuring instrument, and the rate of temperature change.

[0084]

[0085] Hereinafter, the present invention will be described in detail.

[0086]

[0087] [1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate]

[0088]

[0089] The free base form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one is known to have poor stability. Therefore, in order to improve the stability of this compound, we conducted a preliminary study on tartaric acid and confirmed that when the compound and tartaric acid are combined at a specific equivalent ratio, stability and crystallinity can be improved.

[0090]

[0091] The tartrate salt of the above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one is composed of the group consisting of diffraction angles (2θ±0.2°) of 5.2°, 8.0°, 10.4°, 12.5°, 13.1°, 13.7°, 15.4°, 16.5°, 16.9°, 17.9°, 18.3°, 18.8°, 20.1°, 20.5°, 21.3° and 21.6° in the X-ray powder diffraction pattern irradiated with a Cu light source. It can have three or more peaks selected. Since the crystalline form as well as the free base are produced together during the production of the above tartrate, an X-ray powder diffraction pattern is observed.

[0092]

[0093] In addition, the tartrate salt of the above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one can exhibit an endothermic onset temperature of 171.48 ± 1.0 °C and a maximum endothermic peak at an endothermic temperature of 175.86 ± 1.0 °C in differential scanning calorimetry.

[0094]

[0095] Meanwhile, the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one is prepared through the following reaction scheme 1:

[0096] [Reaction Formula 1]

[0097]

[0098] In the above reaction formula 1, P1 represents a protecting group.

[0099]

[0100] More specifically, P1 may be any one protecting group selected from the group consisting of tert-butoxycarbonyl (Boc), carbobenzyloxy (Cbz), para-methoxybenzylcarbonyl (Moz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), and para-methoxybenzyl (PMB).

[0101]

[0102] At this time, in terms of ease of manufacturing and yield, it is preferable that P1 is tert-butoxycarbonyl (Boc).

[0103]

[0104] The above manufacturing method does not involve a separate protecting group substitution reaction, thereby reducing the number of process steps compared to conventional manufacturing methods. Furthermore, the absence of a column purification step improves the yield and / or purity of the final product, and crystallization purification is performed in at least one step, making it advantageous for mass production. Furthermore, the absence of the previously used explosive base (e.g., NaH) ensures safety during the process, and the lower reaction temperature in some steps compared to conventional methods makes it advantageous for application to general production plants and offers economic benefits.

[0105]

[0106] Meanwhile, each step described below may further include a post-reaction purification step to produce a compound with high purity and yield. Examples of the purification method include extraction utilizing differences in solubility, adsorption using activated carbon and / or silica-based materials, filtration, precipitation, crystallization, etc. However, column chromatography, which is not suitable for mass production, is not used as a purification method. Preferably, the purification step may be performed as described in each step.

[0107]

[0108] Additionally, each step may further include a crystallization step using a crystallization solvent as the final step. If the purification step is performed, the crystallization step may be performed after the purification step. If the purification step is not performed, the crystallization step may be performed after the reaction. By further including the crystallization step, mass production is possible. The crystallization solvent may be used according to the product of each step, but is not particularly limited. Preferably, the crystallization step may be performed as described in each step.

[0109]

[0110] (Step 1)

[0111] Step 1 above is a step of producing a compound represented by Chemical Formula 1-3 by reacting a compound represented by Chemical Formula 1-1 and a compound represented by Chemical Formula 1-2 in the presence of a base. The reaction is a nucleophilic aromatic substitution reaction, and is performed in the presence of a base to make the compound represented by Chemical Formula 1-2 added into a nucleophile.

[0112]

[0113] In the above step 1, the compound represented by the above chemical formula 1-2 can be used in an amount of 0.1 to 10 equivalents relative to 1 equivalent of the compound represented by the above chemical formula 1-1. Specifically, the compound represented by the above chemical formula 1-2 can be used in an amount of 0.2 to 5 equivalents, 0.3 to 3 equivalents, 0.5 to 2 equivalents, 0.7 to 1.5 equivalents, 1 to 1.5 equivalents, 1 to 1.3 equivalents, 1 to 1.05 equivalents, or 1.05 equivalents relative to 1 equivalent of the compound represented by the above chemical formula 1-1.

[0114]

[0115] In addition, in the above step 1, the base may be at least one selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, potassium tert-pentoxide, sodium tert-pentoxide, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, calcium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium carbonate. Among these, it is preferable to use potassium tert-butoxide in terms of reaction speed and yield. Since the base used is sufficiently non-explosive, safety is ensured, and thus it is advantageous for industrialization.

[0116]

[0117] And, the base can be used in an amount of 0.1 to 10 equivalents relative to 1 equivalent of the compound represented by the chemical formula 1-1. Preferably, the base can be used in an amount of 0.5 to 5 equivalents, 1 to 5 equivalents, 2 to 5 equivalents, 2 to 3 equivalents, or 3 equivalents relative to 1 equivalent of the compound represented by the chemical formula 1-1. If the base is used in an excessively small amount, there is a concern that the reaction time may be prolonged, and even if it is used in an excessively large amount, there is no difference in the reaction time, so it is preferable to use the base in the above-mentioned range.

[0118]

[0119] In the above step 1, the reaction may be carried out in one or more organic solvents selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, heptane, 3-methyltetrahydrofuran, dichloromethane, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide (DMAC), and dimethyl sulfoxide (DMSO). For example, one type of the solvent may be used, or a mixed solvent of two or more types may be used. Preferably, 1,4-dioxane may be used as the organic solvent. 1,4-Dioxane yields a higher purity product than other solvents and facilitates layer separation during extraction. Other solvents, however, often produce relatively large amounts of impurities or exhibit slow reaction rates.

[0120]

[0121] Additionally, the organic solvent may be used in an amount (mL / g) of 5 to 30 times the volume of the compound represented by the chemical formula 1-1, more specifically, in an amount (mL / g) of 5 to 15 times the volume of the compound represented by the chemical formula 1-1.

[0122]

[0123] Additionally, the above reaction can be carried out at 30 to 60°C for 2 to 10 hours. If the reaction is carried out at a temperature lower than the above-described range and / or for a short reaction time, the reaction may not proceed sufficiently, resulting in a low production yield. Furthermore, even if the reaction is carried out at a temperature higher than the above-described range and / or for a long reaction time, the production yield does not substantially increase, which is undesirable from a process cost perspective.

[0124]

[0125] Meanwhile, after the reaction of Step 1 is completed, a purification step of extracting the product of the reaction using ethyl acetate and / or water may be further included. Specifically, the product of the reaction may be extracted using ethyl acetate and water. That is, the compound represented by the above chemical formula 1-3 may be extracted using ethyl acetate and water after the completion of the reaction. The extraction using ethyl acetate and water may be carried out by stirring a mixture containing the product of the reaction and each solvent for 30 minutes or more, allowing it to stand for 30 minutes or more, separating the layers, discarding the aqueous layer (lower layer), and taking the organic layer (upper layer). The extraction using ethyl acetate and water may be repeated one or more times. In the case of extraction in this manner, impurities having a relative retention time of less than 1.0 as separated by high-performance liquid chromatography (HPLC) can be effectively removed in the aqueous layer, compared to the case of extraction using a methylene chloride / water mixed solvent.

[0126]

[0127] In addition, the above step 1 may further include a step of vacuum concentration and / or azeotropic concentration after filtering the extracted mixture. It is preferable that the vacuum concentration and / or azeotropic concentration step is performed after the extraction step using ethyl acetate and / or water.

[0128]

[0129] In addition, the step 1 may further include a step of crystallizing the product of the reaction in order to purify the compound represented by the chemical formula 1-3. This crystallization step is preferably performed after the extraction purification step. In other words, the step 1 may be performed as a step of preparing the compound represented by the chemical formula 1-3 by adding a crystallization solvent to the concentrated product after the extraction purification step and stirring the mixture at a temperature of about 20 to 50°C for 30 minutes to 4 hours.

[0130] In this way, when a reaction product is manufactured through crystallization using a crystallization solvent, unlike column chromatography that purifies using a silica column, it can be applied to industrialization, and is advantageous in terms of industrial mass production, and has the advantage of being able to obtain a high yield.

[0131]

[0132] Specifically, the crystallization step can be performed by crystallization using water as a crystallization solvent. The crystallization step can be performed by repeating the crystallization process in the order of 'injecting the crystallization solvent and then stirring' one or more times. In this way, when the crystallization process is repeated while injecting the solvent several times instead of all at once, even the crystals stuck to the wall during the solvent injection process can be obtained, thereby preventing a decrease in yield, byproducts remaining after the reaction can be effectively removed, and products that were not crystallized can be crystallized through the repeated crystallization process. Accordingly, compared to a process of purifying in the form of a slurry using a solvent such as ethyl acetate, a high-purity compound can be obtained in a high yield.

[0133]

[0134] The crystallization solvent used in the above crystallization process once may be used in an amount (mL / g) of 3 to 20 times the volume of the compound represented by the above chemical formula 1-1, more specifically, in an amount (ml / g) of 3 to 10 times the volume. The single crystallization process may be carried out by stirring at a temperature range of 5 to 30°C, preferably at room temperature (20 to 25°C) for 10 minutes to 2 hours. The progress time may be appropriately adjusted, such as increasing when the number of repetitions of the crystallization process is small, or decreasing when the number of repetitions is large.

[0135]

[0136] That is, when the steps of purifying and crystallizing the reaction product of step 1 are all performed to produce the compound represented by the chemical formula 1-3, step 1 may be performed including the following steps, but is not limited to the following steps:

[0137] A step of reacting a compound represented by the above chemical formula 1-1 and a compound represented by the above chemical formula 1-2 in the presence of a base;

[0138] A step of adding ethyl acetate and water, discarding the aqueous layer (lower layer) and separating and extracting the organic layer (upper layer), and a step of vacuum concentrating and / or azeotropically concentrating the purified mixture; and

[0139] A step of crystallizing the above concentrate.

[0140]

[0141] After purifying the compound represented by the above chemical formula 1-3, the moisture content contained in the compound represented by the above chemical formula 1-3 can be reduced by drying at 40 to 60°C for 10 to 14 hours. More specifically, by significantly reducing the moisture content of the compound represented by the above chemical formula 1-3 by drying at 50 to 60°C, the conversion rate of the next step (i.e., step 2 below) can be increased.

[0142]

[0143] (Step 2 and Step 3)

[0144] Step 2 above is a step of producing a compound represented by Chemical Formula 1-5 by reacting a compound represented by Chemical Formula 1-3 and a compound represented by Chemical Formula 1-4 in the presence of a palladium catalyst and a base, and a Buchwald-Hartwig amination reaction is performed. The Buchwald-Hartwig amination reaction is a reaction in which a carbon and nitrogen bond is formed through a palladium-catalyzed coupling reaction of an amine and an aryl halide. In addition, Step 3 above is a step of producing a compound represented by Chemical Formula 1-6 below by reacting a compound represented by Chemical Formula 1-5 with an acid, and is a step of removing a protecting group P1 included in Chemical Formula 1-5.

[0145]

[0146] The concentrated residue containing the compound represented by Chemical Formula 1-5 generated in Step 2 above can be used as is in the next step without a separate purification process, enabling a stable reaction without any decrease in yield or purity. Therefore, considering the economic effect resulting from the omission of the purification step and the ease and convenience of the process, the concentrated residue of Step 2 above can be used as is to perform Steps 2 and 3 in situ.

[0147]

[0148] In the above step 2, the compound represented by the above chemical formula 1-4 can be used in an amount of 0.1 to 10 equivalents relative to 1 equivalent of the compound represented by the above chemical formula 1-3. Specifically, the compound represented by the above chemical formula 1-4 can be used in an amount of 0.2 to 5 equivalents, 0.5 to 5 equivalents, 0.5 to 3 equivalents, 0.5 to 2 equivalents, 0.5 to 1.5 equivalents, 1 to 1.5 equivalents, or 1.5 equivalents relative to 1 equivalent of the compound represented by the above chemical formula 1-3.

[0149]

[0150] In the above step 2, the palladium catalyst may be a palladium(0) catalyst in which the valency of palladium (Pd) in the compound is 0, or a palladium(II) catalyst in which the valency is +2. For example, the palladium catalyst may be at least one selected from the group consisting of tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), bis[tris(2-methylphenyl)phosphine]palladium, palladium(II) acetate, 1,1-(bis(diphenylphosphino)ferrocene)palladium(II) dichloride, and palladium(II) chloride.

[0151]

[0152] In addition, in the above step 2, the base may be at least one selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, potassium tert-pentoxide, sodium tert-pentoxide, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, calcium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and cesium carbonate. A non-explosive base is sufficient as the base used, ensuring safety and thus being advantageous for industrialization.

[0153]

[0154] In addition, the above reaction can be carried out in the presence of a phosphine compound together with the palladium catalyst and the base. As the phosphine compound, at least one selected from the group consisting of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2,4'6'-triisopropyl-1,1'-biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, and dicyclohexylphosphino-2',6'-diisopropoxybiphenyl can be used.

[0155]

[0156] Preferably, in the step 2, the base may be used in an amount of 0.1 to 10 equivalents relative to 1 equivalent of the compound represented by the chemical formula 1-3. Preferably, the base may be used in an amount of 0.5 to 5 equivalents, 1 to 5 equivalents, 2 to 5 equivalents, 3 to 5 equivalents, or 3 equivalents relative to 1 equivalent of the compound represented by the chemical formula 1-3. If the base is used in an excessively small amount, there is a concern that the reaction time may be prolonged, and even if it is used in an excessively large amount, there is no difference in the reaction time, so it is preferable to use the base in the above-described range.

[0157]

[0158] The reaction solvent of step 2 above may be a solvent that is inactive for the amine substitution reaction. For example, the reaction may be performed in one or more organic solvents selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, sec-butyl alcohol, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, tert-butyl alcohol, acetone, methyl ethyl ketone, ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, xylene, heptane, 3-methyltetrahydrofuran, dichloromethane, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide (DMAC), and dimethyl sulfoxide (DMSO). For example, one type of the solvent may be used, or a mixed solvent of two or more types may be used, but secbutyl alcohol is preferable in terms of reaction speed and yield.

[0159]

[0160] The organic solvent may be used in an amount (mL / g) of 0.5 to 10 times the volume of the compound represented by the chemical formula 1-3, specifically, 4 to 8 times, or 4 to 6 times the volume of the compound represented by the chemical formula 1-3. If the solvent is used in excess during the reaction in step 2, there is a problem in that the reaction does not proceed.

[0161]

[0162] In addition, the reaction can be carried out at a temperature of 80 to 100°C for 1 to 10 hours. If the reaction is carried out at a temperature lower than the above-mentioned range and / or for a short reaction time, the reaction may not proceed sufficiently, resulting in a low production yield. In addition, even if the reaction is carried out at a temperature higher than the above-mentioned range and / or for a long reaction time, the production yield does not substantially increase, which is not preferable in terms of process cost. More specifically, the reaction can be carried out at a temperature of 85 to 95°C or 88 to 92°C for 1 to 6 hours, 1 to 4 hours, preferably 1 to 3 hours, and more preferably 1.5 to 2 hours. The temperature of the reaction is in a range far below the boiling point of the reaction solvent, which is significantly lower than the conventional reaction temperature, making it easy to apply in the process and having the effect of saving time and cost.

[0163]

[0164] Additionally, the above reaction can be carried out in a conventionally known reactor using the combination of the above-described palladium catalyst, base, and phosphine compound. Accordingly, Step 2 can be applied as a step in a process for mass-producing the compound represented by the above chemical formula 1.

[0165]

[0166] Meanwhile, after the reaction of Step 2 is completed, a purification step of extracting the product of the reaction using ethyl acetate and water or using ethyl acetate and an aqueous sodium chloride solution may be further included. Specifically, the product of the reaction may be extracted using ethyl acetate and water or using ethyl acetate and an aqueous sodium chloride solution, or using both of the above methods. That is, the compound represented by the above Chemical Formula 1-5 may be extracted using ethyl acetate and water or using ethyl acetate and an aqueous sodium chloride solution after the completion of the reaction. The extraction using ethyl acetate and water or using ethyl acetate and an aqueous sodium chloride solution may be carried out by stirring a mixture containing the product of the reaction and each solvent for 30 minutes or more, allowing it to stand for 30 minutes or more, separating the layers, discarding the aqueous layer (lower layer), and taking the organic layer (upper layer). The extraction using ethyl acetate and water or using ethyl acetate and an aqueous sodium chloride solution may each be repeated one or more times. In this extraction, compared to extraction using a methylene chloride / water mixture solvent, impurities with a relative retention time of less than 1.0 separated by high-performance liquid chromatography (HPLC) can be effectively removed into the water layer.

[0167]

[0168] In addition, the above step 2 may further include a step of vacuum concentration and / or azeotropic concentration of the extracted mixture. It is preferable that the vacuum concentration and / or azeotropic concentration step be performed after the extraction step using ethyl acetate and water or ethyl acetate and an aqueous sodium chloride solution.

[0169]

[0170] That is, when performing all steps of purifying the reaction product of step 2 to produce a compound represented by the chemical formula 1-5, step 2 may include the following steps, but is not limited to the following steps:

[0171] A step of reacting a compound represented by the above chemical formula 1-3 and a compound represented by the above chemical formula 1-4 in the presence of a palladium catalyst and a base;

[0172] A step of extracting by adding ethyl acetate and water, or ethyl acetate and sodium chloride aqueous solution, discarding the aqueous layer (lower layer) and separating the organic layer (upper layer); and

[0173] A step of vacuum concentrating and / or azeotropically concentrating the above purified mixture.

[0174]

[0175] Meanwhile, after the reaction is completed, the process of step 2 and step 3 described below can be performed in situ in the same reaction vessel without a process of purifying or separating the compound represented by the chemical formula 1-5. In this way, since the process of purifying and separating the compound in step 2 is not required, the method for producing the compound represented by the chemical formula 1 including step 2 can be advantageous in terms of industrial mass production of the compound.

[0176]

[0177] The above step 3 is a step of reacting the compound represented by the above chemical formula 1-5 with an acid to produce the compound represented by the above chemical formula 1-6, and is a step of removing the protecting group P1 included in the above chemical formula 1-5.

[0178]

[0179] The acid used in the reaction of step 3 may be at least one selected from the group consisting of hydrochloric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, hydrobromic acid, sulfuric acid, nitric acid, and iodic acid. Among these, considering yield and cost, it is preferable to use hydrochloric acid. Here, concentrated hydrochloric acid (c-HCl) may be used as the hydrochloric acid. For example, concentrated hydrochloric acid having a concentration of about 30 to 40 wt% may be used.

[0180]

[0181] The above acid can be used in an amount (mL / g) of 1 to 10 times the volume of the compound represented by the above chemical formula 1-5, more specifically, in an amount (mL / g) of 2 to 5 times the volume.

[0182]

[0183] The reaction solvent of the above step 3 may be at least one organic solvent selected from the group consisting of ethyl acetate, dichloromethane, butyl acetate, trichloromethane, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, methyl tert-butyl ether, acetonitrile, toluene, heptane, tetrahydrofuran, 3-methyltetrahydrofuran, 1,4-dioxane, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide (DMAC), and dimethyl sulfoxide (DMSO). For example, one solvent may be used, or a mixed solvent of two or more solvents may be used.

[0184]

[0185] The organic solvent may be used in an amount (mL / g) of 5 to 30 times the volume of the compound represented by the chemical formula 1-5, more specifically, 5 to 15 times, or 5 to 6 times the volume of the compound represented by the chemical formula 1-5.

[0186]

[0187] In addition, the above reaction can be carried out at 0℃ to 50℃, and can be carried out for 1 hour to 10 hours, preferably 3 hours to 5 hours. The removal reaction of the tertbutoxycarbonyl group, which is a protecting group, is a reaction that easily occurs without additional heat treatment and can proceed within the above temperature range. However, if the reaction time is less than 1 hour, the reaction may not proceed sufficiently, and if the reaction time exceeds 10 hours, the production yield does not substantially increase, so the above-mentioned reaction time is preferable.

[0188]

[0189] Meanwhile, after the reaction of step 3 is completed, a purification step for extracting the product of the reaction may be further included. Preferably, there is no limitation on the solvent used for the extraction, but for example, the extraction step may extract the product of the reaction using dichloromethane and water, or using ethyl acetate and water. That is, the compound represented by the chemical formula 1-6 may be extracted using dichloromethane and water, or using ethyl acetate and water, or using both of the above methods after the reaction is completed.

[0190] The extraction using dichloromethane and water can be carried out by stirring the mixture containing the reaction product and each solvent for 30 minutes or more, allowing it to stand for 30 minutes or more, separating the layers, discarding the organic layer (lower layer) and taking the aqueous layer (upper layer). The extraction using ethyl acetate and water can be carried out by stirring the mixture containing the reaction product and each solvent for 30 minutes or more, allowing it to stand for 30 minutes or more, separating the layers, discarding the aqueous layer (lower layer), and taking the organic layer (upper layer). The extraction using dichloromethane and water or the extraction using ethyl acetate and water can each be repeated one or more times. Meanwhile, the extraction using ethyl acetate and water is preferably carried out in the presence of a base such as sodium hydroxide while maintaining the pH of the reaction product at 9 to 11.

[0191]

[0192] Additionally, the step 3 may further include a step of vacuum concentration and / or azeotropic concentration of the extracted mixture. It is preferable that the vacuum concentration and / or azeotropic concentration step be performed after the extraction step using dichloromethane and water; or ethyl acetate and water.

[0193]

[0194] In addition, the step 3 may further include a step of crystallizing the product of the reaction in order to purify the compound represented by the chemical formula 1-6. This crystallization step is preferably performed after the extraction purification step. In other words, the step 3 may be performed as a step of preparing the compound represented by the chemical formula 1-6 by adding a crystallization solvent to the concentrated product after the extraction purification step and stirring the mixture at a temperature of about 20 to 40°C for 30 minutes to 4 hours. Preferably, the crystallization step may be performed at room temperature of 20 to 30°C, or 20 to 25°C.

[0195] In this way, when a reaction product is manufactured through crystallization using a crystallization solvent, unlike when purification is performed using a silica column, it can be applied to industrialization, and is advantageous in terms of industrial mass production, and has the advantage of being able to obtain a high yield.

[0196]

[0197] Specifically, the crystallization step can be performed using methyl isobutyl ketone or normal heptane as a crystallization solvent. When both solvents are used, there is no limitation on the order, but it is preferable to proceed in the order of crystallization using methyl isobutyl ketone and then crystallization using normal heptane. The crystallization step can be performed by repeating the crystallization process in the order of 'injecting crystallization solvent and then stirring' one or more times. In this way, when the solvent is injected multiple times instead of all at once and the crystallization process is repeated, even the crystals that are stuck to the wall during the solvent injection process can be obtained, thereby preventing a decrease in yield and effectively removing byproducts remaining after the reaction. In addition, products that were not crystallized can be crystallized through repeated crystallization processes. Accordingly, compared to a process of purifying in the form of a slurry using a solvent, a high-purity compound can be obtained in a high yield.

[0198]

[0199] The crystallization solvent used in one of the above crystallization processes may be used in an amount (mL / g) of 3 to 20 times the weight of the compound represented by the above chemical formula 1-5, more specifically, in an amount (ml / g) of 3 to 15 times the weight of the compound represented by the above chemical formula 1-5, and one crystallization process may be carried out by stirring at a temperature range of 5 to 30°C for 10 minutes to 3 hours. The progress time may be appropriately adjusted, such as by increasing it when the number of repetitions of the crystallization process is small, or by decreasing it when the number of repetitions is large.

[0200]

[0201] That is, when the steps of purifying and crystallizing the reaction product of step 3 are all performed sequentially to produce the compound represented by the chemical formula 1-6, step 3 may proceed including the following steps, but is not limited to the following steps:

[0202] A step of reacting a compound represented by the above chemical formula 1-5 with an acid;

[0203] A step of extracting by adding water and dichloromethane, discarding the organic layer (lower layer) and separating the aqueous layer (upper layer), a step of adding water and ethyl acetate, discarding the aqueous layer (lower layer) and separating the organic layer (upper layer), and a step of vacuum concentrating and / or azeotropically concentrating the purified mixture; and

[0204] A step of crystallizing the above concentrate.

[0205]

[0206] After crystallizing and purifying the compound represented by the above chemical formula 1-6, the moisture content contained in the compound represented by the above chemical formula 1-6 can be reduced by drying at 30 to 60°C for 10 to 14 hours. More specifically, by drying at 50°C or lower to significantly reduce the moisture content of the compound represented by the above chemical formula 1-6, the conversion rate of the next step (i.e., step 4 below) can be increased.

[0207]

[0208] (Step 4)

[0209] The above step 4 is an acrylation reaction step for producing a compound represented by the above chemical formula 1 by reacting a compound represented by the above chemical formula 1-6 and a compound represented by the above chemical formula 1-7 in the presence of a base.

[0210]

[0211] In the above step 4, the compound represented by the above chemical formula 1-7 may be used in an amount of 0.1 to 10 equivalents relative to 1 equivalent of the compound represented by the above chemical formula 1-6. Specifically, the compound represented by the above chemical formula 1-7 may be used in an amount of 0.2 to 5 equivalents, 0.5 to 5 equivalents, 0.5 to 3 equivalents, 0.5 to 2 equivalents, 0.5 to 1.5 equivalents, 1 to 1.5 equivalents, 1 to 1.1 equivalents, or 1.1 equivalents relative to 1 equivalent of the compound represented by the above chemical formula 1-6.

[0212]

[0213] As the base used in the reaction of the above step 4, at least one selected from the group consisting of potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylamine, diisopropylethylamine, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium methylate, and potassium butyrate may be used. Among these, in terms of completion of the reaction and generation of by-products, it is preferable to use potassium carbonate, sodium carbonate, sodium bicarbonate, or potassium bicarbonate.

[0214]

[0215] A mixed solvent of tetrahydrofuran (THF) and water can be used as a solvent for this reaction. At this time, the tetrahydrofuran can be used in an amount (mL / g) of 5 to 40 times, or 5 to 10 times, the volume relative to the weight of the compound represented by the chemical formula 1-6, and the water can be used in an amount (mL / g) of 2 to 10 times, or 2 to 5 times, the volume relative to the weight of the compound represented by the chemical formula 1-6.

[0216]

[0217] In addition, the reaction of step 4 can be carried out at a temperature of -10°C to 50°C for 1 to 5 hours. Preferably, it can be carried out at a temperature of 0°C or higher, more preferably at a temperature of 0°C or higher and 10°C or lower. Accordingly, it is preferable that all reaction reagents, such as reactants and organic solvents, used to suppress the reaction temperature from rising during the reaction are cooled to a temperature of 0°C or lower before use.

[0218]

[0219] Meanwhile, after the reaction of step 4 is completed, a purification step for extracting the product of the reaction may be further included. Specifically, the product of the reaction may be extracted using ethyl acetate and water. That is, the compound represented by the above chemical formula 1 may be extracted using ethyl acetate and water after the completion of the reaction. The extraction using ethyl acetate and water may be carried out by stirring a mixture containing the product of the reaction and each solvent for 30 minutes or more, allowing it to stand for 30 minutes or more, separating the layers, discarding the aqueous layer (lower layer), and using the organic layer (upper layer). In the case of extraction in this way, impurities having a relative retention time of less than 1.0 as separated by high-performance liquid chromatography (HPLC) can be effectively removed in the aqueous layer, compared to the case of extraction using a methylene chloride / water mixed solvent. Additionally, if necessary, a purification process for removing byproducts or foreign substances may be carried out using activated carbon and / or silica-based materials.

[0220]

[0221] Additionally, the step 4 may further include a step of filtering and then vacuum concentrating the organic layer containing the extracted mixture. This vacuum concentration step is preferably performed after the extraction step using ethyl acetate and / or water.

[0222]

[0223] Preferably, the step 4 may further include a step of crystallizing the product of the reaction in order to purify the compound represented by the chemical formula 1. This crystallization step is preferably performed after the extraction purification and vacuum concentration processes. In other words, the step 4 may be performed by adding a crystallization solvent to the concentrated product after the extraction purification step and stirring the resultant product at a temperature of about 20 to 40°C for 30 minutes to 4 hours. Preferably, the crystallization step may be performed at room temperature of 20 to 30°C, or 20 to 25°C. The progress time may be appropriately adjusted, such as increasing when the number of repetitions of the crystallization process is small, or decreasing when the number of repetitions is large.

[0224] In this way, when a reaction product is manufactured through crystallization using a crystallization solvent, unlike when purification is performed using a silica column, it can be applied to industrialization, and is advantageous in terms of industrial mass production, and has the advantage of being able to obtain a high yield.

[0225]

[0226] Specifically, the above crystallization step can be performed by crystallization using ethyl alcohol or normal heptane as a crystallization solvent. When both of the above solvents are used, there is no limitation on the order. The crystallization step can be performed by repeating the crystallization process in the order of 'injecting crystallization solvent and then stirring' one or more times. In this way, when the crystallization process is repeated while injecting the solvent multiple times instead of all at once, even the crystals that are stuck to the wall during the solvent injection process can be obtained, thereby preventing a decrease in yield and effectively removing byproducts remaining after the reaction. In addition, products that were not crystallized can be crystallized through the repeated crystallization process. Accordingly, compared to the process of purifying in the form of a slurry using a solvent, a high-purity compound can be obtained in a high yield.

[0227]

[0228] The above crystallization solvent can be used in an amount (mL / g) of 0.5 to 15 times the weight of the compound represented by the above chemical formula 1-6, more specifically, in an amount (ml / g) of 0.5 to 10 times the weight of the compound represented by the above chemical formula 1-6. One crystallization process can be carried out by stirring at a temperature range of 5 to 30°C, preferably at room temperature (20 to 25°C) for 10 minutes to 2 hours. The above progress time can be appropriately adjusted, such as increasing when the number of repetitions of the crystallization process is small, or decreasing when the number of repetitions is large.

[0229]

[0230] Meanwhile, for faster crystallization, crystals of the compound represented by Chemical Formula 1, which is a reaction product, may be added as a seed together with a solvent at least once during the crystallization process. The seed may be added in an amount of 0.01 part by weight or less relative to 1 part by weight of the compound represented by Chemical Formula 1-6.

[0231]

[0232] That is, when the steps of purifying and crystallizing the reaction product of step 4 are all performed sequentially to produce the compound represented by the chemical formula 1, step 4 may be performed including the following steps, but is not limited to the following steps:

[0233] A step of reacting a compound represented by Chemical Formula 1-6 and a compound represented by Chemical Formula 1-7 in the presence of a base;

[0234] A step of adding ethyl acetate and water, discarding the aqueous layer (lower layer) and separating and extracting the organic layer (upper layer), and a step of vacuum concentrating the purified mixture; and

[0235] A step of crystallizing the above concentrate.

[0236]

[0237] After crystallizing the compound represented by the above chemical formula 1, the moisture content contained in the compound represented by the above chemical formula 1 can be reduced by drying at 30 to 60°C for 8 to 14 hours. More specifically, it can be dried at 50°C or lower.

[0238]

[0239] (Step 5)

[0240] The above step 5 is a step of preparing a tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one by reacting a compound represented by chemical formula 1 with tartaric acid.

[0241]

[0242] Specifically, the above steps may be performed according to a manufacturing method including the following steps.

[0243] 5-1) A step of dissolving 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one in an organic solvent;

[0244] 5-2) A step of dissolving tartaric acid in the same organic solvent as the organic solvent; and

[0245] 5-3) Step of mixing and stirring the solutions of 5-1) and 5-2).

[0246]

[0247] The above step 5-3 is a step for preparing a salt in which 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one and tartaric acid are chemically bound. The salt in which 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one and tartaric acid are chemically bound may have a crystalline structure.

[0248]

[0249] In the above reaction, one or more organic solvents selected from the group consisting of methanol, ethanol, isopropanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, heptane, tetrahydrofuran, 3-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide (DMAC), and dimethyl sulfoxide (DMSO) may be used. Such organic solvent can be used in an amount (mL / g) of 5 to 60 times the volume relative to the weight of the free base of the 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one. Preferably, the organic solvent can be used in an amount (mL / g) of 10 to 40 times the volume relative to the weight of the free base of the 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0250]

[0251] In the above step 5, tartaric acid can be used in an amount of 0.8 to 1.2 equivalents, preferably 1.0 to 1.2 equivalents, based on 1 equivalent of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0252]

[0253] Next, the step of stirring the mixed solution of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one, tartaric acid and organic solvent can be performed at a temperature of 50°C to 70°C for 30 minutes to 30 hours.

[0254]

[0255] The tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one prepared by the above preparation method can be recovered from the solution by a vacuum filtration process. If necessary, the recovered tartrate salt can be washed and vacuum-dried to obtain a high-purity tartrate salt. In addition, the reaction conditions such as the ratio of the solvent, the temperature range, and the process time described in the above preparation methods can be adjusted depending on the selected solvent.

[0256]

[0257] [Crystal form of tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one]

[0258]

[0259] The tartrate salt of the above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one is obtained in crystalline form, and the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one and The tartrate salt crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one can be regarded as substantially the same substance. That is, the substance obtained in step 5 above without an additional preparation step can be regarded as the tartrate salt crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0260]

[0261] The crystalline form of the tartrate salt of the above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one is selected from the group consisting of diffraction angles (2θ±0.2°) of 5.2°, 8.0°, 10.4°, 12.5°, 13.1°, 13.7°, 15.4°, 16.5°, 16.9°, 17.9°, 18.3°, 18.8°, 20.1°, 20.5°, 21.3° and 21.6° in the X-ray powder diffraction pattern. It can have more than three peaks.

[0262]

[0263] In addition, the crystalline form of tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one can exhibit an endothermic onset temperature of 171.48 ± 1.0 °C and a maximum endothermic peak at an endothermic temperature of 175.86 ± 1.0 °C in differential scanning calorimetry.

[0264]

[0265] The use of the crystalline form of the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one or the crystalline form of the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one has the effect of improving pK, solubility and excellent stability compared to the case of using the free base.

[0266]

[0267] Meanwhile, the present invention provides a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate and a crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate.

[0268]

[0269] More specifically, the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, an autoimmune disease, a proliferative disease, a hyperproliferative disease, an immunologically mediated disease, a cancer, or a tumor, comprising at least one selected from the group consisting of a crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate and a crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate.

[0270]

[0271] These pharmaceutical compositions may include a pharmaceutically acceptable carrier that is commonly used. The carrier is one that is commonly used in the manufacture of a formulation, and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above ingredients, the pharmaceutical composition may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.

[0272]

[0273] The pharmaceutical composition may be administered orally or parenterally, including intravenously, intramuscularly, intraperitoneally, subcutaneously, and transdermally.

[0274]

[0275] At this time, the pharmaceutical composition may be administered in a therapeutically effective amount, for example, from about 0.001 mg / kg to about 100 mg / kg per day. The dosage may vary depending on the formulation method, administration method, patient's age, weight, sexually transmitted disease status, food, administration time, administration route, excretion rate, or response sensitivity.

[0276]

[0277] The above pharmaceutical composition can be manufactured in a unit dosage form or can be manufactured by inserting it into a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains. In this case, the dosage form may be used without limitation as long as it is in a form suitable for pharmaceutical preparation, including oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations such as ointments and creams, suppositories, and sterile injection solutions, and may additionally include a dispersing agent or stabilizer.

[0278]

[0279] The tartrate salt and crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one according to the present invention have lower hygroscopicity and improved stability and solubility compared to the free base, making them suitable for pharmaceutical use. In addition, the method for producing the tartrate salt or crystalline form has the advantage of allowing mass production, and improving the safety of the manufacturing process by using safer substances compared to the reactants used in conventional manufacturing methods.

[0280]

[0281] Figure 1 shows the NMR measurement results of the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one prepared in Example 1.

[0282] Figure 2 shows an X-ray powder diffraction pattern for the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one prepared in Example 1.

[0283] Figure 3 shows the results of differential scanning calorimetry analysis of the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one prepared in Example 1.

[0284] Figure 4 shows the results of thermogravimetric analysis of the tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one prepared in Example 1.

[0285]

[0286] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only intended to illustrate the present invention, and the scope of the present invention is not limited to these examples. In addition, "volume" in the following may be understood to mean the volume ratio relative to the weight of the starting material in each step, "parts by weight" may be understood to mean the weight ratio relative to the starting material in each step, and "eq" may be understood to mean the equivalent weight of each material.

[0287]

[0288] Manufacturing example: Manufacturing of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one (compound represented by chemical formula 1)

[0289]

[0290]

[0291] Step 1) Preparation of compounds 1-3

[0292] Compound 1-1, 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100.00 g, 1 eq) and compound 1-2, tert-butyl(3S,4R)-4-fluoro-3-hydroxypiperidine-1-carboxylate (122.45 g, 1.05 eq) were dissolved in a mixture of 1,4-dioxane 1000.0 mL (10 volume) and purified water 10.0 mL (0.1 volume), potassium tert-butoxide (179.05 g, 3 eq) was added, and the mixture was stirred at 48 to 52°C for 5 hours to complete the reaction.

[0293] After this, 1000.0 mL (10 volume) of ethyl acetate and 500.0 mL (5 volume) of purified water were added, stirred for more than 30 minutes, allowed to stand for more than 30 minutes, then the layers were separated and the aqueous layer (lower layer) was discarded. 500.0 mL (5 volume) of purified water was added to the remaining organic layer, stirred for more than 30 minutes, allowed to stand for more than 30 minutes, then the layers were separated and the aqueous layer (lower layer) was discarded. The remaining organic layer was concentrated under vacuum at an external temperature of 50°C or lower, and 200.0 mL (2 volume) of 1,4-dioxane was added and azeotropically concentrated at an external temperature of 50°C or lower.

[0294] After adding 200.0 mL (2 volume) of 1,4-dioxane, the internal temperature was raised to 40 to 50 ℃ to completely dissolve, 400.0 mL (4 volume) of purified water was added, and the mixture was stirred at room temperature for more than 1 hour. Additionally, 600.0 mL (6 volume) of purified water was added, and the mixture was stirred for more than 1 hour. The mixture was filtered under reduced pressure using a filter, and washed with 500.0 mL (5 volume) of purified water. This was vacuum-dried at an external temperature of 50 ℃ for 12 hours to obtain tert-butyl (3S,4R)-3-((6-chloro-1H-indol-4-yl)oxy)-4-fluoropiperidine-1-carboxylate (181.4 g, yield 92.0%), which is the compound 1-3.

[0295] 1H NMR (500 MHz, CD3OD): δ 7.206 (s, 1H), 6.552 (s, 1H), 5.461 (s, 1H), 5.093-4.997 (d, 1H), 3.908-3.793 (d, 2H), 3.559 (s, 2H), 2.210 (s, 1H), 1.926 (s, 1H), 1.287(s, 9H)

[0296]

[0297] Step 2) Preparation of compounds 1-5

[0298] Compound 1-3 (181.40 g, 1 eq), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (8.31 g, 0.04 eq), tris(dibenzylideneacetone)dipalladium(0) (8.96 g, 0.02 eq), and potassium tert-butoxide (164.73 g, 3 eq) obtained in the above step 1 were added to 907.2 mL (5 volume) of secbutyl alcohol and stirred at room temperature. Thereafter, compound 1-4, 1-ethyl-1H-pyrazol-4-amine (81.58 g, 1.5 eq), was added, and then 181.4 mL (1 volume) of secbutyl alcohol was added while washing the reactor wall and injection line so that all remaining reagents and raw materials were used for the reaction. The reaction was completed by stirring at an internal temperature of 88 to 92°C for 2 hours.

[0299] After this, 907.2 mL (5 volume) of purified water and 907.2 mL (5 volume) of ethyl acetate were added, filtered at an internal temperature of 50 ℃, and washed with 907.2 mL (5 volume) of ethyl acetate. 907.2 mL (5 volume) of purified water was added once more to the filtrate, stirred for more than 30 minutes, allowed to stand for more than 30 minutes, separated into layers, and the aqueous layer (lower layer) was discarded. 907.2 mL (5 volume) of purified water was added to the remaining organic layer, stirred for more than 30 minutes, allowed to stand for more than 30 minutes, separated into layers, and the aqueous layer (lower layer) was discarded. 544.3 mL (3 volume) of a 25 wt% sodium chloride solution was added to the remaining organic layer, stirred for more than 30 minutes, allowed to stand for more than 30 minutes, separated into layers, and the aqueous layer (lower layer) was discarded. This was filtered and washed with 907.2 mL (5 volume) of ethyl acetate. The filtrate was concentrated under vacuum at an external temperature of 60°C or lower, and 544.3 mL (3 volumes) of ethyl acetate was added thereto. The resulting mixture was azeotropically concentrated at an external temperature of 60°C or lower to obtain tert-butyl (3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidine-1-carboxylate (217.9 g, yield 100.0%), which is the compound 1-5. The obtained compound was used in the next step without purification.

[0300]

[0301] Step 3) Preparation of compounds 1-6

[0302] The concentrated residue (217.9 g, 1 eq) of compound 1-5 obtained in step 2 above was dissolved in 1090.0 mL (6 volume) of dichloromethane. The solution was cooled to 0 to 5°C, and 414.2 mL (2.28 volume) of concentrated hydrochloric acid was slowly added so that the internal temperature did not exceed 5°C, and the reaction was completed by stirring at 0 to 5°C for 4 hours.

[0303] After this, 1090.0 mL (6 volume) of dichloromethane and 1090.0 mL (6 volume) of purified water were added, stirred for more than 30 minutes, allowed to stand for more than 30 minutes, then the layers were separated and the organic layer (lower layer) was discarded. 1090.0 mL (6 volume) of dichloromethane was added to the remaining aqueous layer, stirred for more than 30 minutes, allowed to stand for more than 30 minutes, then the layers were separated and the organic layer (lower layer) was discarded. After filtering, the mixture was washed with 1090.0 mL (6 volume) of purified water, 2179.9 mL (12 volume) of ethyl acetate was added, and then cooled to 0 to 5 ℃. Approximately 1300.0 mL (7.17 volume) of 8N sodium hydroxide solution was added to adjust the pH to 9 to 11, allowed to stand for more than 30 minutes, the layers were separated, and the aqueous layer (lower layer) was discarded. Additionally, 1090.0 mL (6 volume) of purified water was added, stirred for more than 30 minutes, allowed to stand for more than 30 minutes, and the layers were separated, with the aqueous layer (lower layer) discarded. Afterwards, vacuum concentration was performed at an external temperature of 50°C or lower, and 654.0 mL (3.6 volume) of methyl isobutyl ketone was added and azeotropic concentration was performed.

[0304] Additionally, 1090.0 mL (6 volume) of methyl isobutyl ketone was added, refluxed and stirred for more than 1 hour, and then the internal temperature was cooled to 20 to 25 ℃. 2179.9 mL (12 volume) of normal heptane was slowly added and stirred for 2 hours. After filtering, the resulting solution was washed with 1090.0 mL (6 volume) of normal heptane, and the washed filtrate was vacuum-dried at an external temperature of 50 ℃ or lower for 12 hours to obtain 126.75 g (2 step in-situ yield: 75.0%) of N-(1-ethyl-1H-pyrazol-4-yl)-4-(((3S,4R)-4-fluoropiperidin-3-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, which is the compound 1-6.

[0305] 1H NMR (500 MHz, CD3OD): δ 8.902 (s, 1H), 7.906 (s, 1H), 7.528 (s, 1H), 6.932 (s, 1H), 6.277 (s, 1H), 5.375-5.330 (d, 1H), 5.166-5.066 (d, 1H), 4.104-4.061 (d, 2H), 3.011-3.002 (d, 2H), 2.826-2.664 (dd, 2H), 2.006-1.776 (m, 2H), 1.370 (s, 3H)

[0306]

[0307] Step 4) Preparation of compound 1

[0308] Compound 1-6 (126.75 g, 1 eq, 1 part by weight) and sodium bicarbonate (61.66 g, 2 eq) obtained in the above step 3 were added to a mixed solution of 760.5 mL (6 volume) of tetrahydrofuran and 316.9 mL (2.5 volume) of purified water, cooled to 0 to 5 °C, and stirred for 1 hour. Acryloyl chloride (6.54 g, 1.1 eq), which is compound 1-7, was dissolved in 190.1 mL (1.5 volume) of tetrahydrofuran, and slowly added thereto so as not to exceed 5 °C. After the addition was completed, the mixture was stirred at 0 to 5 °C for 2 hours to complete the reaction.

[0309] After this, 1267.5 mL (10 volume) of purified water and 1267.5 mL (10 volume) of ethyl acetate were added, stirred for more than 30 minutes, allowed to stand for more than 30 minutes, and the layers were separated and the aqueous layer (lower layer) was discarded. This was filtered and washed with 380.3 mL (3 volume) of ethyl acetate. The filtrate was concentrated in vacuum at an external temperature of 50 ℃ or lower, and then 380.3 mL (3 volume) of ethyl alcohol was added and concentrated in vacuum at an external temperature of 60 ℃ or lower.

[0310] Additionally, 316.9 mL (2.5 volume) of ethyl alcohol was added and dissolved while stirring at 20 to 25 °C. 1.27 g (0.01 part by weight) of compound 1 as a seed was added at 20 to 25 °C and stirred for 2 hours. When precipitation was sufficient, 63.4 mL (0.5 volume) of ethyl alcohol was added, and the fluidity was checked and stirred for 2 hours. After that, 1140.7 mL (9 volume) of normal-heptane was added and stirred for 2 hours. The crystallized liquid was filtered and washed with 253.5 mL (2 volume) of normal-heptane. After washing, the filtrate was placed in a dryer and vacuum dried at an external temperature of 50°C or lower for 10 hours to obtain 114.34 g (yield: 78%) of compound 1, 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

[0311] 1H NMR (500 MHz, CD3OD): δ 7.678 (s, 1H), 7.543-7.491 (d, 1H), 6.612-6.424 (m, 2H), 6.320-5.523 (m, 3H), 5.360-5.241 (m, 1H), 5.185-5.007 (m, 1H), 4.709-3.400 (m, 6H), 2.192-1.839 (m, 2H), 1.358-1.303 (m, 3H)

[0312]

[0313] Example 1: Preparation of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate

[0314]

[0315] In the above manufacturing example, 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one (114.34 g, 1 eq) was added 1372.1 mL (12 volume) of ethyl alcohol and the internal temperature was raised to 60 to 65 ℃ to dissolve. After filtering out foreign substances using a housing filter (0.45 / 0.22 μm) and transferring, the residue in the reactor was washed with 228.6 mL (2 volume) of ethyl alcohol and further transfer was performed using a housing filter (0.45 / 0.22 μm). Thereafter, the internal temperature was raised to 60 to 65 ℃ and stirred.

[0316] Into another reactor, L-(+)tartaric acid (49.58 g, 1.15 eq) and 686.0 mL (6 volume) of ethyl alcohol were added, heated to 60 to 65 °C to dissolve, and the solution was filtered using a Housing filter (0.45 / 0.22 μm) and transferred to the above free base reactor. At this time, the tartaric acid reactor was washed with 114.3 mL (1 volume) of ethyl alcohol and transferred using a Housing filter (0.45 / 0.22 μm).

[0317] After mixing the materials of the two reactors, the mixture was stirred at an internal temperature of 60 to 65 ℃ for more than 2 hours to confirm precipitation. The remaining reaction solution was cooled to -5 to 5 ℃, stirred for more than 1 hour, filtered, and washed with 228.7 mL (2 volume) of ethyl alcohol cooled to -5 to 5 ℃. The obtained filtrate was placed in a dryer and dried under vacuum at an external temperature of 65 ℃ or lower to obtain 149.44 g (yield 95.0%) of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate. The NMR measurement results of the obtained 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate are shown in Figure 1. The above 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate was obtained in a crystalline form.

[0318]

[0319] Experimental Example 1

[0320] (1) Analysis of X-ray powder diffraction pattern of tartrate

[0321] X-ray powder diffraction analysis was performed on the tartrate of Example 1, and the results are shown in Fig. 2. At this time, the X-ray powder diffraction analysis was performed using a PANalytical X' pert 3 powder x-ray diffractometer (Malvern Panalytical) by supplying CuK radiation (λ = 1.54056 Å) as the incident radiation to a copper cathode tube (45 kV / 40 mA). The step width was 0.02 °, the measuring range was 4-50 °, and the scan speed was 0.164129 ° / sec.

[0322]

[0323] Referring to FIG. 2, 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate prepared in Example 1 has X-ray powder diffraction patterns irradiated with a Cu light source at wavelengths of 5.2°, 8.0°, 10.4°, 12.5°, 13.1°, 13.7°, 15.4°, 16.5°, 16.9°, 17.9°, 18.3°, 18.8°, 20.1°, 20.5°, 21.3° and 21.6°. It can be confirmed that there is a peak at the diffraction angle (2θ±0.2°).

[0324]

[0325] (2) Differential scanning calorimetry and thermogravimetric analysis of tartrate

[0326] Differential scanning calorimetry was performed on the tartrate of Example 1, and the results are shown in Figure 3 below. At this time, DSC Q2000 (TA Instruments) was used for differential scanning calorimetry. The sample was temperature programmed from 30°C to 300°C at a heating rate of 10°C / min, and 2 to 5 mg of the product was placed in a crimped aluminum capsule for analysis.

[0327]

[0328] According to FIG. 3, 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate prepared in Example 2 above exhibits an endothermic onset temperature of 171.48 ± 1.0 °C in differential scanning calorimetry, and an endothermic peak maximum at an endothermic temperature of 175.86 ± 1.0 °C.

[0329]

[0330] (3) Comparison of the properties of the free base of the manufacturing example and the tartrate of the example

[0331] The properties of the free base (compound 1) obtained in the above manufacturing example and the tartrate obtained in Example 1 were measured as follows.

[0332]

[0333] 1) Melting Point: Measured using Mettler Toledo's MP70. After collecting the sample through a capillary tube, the sample was allowed to fall freely using a specified glass rod. This was repeated several times to ensure no empty space was left in the capillary tube. Then, starting at 168°C, the temperature was increased by 1°C per minute, and the transmittance was measured to determine the melting point. The measurement results are shown in Table 2 below.

[0334] 2) Thermogravimetric analysis: Measured using Mettler Toledo's TGA2. 50 mg of the sample was placed on an Al2O3 pan, and the temperature was increased from 30.0 ℃ to 600.0 ℃ at a rate of 10.00 ℃ per minute to confirm the weight change. As a result of the measurement, weight changes were confirmed three times at the midpoint of 50.4 ℃ (dehydration), 206.7 ℃ (endothermic), and 378.4 ℃ (exothermic behavior). The specific thermogravimetric analysis results are shown in Fig. 4.

[0335] 3) Hygroscopicity Analysis (DVS Hygroscopicity): Measured using Surface Measurement Systems' DVS Adventure. Hygroscopicity was confirmed by exposing the sample to 0-95% RH at 25°C using DVS. Depending on the degree of moisture adsorption, it was classified as Non-hygroscopic (0-0.12%) / Slightly Hygroscopic (0.2-2%) / Moderately Hygroscopic (2.0-15.0%) / Very Hygroscopic (>15.0%). The measurement results are shown in Table 2 below.

[0336] 4) Water Solubility: Measured using Waters HPLC. The sample was supersaturated with water at 23–26°C, stirred for more than 18 hours, and allowed to stand for more than 18 hours. The supernatant was extracted using a centrifuge and filtered to a 0.45 μm pore size. The HPLC area of ​​the filtrate was measured to determine the solubility. The measurement results are shown in Table 2 below.

[0337] 5) Stability: Purity was measured after 2 weeks under the accelerated test standard of 40±2℃ / 75±5% relative humidity. Approximately 1 mg of the tartrate salt solid obtained in Example 1 was dissolved in 1 ml of 100% methanol, and then 300 μl of this solution was diluted by adding 700 μl of acetonitrile, and the purity was measured by HPLC. The measurement results are shown in Table 2 below.

[0338]

[0339] The HLPC measurement conditions in 4) and 5) above are as follows.

[0340] - Detector: UV spectrophotometer (measurement wavelength: 230 nm)

[0341] - Dilution: 100% methanol

[0342] - Sample temperature: 15 ℃

[0343] - Injection volume: 15 μl

[0344] - Column: X Bridge C18 3.0 * 150 mm, 3.5 μm

[0345] - Column temperature: 30 ℃

[0346] - Analysis time: 40 minutes

[0347] - Flow rate: 0.6 ml / min

[0348] - Mode: Gradient

[0349] - Mobile phase A: 20 mM ammonium acetate

[0350] - Mobile phase B: 100% acetonitrile

[0351] - Mobile phase A and mobile phase B were controlled with a concentration gradient as shown in Table 1 below.

[0352]

[0353] Time (min)Mobile Phase A(%)Mobile Phase B(%)0752517525186040302080332080377525407525

[0354]

[0355] Free base of the manufacturing example Tartrate of the example Crystalline form Amorphous form Crystalline form Melting point Tg 51 ℃ 173.4 ~ 181.4 ℃ Hygroscopicity Moderately hygroscopic (~6%) Moderately hygroscopic (~3%) Solubility in water 0.568 mg / mL 2.4 mg / mL Stability 94.87% (2 weeks) 99.26% (2 weeks)

[0356]

[0357] 6) Pharmacokinetic evaluation (dog PK): For the free base and tartrate prepared in the above manufacturing example, a blood pharmacokinetic evaluation was conducted by oral single administration using a beagle dog as an experimental animal.

[0358] Three male rats (1.8 to 2.8 years old, KPC) were used for each dose. Healthy animals suitable for the experiment were used after a one-week quarantine and acclimatization period. Administration was performed after fasting, and the first blood sample was collected immediately before administration, and a total of 10 blood samples were collected over 24 hours. The collected blood was centrifuged and aliquoted as plasma supernatant. The peak area ratio of the test substance to the peak area of ​​the internal standard was extrapolated to the calibration curve to calculate the blood concentration. The measurement results are shown in Table 3 below.

[0359]

[0360] Beagle dog salt tartrate free base dose (mg / kg) 50 100 50 150 peak blood concentration C max (ng / mL)3,534 ± 1,2016,423 ± 1,7921,740 ± 8061,197 ± 728Area under the blood concentration curve AUC last (ng·h / mL)11,707 ± 5,68734,518 ± 9349,377 ± 8,8525,370 ± 4,287

[0361]

[0362] When the free base was administered orally as a single dose of 150 mg / kg, the peak blood concentration was 1,197 ng / mL, and the area under the blood concentration curve was 5,370 ng·h / mL, which was confirmed to be at a similar level to the results obtained when the free base was administered at 50 mg / kg.

[0363] On the other hand, when tartrate was administered, the peak blood concentration was 6,423 ng / mL at a lower dose of 100 mg / kg, and the area under the blood concentration curve was confirmed to be 34,518 ng·h / mL. Since the body exposure was confirmed to be higher than 50 mg / kg, dose linearity and a higher level of body exposure could be confirmed through salt change.

Claims

1. 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate salt.

2. In paragraph 1, The above tartrate has at least three peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 5.2°, 8.0°, 10.4°, 12.5°, 13.1°, 13.7°, 15.4°, 16.5°, 16.9°, 17.9°, 18.3°, 18.8°, 20.1°, 20.5°, 21.3° and 21.6° in an X-ray powder diffraction pattern irradiated with a Cu light source. Tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

3. In paragraph 1, The above tartrate has an endothermic onset temperature of 171.48 ± 1.0 ℃ in differential scanning calorimetry and a maximum endothermic peak at 175.86 ± 1.0 ℃. Tartrate salt of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

4. (Step 1) A step of producing a compound represented by the following chemical formula 1-3 by reacting a compound represented by the following chemical formula 1-1 and a compound represented by the following chemical formula 1-2 in the presence of a base; (Step 2) a step of producing a compound represented by the following chemical formula 1-5 by reacting a compound represented by the following chemical formula 1-3 and a compound represented by the following chemical formula 1-4 in the presence of a palladium catalyst and a base; (Step 3) A step of reacting a compound represented by the following chemical formula 1-5 with an acid to produce a compound represented by the following chemical formula 1-6; (Step 4) a step of producing a compound represented by the following chemical formula 1 by reacting a compound represented by the following chemical formula 1-6 and a compound represented by the following chemical formula 1-7 in the presence of a base; and (Step 5) A step of reacting a compound represented by the following chemical formula 1 with tartaric acid to produce a tartrate salt of a compound represented by the following chemical formula 1, Further comprising a step of crystallizing in at least one of the steps 1 to 4 above. Method for preparing tartrate of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one: [Chemical Formula 1] [Chemical Formula 1-1] [Chemical Formula 1-2] [Chemical Formula 1-3] [Chemical Formula 1-4] [Chemical Formula 1-5] [Chemical Formula 1-6] [Chemical Formula 1-7] In the above chemical formulas 1-1 to 1-7, P 1 Silver means protector.

5. In paragraph 4, In the above step 1, the compound represented by the chemical formula 1-2 is used in an amount of 0.1 to 10 equivalents relative to 1 equivalent of the compound represented by the chemical formula 1-1. Manufacturing method.

6. In paragraph 4, In the above step 1, the base is at least one selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, potassium tert-pentoxide, sodium tert-pentoxide, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, calcium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate. Manufacturing method.

7. In paragraph 4, In the above step 1, the base is used in an amount of 0.1 to 10 equivalents per 1 equivalent of the compound represented by the above chemical formula 1-1. Manufacturing method.

8. In paragraph 4, In the above step 1, the reaction is performed in one or more organic solvents selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, heptane, 3-methyltetrahydrofuran, dichloromethane, methyl isobutyl ketone, dimethyl formamide (DMF), dimethyl acetamide (DMAC), and dimethyl sulfoxide (DMSO). Manufacturing method.

9. In paragraph 8, In the above step 1, the reaction is performed at 30 to 60°C. Manufacturing method.

10. In paragraph 4, The above step 1 further includes a step of reacting a compound represented by the above chemical formula 1-1 and a compound represented by the above chemical formula 1-2 in the presence of a base, and then crystallizing the reaction product. Manufacturing method.

11. In paragraph 4, In the above step 2, the compound represented by the chemical formula 1-4 is used in an amount of 0.1 to 10 equivalents relative to 1 equivalent of the compound represented by the chemical formula 1-3. Manufacturing method.

12. In paragraph 4, In the above step 2, the palladium catalyst is at least one selected from the group consisting of tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), bis[tris(2-methylphenyl)phosphine]palladium, palladium(II) acetate, 1,1-(bis(diphenylphosphino)ferrocene)palladium(II) dichloride, and palladium(II) chloride. Manufacturing method.

13. In paragraph 4, In the above step 2, the base is at least one selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, potassium tert-pentoxide, sodium tert-pentoxide, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, calcium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate. Manufacturing method.

14. In paragraph 4, In the above step 2, the reaction is performed in one or more organic solvents selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, secbutyl alcohol, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, tertbutyl alcohol, acetone, methyl ethyl ketone, ethyl acetate, methyl tertbutyl ether, acetonitrile, toluene, xylene, heptane, 3-methyltetrahydrofuran, dichloromethane, methyl isobutyl ketone, dimethyl formamide (DMF), dimethylacetamide (DMAC), and dimethyl sulfoxide (DMSO). Manufacturing method.

15. In paragraph 4, The reaction of step 2 above is carried out at 80°C to 100°C. Manufacturing method.

16. In paragraph 4, In the above step 3, the acid is at least one selected from the group consisting of hydrochloric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, hydrobromic acid, sulfuric acid, nitric acid and iodic acid. Manufacturing method.

17. In paragraph 4, In the above step 3, the reaction is performed in one or more organic solvents selected from the group consisting of ethyl acetate, dichloromethane, butyl acetate, trichloromethane, methanol, ethanol, isopropanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, methyl tert-butyl ether, acetonitrile, toluene, heptane, tetrahydrofuran, 3-methyltetrahydrofuran, 1,4-dioxane, methyl isobutyl ketone, dimethyl formamide (DMF), dimethyl acetamide (DMAC), and dimethyl sulfoxide (DMSO). Manufacturing method.

18. In paragraph 4, The reaction of step 3 above is carried out at 0°C to 50°C. Manufacturing method.

19. In paragraph 4, The above step 3 further includes a step of reacting the compound represented by the above chemical formula 1-5 with an acid and then crystallizing the reaction product. Manufacturing method.

20. In paragraph 4, In the above step 4, the compound represented by the chemical formula 1-7 is used in an amount of 0.1 to 10 equivalents relative to 1 equivalent of the compound represented by the chemical formula 1-6. Manufacturing method.

21. In paragraph 4, The base of the above step 4 is at least one selected from the group consisting of potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylamine, diisopropylethylamine, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium methylate and potassium butyrate. Manufacturing method.

22. In paragraph 4, The reaction of step 4 above is carried out at a temperature of -10 ℃ to 50 ℃. Manufacturing method.

23. In paragraph 4, The above step 4 further includes a step of reacting a compound represented by the above chemical formula 1-6 with a compound represented by the following chemical formula 1-7 in the presence of a base, and then crystallizing the reaction product. Manufacturing method.

24. In paragraph 4, In the above step 5, the reaction is performed in one or more organic solvents selected from the group consisting of methanol, ethanol, isopropanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, heptane, tetrahydrofuran, 3-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, methyl isobutyl ketone, dimethyl formamide (DMF), dimethyl acetamide (DMAC), and dimethyl sulfoxide (DMSO). Manufacturing method. Crystalline form of 25.1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate salt.

26. In paragraph 25, An X-ray powder diffraction pattern having at least three peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 5.2°, 8.0°, 10.4°, 12.5°, 13.1°, 13.7°, 15.4°, 16.5°, 16.9°, 17.9°, 18.3°, 18.8°, 20.1°, 20.5°, 21.3° and 21.6°, Crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate salt.

27. In paragraph 25, In differential scanning calorimetry, the endothermic onset temperature was 171.48 ± 1.0 ℃ and the maximum endothermic peak was observed at 175.86 ± 1.0 ℃. Crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate salt. A pharmaceutical composition for the prevention or treatment of an inflammatory disease, an autoimmune disease, a proliferative disease, a hyperproliferative disease, an immunologically mediated disease, a cancer, or a tumor, comprising at least one selected from the group consisting of a crystalline form of 28.1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one tartrate and a crystalline form of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one.

29. A compound comprising the following chemical formula 1-5 as an intermediate, Method for preparing tartrate of 1-((3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidin-1-yl)prop-2-en-1-one: [Chemical Formula 1-5] In the above chemical formula 1-5, P 1 Silver means protector.

30. In paragraph 29, P 1 It is tert-butoxycarbonyl (Boc), Manufacturing method.

31. A compound represented by the following chemical formula 1-5: [Chemical Formula 1-5] In the above chemical formula 1-5, P 1 Silver means protector.

32. In paragraph 31, P1 is tert-butoxycarbonyl (Boc), compound.

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