Method for 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, and intermediate compounds thereof

Abstract

The present invention relates to a method for 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, and intermediate compounds thereof.

Description

Method for preparing 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 intermediate compounds 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, and Korean Patent Application No. 10-2024-0006933, filed January 16, 2024, the entire contents of which are incorporated herein by reference.

[0003]

[0004] The present invention relates to a method for preparing 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 an intermediate compound thereof.

[0005]

[0006] Protein kinases are enzymes that catalyze the phosphorylation of specific residues in other proteins. They play a central role in signal transduction pathways that transduce extracellular signals to the nucleus and are involved in various diseases in vivo. There is ample evidence that T cells (or T lymphocytes) and B cells (or B lymphocytes) play a key role in the pathogenesis of inflammatory diseases, autoimmune diseases, proliferative or hyperproliferative diseases, and / or immunologically mediated diseases.

[0007]

[0008] Janus kinase (hereinafter referred to as 'JAK') is a cytoplasmic protein tyrosine kinase that plays a central role in regulating cellular functions in the lympho-hematopoietic system. Cytokines are known to play an important role in regulating inflammation, immunity, and normal cellular functions, and JAK provides a rapid signal transduction pathway for cytokines by activating STAT (Signal Transducer and Activator of Transcription) proteins through tyrosine phosphorylation. JAK / STAT signaling is known to be related to allergies, asthma, autoimmune diseases (e.g., transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis, multiple sclerosis, etc.), solid tumors, and blood cancers (e.g., leukemia, lymphoma, etc.).

[0009]

[0010] The JAK family is divided into four types: JAK1, JAK2, JAK3, and TYK2. JAK family members pair with each other to mediate the signal transduction of different cytokines. JAK2 and JAK1 are involved in hematopoietic growth factor signaling, while TYK2 in combination with JAK2 is important for interferon signaling and contributes to host resistance. JAK2 is particularly involved in hematopoietic growth factor signaling, and excessive inhibition can cause anemia, thrombocytopenia, and leukopenia.

[0011]

[0012] While JAK1, JAK2, and TYK2 are found to be expressed ubiquitously, JAK3 expression is restricted to lymphoid cells and is involved in signaling of the common gamma chain, a component of the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors, particularly the common γ chain of the IL-2 family. Upon cytokine binding, the receptor brings JAK3 into close proximity, which triggers autophosphorylation of the C-terminus of the β-chain. Consequently, this triggers the activation of STAT proteins, a crucial step in retransmitting the signal to the nucleus. Through this process, JAK3 regulates various cytokine signaling pathways, making it an attractive target for immunosuppression.

[0013]

[0014] B cells play a key role in the development of autoimmune and / or inflammatory diseases. Protein-based therapeutics that deplete B cells, such as Rituxan, are effective in treating autoantibody-induced inflammatory diseases, such as rheumatoid arthritis. Therefore, protein kinase inhibitors that play a role in B cell activation are useful treatments for B cell-mediated diseases, such as autoantibody production.

[0015]

[0016] Signaling through the B cell receptor (BCR) controls a variety of B cell responses, including proliferation and differentiation into mature antibody-producing cells. The BCR is a key regulatory element for B cell activity, and aberrant signaling can lead to the formation of pathogenic autoantibodies and deregulated B cell proliferation, which contribute to numerous autoimmune and / or inflammatory diseases.

[0017]

[0018] Bruton's tyrosine kinase (BTK) is a key regulator of B-cell development, activation, signaling, and survival. BTK participates in signaling pathways initiated by the binding of various extracellular ligands to their cell surface receptors. Following ligation of the B-cell antigen receptor (BCR), BTK activation, mediated by the coordinated actions of the protein tyrosine kinases Lyn and Syk, is required for the induction of phospholipase C-γ2-mediated calcium mobilization. Therefore, inhibition of BTK may be a useful therapeutic approach for blocking the pathogenesis of B-cell-mediated diseases.

[0019]

[0020] As described above, Janus kinases and TEC family kinases play an important role in the activation of T cells and / or B cells involved in the pathogenesis of inflammatory diseases, autoimmune diseases, proliferative diseases or hyperproliferative diseases, and immunologically mediated diseases, and therefore the development of substances that effectively inhibit them may be useful as related therapeutic agents. Diseases that can be treated and prevented include, specifically, cancer, transplant rejection, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, psoriasis, asthma, allergic dermatitis, atopic dermatitis, eczema, type I diabetes, diabetic complications, ulcerative colitis, Crohn's disease, autoimmune thyroid disorders, alopecia universalis, and Sjogren's syndrome.

[0021]

[0022] Currently, Pfizer's tofacitinib (CP-690550), a JAK3 kinase inhibitor, is approved and marketed for the treatment of rheumatoid arthritis. Pharmacyclics' ibrutinib (PCI-32765), a BTK kinase inhibitor, is in clinical trials, but serious adverse effects, such as skin rash and diarrhea, have been reported in the trials. Therefore, there is a need for the development of substances that inhibit JAK and / or BTK more stably and effectively (see Nat Rev Rheumatol. 2009 Jun 5(6) 317-24; Expert Opin Investig Drugs. 2014 Aug 23(8) 1067-77; Drug Discov Today 2014 Aug 19(8) 1200-4; WO2002 / 096909; WO2010-009342).

[0023]

[0024] Accordingly, the inventors of the present invention have confirmed that an oxy-fluoropiperidine derivative having a chemical structure different from that of kinase inhibitors reported to date has excellent inhibitory activity as a kinase inhibitor. As a result of extensive research into a manufacturing method capable of producing a novel oxy-fluoropiperidine derivative, the inventors have confirmed that, when using the manufacturing method described below, commercial mass production is possible, and furthermore, an overall yield and quality are improved while impurities are reduced, thereby completing the present invention.

[0025]

[0026] The present invention provides a method for preparing 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] In addition, the present invention provides a novel intermediate compound obtained during the process for preparing 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.

[0029]

[0030] In order to solve the above problem, a method for preparing 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 compound represented by the following chemical formula 1, is provided, and more specifically, a method for preparing the compound includes the following steps, but at least one of the following steps 1 to 4 further includes a crystallization step is provided:

[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; and

[0034] (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:

[0035] [Chemical Formula 1]

[0036]

[0037] [Chemical Formula 1-1]

[0038]

[0039] [Chemical Formula 1-2]

[0040]

[0041] [Chemical Formula 1-3]

[0042]

[0043] [Chemical Formula 1-4]

[0044]

[0045] [Chemical Formula 1-5]

[0046]

[0047] [Chemical Formula 1-6]

[0048]

[0049] [Chemical Formula 1-7]

[0050]

[0051] In the above chemical formulas 1-1 to 1-7,

[0052] P1 stands for protector.

[0053]

[0054] In addition, the present invention provides a method for producing a compound represented by the following chemical formula 1, which comprises a compound represented by the following chemical formula 1-5 as an intermediate:

[0055] [Chemical Formula 1]

[0056]

[0057] [Chemical Formula 1-5]

[0058]

[0059] In the above chemical formula 1-5,

[0060] P1 stands for protector.

[0061]

[0062] In addition, the present invention provides a compound represented by the following chemical formula 1-5:

[0063] [Chemical Formula 1-5]

[0064]

[0065] In the above chemical formula 1-5,

[0066] P1 stands for protector.

[0067]

[0068] 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 at least one step of crystallization purification facilitates 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 in general production plants and offers economic benefits.

[0069]

[0070] Hereinafter, a method for producing a compound represented by the above chemical formula 1 will be described in detail.

[0071]

[0072] The compound represented by the above chemical formula 1 is prepared through the following reaction scheme 1:

[0073] [Reaction Formula 1]

[0074]

[0075] In the above reaction formula 1, P1 represents a protecting group.

[0076]

[0077] 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).

[0078]

[0079] At this time, in terms of ease of manufacturing and yield, it is preferable that P1 is tert-butoxycarbonyl (Boc).

[0080]

[0081] 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.

[0082]

[0083] 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.

[0084]

[0085] (Step 1)

[0086] 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.

[0087]

[0088] 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.

[0089]

[0090] 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.

[0091]

[0092] 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.

[0093]

[0094] 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.

[0095]

[0096] 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.

[0097]

[0098] 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.

[0099]

[0100] 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 dichloromethane / water mixed solvent.

[0101]

[0102] 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.

[0103]

[0104] 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.

[0105] 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.

[0106]

[0107] 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.

[0108]

[0109] 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.

[0110]

[0111] 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:

[0112] 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;

[0113] 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

[0114] A step of crystallizing the above concentrate.

[0115]

[0116] 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.

[0117]

[0118] (Step 2 and Step 3)

[0119] 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 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.

[0120]

[0121] 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.

[0122]

[0123] 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.

[0124]

[0125] 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.

[0126]

[0127] 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.

[0128]

[0129] 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.

[0130]

[0131] 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.

[0132]

[0133] 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 sec-butyl alcohol is preferable in terms of reaction speed and yield.

[0134]

[0135] The organic solvent may be used in an amount (mL / g) of 0.5 to 10 times the weight of the compound represented by the chemical formula 1-3, specifically, in an amount (mL / g) of 4 to 8 times the weight. If the solvent is used in excess during the reaction in step 2, there is a problem in that the reaction does not proceed.

[0136]

[0137] 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.

[0138]

[0139] 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.

[0140]

[0141] 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 dichloromethane / water mixed 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.

[0142]

[0143] 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.

[0144]

[0145] 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:

[0146] 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;

[0147] A step of extracting the organic layer (upper layer) by adding ethyl acetate and water, or ethyl acetate and sodium chloride aqueous solution, discarding the aqueous layer (lower layer), and then vacuum concentrating and / or azeotropically concentrating the purified mixture.

[0148]

[0149] Meanwhile, after the reaction is completed, the processes up to 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.

[0150]

[0151] 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.

[0152]

[0153] 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.

[0154]

[0155] 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.

[0156]

[0157] 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.

[0158]

[0159] 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.

[0160]

[0161] 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.

[0162]

[0163] 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.

[0164] 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.

[0165]

[0166] 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.

[0167]

[0168] 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.

[0169] 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.

[0170]

[0171] 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.

[0172]

[0173] 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.

[0174]

[0175] 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:

[0176] A step of reacting a compound represented by the above chemical formula 1-5 with an acid;

[0177] 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

[0178] A step of crystallizing the above concentrate.

[0179]

[0180] 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.

[0181]

[0182] (Step 4)

[0183] 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.

[0184]

[0185] 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.

[0186]

[0187] 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.

[0188]

[0189] 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.

[0190]

[0191] 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.

[0192]

[0193] 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 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 dichloromethane / 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.

[0194]

[0195] 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.

[0196]

[0197] 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.

[0198] 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.

[0199]

[0200] 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.

[0201]

[0202] 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.

[0203]

[0204] 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.

[0205]

[0206] 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:

[0207] 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;

[0208] 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

[0209] A step of crystallizing the above concentrate.

[0210]

[0211] 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.

[0212]

[0213] As described above, the manufacturing method according to the present invention has the advantage of being able to manufacture 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 a high yield even with a shortened process, enabling mass production, and using a safer substance compared to the reactants used in conventional manufacturing methods, thereby improving the safety of the manufacturing process.

[0214]

[0215] 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.

[0216]

[0217] Example 1: Preparation of a compound represented by chemical formula 1

[0218]

[0219] Step 1) Preparation of compounds 1-3

[0220] 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.

[0221] 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.

[0222] 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-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidine-1-carboxylate (181.4 g, yield 92.0%), which is the compound 1-3.

[0223] 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)

[0224]

[0225] Step 2) Preparation of compounds 1-5

[0226] 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 sec-butyl 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 sec-butyl 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.

[0227] 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.

[0228]

[0229] Step 3) Preparation of compounds 1-6

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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)

[0234]

[0235] Step 4) Preparation of compound 1

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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)

[0240]

[0241] Comparative Example 1

[0242]

[0243] Step 1) Preparation of 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0244] 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5.3 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), and sodium hydride (234.0 mg, 5.9 mmol) was added at 0 °C and stirred for 30 minutes. (2-(chloromethoxy)ethyl)trimethylsilane (975.0 mg, 5.9 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. Ethyl acetate was added, followed by distilled water, and the organic layer was separated. The organic layer was treated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.7 g (yield: 100.0%) of the title compound.

[0245]

[0246] Step 2) Preparation of tert-butyl (3S,4R)-3-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidine-1-carboxylate

[0247] Tert-Butyl (3S,4R)-4-fluoro-3-hydroxypiperidine-1-carboxylate (826.6 mg, 3.8 mmol) was dissolved in tetrahydrofuran (10.0 mL), and sodium hydride (180.9 mg, 4.5 mmol) was added at 0 °C, followed by stirring for 30 minutes. 2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 3.8 mmol) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Ethyl acetate was added, followed by distilled water, and the organic layer was separated. The organic layer was treated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 1.6 g (yield: 83.1%) of the title compound.

[0248]

[0249] Step 3) Preparation of tert-butyl (3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidine-1-carboxylate

[0250] Tert-butyl (3S,4R)-3-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidine-1-carboxylate (1.4 g, 2.7 mmol) and 1-ethyl-1H-pyrazol-4-amine (333.8 mg, 3.0 mmol) were added tert-butanol (40.0 mL). Tris(dibenzylideneacetone)dipalladium (125.0 mg, 0.1 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (128.6 mg, 0.3 mmol), and potassium carbonate (754.6 mg, 5.5 mmol) were added, stirred at 150 °C for 2 to 3 hours, and then cooled to room temperature. Ethyl acetate was added, followed by distilled water, and the organic layer was separated. The organic layer was treated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 1.3 g (yield: 83.4%) of the title compound.

[0251]

[0252] Step 4) Preparation of N-(1-ethyl-1H-pyrazol-4-yl)-4-(((3S,4R)-4-fluoropiperidin-3-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0253] Tert-Butyl(3S,4R)-3-((2-((1-ethyl-1H-pyrazol-4-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-4-fluoropiperidine-1-carboxylate (1.3 g, 2.3 mmol) was added 6 N hydrochloric acid solution in methanol (10.0 mL), and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture, 1,4-dioxane (20.0 mL) and aqueous ammonia (10.0 mL) were added to the residue. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to obtain 785.8 mg (yield: 100.0%) of the title compound without further purification.

[0254]

[0255] Step 5) 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

[0256] N-(1-Ethyl-1H-pyrazol-4-yl)-4-(((3S,4R)-4-fluoropiperidin-3-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (785.8 mg, 2.3 mmol) and sodium bicarbonate (599.8 mg, 6.9 mmol) were dissolved in tetrahydrofuran / distilled water (15.0 mL / 3.0 mL), and acryloyl chloride (212.7 uL, 2.6 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Ethyl acetate was added, followed by distilled water, and the organic layer was separated. The organic layer was treated with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 250.0 mg (yield: 27.5%) of the title compound of compound 1.

[0257] 1H NMR (500 MHz, CD3OD) δ 7.98 (s, 1H), 7.57-7.55 (m, 1H), 6.88-6.45 (m, 2H), 6.30-5.98 (m, 2H), 5.80-5.44 (m, 2H), 5.20-5.05 (m, 1H), 4.40-4.12 (m, 3H), 4.05-3.52 (m, 3H), 2.24-2.21 (m, 1H), 2.01-1.94 (m, 1H), 1.47-1.43 (m, 3H)

[0258]

[0259] Experimental example

[0260] The purity of the compound represented by the above chemical formula 1 manufactured by the manufacturing method of the above examples and comparative examples was measured as follows, and is shown in Table 2 below along with the yield.

[0261]

[0262] (1) Purity measurement method (Related substance)

[0263] When tested according to the following test method, the total amount of related substances in 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 was 1.0% or less. Unknown related substances detected at 0.04% or more were indicated by the peak name and relative peak retention time, and the detected amount was recorded together.

[0264] 1) Dilution

[0265] Acetonitrile and purified water mixture (weight ratio 4:1)

[0266] 2) Preparation of standard solution (1 time)

[0267] Weigh accurately about 30 mg 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 standard, place in a 100 mL volumetric flask, add dilution solution to completely dissolve, adjust to the mark, take an appropriate amount, filter the solution, and use it as a standard solution.

[0268] 3) Preparation of test solution (3 times)

[0269] Weigh precisely about 30 mg of this drug, place it in a 100 mL volumetric flask, add diluent, dissolve completely, adjust to the mark, take an appropriate amount, filter the solution, and use it as a test solution.

[0270] This solution was prepared three times each and designated as test solutions 1, 2, and 3.

[0271] 4) Preparation of sensitivity test solution (1 time)

[0272] Accurately measure 4.0 mL of the test solution, place it in a 100 mL volumetric flask, add diluent until completely dissolved, and adjust to the marked line. Accurately measure 1.0 mL of this solution, place it in a 100 mL volumetric flask, add diluent until completely dissolved, and adjust to the marked line. This solution was used as the sensitivity test solution.

[0273] 5) Operating conditions

[0274] 10 μL each of blank test solution, standard solution, and test solution were tested according to the liquid chromatography method of the general test methods of the Korean Pharmacopoeia under the following operating conditions.

[0275] [Operating Conditions]

[0276] - Detector: UV spectrophotometer (measurement wavelength: 235 nm)

[0277] - Column: X-Bridge C18 (150 x 4.6 mm, 3.5 μm) or equivalent column

[0278] - Flow rate: 1.0 mL / min

[0279] - Injection volume: 10 μL

[0280] - Column temperature: 40 ℃

[0281] - Mobile phase: Mobile phase A 1) Wow, moving B 2) The concentration gradient was controlled as shown in Table 1 below.

[0282] 1) Mobile phase A: A solution prepared by precisely weighing 1.0 mL of trifluoroacetic acid and dissolving it in 1000 mL of water at room temperature (20 ℃).

[0283] 2) Mobile phase B: A solution prepared by precisely weighing 1.0 mL of trifluoroacetic acid and dissolving it in 1000 mL of acetonitrile at room temperature (20 ℃).

[0284] Time (min)Mobile Phase A(%)Mobile Phase B(%)0.0095520.0059525.0059525.1095530.00955

[0285]

[0286] Example 1 Yield (%) / Purity (%) Comparative Example 1 Yield (%) / Purity (%) -- Step 1100 / - Step 192.0 / 92.6 Step 283.1 / 89.3 Step 2100 / 80.8 Step 383.4 / - Step 375 / 98.7 Step 4100 / 95.7 Step 478 / 99.3 Step 527.5 / 95.9 Final 53.8 / 99.6 Final 19.06 / 95.9

[0287]

[0288] As shown in Table 2 above, when producing a compound represented by Chemical Formula 1 by the production method of the embodiment, unlike the production method of Comparative Example 1 in which separation and purification of the produced compound are performed through a column, steps 2 and 3 are performed in-situ, and separation and purification of the compound are performed through crystallization, which is advantageous for industrial production, and it is confirmed that it has a better yield than Comparative Example 1.

[0289] Accordingly, it was confirmed that the compound represented by chemical formula 1 having high quality can be industrially mass-produced by the manufacturing method according to the present invention.

Claims

1. (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; and (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, At least one of the steps 1 to 4 further comprises a crystallizing step, A method for producing a compound represented by the following chemical formula 1: [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.

2. In paragraph 1, 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.

3. In paragraph 1, 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.

4. In paragraph 1, 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.

5. In paragraph 1, 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.

6. In paragraph 5, In the above step 1, the reaction is performed at 30 to 60°C. Manufacturing method.

7. In paragraph 1, 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.

8. In paragraph 1, 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.

9. In paragraph 1, 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.

10. In paragraph 1, 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.

11. In paragraph 1, 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, 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, dimethyl formamide (DMF), dimethylacetamide (DMAC), and dimethyl sulfoxide (DMSO). Manufacturing method.

12. In paragraph 1, The reaction of step 2 above is carried out at 80°C to 100°C. Manufacturing method.

13. In paragraph 1, 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.

14. In paragraph 1, 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.

15. In paragraph 1, The reaction of step 3 above is carried out at 0°C to 50°C. Manufacturing method.

16. In paragraph 1, 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.

17. In paragraph 1, 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.

18. In paragraph 1, 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.

19. In paragraph 1, The reaction of step 4 above is carried out at a temperature of -10 ℃ to 50 ℃. Manufacturing method.

20. In paragraph 1, 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.

21. A compound comprising the following chemical formula 1-5 as an intermediate, A method for producing a compound represented by the following chemical formula 1: [Chemical Formula 1] [Chemical Formula 1-5] In the above chemical formula 1-5, P 1 Silver means protector.

22. In paragraph 21, P 1 It is tert-butoxycarbonyl (Boc), Manufacturing method.

23. 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.

24. In paragraph 23, P 1 It is tert-butoxycarbonyl (Boc), compound.