Method for manufacturing monocyclic pyridine derivatives

Abstract

The present invention provides a compound (3d) or a salt thereof, wherein the content of compound (IM-7) is less than 0.48% by mass.

Description

Technical Field

[0001] This invention relates to a method for manufacturing a monocyclic pyridine derivative that can be used as an FGFR inhibitor. Prior Technology

[0002] 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzylamine)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide succinate (2:3) is a monocyclic pyridine derivative. [Chemistry 1] (Hereinafter also referred to as "E7090") has a strong FGFR (fibroblast growth factor receptor) inhibitory effect and can be used as a therapeutic agent for FGFR kinase-related intrahepatic bile duct carcinoma, breast cancer, etc. (Patent Documents 1 and 2). [Existing Technical Documents] [Patent Literature]

[0003] [Patent Document 1] International Publication No. 2014 / 129477 [Patent Document 2] International Publication No. 2016 / 027781 Summary of the Invention

[0004] [The problem the invention aims to solve]

[0005] The manufacturing method of E7090 is described in Patent Document 1 (Example 22, etc.) and Patent Document 2 (Example 1, etc.).

[0006] The synthesis of compound (3d) described in Patent Document 1 has the following problems, such as: 1) the preparation of formaldehyde (compound (P 3-1)) using thionyl chloride is relatively complicated; 2) byproducts of compound (IM-1) are observed in the reaction of compound (2i) with formaldehyde (compound (P 3-1)); 3) in the process of converting compound (3b) into compound (3c), trifluoroacetic acid is used as an acid catalyst in dichloromethane solvent, but dichloromethane and trifluoroacetic acid are not suitable for commercial use from an environmental perspective; therefore, improvements are required. [Chemistry 2] [Chemistry 3]

[0007] Furthermore, the inventors have discovered a new problem: in the manufacture of E7090, compounds (2i), (3c), (IM-2), (IM-3), (IM-4), (IM-5), (IM-6), (IM-7), and (IM-8) are formed using similar substances. [Chemistry 4] [Chemistry 5]

[0008] The purpose of this application is to provide a method for manufacturing high-quality E7090 with a lower total content of similar substances that can be synthesized with higher yield and better operating efficiency, as well as high-quality E7090. [Problem-solving methods]

[0009] This specification provides a method for manufacturing E7090, which can be used as an FGFR inhibitor. Additionally, this specification provides an E7090 with a lower total content of similar substances. That is, the present invention provides [1] to

[54] . [1] A method for manufacturing a compound (3d) or a salt thereof, [Chemistry 6] It includes the following steps: a), b), c), and d). a) Compound (2i) or its salt is reacted with compound (3a) in the presence of a condensing agent to produce compound (3b). [Chemistry 7] [Chemistry 8] (In the formula, PG 2 represents the protecting group of the nitrogen atom) [Chemistry 9] (In the formula, PG 2 represents the same group as above); b) Remove PG 2 from compound (3b) obtained in step a) to produce compound (3c). [Chemistry 10] ; c) React the compound (3c) obtained in step b) with a hydroxyethylating agent to produce compound (3d). [Chemistry 11] ;and d) If necessary, convert the compound (3d) obtained in step c) into a pharmaceutically acceptable salt. [2] According to the manufacturing method described in [1], wherein PG 2 is a tertiary butoxycarbonyl group. [3] The manufacturing method according to [1], wherein the condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. [4] The manufacturing method according to [2] includes the use of formic acid or hydrochloric acid in step b). [5] The manufacturing method according to [1], wherein the hydroxyethylating agent is 1,4-diethyl-2,5-diol, includes the use of a reducing agent in step c). [6] The manufacturing method described in [1] wherein the pharmaceutically acceptable salt is a succinate. [7] A compound (3d) or a salt thereof, wherein the content of compound (IM-7) is less than 0.48% by mass. [Chemistry 12] . [8] A compound (3d) or a salt thereof, wherein the content of compound (IM-5) is less than 0.40% by mass. [Chemistry 13] . [9] A compound (3d) or a salt thereof, wherein the content of compound (IM-2) is less than 0.30% by mass. [Chemistry 14] .

[10] A compound (3d) or a salt thereof, wherein the content of compound (IM-2) is less than 0.15% by mass. [Chemistry 15] .

[11] A compound (3d) or a salt thereof, wherein the content of compound (3c) is less than 0.30% by mass. [Chemistry 16] .

[12] A compound (3d) or a salt thereof, wherein the content of compound (IM-3) is less than 0.30% by mass. [Chemistry 17] .

[13] A compound (3d) or a salt thereof, wherein the content of compound (IM-3) is less than 0.15% by mass. [Chemistry 18] .

[14] A compound (3d) or a salt thereof, wherein the content of compound (2i) is less than 0.15% by mass. [Chemistry 19] .

[15] A compound (3d) or a salt thereof, wherein the content of compound (IM-4) is less than 0.15% by mass. [Chemistry 20] .

[16] A compound (3d) or a salt thereof, wherein the content of compound (IM-6) is less than 0.15% by mass. [Chemistry 21] .

[17] A compound (3d) or a salt thereof, wherein the content of compound (IM-8) is less than 0.15% by mass. [Chemistry 22] .

[18] A compound (3d) or a salt thereof, wherein the total content of similar substances is less than 2.0% by mass. [Chemistry 23] .

[19] A compound (3d) or a salt thereof, wherein the content of compound (IM-7) is 0.48% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 24] .

[20] A compound (3d) or a salt thereof, wherein the content of compound (IM-5) is 0.40% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 25] .

[21] A compound (3d) or a salt thereof, wherein the content of compound (IM-2) is 0.30% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 26] .

[22] A compound (3d) or a salt thereof, wherein the content of compound (IM-2) is 0.15% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 27] .

[23] A compound (3d) or a salt thereof, wherein the content of compound (3c) is 0.30% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 28] .

[24] A compound (3d) or a salt thereof, wherein the content of compound (IM-3) is 0.30% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 29] .

[25] A compound (3d) or a salt thereof, wherein the content of compound (IM-3) is 0.15% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 30] .

[26] A compound (3d) or a salt thereof, wherein the content of compound (2i) is 0.15% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 31] .

[27] A compound (3d) or a salt thereof, wherein the content of compound (IM-4) is 0.15% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 32] .

[28] A compound (3d) or a salt thereof, wherein the content of compound (IM-6) is 0.15% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 33] .

[29] A compound (3d) or a salt thereof, wherein the content of compound (IM-8) is 0.15% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 34] .

[30] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more. [Chemistry 35] .

[31] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-7) is 0.48% by mass or less. [Chemistry 36] .

[32] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-5) is 0.40% by mass or less. [Chemistry 37] .

[33] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-2) is 0.30% by mass or less. [Chemistry 38] .

[34] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-2) is 0.15% by mass or less. [Chemistry 39] .

[35] A compound (3d) or a salt thereof, wherein the content of compound (3d) or the salt thereof is 97.0% by mass or more, and the content of compound (3c) is 0.30% by mass or less. [Chemistry 40] .

[36] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-3) is 0.30% by mass or less. [Chemistry 41] .

[37] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-3) is 0.15% by mass or less. [Chemistry 42] .

[38] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (2i) is 0.15% by mass or less. [Chemistry 43] .

[39] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-4) is 0.15% by mass or less. [Chemistry 44] .

[40] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-6) is 0.15% by mass or less. [Chemistry 45] .

[41] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-8) is 0.15% by mass or less. [Chemistry 46] .

[42] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-7) is 0.48% by mass or less, and the content of the total similar substances is 2.0% by mass or less. [Chemistry 47] .

[43] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-5) is 0.40% by mass or less, and the content of the total similar substances is 2.0% by mass or less. [Chemistry 48] .

[44] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-2) is 0.30% by mass or less, and the content of the total similar substances is 2.0% by mass or less. [Chemistry 49] .

[45] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-2) is 0.15% by mass or less, and the content of the total similar substances is 2.0% by mass or less. [Transformation 50] .

[46] A compound (3d) or a salt thereof, wherein the content of compound (3d) or the salt thereof is 97.0% by mass or more, and the content of compound (3c) is 0.30% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 51] .

[47] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-3) is 0.30% by mass or less, and the content of the total similar substances is 2.0% by mass or less. [Chemistry 52] .

[48] ​​A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-3) is 0.15% by mass or less, and the content of the total similar substances is 2.0% by mass or less. [Chemistry 53] .

[49] A compound (3d) or a salt thereof, wherein the content of compound (3d) or the salt thereof is 97.0% by mass or more, and the content of compound (2i) is 0.15% by mass or less, and the content of total similar substances is 2.0% by mass or less. [Chemistry 54] .

[50] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-4) is 0.15% by mass or less, and the content of the total similar substances is 2.0% by mass or less. [Chemistry 55] .

[51] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-6) is 0.15% by mass or less, and the content of the total similar substances is 2.0% by mass or less. [Chemistry 56] .

[52] A compound (3d) or a salt thereof, wherein the content of the compound (3d) or the salt thereof is 97.0% by mass or more, and the content of the compound (IM-8) is 0.15% by mass or less, and the content of the total similar substances is 2.0% by mass or less. [Chemistry 57] .

[53] A 1,5-succinate of compound (3d), wherein the succinic acid content of the 1,5-succinate of compound (3d) is 20.8% by mass or more and 25.5% by mass or less. [Chem.58] .as well as

[54] A 1,5-succinate of compound (3d), wherein the succinic acid content of the 1,5-succinate of compound (3d) is 21.9% by mass or more and 24.3% by mass or less. [Chemistry 59] . [The effects of the invention]

[0010] According to the present invention, a method for manufacturing high-quality E7090 with a lower content of total similar substances can be provided, as well as high-quality E7090. Simple Explanation of the Diagram

[0011] [Figure 1] is a flowchart of the flow reaction using the microreactor device in Example 3. Implementation

[0012] Secondly, the meanings of the symbols or terms used in this manual will be explained, and this manual will be described in detail.

[0013] In this specification, "base" can be exemplified by, for example, inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, potassium tributoxide, sodium tributoxide, sodium bicarbonate, potassium bicarbonate, and cesium carbonate; organometallic reagents such as butyllithium, methyllithium, bis(trimethylsilyl)aminolithium, bis(trimethylsilyl)aminosodium, and bis(trimethylsilyl)aminopotassium; hydrides such as lithium hydride, sodium hydride, and potassium hydride; heterocyclic compounds such as imidazole, pyridine, dimethylpyridine, trimethylpyridine, and N,N-dimethylaminopyridine; and organic amines such as triethylamine, N,N-diisopropylethylamine, and diazabicycloundecene.

[0014] In this specification, "compound" includes anhydrous substances, hydrates, and solvates. Furthermore, in this specification, "compound (3d)" and the like refer to compounds that are the same as "the compound represented by formula (3d)".

[0015] "Similar substances" refers to organic compounds of known and unknown structure other than compound (3d) or its salts, as described below: starting materials, intermediates and reagents used in the manufacturing process of compound (3d) or its salts; organic compounds generated as byproducts of starting materials, intermediates or reagents in the manufacturing process of compound (3d) or its salts, or organic compounds generated due to the decomposition of starting materials, intermediates or reagents; or organic compounds generated due to the decomposition of compound (3d) or its salts during storage, etc.

[0016] Examples of organic compounds with known structures include: compound (2i), compound (3c), compound (IM-2), compound (IM-3), compound (IM-4), compound (IM-5), compound (IM-6), compound (IM-7), and compound (IM-8).

[0017] "Total similar substances" refers to all similar substances, both those with known and unknown structures, contained in the compound (3d) or its salts.

[0018] "Total content of similar substances" is the total amount (mass%) of similar substances determined by specific test methods, such as Test Example 1.

[0019] Therefore, in this specification, "compound or salt thereof" can contain similar substances, and thus has a form referred to as a "composition". Furthermore, the term "composition" as used herein indicates that "compound or salt thereof" contains similar substances in addition to the compound or salt thereof, and is therefore different from the term "pharmaceutical composition" as described below. As one embodiment, it can contain 90% or more of the compound or salt thereof and contain similar substances.

[0020] In this specification, "pharmaceutical composition" means a composition containing a compound or salt thereof with pharmacological activity and a pharmaceutically acceptable carrier. For example, compound (3d) or its salt may be cited as a compound or salt with pharmacological activity.

[0021] In this specification, the term "salt" may include, for example, inorganic acid salts (sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorates, hydrochlorides, hydrobromates, hydroiodates, etc.), organic carboxylates (acetates, oxalates, maleates, fumarates, succinates, tartrates, and citrates, etc.), organic sulfonates (methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, and camphorsulfonates, etc.), and salts of acidic amino acids (aspartate and glutamate, etc.).

[0022] In one embodiment, the compounds described herein can be provided in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the parent compound but do not impart undesirable toxicological effects. Specific examples of pharmaceutically acceptable salts include: inorganic acid salts (sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorates, hydrochlorides, hydrobroms, and hydroiodates, etc.), organic carboxylates (acetates, oxalates, maleates, fumarates, succinates, tartrates, and citrates, etc.), organic sulfonates (methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, and camphorsulfonates, etc.), amino acid salts (aspartate and glutamate, etc.), quaternary ammonium salts, alkali metal salts (sodium and potassium salts, etc.), and alkaline earth metal salts (magnesium and calcium salts, etc.).

[0023] There are no particular limitations on the salts of compound (3d), for example, salts with inorganic acids, salts with organic acids, salts with acidic amino acids, etc.

[0024] There are no particular limitations on the salts of compound (2i), for example, salts with inorganic acids, salts with organic acids, salts with acidic amino acids, etc.

[0025] The compound (3d) or its salt may be any of anhydrous, hydrated, or solvate.

[0026] This invention also includes isotopically labeled compounds of the compounds described in the specification and methods for manufacturing them. The isotopically labeled compounds are identical to the compounds described in the specification, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. Isotopes that can be incorporated into the compounds of this invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, phosphorus, sulfur, and iodine, including 2H, 3H, 11C, 14C, 13N, 15O, 18F, 32P, 35S, 123I, and 125I. The compounds of this invention containing these isotopes and / or other isotopes, and their pharmaceutically acceptable derivatives (e.g., salts), are also included within the scope of this application.

[0027] The isotope-labeled compounds of the present invention, such as those incorporating radioisotopes like 3H and / or 14C, can be used for tissue distribution analysis in pharmaceuticals and / or matrices. 3H and 14C are considered usable because they are easy to prepare and detect. Isotopes 11C and 18F are considered usable in PET (positron emission tomography), and isotope 125I is considered usable in SPECT (single-photon emission computed tomography); both are used in brain imaging. Substitution with heavier isotopes such as 2H may offer certain therapeutic advantages due to increased metabolic stability, such as prolonged in vivo half-life or reduced required dose, and is therefore considered usable in certain situations.

[0028] The manufacturing method of the present invention will be described in detail below.

[0029] Method for manufacturing compound (3d) or its salt [Transformation 60]

[0030] Step a) is the step of reacting compound (2i) or its salt with compound (3a) in the presence of a condensing agent to obtain compound (3b). [Chemistry 61]

[0031] Compound (2i) can also be its salt. When using a salt of compound (2i), a methanesulfonate is preferred.

[0032] The protecting group of piperidinium in compound (3a) can be tertiary butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl. Tertiary butoxycarbonyl is preferred.

[0033] The condensing agent may be: diethyl cyanophosphate (DEPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC-HCl / EDC-HCl), dicyclohexylcarbodiimide (DCC), 2-chloro-N-methylpyridinium iodide (CMPI), 2,4,6-trichlorobenzoxyl chloride, propylphosphonic anhydride (cyclic trimer), hexafluorophosphate (benzotriazol-1-yloxy)tripyrrolylphosphonium (PyBOP), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyluronium hydrochloride n-hydrate (DMT-MM). Preferred is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC-HCl / EDC-HCl). The condensing agent can be from 1.0 to 3.0 equivalents relative to compound (2i). More preferably, it is from 1.5 to 2.5 equivalents.

[0034] When compound (3a) is 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (3a), the amount of compound (3a) relative to compound (2i) can be from 1.0 equivalents to 2.0 equivalents. Preferably, it is from 1.1 equivalents to 1.3 equivalents.

[0035] In step a), triethylamine, N,N-dimethylaminopyridine (DMAP), 1-methylimidazole, diisopropylethylamine, or 1-methylpiperazine can be used as the base. N,N-dimethylaminopyridine (DMAP) is preferred. The base can be 0.1 to 5 equivalents relative to compound (2i). 1 to 3 equivalents is more preferred.

[0036] In step a), N,N-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt) can be used as activators. N,N-dimethylaminopyridine (DMAP) is preferred. The activator can be from 1.0 equivalent to 3.0 equivalents relative to compound (2i). Preferably, it is from 1.5 equivalents to 2.5 equivalents.

[0037] There are no particular restrictions on the solvent, as long as it can dissolve the starting material and does not inhibit the reaction; it can be DMF, DMSO, acetonitrile, or 1,2-dimethoxyethane. 1,2-dimethoxyethane is preferred.

[0038] The reaction temperature typically varies depending on the starting material, solvent, and other reagents used in the reaction, and can be carried out at temperatures ranging from 20°C to 80°C. A preferred temperature is 40°C to 70°C.

[0039] In step a), 1-methylpiperazine, 1-ethylpiperazine, and water can be used as aceimino cleavage reagents. 1-methylpiperazine is preferred. The amount of aceimino cleavage reagent can be from 0.1 equivalents to 1.0 equivalents relative to compound (2j), preferably from 0.2 equivalents to 0.4 equivalents.

[0040] The reaction temperature for aceimine cleavage typically varies depending on the starting material, solvent, and other reagents used in the reaction, and can be carried out at temperatures ranging from 20°C to 80°C. A preferred temperature is 40°C to 70°C.

[0041] Step b) is the step of removing PG 2 from compound (3b) to obtain compound (3c). [Chemistry 62]

[0042] In step b), deprotection conditions corresponding to the protecting group can be used. For example, in the case of tert-butoxycarbonyl, deprotection can be performed under acidic conditions; in the case of benzyloxycarbonyl, deprotection can be performed under basic or reducing conditions; in the case of 9-fluorenylmethoxycarbonyl, deprotection can be performed by using a secondary amine such as piperidine; and in the case of 2-nitrobenzenesulfonyl, deprotection can be performed by using a thiol under basic conditions.

[0043] When the protecting group is a tertiary butoxycarbonyl group, the acid can be, for example, trifluoroacetic acid, formic acid, sulfuric acid, hydrochloric acid, phosphoric acid, potassium hydrogen sulfate, or methanesulfonic acid. Formic acid and hydrochloric acid are preferred.

[0044] The solvent is not particularly limited as long as it can dissolve the starting material and does not inhibit the reaction. It can be: methanol, ethanol, 2-propanol, 1,2-dimethoxyethane, tetrahydrofuran, dimethyl ether, mixtures of these organic solvents with water, or no solvent. 2-propanol is preferred.

[0045] The reaction temperature typically varies depending on the starting material, solvent, and other reagents used in the reaction, ranging from room temperature to 70°C, with 20°C to 50°C being more preferred.

[0046] Step c) is the step of reacting compound (3c) with a hydroxyethylating agent to obtain compound (3d). [Chemistry 63]

[0047] As a hydroxyethylating agent, 1,4-diethyl-2,5-diol can be used, for example. When the hydroxyethylating agent is 1,4-diethyl-2,5-diol, its equivalent amount relative to compound (3c) can be from 1.0 equivalent to 3.0 equivalents. Preferably, it is from 0.6 equivalents to 1.0 equivalents.

[0048] When the hydroxyethylating agent is 1,4-diethyl-2,5-diol, it is preferable to use a reducing agent in step c). The reducing agent can be: sodium borohydride, sodium triethoxyborohydride, sodium borohydride, or sodium cyanoborohydride. Sodium triethoxyborohydride is preferred. The equivalent amount of the reducing agent relative to compound (3c) can be from 0.5 equivalents to 4.0 equivalents. Preferably, it is from 2.0 equivalents to 4.0 equivalents.

[0049] There are no particular restrictions on the reaction solvent, as long as it can dissolve the starting material and does not inhibit the reaction. For example, it can be dimethoxyethane, tetrahydrofuran, acetonitrile, 1-butanol, ethanol, methanol, or mixtures thereof. Methanol is preferred.

[0050] The reaction temperature typically varies depending on the starting material, solvent, and other reagents used in the reaction, and can be carried out from -35°C to room temperature. A preferred range is -15°C to 10°C.

[0051] Step d) is the step of making compound (3d) its salt. [Chemistry 64]

[0052] Compound (3d) can, for example, be made into a pharmaceutically acceptable salt by the method described in Patent Document 2.

[0053] The compound (3d) or its salt used for crystallization can be in any form, and can be a solvate, hydrate or anhydrous, and can be amorphous or crystalline (including crystalline substances composed of multiple polymorphs), or a mixture thereof.

[0054] The acid can be 1.0 to 3.0 equivalents relative to compound (3d). The succinic acid can be 1.7 to 2.0 equivalents relative to compound (3d).

[0055] Solvents used for crystallization include, for example, alcohols such as methanol, ethanol, 1-propanol, and 2-propanol; acetonitrile; amides such as N,N-dimethylformamide; esters such as ethyl acetate; saturated hydrocarbons such as hexane and heptane; ketones such as acetone and 2-butanone; ethers such as tributyl methyl ether; or water. These solvents can be used alone or in mixtures of two or more. A mixture of 2-propanol and water is preferred for the crystallization of succinates.

[0056] The amount of solvent used can be appropriately selected as follows: the lower limit is the amount of compound (3d) or its salt that dissolves by heating or the amount that can be stirred in the suspension, and the upper limit is the amount that does not significantly reduce the yield of crystals.

[0057] In crystallization, seed crystals (such as crystals of the salt of the desired compound (3d)) may or may not be added. There is no particular limitation on the temperature at which seed crystals are added, but 0 to 60°C is preferred. Furthermore, seed crystals can be crystals manufactured using the method described in Patent Document 2.

[0058] Regarding the temperature at which compound (3d) or its salt is heated to dissolve it, the temperature at which compound (3d) or its salt is dissolved can be appropriately selected according to the solvent. Preferably, it is in the range of 30°C to the temperature at which the recrystallization solvent begins to reflux, and more preferably, it is 30°C to 70°C.

[0059] Regarding cooling during crystallization, rapid cooling may result in crystals with different inclusion states (polymorphism). Therefore, it is ideal to adjust the cooling rate appropriately, taking into account the impact on crystal quality and fineness, for example, a cooling rate of 5°C to 40°C / hour. More preferably, for example, a cooling rate of 5°C to 25°C / hour.

[0060] In addition, the final crystallization temperature can be appropriately selected based on the crystal yield and quality, with -25°C to 30°C being the preferred range.

[0061] The crystallized crystals can be separated using conventional filtration. If necessary, the filtered crystals can be washed with a solvent and then dried to obtain the target crystals. The solvent used for washing the crystals can be the same as the crystallization solvent. Preferred solvents include ethanol, acetone, 2-propanol, 2-butanone, ethyl acetate, diethyl ether, tributyl methyl ether, and hexane. These solvents can be used alone or in mixtures of two or more.

[0062] Crystals separated by filtration can be dried by placing them under atmospheric or nitrogen gas flow, or by heating.

[0063] Regarding the drying time, it is sufficient to select a time when the residual solvent is below a specific level, based on the production volume, drying equipment, and drying temperature. Furthermore, drying can be carried out under ventilation or reduced pressure. The reduced pressure can be appropriately selected based on the production volume, drying equipment, and drying temperature. The obtained crystals can also be placed in the atmosphere after drying, if necessary.

[0064] Another embodiment of the present invention is a pharmaceutical composition comprising "compound (3d) or a salt thereof" or crystals thereof, and pharmaceutically acceptable additives. The pharmaceutical composition can be manufactured by mixing the pharmaceutically acceptable additives with "compound (3d) or a salt thereof" or crystals thereof. The pharmaceutical composition of the present invention can be manufactured, for example, by known methods such as those described in the General Principles of Formulations of the 18th Revision of the Japanese Pharmacopoeia.

[0065] The pharmaceutical composition of this embodiment can be appropriately administered to patients according to its dosage form.

[0066] The dosage of the "compound (3d) or its salt" or its crystals of the present invention varies depending on the severity of symptoms, age, sex, weight, form of administration / type of salt, specific type of disease, etc. Generally, when administered orally to an adult (weight 60 kg), the dosage is 1 mg to 500 mg daily, 10 mg to 300 mg in one embodiment, and 20 mg to 200 mg in another embodiment. The dosage can be divided into 1 to 3 doses per day. [Example]

[0067] The present invention will now be described in detail by way of examples. However, the present invention is not limited to these examples. Moreover, the abbreviations used below are commonly used abbreviations known to those skilled in the art, and some abbreviations are shown below.

[0068] ¹H-NMR spectra were determined using BRUCKER AVANCE NEO 400 (400 MHz), BRUCKER AVANCE III 500 (500 MHz), BRUCKER AVANCE 600 (600 MHz), or BRUCKER AVANCE NEO 700 (700 MHz).

[0069] Chemical shifts in proton nuclear magnetic resonance (¹H-NMR) spectra were recorded in δ units (ppm) relative to tetramethylsilane, and coupling constants were recorded in Hertz (Hz). The patterns are interpreted as follows: s: singlet, d: doublet, br: broad peak, m: multiplet.

[0070] In the following examples, "room temperature" typically refers to approximately 10°C to approximately 35°C. Unless otherwise stated, % indicates a percentage by mass.

[0071] Example 1: Preparation of 5-({2-[({4-[1-(2-hydroxyethyl)piperidin-4-yl]phenyl}carbonyl)amino]pyridin-4-yl}oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide succinate (2:3) (E7090) [Chemistry 65]

[0072] Manufacturing Example 1: Manufacturing of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide (2i) [Chemistry 66]

[0073] Under a nitrogen atmosphere, a 1 N sodium hydroxide aqueous solution (2.71 kg of flake caustic soda, 67.7 mol, 1.54 eq., water) was added to a suspension of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methyleneamine methanesulfonate (19.9 kg, 44.0 mol) in tetrahydrofuran (159.2 kg), and the mixture was stirred at 25°C for 30 minutes. Isopropyl acetate (156.2 kg) was added to the reaction solution, and after separation, the organic layer was washed with 5% brine (2.99 kg of sodium chloride, 56.7 kg of water). The obtained organic layer was washed with water (59.7 kg), clarified, filtered, and rinsed with isopropyl acetate (8.7 kg). After being concentrated to 100 L under reduced pressure below 40°C, the solution was further subjected to four azeotropic reactions using acetonitrile (78.2 kg). Acetonitrile (15.6 kg) was added to the concentrate, and the mixture was stirred at 48°C for 1 hour. The suspension was cooled to 0°C and filtered, then washed with acetonitrile (23.5 kg). The obtained crystals were dried under reduced pressure below 50°C to obtain 13.91 kg of the title compound. 1H NMR spectrum (DMSO-d 6) δ (ppm): 2.83 (3H, d, J = 4.4 Hz), 3.18 (3H, s), 3.50-3.54 (2H, m), 4.04-4.08 (2H, m), 5.69 (1H, d, J = 1.8 Hz), 5.76 (2H, s), 6.09 (1H, dd, J = 5.7, 2.2 Hz), 6.59 (1H, d, J = 3.5 Hz), 7.33 (1H, s), 7.71-7.74 (2H, m), 8.03 (1H, s), 8.10-8.14 (1H, m)

[0074] Manufacturing Examples 1-2: Manufacturing of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide (2i) [Chemistry 67]

[0075] Under a nitrogen atmosphere, a 1 N sodium hydroxide aqueous solution (5.5 kg of flake caustic soda, 137.5 mol, 1.70 eq., water) was added to a suspension of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methyleneamine methanesulfonate (36.6 kg, 80.9 mol) in tetrahydrofuran (292.5 kg), and the mixture was stirred at 20°C for 30 minutes. Isopropyl acetate (287 kg) was added to the reaction solution, and after separation, the organic layer was washed with 5% brine (5.5 kg of sodium chloride, 104 kg of water). The obtained organic layer was washed with water (110 L), clarified, filtered, and rinsed with isopropyl acetate (47.9 kg). After being concentrated to 184 L under reduced pressure below 40°C, the solution was further subjected to four azeotropic reactions using acetonitrile (144 kg). Acetonitrile (28.8 kg) was added to the concentrate, and the mixture was stirred at 45°C–46°C for 1 hour. The suspension was cooled to 2°C and filtered, then washed with acetonitrile (43.2 kg). The obtained crystals were dried under reduced pressure below 50°C to yield 25.92 kg of the title compound.

[0076] Manufacturing Example 2: Manufacturing of 4-(4-((4-((6-(2-methoxyethoxy)-1-(methylaminomethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)aminomethoxy)phenyl)piperidine-1-carboxylic acid tributyl ester (3b-1) [Chemistry 68]

[0077] Under a nitrogen atmosphere, a suspension of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide (15.0 kg, 42.1 mol), 4-(1-(tributoxycarbonyl)piperidin-4-yl)benzoic acid (15.4 kg, 50.5 mol, 1.2 eq.), N,N-dimethyl-4-aminopyridine (10.3 kg, 84.2 mol, 2.0 eq.), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16.1 kg, 84.2 mol, 2.0 eq.) in 1,2-dimethoxyethane (105 L) was stirred at 55°C for 1 hour. After the reaction was complete, 1-methylpiperazine (1.3 kg, 12.6 mol, 0.30 eq.) was added, and the mixture was stirred further at 55°C for 1 hour. After the reaction was complete, the reaction solution was cooled to an internal temperature of 10°C–15°C, and ethyl acetate (225 L) and 2N hydrochloric acid (17.7 kg concentrated hydrochloric acid, 75 L water) were added, followed by separation. 5% sodium bicarbonate solution (3.8 kg sodium bicarbonate, 71.3 kg water) was added to the organic layer, and the mixture was separated. The obtained organic layer was concentrated under reduced pressure to 115 L at an external temperature of 50°C, and then ethyl acetate (13 L) was added to prepare 128 L. Ethyl acetate (38 L) was added to the concentrate, and the mixture was stirred at 25°C for 2 hours. Then, n-heptane (150 L) was added dropwise, and the mixture was stirred at 25°C. The solution was filtered and washed with a mixture of ethyl acetate and n-heptane (ethyl acetate / n-heptane = 2.5 / 2.5 vol., 76 L). The obtained crystals were dried under reduced pressure at 50°C to obtain 24.4 kg of the title compound. 1H NMR spectrum (DMSO-d 6) δ (ppm): 1.40 (9H, s), 1.45-1.53​​ (2H, m), 1.75 (2H, br d, J = 13.4 Hz), 2.70-2.90 (6H, m), 3.11 (3H, s), 3.46-3.49 (2H, m), 4.00-4.11 (4H, m), 6.62 (1H, d, J = 3.6 Hz), 6.66 (1H, dd, J = 5.7, 2.3 Hz), 7.33 (2H, d, J = 8.3 Hz), 7.43 (1H, s), 7.68 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 3.6 Hz), 7.89 (2H, d, J = 8.3 Hz), 8.07 (1H, s), 8.14 (1 H, q, J = 4.5 Hz), 8.18 (1H, d, J = 5.7 Hz), 10.61 (1H, s)

[0078] Manufacturing Example 2-2: Manufacturing of 4-(4-((4-((6-(2-methoxyethoxy)-1-(methylaminomethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)aminomethoxy)phenyl)piperidine-1-carboxylic acid tributyl ester (3b-1) [Chemistry 69]

[0079] Under a nitrogen atmosphere, triethylamine (11.3 kg, 111.7 mol) was added to a suspension of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methanemethylamine methanesulfonate (26.0 kg, 76.5% purity, equivalent to 19.9 kg, 55.8 mol of free volume), 4-(1-(tributoxycarbonyl)piperidin-4-yl)benzoic acid (20.5 kg, 67.0 mol, 1.2 eq.), N,N-dimethyl-4-aminopyridine (13.6 kg, 111.7 mol, 2.0 eq.), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.4 kg, 111.7 mol, 2.0 eq.) in 1,2-dimethoxyethane (139 L). 1.7 kg (16.8 mol, 0.3 eq.) was added, and the mixture was stirred at 55°C for 1 hour. After the reaction was complete, 1-methylpiperazine (1.7 kg, 16.8 mol, 0.3 eq.) was added, and the mixture was stirred further at 55°C for 1 hour. After the reaction was complete, the reaction solution was cooled to an internal temperature of 10°C ~ 15°C, and ethyl acetate (299 L) and 2N hydrochloric acid (35.3 kg concentrated hydrochloric acid, 150.0 L water) were added, and the mixture was separated. 5% sodium bicarbonate solution (6.0 kg sodium bicarbonate, 113.4 kg water) was added to the organic layer, and the mixture was separated. The obtained organic layer was concentrated under reduced pressure to 165 L at an external temperature of 50°C, and then ethyl acetate (4 L) was added to prepare 169 L. Ethyl acetate (50 L) was added to the concentrate, and the mixture was stirred at 30°C for 2 hours. Then, n-heptane (199 L) was added dropwise, and the mixture was stirred at 30°C. The mixture was filtered and washed with a mixture of ethyl acetate and n-heptane (ethyl acetate / n-heptane = 2.5 / 2.5 vol., 100 L). The obtained crystals were dried under reduced pressure at 50°C to obtain 35.0 kg of the title compound.

[0080] Manufacturing Examples 2-3: Manufacturing of 4-(4-((4-((6-(2-methoxyethoxy)-1-(methylaminomethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)aminomethoxy)phenyl)piperidine-1-carboxylic acid tributyl ester (3b-1) [Chemistry 70]

[0081] Under a nitrogen atmosphere, a suspension of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide (24.0 kg, 67.3 mol), 4-(1-(tributoxycarbonyl)piperidin-4-yl)benzoic acid (24.7 kg, 80.9 mol), N,N-dimethyl-4-aminopyridine (16.5 kg, 135.1 mol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25.8 kg, 134.6 mol) in 1,2-dimethoxyethane (168 L) was stirred at 57°C for 2 hours. Then, 1-methylpiperazine (2.0 kg, 20.2 mol) was added, and the mixture was stirred further at 57°C for 2 hours. The reaction solution was cooled to an internal temperature of 10°C–15°C, and ethyl acetate (360 L), water (86 L), and 5N hydrochloric acid (62.2 kg) were added, followed by separation. A 5% sodium bicarbonate solution (6.0 kg sodium bicarbonate, 114 L water) was added to the organic layer, and separation was repeated. The obtained organic layer was concentrated to 200 L under reduced pressure at an external temperature of 50°C, and then ethyl acetate (4 L) was added to prepare 204 L. Ethyl acetate (60 L) was added to the concentrate, and the mixture was stirred at 60°C for 1 hour, then cooled to an internal temperature of 25°C and stirred for 3 hours. After the addition of n-heptane (240 L), the mixture was filtered and washed with a mixture of ethyl acetate and n-heptane (ethyl acetate / n-heptane = 2.5 / 2.5 vol., 120 L). The obtained crystals were dried under reduced pressure at 50°C to obtain 41.2 kg of the title compound.

[0082] Manufacturing Example 3: Manufacturing of 6-(2-methoxyethoxy)-N-methyl-5-{[2-({[4-(piperidin-4-yl)phenyl]carbonyl}amino)pyridin-4-yl]oxy}-1H-indole-1-methylamine (3c) [Chemistry 71]

[0083] Under a nitrogen atmosphere, 79.1 kg of 5N hydrochloric acid was added to a suspension of 2-propanol (49 L) of tributyl 4-(4-((4-(((6-(2-methoxyethoxy)-1-(methylaminomethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)aminomethoxy)phenyl)piperidin-1-carboxylic acid (24.4 kg, 37.9 mol) and 2-propanol. The mixture was stirred at 35°C for 2 hours. After the reaction was complete, the reaction solution was cooled to an internal temperature of 0-5°C, and 73 L of water, 244 L of tetrahydrofuran, and 22.0 kg of 5N sodium hydroxide aqueous solution were added. The mixture was stirred at 25°C and then separated. 5% brine (12.2 kg of salt and 109.8 kg of water) and 24 L of toluene were added to the organic layer, and the mixture was then separated. Ethanol (244 L) was added to the obtained organic layer, and the mixture was concentrated to 122 L under reduced pressure at an external temperature of 50°C. Then, ethanol (49 L) was added to the concentrate, and the mixture was stirred at 45°C for 1 hour. The suspension was cooled to an internal temperature of 3°C, filtered, and washed with ethanol (98 L). The obtained crystals were dried under reduced pressure at 50°C to obtain 18.5 kg of the title compound. 1H NMR spectrum (DMSO-d 6) δ (ppm): 1.45-1.55 (2H, m), 1.67 (2H, br dd, J = 12.1, 1.7 Hz), 2.53-2.58 (2H, m), 2.59-2.65 (1H, m), 2.84 (3H, d, J = 4.2 Hz), 2.95-3.02 (2H, m), 3.12 (3H, s), 3.45-3.49 (2H, m), 4.05-4.09 (2H, m), 6.62 (1H, br d, J = 3.4 Hz), 6.66 (1H, dd, J = 5.7, 2.3 Hz), 7.30 (2H, d, J = 8.5 Hz), 7.43 (1H, s), 7.68 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 3.6 Hz), 7.89 (2H, d, J = 8.3 Hz), 8.07 (1H, s), 8.12-8.16 (1H, m), 8.18 (1H, d, J = 5.7 Hz), 10.59 (1H, br s)

[0084] Manufacturing Example 3-2: Manufacturing of 6-(2-methoxyethoxy)-N-methyl-5-{[2-({[4-(piperidin-4-yl)phenyl]carbonyl}amino)pyridin-4-yl]oxy}-1H-indole-1-methylamine (3c) [Chemistry 72]

[0085] Under a nitrogen atmosphere, 133.5 kg of 5N hydrochloric acid was added to a suspension of 41.2 kg (64.0 mol) of tributyl piperidine-1-carboxylic acid in 82 L of 2-propanol, and the mixture was stirred at 35°C for 3 hours. The reaction mixture was cooled to an internal temperature of 25°C, and 124 L of water and 412 L of toluene were added and stirred. The mixture was then separated. The resulting aqueous layer was cooled to an internal temperature of 0–5°C, and 412 L of tetrahydrofuran and a 5N aqueous solution of sodium hydroxide (37.1 kg of sodium hydroxide and 181 L of water) were added. The mixture was stirred at 20°C and then separated. The organic layer was treated with 10% brine (20.6 kg salt, 185 L water) and 41 L toluene, followed by separation. Ethanol (424 L) was added to the resulting organic layer, and the mixture was concentrated to 210 L under reduced pressure at an external temperature of 50°C. Ethanol (82 L) was then added to the concentrate, and the mixture was stirred at 47°C for 1 hour. The suspension was cooled to an internal temperature of 3°C, filtered, and washed with 165 L of ethanol. The resulting crystals were dried under reduced pressure at 50°C to obtain 31.3 kg of the title compound.

[0086] Manufacturing Example 4: Manufacturing of 5-({2-[({4-[1-(2-hydroxyethyl)piperidin-4-yl]phenyl}carbonyl)amino]pyridin-4-yl}oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methylamine (3d) [Chemistry 73]

[0087] Methanol (268 L) was added to 18.5 kg (34.0 mol) of 6-(2-methoxyethoxy)-N-methyl-5-{[2-({[4-(piperidin-4-yl)phenyl]carbonyl}amino)pyridin-4-yl]oxy}-1H-indole-1-methamide, and the mixture was stirred at -5°C or below. Triacetoxyborohydride (21.6 kg, 102 mol, 3.0 eq.) was added in portions under a nitrogen atmosphere, followed by rinsing with methanol (9 L). A methanol solution (83 L) of 1,4-dichloro-2,5-diol (3.3 kg, 27 mol, 0.80 eq.) was added dropwise over 2 hours at an internal temperature of -10°C to -5°C, followed by rinsing with methanol (9 L) and stirring at an internal temperature of -5°C to 0°C for 1 hour. After the reaction was complete, water (166.5 kg) was added dropwise to the reaction mixture. The mixture was stirred at 25°C and then concentrated under reduced pressure to 185 L at an external temperature of 35°C. 1,2-Dimethoxyethane (56 L) was added to the concentrated solution, followed by the dropwise addition of 5N sodium hydroxide aqueous solution (54.4 kg) at an internal temperature of 5°C to confirm crystal precipitation. n-Butanol (370 L) was added to the suspension, and after confirming dissolution, the mixture was stirred at an internal temperature of 25°C for 4 hours and separated. A 10% ethylenediamine aqueous solution (18.5 kg ethylenediamine, 166.5 kg water) was added to the organic layer. After separation at an internal temperature of 35°C, the mixture was washed with water (185.0 kg). 1,2-Dimethoxyethane (37 L) and water (185.0 kg) were added to the organic layer. After separation, the organic layer was concentrated under reduced pressure to 105 L at an external temperature of 50°C. Toluene (93 L) was added to the concentrate, and after stirring at an internal temperature of 50°C for 1 hour, toluene (278 L) was added dropwise at an internal temperature of 55°C for 1 hour and 12 minutes. The suspension was cooled to an internal temperature of -8°C, filtered, and washed with a mixture of toluene and n-butanol (toluene / n-butanol = 4.0 / 1.0 vol., 93 L). The obtained crystals were dried under reduced pressure at 50°C to give 16.353 kg of the title compound as a solid. 1H NMR spectrum (DMSO-d 6) δ (ppm): 1.60-1.68 (2H, m), 1.71 (2H, br d, J = 12.1 Hz), 2.02-2.08 (2H, m), 2.40 (2H, t, J = 6.4 Hz), 2.50-2.56 (1H, m), 2.84 (3H, d, J = 4.2 Hz), 2.96 (2H, br d, J = 11.4 Hz), 3.11 (3H, s), 3.45-3.52 (4H, m), 4.06-4.09 (2H, m), 4.34 (1H, t, J = 5.3 Hz), 6.62 (1H, d, J = 3.6 Hz), 6.66 (1H, dd, J = 5.7, 2.1 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.43 (1H, s), 7.68 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 3.8 Hz), 7.89 (2H, d, J = 8.3 Hz), 8.07 (1H, s), 8.14 (1H, q, J = 4.2 Hz), 8.18 (1H, d, J = 5.7 Hz), 10.59 (1H, br s)

[0088] Manufacturing Example 5: Manufacturing of 5-({2-[({4-[1-(2-hydroxyethyl)piperidin-4-yl]phenyl}carbonyl)amino]pyridin-4-yl}oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamine succinate (2:3) (E7090) [Chemistry 74]

[0089] Under a nitrogen atmosphere, a mixture of 45 L of 2-propanol and water (28.1 kg) of 5-({2-[({4-[1-(2-hydroxyethyl)piperidin-4-yl]phenyl}carbonyl)amino]pyridin-4-yl}oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methacrylamine (16.353 kg, 27.8 mol) was stirred at an internal temperature of 45°C to 50°C. Succinic acid (5.9 kg, 50 mol, 1.8 eq.) was then added, followed by rinsing with water (1.6 kg) to confirm dissolution. The reaction solution was clarified and filtered, then rinsed with a mixture of 4 L of 2-propanol and water (6.4 kg). 53 L of 2-propanol was then added dropwise over 39 minutes at an internal temperature of 35°C to 45°C. The solution was cooled to an internal temperature of 25°C, and seed crystals (16.4 g) were added during cooling at an internal temperature of 35°C. 2-Propanol (191 L) was added dropwise to the suspension, and the mixture was stirred at an internal temperature of 20°C. The suspension was filtered and washed with 2-propanol (128 L). The obtained crystals were dried under reduced pressure at 50°C to obtain 19.032 kg (unpulverized) of the title compound as a solid. 18.832 kg (unpulverized) of the title compound was pulverized to obtain 18.677 kg (unpulverized) of the title compound as a solid. 1H NMR spectrum (CD 3OD) δ (ppm): 1.97-2.10 (4H, m), 2.53 (6H, s), 2.89-2.97 (4H, m), 2.97-3.05 (2H, m), 3.17 (2H, t, J = 5.3 Hz), 3.22 (3H, s), 3.54-3.58 (2H, m), 3.62 (2H, br d, J = 12.5 Hz), 3.85-3.89 (2H, m), 4.13-4.16 (2H, m), 6.60 (1H, d, J = 3.7 Hz), 6.68 (1H, dd, J = 5.9, 2.4 Hz), 7.37 (1H, s), 7.40-7.43 (2H, m), 7.58 (1H, d, J = 3.7 Hz), 7.73 (1H, d, J = 2.3 Hz), 7.86-7.89 (2H, m), 8.08 (1H, s), 8.14 (1H, d, J = 5.8 Hz)

[0090] Experimental Example 1: Purity Test of E7090 (1) A standard of E7090 obtained by crystallization (using a sample of E7090 with particularly high purity produced by the method described in Manufacturing Example 5 as the standard) was used as an external control. The peak areas of each peak corresponding to E7090 in the standard and the sample obtained in Manufacturing Example 5 were compared to calculate the content of E7090 in the sample. Next, in order to correct for differences in absorbance per unit mass of each similar substance, each similar substance was identified according to the order described in Experimental Example 2. After synthesizing samples of each similar substance, the absorbance (sensitivity coefficient) of each similar substance was calculated when the absorbance of E7090 was set to 1. Then, the mass percentage of each similar substance was calculated using the peak area and sensitivity coefficient of the similar substances in the sample. The total content of the similar substances detected exceeding 0.05 mass percentage was taken as the total content of the similar substances. On the other hand, for similar substances without samples, the operation was performed as if the area percentage and mass percentage were equivalent. The results are shown in Table 1. In addition, the retention time and detection limit of each similar substance in liquid chromatography are recorded in Table 3.

[0091] [Table 1] Manufacturing Example 5 E7090 99.9% quality Total content of similar substances 0.12% by mass

[0092] Determination conditions of liquid chromatography Detector: Ultraviolet absorber (measurement wavelength: 239 nm) Column: X-Bridge (manufactured by Waters), inner diameter: 4.6 mm, length: 25 cm, packing particle size: 5 μm Column temperature: a certain temperature around 23°C Mobile phase: Elute solutions A and B, which contain the following components, according to the linear gradient shown in Table 2 below. Solution A: Ammonium bicarbonate buffer (pH 10.0) / methanol (1:1, v / v) Solution B: Methanol Flow rate: 0.7 mL / min Injection volume: 10 μL Sample rack temperature: a certain temperature around 10°C Area measurement range: 50 minutes

[0093] [Table 2] time (minute) The content ratio of solution B in the mobile phase (volume%) 0 26 30 26 40 95 50 95 50.01 26 70 stop

[0094] [Table 3] Similar substances Duration (minute) Detection Limit (quality%) content (quality%) Compound (2i) 6.5 0.0003 ≤ 0.05 Compound (3c) 13.9 0.001 ≤ 0.05 Compound (IM-2) 40.1 0.0002 0.06 Compound (IM-3) 7.6 0.0002 ≤ 0.05 Compound(IM-4) 41.9 0.003 ≤ 0.05 Compound (IM-5) 9.5 0.0004 ≤ 0.05 Compound (IM-6) 21.4 0.002 0.06 Compound (IM-7) 38 0.0004 ≤ 0.05 Compound (IM-8) 46.9 0.0004 ≤ 0.05 E7090 17.3 0.0006 99.9

[0095] Experimental Example 2: Purity Test of E7090 (2) The purity of E7090 manufactured according to the contents of Patent Documents 1 and 2 was determined under the following conditions. 10 mg of the sample was weighed into a 10 ml volumetric flask and accurately diluted to volume with 50% acetonitrile solution. 5 ml of the solution was added to another 10 ml volumetric flask and accurately diluted to volume. These solutions were then analyzed by HPLC. Furthermore, the retention time and area percentage in the liquid chromatography method are shown in Table 5.

[0096] Determination conditions of liquid chromatography Detector: Ultraviolet absorber (measurement wavelength: 239 nm) Column: InertSustain C-18, inner diameter: 4.6 mm, length: 15 cm, packing particle size: 3 μm Column temperature: 40°C Mobile phase: Elute solutions A and B, which contain the following components, according to the linear gradient shown in Table 4 below. Solution A: 12.5 mM phosphate buffer (pH 7) / acetonitrile (9:1, v / v) Solution B: 12.5 mM phosphate buffer (pH 7) / acetonitrile (1:3, v / v) Flow rate: 1.0 mL / min Injection volume: 10 μL Sample rack temperature: a certain temperature around 25°C Area measurement range: 70 minutes

[0097] [Table 4] time (minute) The content ratio of solution B in the mobile phase (volume%) 0 25 3 25 30 45 50 90 60 90 60.01 25 70 stop

[0098] [Table 5] Holding time (minutes) area% 10.062 0.906 15.251 0.113 15.704 0.057 20.648 97.785 22.237 0.054 26.054 0.287 31.884 0.063 48.311 0.583 54.165 0.151 100.000

[0099] Experimental Example 3: Purity Test of E7090 (3) The content of succinic acid in E7090 obtained by the method described in Manufacturing Example 5 was determined under the following conditions. The results are shown in Table 6. Furthermore, the holding time of succinic acid in liquid chromatography was 12 minutes.

[0100] [Table 6] Manufacturing Example 5 Succinic acid content 22.9% of mass

[0101] Determination conditions of liquid chromatography Detector: Ultraviolet absorber (measurement wavelength: 210 nm) Column: Inertsustain AQ-C18 (manufactured by GL Science), inner diameter: 4.6 mm, length: 25 cm, filler particle size: 5 μm Column temperature: a certain temperature around 30°C Mobile phase: Elute solutions A and B, which contain the following components, according to the linear gradient shown in Table 7 below. Solution A: Water / Phosphoric A (500:1, v / v) Solution B: Acetonitrile Flow rate: 1.0 mL / min Injection volume: 10 μL Sample rack temperature: a certain temperature around 15°C Area measurement range: 15 minutes

[0102] [Table 7] time (minute) The content ratio of solution B in the mobile phase (volume%) 0 0 15 0 15.01 100 25 100 25.01 0 40 stop

[0103] Example 2: Synthesis of similar substances

[0104] Preparation Example 6: Synthesis of 5,5'-{ethane-1,2-dimethylbis[(piperidin-1,4-diyl)-4,1-phenylenecarbonylazadipyridin-2,4-diyloxy]}bis[6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide] (compound (IM-4)) [Chemistry 75]

[0105] Chloroform (195 mL) was added to 13.0 g of 6-(2-methoxyethoxy)-N-methyl-5-{[2-({[4-(piperidin-4-yl)phenyl]carbonyl}amino)pyridin-4-yl]oxy}-1H-indole-1-methamide, and the mixture was heated and stirred at 50°C under a nitrogen atmosphere. Glyoxal (2.0 mL) and sodium borohydride (9.50 g) were added, and the mixture was stirred at 50°C for 1 hour. After cooling the reaction mixture to room temperature, it was filtered through NH silica gel (205 g), and the NH silica gel was washed with chloroform (1300 mL). The filtrate was concentrated under reduced pressure at 40°C, and tetrahydrofuran (65 mL) and methanol (65 mL) were added to the concentrated residue. The suspension was stirred at 60°C. After cooling to room temperature, the suspension was filtered and washed with a mixture of tetrahydrofuran and methanol (tetrahydrofuran / methanol = 1 / 1, 39 mL). The obtained solid was dried under reduced pressure to give 8.14 g (61.1%) of the title compound. 1H NMR (DMSO-d 6) δ (ppm): 1.60-1.68 (4H, m), 1.73 (4H, br d, J = 11.7 Hz), 2.00-2.07 (4H, m), 2.45 (4H, s), 2.51-2.57 (2H, m), 2.84 (6H, d, J = 4.5 Hz), 2.98 (4H, br d, J = 11.0 Hz), 3.12 (6H, s), 3.45-3.49 (4H, m), 4.05 -4.09 (4H, m), 6.62 (2H, d, J = 3.8 Hz), 6.66 (2H, dd, J = 5.7, 2.3 Hz), 7.33 (4H, d, J = 8.3 Hz), 7.43 (2H, s), 7.68 (2H, d, J = 2.3 Hz), 7.77 (2H, d, J = 3.4 Hz), 7.89 (4H, d, J = 7.9 Hz), 8.07 (2H, s), 8.14 (2H, q, J = 4.5 Hz), 8.19 (2H, d, J = 6.0 Hz), 10.60 (2H, br s)

[0106] Example 7: Synthesis of 4-[2-(4-{4-[(4-{[6-(2-methoxyethoxy)-1-(methylaminomethoxy)-1H-indol-5-yl]oxy}pyridin-2-yl)aminomethoxy]phenyl}piperidin-1-yl)ethoxy]-4-sideoxybutyric acid (compound (IM-5)) [Chemistry 76]

[0107] Under a nitrogen atmosphere, tetrahydrofuran (20 mL), triethylamine (2.9 mL), and N,N-dimethylaminopyridine (83 mg) were added to 5-({2-[({4-[1-(2-hydroxyethyl)piperidin-4-yl]phenyl}carbonyl)amino]pyridin-4-yl}oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indol-1-methoxyamine (4.01 g) and succinic anhydride (1.23 g), and stirred at 60°C for 3 hours. The reaction mixture was cooled in an ice bath, the precipitated solid was filtered, and washed with tetrahydrofuran (8 mL). The obtained solid was dried under reduced pressure to obtain 4.76 g of the title compound. 1H NMR (DMSO-d 6) δ (ppm): 1.60-1.77 (4H, m), 2.09-2.15 (2H, m), 2.45-2.56 (5H, m), 2.58 (2H, t, J = 6.0 Hz), 2.84 (3H, d, J = 4.5 Hz), 2.97 (2H, br d, J = 11.0 Hz), 3.11 (3H, s), 3.45-3.49 (2H, m), 4.05-4.09 (2H, m), 4.13 (2H, t, J = 6.1 Hz), 6.62 (1H, d, J = 3.4 Hz), 6.66 (1H, dd, J = 5.7, 2.4 Hz), 7.33 (2H, d, J = 8.3 Hz), 7.43 (1H, s), 7.68 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 3.4 Hz), 7.89 (2H, d, J = 8.3 Hz), 8.07 (1H, s), 8.15 (1H, q, J = 4.2 Hz), 8.18 (1H, d, J = 5.7 Hz), 10.61 (1H, br s)

[0108] Example 8: Synthesis of 4-[1-(2-hydroxyethyl)piperidin-4-yl]-N-(4-{[6-(2-methoxyethoxy)-1H-indol-5-yl]oxy}pyridin-2-yl)benzamide (synthesis of compound (IM-6)) [Chemistry 77]

[0109] Tetrahydrofuran (100 mL) and tetrabutylammonium fluoride (128 mL, 1 mol / L, 128 mmol, 5.0 eq.) were added to 5-({2-[({4-[1-(2-hydroxyethyl)piperidin-4-yl]phenyl}carbonyl)amino]pyridin-4-yl}oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide (15.0 g, 25.5 mmol), and the mixture was stirred at 50°C. After cooling to room temperature, ethyl acetate (300 mL) and water (100 mL) were added, and the mixture was separated. The organic layer was washed seven times with 5% sodium bicarbonate aqueous solution (150 mL), followed by washing with water (150 mL). The organic layer was concentrated under reduced pressure, and the resulting residue was purified by NH-silicone column chromatography (NH-silicone, ethyl acetate: methanol = 20:1 → 10:1 → 1:1). The target fraction was concentrated under reduced pressure to obtain 1.81 g (13.4%) of the title compound in solid form. 1H NMR (DMSO-d 6) δ (ppm): 1.60-1.68 (2H, m), 1.72 (2H, br d, J = 11.7 Hz), 2.01-2.09 (2H, m), 2.40 (2H, t, J = 6.4 Hz), 2.51-2.57 (1H, m), 2.96 (2H, br d, J = 11.0 Hz), 3.12 (3H, s), 3.43-3.53 (4H, m), 4.03-4.08 (2H, m), 4.34 (1H, t, J = 5.3 Hz), 6.35-6.38 (1H, m), 6.62 (1H, dd, J = 5.7, 2.3 Hz), 7.14 (1H, s), 7.28 (1H, dd, J = 2.7, 2.3 Hz), 7.32 (2 H, d, J = 8.3 Hz), 7.34 (1H, s), 7.67 (1H, d, J = 2.3 Hz), 7.88 (2H, d, J = 7.9 Hz), 8.16 (1H, d, J = 5.7 Hz), 10.56 (1H, br s), 11.05 (1H, br s)

[0110] Production Example 9: Synthesis of 5-({2-[4-(1-ethylpiperidin-4-yl)benzamide]pyridin-4-yl}oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide (compound (IM-7)) [Chemistry 78]

[0111] Methanol (300 mL) was added to 6-(2-methoxyethoxy)-N-methyl-5-{[2-({[4-(piperidin-4-yl)phenyl]carbonyl}amino)pyridin-4-yl]oxy}-1H-indole-1-methamide (15.00 g, 27.59 mmol), and the mixture was stirred at 0°C. Acetaldehyde (4.70 mL, 8.38 mmol, 3.04 eq.) and sodium triethoxyborohydride (17.55 g, 82.81 mol, 3.00 eq.) were added, and the mixture was stirred for 4 hours. Water (135 mL) was added to the reaction mixture, and after stirring at room temperature, the mixture was concentrated under reduced pressure at 35°C to approximately 135 mL. Tetrahydrofuran (210 mL) and toluene (105 mL) were added to the concentrated solution, and then 52.5 mL of 5N sodium hydroxide aqueous solution was added at 0°C, followed by separation. The organic layer was washed twice with water (150 mL) and concentrated under reduced pressure at 35°C. The obtained residue was purified by NH-silicone column chromatography (NH-silicone 682 g, ethyl acetate: methanol = 100:0 → 100:1 → 29:1). The target fraction was concentrated under reduced pressure at 35°C. Tetrahydrofuran (28.9 mL) was added to the obtained concentrated residue, stirred at 60°C to dissolve it, cooled in an ice bath, and then methyl tributyl ether (57.8 mL) was added and stirred. The suspension was filtered, and the filtered solid was washed with a mixture of tetrahydrofuran (4.8 mL) and methyl tributyl ether (9.6 mL). The obtained solid was dried under reduced pressure at 50°C to obtain 8.82 g (56.0%) of the title compound. 1H NMR (DMSO-d 6) δ (ppm): 1.00 (3H, t, J = 7.2 Hz), 1.64 (2H, qd, J = 12.3, 4.4 Hz), 1.71-1.77 (2H, m), 1.94 (2H, td, J = 11.5, 1.9 Hz), 2.34 (2H, q, J = 7.2 Hz), 2.51-2.56 (1 H, m), 2.84 (3H, d, J = 4.5 Hz), 2.96 (2H, br d, J = 11.5 Hz), 3.12 (3H, s), 3.45-3.49 (2H, m), 4.05-4.09 (2H, m), 6.62 (1H, d, J = 3.6 Hz), 6.66 (1H, dd, J = 5.7, 2.3 Hz), 7.33 (2H, d, J = 8.3 Hz), 7.43 (1H, s), 7.68 (1 , d, J = 2.3 Hz), 7.77 (1H, d, J = 3.6 Hz), 7.89 (2H, d, J = 8.3 Hz), 8.07 (1H, s), 8.14 (1H, q, J = 4.2 Hz), 8.18 (1H, d, J = 5.7 Hz), 10.60 (1H, br s)

[0112] Example 10: Synthesis of 5,5'-{(2-methylpropane-1,3-diyl)bis[(piperidine-1,4-diyl)-4,1-phenylenecarbonylazadiylpyridin-2,4-diyloxy]}bis[6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide] (compound (IM-8)) [Chemistry 79]

[0113] Tetrahydrofuran (30 mL), diazabicycloundecene (0.17 mL, 1.1 mmol, 0.2 eq.), and methacrolein (0.69 mL, 8.3 mmol, 1.5 eq.) were added to 6-(2-methoxyethoxy)-N-methyl-5-{[2-({[4-(piperidin-4-yl)phenyl]carbonyl}amino)pyridin-4-yl]oxy}-1H-indole-1-methacrylamide (3.0 g, 5.5 mmol) and stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure at 40°C. 6-(2-methoxyethoxy)-N-methyl-5-{[2-({[4-(piperidin-4-yl)phenyl]carbonyl}amino)pyridin-4-yl]oxy}-1H-indole-1-methamide (2.4 g, 4.4 mmol, 0.8 eq.) and methanol (34 mL) were added to the concentrated residue and the mixture was cooled in an ice bath. Under a nitrogen atmosphere, sodium triethoxyborohydride (3.51 g, 16.6 mmol, 3.0 eq.) was added, and the mixture was stirred for 2.5 hours under ice bath cooling. Water (20 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure at 40°C. Tetrahydrofuran (50 mL) was added to the concentrated solution, followed by the addition of 25 mL of 5N sodium hydroxide aqueous solution at 0°C, and the mixture was separated. The organic layer was washed twice with saturated brine and then concentrated under reduced pressure at 40°C. The obtained residue was dissolved in tetrahydrofuran and purified by NH-silicone column chromatography (NH-silicone 110 g, ethyl acetate: methanol = 100:0 → 95:5). The target fraction was concentrated under reduced pressure at 40°C. Methanol (200 mL) was added to the obtained concentrated residue, and the suspension was stirred at room temperature. The suspension was filtered, and the solid obtained from the filtration was washed with methanol and dried under reduced pressure at 40°C to obtain 2.19 g (39.7%) of the title compound. 1H NMR (DMSO-d 6) δ (ppm): 0.89 (3H, d, J = 6.2 Hz), 1.59-1.69 (4H, m), 1.73 (4H, br d, J = 11.0 Hz), 1.87-1.96 (3H, m), 1.98-2.07 (4 H, m), 2.26 (2H, dd, J = 11.9, 5.7 Hz), 2.50-2.57 (2H, m), 2.84 (6H, d, J = 4.4 Hz), 2.88-2.95 (4H, m), 3.11 (6H, s), 3.45-3.49 (4H, m), 4.05-4.09 (4H, m), 6.62 (2H, d, J = 3.5 Hz), 6.66 (2H, dd, J = 5.7, 2.2 Hz), 7.33 (4H, d, J = 8.4 Hz), 7.44 (2H, s), 7.68 (2H, d, J = 2.2 Hz), 7.77 (2H, d, J = 4.0 Hz), 7.89 (4H, d, J = 8.4 Hz), 8.07 (2H, s), 8.16 (2H, q, J = 4.4 Hz), 8.18 (2H, d, J = 5.7 Hz), 10.63 (2H, br s)

[0114] Example 11: Synthesis of 5-({2-[4-(1-tert-butylpiperidin-4-yl)benzamide]pyridin-4-yl}oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide (synthesis of compound (IM-2))

[0115] Example 11-1: Synthesis of 4-{4-[(benzyloxy)carbonyl]phenyl}piperidine-1-carboxylic acid tributyl ester (compound (21-1)) [Chemistry 80]

[0116] N,N-dimethylformamide (1150 mL), potassium carbonate (67.7 g, 489.6 mmol, 1.30 eq.), and benzyl bromide (49.2 mL, 414.2 mmol, 1.10 eq.) were added to 4-(1-(tributoxycarbonyl)piperidin-4-yl)benzoic acid (115.0 g, 376.6 mmol), and the mixture was stirred at room temperature for 21 hours. Ethyl acetate (4.6 L) and water (2.6 L) were added to the reaction mixture, and the mixture was separated. The organic layer was washed with water (690 mL) and then with brine (690 mL water, 13.8 g sodium chloride). The mixture was concentrated under reduced pressure at 40°C, and ethyl acetate (230 mL) was added to the concentrated residue. The mixture was stirred at 70°C until dissolved, cooled to room temperature, and stirred. After cooling to 0°C, n-heptane (920 mL) was added dropwise. The suspension was filtered, and the filtered solid was washed with a mixture of ethyl acetate and n-heptane (ethyl acetate / n-heptane = 1 / 4, 230 mL). The obtained solid was dried under reduced pressure at 40°C to give 120.4 g (80.8%) of the title compound.

[0117] Example 11-2: Synthesis of 4-[1-(2-cyanopropane-2-yl)piperidin-4-yl]benzyl benzoate (compound (21-2)) [Chemistry 81]

[0118] Under a nitrogen atmosphere and with ice bath cooling, 120.4 g (304.4 mmol) of 4-{4-[(benzyloxy)carbonyl]phenyl}piperidine-1-carboxylic acid tributyl ester (compound (21-1)) was added to trifluoroacetic acid (241 mL) and stirred for 1 hour. The reaction mixture was then concentrated under reduced pressure at 35°C. Water (310 mL), toluene (602 mL), and tetrahydrofuran (602 mL) were added to the concentrated solution, followed by the addition of 146 mL of 25% sodium hydroxide aqueous solution under ice bath cooling. The mixture was separated from the aqueous layer. Re-extraction was performed using a mixture of tetrahydrofuran and toluene (tetrahydrofuran / toluene = 1 / 1, 602 mL). The combined organic layer was washed with water (240 mL) and concentrated under reduced pressure at 40°C to obtain an oil (90.5 g). Acetone (680 mL) and acetone cyanohydrin (27.2 mL, 297.9 mol) were added to the obtained oily substance (80.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was then concentrated under reduced pressure at 40°C. Methanol (240 mL) was added to the concentrated residue, and the mixture was stirred at 0°C. The suspension was filtered, and the filtered solid was washed with methanol (160 mL). The obtained solid was dried under reduced pressure at 40°C to give 90.5 g (93.4%) of the title compound.

[0119] Example 11-3: Synthesis of 4-(1-tert-butyl)piperidin-4-yl)benzyl benzoate (compound (21-3)) [Chemistry 82]

[0120] Toluene (23 g) and tetrahydrofuran (900 mL) were added to compound (21-2) (90.0 g, 248.3 mmol), and the mixture was stirred at -40°C. A tetrahydrofuran solution of methylmagnesium bromide (730 mL, 1.06 mol / L, 774.1 mmol, 3.1 eq.) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at -25°C for 9 hours. The reaction mixture was then added to a mixture of toluene (1630 mL) and an aqueous solution of ammonium acetate (163 g ammonium acetate, 815 mL water) under ice bath cooling and stirred, followed by separation. The organic layer was washed with water (270 mL), and the mixture was concentrated under reduced pressure at 40°C. Methanol (250 mL) was added to the concentrated residue, and the mixture was stirred at 60°C to dissolve it. The mixture was then cooled under ice bath cooling and stirred. The suspension was filtered, and the filtered solid was washed with methanol (50 mL). The obtained filtrate was concentrated under reduced pressure at 40°C and purified by NH-silicone column chromatography (NH-silicone 600 g, ethyl acetate: n-heptane = 1:9). The target fraction was concentrated under reduced pressure at 40°C. Methanol (50 mL) was added to the obtained concentrated residue, and the mixture was stirred at 60°C to dissolve it. The mixture was then cooled by ice bath while stirring. The suspension was filtered, and the filtered solid was washed with methanol (30 mL). The obtained filtrate was concentrated under reduced pressure at 40°C to obtain 19.1 g (21.9%) of the title compound as a solid.

[0121] Example 11-4: Synthesis of 4-(1-tert-butyl)piperidin-4-yl)benzyl benzoate (compound (21-4)) [Chemistry 83]

[0122] Methanol (348 mL) and water (35 mL) were added to compound (21-3) (19.1 g, 54.3 mmol) and stirred. 10% palladium on carbon (2.87 g, 15 wt%) was added, and the mixture was stirred at room temperature for 16.6 hours under a hydrogen atmosphere. Water (99 mL) was added to the reaction mixture, and the mixture was filtered through diatomaceous earth and washed with a mixture of methanol and water (methanol / water = 2 / 1, 300 mL). The filtrate was concentrated under reduced pressure at 40°C. The concentrated residue was subjected to two azeotropic reactions at 40°C using toluene (100 mL) and methanol (50 mL), two azeotropic reactions using toluene (50 mL) and methanol (10 mL), and one azeotropic reaction using toluene (50 mL). Methanol (57 mL) was added to the concentrated residue, and the suspension was stirred at 70°C, then cooled to 0°C and stirred. The suspension was filtered, and the filtered solid was washed with methanol (5 mL). The obtained solid was dried under reduced pressure at 40°C to obtain 0.87 g (6.2%) of the title compound. The obtained filtrate was concentrated under reduced pressure at 40°C, tetrahydrofuran (73 mL) was added, and the mixture was stirred at 50°C, cooled to room temperature, and stirred again. The suspension was filtered, and the filtered solid was washed with tetrahydrofuran (20 mL), and dried under reduced pressure at 40°C to obtain 4.22 g (29.7%) of the title compound.

[0123] Production Example 11-5: Synthesis of 5-({2-[4-(1-tert-butylpiperidin-4-yl)benzamide]pyridin-4-yl}oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide (compound (IM-2)) [Chemistry 84]

[0124] Under a nitrogen atmosphere, triethylamine (4.3 mL, 31 mmol, 2.0 eq.) was added to a suspension of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methoxymethanesulfonate (7.30 g, 15.4 mmol), compound (21-3) (4.84 g, 18.5 mmol, 1.2 eq.), N,N-dimethyl-4-aminopyridine (3.77 g, 31 mmol, 2.0 eq.), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.92 g, 31.0 mmol, 2.0 eq.) in 1,2-dimethoxyethane (55 mL), and the mixture was stirred at 60°C for 22 hours. The reaction mixture was cooled to room temperature, and tetrahydrofuran (110 mL) and toluene (55 mL) were added, followed by 33.3 g of 2N sodium hydroxide aqueous solution. The mixture was separated. The obtained organic layer was washed three times with water (30 mL) and concentrated under reduced pressure at 40°C. The resulting residue was dissolved in tetrahydrofuran and purified by NH-silicone column chromatography (500 g NH-silicone, ethyl acetate: n-heptane = 6:1). The target fraction was concentrated under reduced pressure at 40°C. Ethanol (65 mL) was added to the concentrated residue, and the suspension was stirred at 40°C and then stirred under ice bath cooling. The suspension was filtered, and the filtered solid was washed with ethanol (22 mL). The obtained solid was dried under reduced pressure at 40°C to obtain 6.50 g (67.2%) of the title compound. 1H NMR (DMSO-d 6) δ (ppm): 1.02 (9H, s), 1.58 (2H, qd, J = 12.2, 3.1 Hz), 1.76 (2H, br d, J = 12.8 Hz), 2.11 (2H, dd, J = 11.0, 11.0 Hz), 2.48-2.52 (1H, m), 2.84 (3H, d, J = 4.4 Hz), 3.08 (2H, br d, J = 11.0 Hz), 3.11 (3H, s), 3.45-3.49 (2H, m), 4.05-4.09 (2H, m), 6.62 (1H, d, J = 3.5 Hz), 6.66 (1H, dd, J = 5.7, 2.6 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.44 (1 H, s), 7.68 (1H, d, J = 2.2 Hz), 7.77 (1H, d, J = 3.5 Hz), 7.88 (2H, d, J = 8.4 Hz), 8.07 (1H, s), 8.15 (1H, q, J = 4.0 Hz), 8.18 (1H, d, J = 5.7 Hz), 10.62 (1H, br s)

[0125] Example 3: Synthesis of 4-(1-tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (compound (3a-1)) [Chemistry 85]

[0126] As shown in Figure 1, a microreactor was used to conduct the flow reaction of N-(tributoxycarbonyl)-4-(4-bromophenyl)piperidine to 1-N-(tributoxycarbonyl)-4-(4'-carboxyphenyl)piperidine. N-(tributoxycarbonyl)-4-(4-bromophenyl)piperidine (0.75 g, 2.2 mmol) was dissolved in dehydrated THF (45 ml) to prepare a 0.05 mol concentration (solution A). n-Butyllithium (n-BuLi) was prepared to a 0.44 mol concentration (solution B) by diluting a 2.64 mol concentration n-hexane solution (2 ml) with dehydrated hexane (10 ml). Methanol was of HPLC grade. Mixer 1 was a DH mixer manufactured by Nakamura Chōhō, mixer 2 was a Y-type mixer with an inner diameter of 1 mm φ, and mixer 3 was a T-type mixer with an inner diameter of 1 mm φ. Carbon dioxide supply uses a mass flow controller (KOFLOC FLOW COMPO CR-100), liquid delivery uses a syringe pump (kd Science KDS-200) and a gas-tight syringe (Trajan SGE syringe), and all piping uses PFA with an inner diameter of 1.0 mm and an outer diameter of 1 / 16 inch. Methanol delivery uses a plunger pump (Tokyo Rika Kaiki UI-22). The connecting piping length between mixer 1 and mixer 2, and between mixer 2 and mixer 3 is set to 23 cm, and the piping length from mixer 3 to the outlet is set to 4 cm. Mixers 1, 2, and 3 are all buried in a constant temperature water bath at -41°C. The piping for solution A introduced into mixer 1 is buried approximately 50 cm, and the piping for solution B is buried approximately 20 cm for pre-cooling. Solution A was initially delivered at a flow rate of 2 ml / min, and solution B at a flow rate of 0.329 ml / min (1.5 eq), and the mixture was carried out in mixer 1 at -41°C. Carbon dioxide was introduced into mixer 2 at a flow rate of 16 ml / min (7.3 eq) to react with the mixture of solutions A and B. Methanol was introduced into mixer 3 at a flow rate of 0.5 ml / min to mix with the reaction mixture, thereby stopping the reaction. Quantitative analysis of the solution obtained by the flow reaction over approximately 17 minutes was performed using HPLC to obtain a calibration curve, which yielded the title compound in 95.5% yield.

[0127] Formula Example The E7090 manufactured by the manufacturing method of the present invention is formulated according to formulations 1 to 5 as described in Table 8 below, using known methods such as those described in the General Principles of Formulations of the 18th Revision of the Japanese Pharmacopoeia. Furthermore, the units in the tables are in mg.

[0128] [Table 8] Element Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 E7090 35.0 35.0 35.0 35.0 35.0 lactose hydrate 67.8 122.8 112.7 144.3 145.7 Polyvinyl alcohol (partially saponified) 1.88 2.40 4.00 2.50 2.80 Low-substituted hydroxypropyl cellulose 19.3 30.0 20.0 22.0 12.0 Polyethylene glycol 4000 0.949 1.212 2.020 1.616 1.454 Hydroxypropyl methylcellulose 5.1 10.0 12.0 3.2 2.9 talc 0.696 0.888 1.480 1.184 1.066 Titanium oxide 1.080 1.378 2.297 1.838 1.654 magnesium stearate 1.1 2.2 1.0 1.2 1.2 Yellow iron oxide 0.095 0.122 0.203 0.162 0.146 total 133.0 206.0 190.7 213.0 203.9

Claims

1. A method for producing a compound (3d) or a pharmaceutically acceptable salt thereof, [Chem. 1] comprising the following steps a), b), c), and d): a) reacting compound (2i) or a pharmaceutically acceptable salt thereof with compound (3a) in the presence of a condensing agent to produce compound (3b), [Chem. 2] [Chem. 3] (wherein PG2 represents a protecting group of nitrogen atom) [Chem. 4] (wherein PG2 represents the same group as above); b) removing PG2 from the compound (3b) obtained in step a) to produce compound (3c), [Chem. 5]; c) reacting the compound (3c) obtained in step b) with a hydroxyethylating agent to produce compound (3d), [Chem. 6]; and d) converting the compound (3d) obtained in step c) into a pharmaceutically acceptable salt as needed.

2. The manufacturing method of claim 1, wherein in step c) the compound (3c) and the hydroxyethylating agent are reacted in a solvent containing methanol.

3. The manufacturing method of claim 1, wherein in step c) the compound (3c) and the hydroxyethylating agent are reacted in dimethoxyethane, tetrahydrofuran, acetonitrile, 1-butanol, ethanol, methanol, or a mixture thereof.

4. The manufacturing method of claim 1, wherein in step c), compound (3c) reacts with the hydroxyethylating agent in methanol.

5. The manufacturing method as claimed in claim 1 or 2, wherein PG2 is a third butoxycarbonyl group.

6. The manufacturing method as claimed in claim 1 or 2, wherein the condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

7. The manufacturing method as claimed in claim 5, wherein step b) includes the use of formic acid or hydrochloric acid.

8. The manufacturing method of claim 1 or 2, wherein the hydroxyethylating agent is 1,4-diethyl-2,5-diol, and in step c), a reducing agent is also used.

9. The manufacturing method as claimed in claim 1 or 2, wherein the pharmaceutically acceptable salt is a succinate.

Images