Method for manufacturing intermediates of monocyclic pyridine derivatives

Abstract

The present invention provides a manufacturing method that can synthesize an important intermediate (compound (2i) or its salt, and compound (1g)) for the manufacture of E7090 with higher yield and higher operating efficiency, which can be used as an FGFR inhibitor.

Description

Technical Field

[0001] This invention relates to a method for manufacturing a synthetic intermediate of 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). [Background 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 the important intermediate of E7090 is described in Patent Document 1 (Examples 20, 22, etc.) and Patent Document 2 (Example 1, etc.).

[0006] In the synthesis of compound (1g) described in Patent Document 1, 1-bromo-3-methoxypropane is reacted with 3,4-dihydroxybenzaldehyde (compound (P1-1)). However, the following problems exist: the alkylation selectivity for phenolic hydroxyl groups is low; the conversion of compound (P1-3) to compound (P1-4) uses highly toxic and hazardous nitromethane; and the nitration of compound (P1-4) to obtain compound (P1-5) is an explosive compound. Furthermore, the steps of converting compound (P1-3) to compound (P1-5) via compound (P1-4) are highly dangerous. Therefore, a novel synthetic route with higher yield, safety, and efficiency is desired. [Chemistry 2]

[0007] In the synthesis of compound (2i) described in Patent Document 1, 4-chloropyridine (compound (P 2-1)) is reacted with compound (1g) in the presence of a base. However, in addition to the phenolic hydroxyl group, the nitrogen atom of the indole is also allylated, resulting in the formation of an N,O-diallyl group in addition to the target compound (P 2-2). Therefore, the yield of compound (P 2-2) is low. Moreover, this reaction requires a high temperature of over 150°C. Therefore, a method for constructing a heteroaryl skeleton under milder conditions is sought. [Chemistry 3]

[0008] The purpose of this application is to provide a manufacturing method that can synthesize an important intermediate for manufacturing E7090 with higher yield and higher operating efficiency, which can be used as an FGFR inhibitor. [Problem-solving methods]

[0009] This specification provides a synthetic intermediate that can be used to manufacture E7090 and a method thereof, wherein the E7090 can be used as an FGFR inhibitor. That is, the present invention provides [1] to [7]. [1] A method for manufacturing a compound (2i) or a salt thereof, [Chemistry 4] It includes: 2-a) Step 2-a) to introduce a protecting group into compound (1g) to produce compound (2a). [Chemistry 5] [Chemistry 6] (In the formula, PG 1 represents the protecting group of the nitrogen atom); 2-b) Step 2-b) involves reacting compound (2a) obtained in step 2-a) with compound (2b) in the presence of a base to produce compound (2c). [Chemistry 7] (In the formula, X1 represents the leaving basis) [Chemistry 8] (In the formula, PG 1 represents the same group as mentioned above); 2-c) Step 2-c) involves reacting the compound (2c) obtained in step 2-b) with compound (2d) in the presence of an activator to produce compound (2e). [Chemistry 9] (In the formula, R1 represents tri-pentyl, tri-butyl, tri-octyl or cumyl) [Chemistry 10] (In the formula, PG 1 and R 1 represent the same groups as those mentioned above); 2-d) Removing PG 1 from compound (2e) obtained in step 2-c) to produce compound (2f) is step 2-d). [Chemistry 11] (In the formula, R1 represents the same group as above); 2-e) Step 2-e) involves reacting the compound (2f) obtained in step 2-d) with compound (2g-1) or compound (2g-2) in the presence of a base to produce compound (2h). [Chemistry 12] (In formula (2g-1), R2 is a C1-6 alkyl or C6-10 aryl group, which may have 1 to 3 substituents selected from the group consisting of halogen atoms and methoxy groups, and may be the same or different. The C6-10 aryl group may have 1 to 3 substituents selected from halogen atoms, methyl, methoxy, and nitro groups, and may be the same or different. In formula (2g-2), X2 represents a halogen atom.) [Chemistry 13] (In the formula, R1 represents the same group as above); 2-f) Step 2-f) involves removing R1 from the compound (2h) obtained in step 2-e) to produce compound (2i). [Chemistry 14] ;as well as Step 2-g involves converting the compound (2i) obtained in step 2-f) into its salt, as needed. [2] According to the manufacturing method described in [1], the compound (2b) is 4-nitropyridine-1-onium-oleate. [3] According to the manufacturing method described in [1], the compound (2d) is 1,1,3,3-tetramethylbutylamine. [4] According to the manufacturing method described in [1], the compound (2d) is cumylamine. [5] According to the manufacturing method described in [1], the activator is p-toluenesulfonyl chloride. [6] A method for manufacturing a compound (1g), [Chemistry 15] It includes: Step 1-a) involves reacting 1,2-(methylenedioxy)-4-nitrobenzene with 4-bromobenzyl alcohol in the presence of a base to prepare compound (1c). [Chemistry 16] ; 1-b) The compound (1c) obtained in step 1-a) is reacted with a methoxyethylating agent in the presence of a base to produce compound (1d) in step 1-b). [Chemistry 17] ; 1-c) Step 1-c) involves reacting the compound (1d) obtained in step 1-b) with a cyanomethylating agent in the presence of a base to produce compound (1f). [Chemistry 18] ; 1-d) The compound (1g) is prepared by converting the nitro group in the compound (1f) obtained in step 1-c) to an amino group, removing the 4-bromobenzyl group, and performing ring closure using an acid catalyst. [Chemistry 19] . [7] According to the manufacturing method described in [6], in step 1-d), palladium catalyst and sulfuric acid are used. [The effects of the invention]

[0010] According to the present invention, a manufacturing method is provided that can synthesize an important intermediate for manufacturing E7090 with higher yield and higher operating efficiency. Implementation

[0011] Next, the meanings of the symbols or terms used in this manual will be explained, and this manual will be described in detail.

[0012] In this specification, "C1-6 alkyl" refers to a monovalent group derived from an aliphatic saturated hydrocarbon having 1 to 6 carbon atoms by removing one arbitrary hydrogen atom; that is, a straight-chain or branched substituent having 1 to 6 carbon atoms. Examples of C1-6 alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-butyl, 2-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, and 3-hexyl, with methyl and ethyl being preferred.

[0013] In this specification, "C 6-10 aryl" refers to an aromatic cyclic hydrocarbon group having 6 to 10 carbon atoms. Examples of C 6-10 aryl groups include phenyl, 1-naphthyl, and 2-naphthyl, with phenyl being preferred.

[0014] In this specification, "halogen atom" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom, preferably a chlorine atom or bromine atom.

[0015] 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 4-dimethylaminopyridine; and organic amines such as triethylamine, N,N-diisopropylethylamine, and diazabicycloundecene.

[0016] In this specification, "compound" includes anhydrous substances, hydrates, and solvates.

[0017] In this specification, the term "salt" may include, for example, inorganic acid salts (sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorates, hydrochlorides, hydrobromates, and 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.).

[0018] The salts of compound (2i) are not particularly limited, for example, salts with inorganic acids, salts with organic acids, salts with acidic amino acids, etc.

[0019] The manufacturing method of the present invention will be described in detail below.

[0020] Manufacturing Method 1: Method for manufacturing compound (1g) [Chemistry 20]

[0021] Step 1-a) is the step of reacting 1,2-(methylenedioxy)-4-nitrobenzene (compound (1a)) with 4-bromobenzyl alcohol (compound (1b)) in the presence of a base to obtain compound (1c). [Chemistry 21]

[0022] 4-Bromobenzyl alcohol can be used in amounts of 1.0 to 2.0 equivalents relative to compound (1a). Preferably, it can be used in amounts of 1.1 to 1.3 equivalents.

[0023] The base can be potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tributoxide, sodium tributoxide, or sodium hydride. Sodium tributoxide is preferred. The base can be used in amounts of 1.0 to 5.0 equivalents relative to compound (1a). 1.0 to 3.0 equivalents are preferred.

[0024] As a solvent, any solvent that can dissolve the starting material and inhibit the reaction is acceptable, with no particular limitations. Examples include N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidineone, tetrahydrofuran, or mixtures thereof. A mixture of dimethyl sulfoxide and tetrahydrofuran is preferred.

[0025] The reaction temperature typically varies depending on the starting material, solvent, and other reagents used in the reaction, and can range from 0°C to 30°C. A preferred temperature is 5°C to 20°C.

[0026] Step 1-b) is the step of reacting compound (1c) with a methoxyethylating agent in the presence of a base to obtain compound (1d). [Chemistry 22]

[0027] As a methoxyethylating agent, for example, it can be 2-chloroethyl methyl ether, 2-bromoethyl methyl ether, or 2-iodoethyl methyl ether. 2-bromoethyl methyl ether is preferred. The methoxyethylating agent can be used in amounts of 1.0 to 2.0 equivalents relative to compound (1c). 1.0 to 1.2 equivalents are preferred.

[0028] The base can be potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tributoxide, sodium tributoxide, or sodium hydride. Potassium carbonate is preferred. The base can be used in amounts of 1.0 to 5.0 equivalents relative to the compound (1d). 1.1 to 1.3 equivalents are preferred.

[0029] As a solvent, any solvent that can dissolve the starting material and inhibit the reaction is acceptable, with no particular limitations. Examples include N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, and 1,3-dimethyl-2-imidazolidinedione. N,N-dimethylformamide is preferred.

[0030] The reaction temperature typically varies depending on the starting material, solvent, and other reagents used in the reaction, and can range from room temperature to 80°C. A preferred temperature is 40°C to 70°C.

[0031] Step 1-c) is the step of reacting compound (1d) with a cyanomethylating agent in the presence of a base to obtain compound (1f). [Chemistry 23]

[0032] Examples of cyanomethylating agents include 4-chlorophenoxyacetonitrile, 4-bromophenoxyacetonitrile, phenoxyacetonitrile, 2-chloroacetonitrile, 2-bromoacetonitrile, 2-iodoacetonitrile, and (cyanomethyl)trimethylammonium iodide. 4-Chlorophenoxyacetonitrile is preferred. The amount of cyanomethylating agent used relative to compound (1d) can be 1.0 to 2.0 equivalents. 1.2 to 1.4 equivalents are preferred.

[0033] The base can be potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tributoxide, sodium tributoxide, or sodium hydride. Potassium tributoxide is preferred. The base can be used in amounts of 1.0 to 5.0 equivalents relative to the compound (1d). 2.0 to 4.0 equivalents are preferred.

[0034] As a solvent, any solvent that can dissolve the starting material and inhibit the reaction is acceptable, with no particular limitations. Examples include N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, and 1,3-dimethyl-2-imidazolidinedione. N,N-dimethylformamide is preferred.

[0035] The reaction temperature typically varies depending on the starting material, solvent, and other reagents used in the reaction, and can range from -70°C to room temperature. A preferred range is -70°C to -50°C.

[0036] Step 1-d) is the process of converting the nitro group in compound (1f) into an amino group, removing the 4-bromobenzyl group, and performing ring closure using an acid catalyst to obtain compound (1g). [Chemistry 24]

[0037] In the process of converting nitro groups to amino groups and removing 4-bromobenzyl groups, a reduction catalyst can be used under a hydrogen atmosphere. Examples of reduction catalysts include palladium on carbon, palladium black, and platinum oxide. Preferably, palladium on carbon is used under a hydrogen atmosphere.

[0038] The reaction solvent can be used as long as it can dissolve the starting material and inhibit the reaction; there are no particular limitations. For example, it can be tetrahydrofuran, methanol, ethanol, water, or a mixture thereof, such as tetrahydrofuran and water, tetrahydrofuran and methanol, or tetrahydrofuran and ethanol. A mixture of tetrahydrofuran and water is preferred.

[0039] The acid catalyst can be hydrochloric acid, sulfuric acid, or acetic acid. Sulfuric acid is preferred. The concentration of the acid catalyst used can be 0.01 N to 1.0 N, preferably 0.01 N to 0.2 N. The reaction temperature usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can be room temperature to 60°C, preferably 30°C to 50°C.

[0040] Manufacturing Method 2: Manufacturing Method of Compound (2i) [Chemistry 25]

[0041] Step 2-a) is the step of introducing a protecting group into compound (1g) to obtain compound (2a). [Chemistry 26]

[0042] The protecting group to be introduced can be tributyloxycarbonyl, benzyloxycarbonyl, benzoyl, acetyl, or trifluoroacetyl. Tributyloxycarbonyl is preferred. To introduce the tributyloxycarbonyl group, dibutyl dicarbonate or tributyloxymethyl chloride can be used. Dibutyl dicarbonate is preferred. The amount of dibutyl dicarbonate relative to 1 g of the compound can be 1 to 5 equivalents. 2.0 to 2.5 equivalents are preferred.

[0043] When using dibutyl dicarbonate, triethylamine, N-methylimidazole, or N,N-dimethylaminopyridine (DMAP) can be used as a base. N,N-dimethylaminopyridine (DMAP) is preferred. When using dibutyl dicarbonate, N,N-dimethylaminopyridine (DMAP) can be used in amounts of 0.01 to 2.0 equivalents relative to the compound (1 g). Preferably, it is 0.05 to 0.2 equivalents.

[0044] As a solvent, any solvent that can dissolve the starting material and inhibit the reaction is acceptable, with no particular limitations. Examples include tetrahydrofuran, N,N-dimethylformamide, acetonitrile, and ethyl acetate. Tetrahydrofuran is preferred.

[0045] The reaction temperature typically varies depending on the starting material, solvent, and other reagents used in the reaction, and can range from 0°C to 60°C. A preferred temperature is 20°C to 30°C.

[0046] In step 2-a), selective deprotection of the hydroxyl group can be performed, and deprotection can be carried out under appropriate conditions depending on the protecting group. For example, for tertiary butoxycarbonyl and benzyloxycarbonyl groups, it can be readily carried out under hydrolysis conditions. Especially in the hydrolysis reaction of the secondary and tertiary butoxycarbonyl groups, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate can be used as bases, for example. Potassium carbonate is preferred. The amount of potassium carbonate relative to the compound (1 g) can be 0.7 to 1.2 equivalents. Preferably, it is 0.7 to 0.9 equivalents.

[0047] The solvent can be used as long as it can dissolve the starting material and inhibit the reaction; there are no particular limitations. For example, it can be methanol, ethanol, isopropanol, acetonitrile, water, or a mixture thereof. Methanol is preferred.

[0048] The reaction temperature typically varies depending on the starting material, solvent, and other reagents used in the reaction, and can range from 25°C to 50°C. A preferred temperature is 30°C to 40°C.

[0049] Step 2-b) is the step of reacting compound (2a) and compound (2b) in the presence of a base to obtain compound (2c). [Chemistry 27]

[0050] As compound (2b), it can be 4-chloropyridine-1-onium-oleate, 4-bromopyridine-1-onium-oleate, or 4-nitropyridine-1-onium-oleate. 4-nitropyridine-1-onium-oleate is preferred. Compound (2b) can be used in amounts of 1.0 to 1.4 equivalents relative to compound (2a). 1.1 to 1.3 equivalents are preferred.

[0051] The base can be potassium carbonate, cesium carbonate, potassium tributoxide, or a 48% aqueous solution of potassium hydroxide. Cesium carbonate is preferred. The base can be used in amounts of 1 to 3 equivalents relative to compound (2a). 1.4 to 1.6 equivalents are preferred.

[0052] The solvent can be used as long as it can dissolve the starting material and inhibit the reaction; there are no particular limitations. For example, it can be N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or 1,3-dimethyl-2-imidazolidineone. Dimethyl sulfoxide is preferred.

[0053] The reaction temperature typically varies depending on the starting material, solvent, and other reagents used in the reaction, and can range from 0°C to 60°C. A preferred temperature is 30°C to 50°C.

[0054] Step 2-c) is the step of reacting compound (2c) and compound (2d) in the presence of an activator to obtain compound (2e). [Chemistry 28]

[0055] As compound (2d), for example, it can be tertiary butylamine, tertiary pentylamine, cumylamine, or tertiary octylamine. Tertiary octylamine is preferred. Compound (2d) can be used in amounts of 1 to 15 equivalents relative to compound (2c). 5 to 10 equivalents are preferred.

[0056] The activator can be p-toluenesulfonyl chloride, benzenesulfonyl chloride, p-chlorosulfonyl chloride, p-methoxysulfonyl chloride, 2-methylsulfonyl chloride, 1-naphthylsulfonyl chloride, 2,4,6-trimethylsulfonyl chloride, or 2,4,6-triphenylsulfonyl chloride. P-Toluenesulfonyl chloride is preferred. Regarding the equivalent amount of the activator, relative to compound (2c), 1 to 5 equivalents can be used. 1.5 to 2.5 equivalents are preferred.

[0057] The solvent can be used as long as it can dissolve the starting material and inhibit the reaction; there are no particular limitations. For example, it can be trifluoromethylbenzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, tributyl methyl ether, dimethoxyethane, cyclopentyl methyl ether, 4-methyltetrahydropyran, water, or a mixture thereof. A mixture of toluene, 4-methyltetrahydropyran, and water is preferred.

[0058] The reaction temperature usually varies depending on the starting material, solvent, and other reagents used in the reaction, ranging from -50°C to room temperature, with -20°C to 10°C being preferred.

[0059] Step 2-d) is the step of removing PG 1 from compound (2e) to obtain compound (2f). [Chemistry 29]

[0060] In step 2-d), deprotection can be carried out under deprotection conditions corresponding to the protecting group. For example, in the case of tert-butoxycarbonyl and benzyloxycarbonyl groups, deprotection can be carried out under basic conditions. Examples of bases include sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, tert-butylamine, sodium methoxide, and sodium ethoxide. Sodium hydroxide is preferred. The base is 1 to 10 equivalents relative to compound (2e), more preferably 2 to 4 equivalents.

[0061] The solvent can be used as long as it can dissolve the starting material and inhibit the reaction; there are no particular limitations. For example, it can be ethanol, tetrahydrofuran, dimethyl sulfoxide, methanol, water, or mixtures thereof. For example, in the case of tert-butoxycarbonyl, a mixture of ethanol, tetrahydrofuran, and water is preferred. The reaction temperature usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can range from 30°C to 70°C. Preferably, it is from 40°C to 60°C.

[0062] Step 2-e) is the step of reacting compound (2f) with compound (2g-1) or compound (2g-2) in the presence of a base to obtain compound (2h). [Chemistry 30]

[0063] Compound (2g-1) or compound (2g-2) can be, for example, phenyl methylcarbamate, ethyl methylcarbamate, methylcarbamate chloride, or methylcarbamate bromide. Phenyl methylcarbamate is preferred. For example, relative to compound (2f), phenyl methylcarbamate can be used in amounts of 1.0 to 2.0 equivalents. More preferably, it can be in amounts of 1.2 to 1.4 equivalents.

[0064] The base can be sodium hydroxide, potassium hydroxide, sodium tert-butoxide, or potassium tert-butoxide. Potassium tert-butoxide is preferred. Regarding the equivalent weight of the base, relative to compound (2f), 0.1 to 3.0 equivalents can be used. 1.0 to 1.5 equivalents are preferred.

[0065] The solvent can be used as long as it can dissolve the starting material and inhibit the reaction; there are no particular limitations. For example, it can be tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or a mixture thereof. A mixture of tetrahydrofuran and dimethyl sulfoxide is preferred.

[0066] The reaction temperature typically varies depending on the starting material, solvent, and other reagents used in the reaction, and can range from -10°C to room temperature. 0°C is preferred.

[0067] Step 2-f) involves removing R1 from compound (2h) to obtain compound (2i), and then obtaining the salt of compound (2i) as needed. [Chemistry 31]

[0068] In step 2-f), the conditions for removing R1 can be selected based on R1. For example, if R1 is cumyl or octyl, hydrochloric acid, sulfuric acid, formic acid, or methanesulfonic acid can be used as the acid. Methanesulfonic acid is preferred.

[0069] Compound (2i) can be converted into its salt by acid treatment. The salt can be, for example, inorganic acid salts (sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorates, hydrochlorides, hydrobromates, and hydroiodates), organic carboxylates (acetates, oxalates, maleates, tartrates, fumarates, and citrates), organic sulfonates (methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, and camphorsulfonates), and amino acid salts (aspartate and glutamate). Methanesulfonate is preferred. By converting compound (2i) into a salt, it can be stored stably for a long period. The following describes an example of a method for synthesizing the methanesulfonate of compound (2i) by removing R1 from compound (2h).

[0070] The amount of methanesulfonic acid relative to compound (2h) can be 1 to 20 equivalents. Preferably, it is 5 to 10 equivalents.

[0071] The reaction solvent is not particularly limited as long as it can dissolve the starting material and inhibit the reaction; for example, it can be ethanol, methanol, dimethoxyethane, or a mixture thereof. A mixture of ethanol and methanol is preferred. The reaction temperature usually varies depending on the starting material, solvent, and other reagents used in the reaction, and can range from room temperature to 80°C. A range of 20°C to 50°C is preferred. [Example]

[0072] 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.

[0073] 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).

[0074] 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 meanings of the patterns are as follows: s: singlet, d: doublet, br: broad peak, m: multiplet.

[0075] In the following examples, "room temperature" typically refers to approximately 10°C to approximately 35°C. Unless otherwise stated, % indicates weight percentage.

[0076] Example 1: Preparation of 6-(2-methoxyethoxy)-1H-indole-5-phenol (compound (1g)) [Chemistry 32]

[0077] Manufacturing Example 1: Manufacturing of 2-[(4-bromobenzyl)oxy]-5-nitrophenol (1c) [Chemistry 33]

[0078] A solution of 4-bromobenzyl alcohol (120.6 kg, 645 mol, 1.2 eq.) and sodium tributoxide (103.3 kg, 1075 mol, 2.0 eq.) in dimethyl sulfoxide (450 L) and tetrahydrofuran (157 L) was prepared at 13°C. A solution of 1,2-(methylenedioxy)-4-nitrobenzene (89.8 kg, 537 mol) in tetrahydrofuran (726 L) and dimethyl sulfoxide (269 L) was added dropwise to this solution at 10°C–15°C. After the addition of tetrahydrofuran (14 L), the mixture was stirred at 14°C for 2 hours. Below 30°C, a mixture of water (500 L) and 35% hydrochloric acid (83 L) was added dropwise to the reaction solution. After the addition of isopropyl acetate (450 L), the organic layer was separated. The organic layer was washed with 7% sodium bicarbonate aqueous solution (290 kg), followed by washing with 9% brine (296 kg). Isopropyl acetate (900 L) was added to the organic layer, and the mixture was concentrated under reduced pressure to 547 L. Isopropyl acetate (900 L) was added to the concentrated residue, and the mixture was concentrated under reduced pressure to 547 L. Hexane (450 L) was added to the concentrated residue at 26°C–32°C, and the mixture was cooled to below 10°C and the precipitated solid was filtered. The crystals were washed with a mixture of isopropyl acetate (90 L) / methanol (27 L) / hexane (180 L), and the obtained crystals were dried under reduced pressure at an internal temperature below 50°C to obtain 125 kg of the title compound. 1H NMR spectrum (DMSO-d 6) δ (ppm): 5.23 (2H, s), 7.17 (1H, d, J = 9.1 Hz), 7.44 (2H, br d, J = 8.3 Hz), 7.60 (2H, br d, J = 8.3 Hz), 7.63 (1H, d, J = 2.6 Hz), 7.71 (1H, dd, J = 9.1, 2.6 Hz)

[0079] Manufacturing Example 2-1: Manufacturing of 1-[(4-bromobenzyl)oxy]-2-(2-methoxyethoxy)-4-nitrobenzene (1d) (1) [Chemistry 34]

[0080] Potassium carbonate (180 g, 1301 mmol, 1.2 eq.) was added to a solution of 2-[(4-bromobenzyl)oxy]-5-nitrophenol (351.4 g, 1084 mmol) in dimethylformamide (1750 mL) and stirred. 2-bromoethyl methyl ether (166 g, 1193 mol, 1.1 eq.) was added, and the mixture was stirred for 6 days. Ethyl acetate (9000 mL) and water (3000 mL) were added, and the mixture was separated. The organic layer was washed four times with water (350 mL) and concentrated under reduced pressure at 50°C. The concentrated residue was suspended in heptane (1500 mL), filtered, and crystals were obtained. The filtrate was concentrated under reduced pressure at 50°C, and the concentrated residue was suspended in heptane (1000 mL), filtered, and crystals were obtained. The obtained crystals were combined and dried under reduced pressure at 50°C to obtain 408 g of the title compound. 1H NMR spectrum (DMSO-d 6) δ (ppm): 3.28 (3H, s), 3.68 (2H, t, J = 4.5 Hz), 4.23 (2H, t, J = 4.2 Hz), 5.26 (2H, s), 7.23 (1H, d, J = 9.1 Hz), 7.41 (2H, br d, J = 7.9 Hz), 7.60 (2H, br d, J = 7.9 Hz), 7.79 (1H, d, J = 2.3 Hz), 7.88 (1H, dd, J = 8.7, 1.9 Hz)

[0081] Manufacturing Example 2-2: Manufacturing of 1-[(4-bromobenzyl)oxy]-2-(2-methoxyethoxy)-4-nitrobenzene (1d) (2) [Chemistry 35]

[0082] To a solution of 2-bromoethyl methyl ether (29.5 kg, 212 mol, 1.1 eq.) in dimethylformamide (294 kg), 62.5 kg ((4-bromobenzyl)oxy)-5-nitrophenol (193 mol) and 32.0 kg (232 mol, 1.2 eq.) potassium carbonate were added, and the mixture was stirred at 56°C–60°C for 6 hours. After cooling, 1252 L of ethyl acetate and 375 L of water were added. After separation, the organic layer was washed with 188 L of water, and 83 L of ethyl acetate and 198 kg of 5% sodium chloride aqueous solution were added to the organic layer, followed by separation. The organic layer was concentrated under reduced pressure to 737 L, and a suspension of 1-[(4-bromobenzyl)oxy]-2-(2-methoxyethoxy)-4-nitrobenzene (22.2 g) in methanol (1.7 kg) was added. Methanol (738 L) was added dropwise at 0 ~ -4°C, and the precipitated crystals were collected by filtration. The crystals were washed with methanol (189 L), and the obtained crystals were dried under reduced pressure at an internal temperature below 50°C to obtain 66.0 kg of the title compound.

[0083] Manufacturing Example 3: Manufacturing of {5-[(4-bromobenzyl)oxy]-4-(2-methoxyethoxy)-2-nitrophenyl}acetonitrile (1f) [Chemistry 36]

[0084] A solution of 1-[(4-bromobenzyl)oxy]-2-(2-methoxyethoxy)-4-nitrobenzene (16.7 kg, 43.7 mol) and 4-chlorophenoxyacetonitrile (9.5 kg, 56.7 mol, 1.3 eq.) in dimethylformamide (80 L) was added dropwise to a solution of potassium terephthaloxide (14.7 kg, 131 mol, 3 eq.) in dimethylformamide (80 L). After adding 21 L of dimethylformamide, the mixture was stirred at -63°C to -58°C for 2 hours. A mixture of ethyl acetate (351 L) and acetic acid (8 L) was added dropwise to the reaction solution. After adding 168 kg of 5% sodium chloride aqueous solution, the organic layer was washed twice with 84 kg and 85 kg of 5% sodium chloride aqueous solution. After adding ethyl acetate (34 L) to the organic layer, it was washed with a 5% sodium chloride aqueous solution (85 kg). The organic layer was concentrated under reduced pressure, and the concentrated residue was treated with tributyl methyl ether (134 L) and methanol (13 L), cooled to 0-2°C, and the precipitated solid was filtered. The obtained crystals were washed with a mixture of tributyl methyl ether (30 L) / ethyl acetate (3 L) / methanol (3 L), and dried under reduced pressure at an internal temperature below 50°C to obtain 10.7 kg of the title compound. 1H-NMR spectrum (CDCl 3) δ (ppm): 3.46 (3H, s), 3.81 (2H, t, J = 4.8 Hz), 4.19 (2H, s), 4.25 (2H, t, J = 4.4 Hz), 5.23 (2H, s), 7.14 (1H, s), 7.35 (2H, d, J = 8.0 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.84 (1H, s)

[0085] Manufacturing Example 4: Manufacturing of 6-(2-methoxyethoxy)-1H-indole-5-phenol (1g) [Chemistry 37]

[0086] A solution of {5-[(4-bromobenzyl)oxy]-4-(2-methoxyethoxy)-2-nitrophenyl}acetonitrile (28.2 kg, 66.9 mol) in tetrahydrofuran (282 L) was added with 10% palladium / carbon (5.7 kg), water (28.2 L), and 98% purified concentrated sulfuric acid (0.21 kg). The mixture was stirred for 5 hours at 40°C–45°C and a hydrogen pressure of 0.02–0.15 MPa. After the reaction, the catalyst was filtered off, and the catalyst residue was washed with ethyl acetate (284 L). The obtained filtrate was then separated. A mixture of water (129 L) and hydrochloric acid (12.8 kg) was added dropwise to the organic layer, and the organic layer was separated. After washing the organic layer with 5% sodium bicarbonate solution (141 kg) and 3% brine (146 kg), the organic layer was concentrated under reduced pressure to 85 L. The concentrated residue was washed with ethyl acetate (144 L) and 10% sodium chloride aqueous solution (57 kg) to remove the organic layer. The organic layer was concentrated under reduced pressure to 85 L. The obtained concentrated residue was then mixed with heptane (28 L) and sodium sulfate (14.1 kg). The mixture was purified by passing it through NH silica gel (28.2 kg) wetted with ethyl acetate (141 L). The NH silica gel was then washed with a mixture of ethyl acetate (226 L) and heptane (57 L) and mixed with the purified solution. The mixture was concentrated under reduced pressure to 85 L at 50°C. The concentrated residue was then concentrated dropwise with heptane (64 L) and concentrated under reduced pressure to 85 L at 50°C. Ethyl acetate (27 L) and heptane (60 L) were added, and the mixture was cooled to 0-10°C and the precipitated solid was filtered. The obtained crystals were washed with a mixture of heptane (45 L) and ethyl acetate (14 L). The obtained crystals were dried under reduced pressure at an internal temperature below 50°C to obtain 7.4 kg of the title compound. 1H NMR spectrum (DMSO-d 6) δ(ppm): 3.32 (3H, s), 3.66-3.69 (2H, m), 4.04-4.07 (2H, m), 6.16 (1H, t, J = 2.1 Hz), 6.88 (2H, d, J = 4.2 Hz), 7.07 (1H, dd, J = 2.8, 2.5 Hz), 8.08 (1H, s), 10.57 (1H, br s)

[0087] Preparation Example 4-2: Recrystallization of 6-(2-methoxyethoxy)-1H-indole-5-phenol [Chemistry 38]

[0088] A mixture of 21.2 kg (102.3 mol) of 6-(2-methoxyethoxy)-1H-indole-5-phenol and ethyl acetate (97 L) was heated and stirred at an internal temperature of 50°C–60°C to confirm dissolution. The solution was clarified by filtration and washed with ethyl acetate (10 L). After cooling to an internal temperature of 40°C–45°C and confirming crystal precipitation, the mixture was stirred at the same temperature for 1 hour. The suspension was cooled to an internal temperature of -10°C–0°C over 6 hours and then stirred for 14 hours. Heptane (145 kg) was added dropwise over 1.5 hours, and the mixture was stirred for 3 hours at an internal temperature of -10°C–0°C. The suspension was filtered and washed with a mixture of ethyl acetate (5.7 kg) and heptane (8.7 kg). The obtained crystals were dried under reduced pressure at 40°C to give 20.2 kg of the title compound.

[0089] Example 2: Preparation of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methylamine methanesulfonate (methanesulfonate of compound (2i)) [Chemistry 39]

[0090] Manufacturing Example 5: Manufacturing of 5-hydroxy-6-(2-methoxyethoxy)-1H-indole-1-carboxylic acid tributyl ester (2a-1) [Chemistry 40]

[0091] Under a nitrogen atmosphere, a tetrahydrofuran (70.4 kg) suspension of 6-(2-methoxyethoxy)-1H-indole-5-phenol (19.8 kg, 95.6 mol) and 4-(dimethylamino)pyridine (1.17 kg, 9.55 mol, 0.1 eq.) was added dropwise to a tetrahydrofuran (26.4 kg) suspension of dibutyl dicarbonate (45.9 kg, 210 mol, 2.2 eq.) at below 25°C, followed by rinsing with tetrahydrofuran (8.8 kg). The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was concentrated to 90 L under reduced pressure at below 40°C. Under a nitrogen atmosphere, methanol (78.3 kg) and potassium carbonate (10.6 kg, 76.4 mol, 0.8 eq.) were added to the obtained concentrate, and the mixture was stirred at 34°C for 14 hours. After cooling the reaction solution to 25°C, ethyl acetate (178.6 kg) and water (138.6 kg) were added, followed by dropwise addition of 5 N hydrochloric acid (15.2 kg of 35% hydrochloric acid and 16.3 kg of water). After separation, the organic layer was washed with 5% brine (3.0 kg of sodium chloride and 56.4 kg of water). The organic layer was concentrated to 100 L under reduced pressure below 50°C and then azeotropically twice with toluene (85.6 kg). Dimethyl sulfoxide (87.1 kg) was added to the obtained concentrate, and the solution was concentrated to 100 L under reduced pressure, yielding the crude product of the title compound (100%, purity 29.4 kg) as a dimethyl sulfoxide solution (100 L). ¹H NMR spectrum (DMSO-d₆) δ (ppm): 1.61 (9H, s), 3.32 (3H, s), 3.68–3.71 (2H, m), 4.08–4.11 (2H, m), 6.49 (¹H, d, J = 3.6 Hz), 6.95 (¹H, s), 7.44 (¹H, d, J = 3.6 Hz), 7.59 (¹H, s), 8.75 (¹H, s)

[0092] Manufacturing Example 6: Manufacturing of 6-(2-methoxyethoxy)-5-[(1-sideoxy-1λ5-pyridin-4-yl)oxy]-1H-indole-1-carboxylic acid tributyl ester (2c-1) [Chemistry 41]

[0093] To a 100 L solution of tributyl 5-hydroxy-6-(2-methoxyethoxy)-1H-indole-1-carboxylic acid (29.4 kg, 95.6 mol) in dimethyl sulfoxide, 16.1 kg, 115 mol, and 1.2 eq. of 4-nitropyridine-1-onium-oleate and 106.5 kg of dimethyl sulfoxide were added. Under a nitrogen atmosphere at 40°C, cesium carbonate (46.7 kg, 143 mol, and 1.5 eq.) was added in seven portions every 30 minutes, followed by stirring for 3 hours. After the reaction was complete, the reaction mixture was cooled to below 15°C, and 252.5 kg of 2-methyltetrahydrofuran was added, followed by dropwise addition of water (293.6 kg) and separation. The aqueous layer was extracted with 126.3 kg of 2-methyltetrahydrofuran, and the combined organic layers were washed with 10% brine (8.8 kg of salt and 79.2 kg of water). The obtained organic layer was concentrated to 130 L under reduced pressure below 50°C and further azeotropically three times with toluene (127.0 kg). Toluene (48.4 kg) was added to the concentrate, and the mixture was heated to 55°C. The suspension was cooled to -15°C and filtered, then washed with toluene (51.0 kg). The obtained crystals were dried under reduced pressure below 50°C to give 28.61 kg of the title compound. 1H NMR spectrum (DMSO-d 6) δ (ppm): 1.63 (9H, s), 3.16 (3H, s), 3.49-3.52 (2H, m), 4.09-4.12 (2H, m), 6.65 (1H, d, J = 3.8 Hz), 6.83-6.87 (2H, m), 7.48 (1H, s), 7.62 (1H, d, J = 3.6 Hz), 7.82 (1H, br s), 8.04-8.07 (2H, m)

[0094] Manufacturing Example 7: Manufacturing of 6-(2-methoxyethoxy)-N-methyl-5-({2-[(2,4,4-trimethylpentan-2-yl)amino]pyridin-4-yl}oxy)-1H-indole-1-methamide (2e-1) [Chemistry 42]

[0095] To a suspension of 6-(2-methoxyethoxy)-5-[(1-sideoxy-1λ-pyridin-4-yl)oxy]-1H-indole-1-carboxylic acid tributyl ester (28.5 kg, 71.2 mol) in toluene (431.4 kg), 1,1,3,3-tetramethylbutylamine (64.4 kg, 498 mol, 7.0 eq.) and water (0.4 kg, 0.3 eq.) was added, followed by washing with toluene (12.3 kg) and stirring below -5°C. Under a nitrogen atmosphere, a mixture of p-toluenesulfonyl chloride (28.5 kg, 149 mol, 2.1 eq.) in 4-methyltetrahydropyran (6.1 kg) and toluene (98.6 kg) was added dropwise, followed by washing with toluene (24.7 kg) and stirring at -10°C for 4 hours. After the reaction was complete, water (159.6 kg) was added dropwise to the reaction solution and the mixture was separated. 5 N hydrochloric acid (20.8 kg of 35% hydrochloric acid and 22.3 kg of water) was added to the organic layer, and after separation, the organic layer was washed with water (142.5 kg). Next, 0.5 N sodium hydroxide aqueous solution (2.8 kg of flake caustic soda and 142.2 kg of water) was added to the organic layer, and after separation, the organic layer was washed with water (142.5 kg). The obtained organic layer was concentrated to 80 L under reduced pressure below 50°C, and then ethanol (67.5 kg) was added, followed by further concentration to 80 L under reduced pressure. Ethanol (67.3 kg) was added to the concentrate, and the mixture was stirred at 0°C for 2 hours. The precipitate was removed by filtration, and the mixture was washed with ethanol (67.8 kg). The filtrate was then concentrated to 80 L under reduced pressure. Ethanol (112.4 kg) was added to the obtained concentrate, and the solution was concentrated under reduced pressure to 80 L to obtain the crude product of the title compound (92%, purity 33.5 kg) as an ethanol solution (80 L).

[0096] Manufacturing Example 8: Manufacturing of 4-{[6-(2-methoxyethoxy)-1H-indol-5-yl]oxy}-N-(2,4,4-trimethylpentan-2-yl)pyridine-2-amine (2f-1) [Chemistry 43]

[0097] Ethanol (26.9 kg) and tetrahydrofuran (89.3 kg) were added to an ethanol solution (80 L) of 6-(2-methoxyethoxy)-N-methyl-5-({2-[(2,4,4-trimethylpentan-2-yl)amino]pyridin-4-yl}oxy)-1H-indole-1-methamide (33.5 kg, 65.5 mol). Under a nitrogen atmosphere, an aqueous solution of 5 N sodium hydroxide (7.9 kg, 197 mol, 3.0 eq. of flake caustic soda, and 38.2 kg of water) was added, and the mixture was stirred at 48°C for 5 hours. After the reaction was complete, the reaction mixture was cooled to 20°C, and methyl tributyl ether (173.8 kg), water (115.1 kg), and 5 N hydrochloric acid (15.0 kg of 35% hydrochloric acid and 15.9 kg of water) were added, followed by separation. Tetrahydrofuran (59.5 kg) and 5% brine (16.8 kg salt and 150.6 kg water) were added to the organic layer, and the mixture was separated. The obtained organic layer was concentrated to 170 L under reduced pressure below 50°C, and then n-propanol (188.1 kg) was added and concentrated to 160 L under reduced pressure. Methyl tributyl ether (49.7 kg) was added to the concentrate, and the mixture was stirred at 48°C for 73 minutes. The suspension was cooled to 0°C, filtered, and washed with n-propanol (53.6 kg). The obtained crystals were dried under reduced pressure below 50°C to obtain 22.93 kg of the title compound. 1H NMR spectrum (CD 3OD) δ (ppm): 0.89 (9H, s), 1.30 (6H, s), 1.64 (2H, s), 3.27 (3H, s), 3.56-3.59 (2H, m), 4.05-4.09 (2H, m), 5.85 (1 H, d, J = 2.3 Hz), 6.15 (1H, dd, J = 6.0, 2.3 Hz), 6.36-6.39 (1H, m), 7.11 (1H, s), 7.17 (1 H, d, J = 3.4 Hz), 7.25 (1H, s), 7.74 (1H, d, J = 6.0 Hz)

[0098] Manufacturing Example 9: Manufacturing of 6-(2-methoxyethoxy)-N-methyl-5-({2-[(2,4,4-trimethylpentan-2-yl)amino]pyridin-4-yl}oxy)-1H-indole-1-methamide (2h-1) [Chemistry 44]

[0099] Add tetrahydrofuran (109.3 kg) to 4-{[6-(2-methoxyethoxy)-1H-indol-5-yl]oxy}-N-(2,4,4-trimethylpentan-2-yl)pyridine-2-amine (20.5 kg, 49.8 mol) and stir at below 5°C. Under a nitrogen atmosphere, add dropwise a solution of potassium terephthaloxide (5.9 kg, 52 mol, 1.05 eq.) in DMSO (22.6 kg), wash with DMSO (2.3 kg), and stir at 0°C for 30 minutes. Add dropwise a solution of phenyl methylcarbamate (9.0 kg, 60 mol, 1.30 eq.) in tetrahydrofuran (18.2 kg), wash with tetrahydrofuran (9.1 kg), and stir at 0°C for 5 minutes. After the reaction was complete, water (143.5 kg) and isopropyl acetate (125.1 kg) were added to the reaction mixture, and the mixture was stirred and separated at 20°C. A 1 N sodium hydroxide aqueous solution (4.1 kg of flake sodium hydroxide and 102.5 kg of water) was added to the organic layer, and the mixture was separated. Then, a 10% ammonium chloride aqueous solution (10.3 kg of ammonium chloride and 92.3 kg of water) was added, and the mixture was separated again. The organic layer was washed with 1% brine (1.0 kg of salt and 102.5 kg of water), and the resulting organic layer was concentrated to 80 L under reduced pressure at below 40°C. The mixture was then subjected to three azeotropic reactions with ethanol (80.9 kg) to obtain the crude product of the title compound (100%, purity 23.34 kg) as an ethanol solution (80 L). 1H NMR spectrum (CD 3OD) δ (ppm): 0.93 (9H, s), 1.35 (6H, s), 1.71 (2H, s), 2.98 (3H, s), 3.30 (3H, s), 3.62-3.64 (2H, m), 4.13-4.16 (2H, m), 5.88 (1H, d, J = 2.3 Hz), 6.18 (1H, dd, J = 5.9, 2.3 Hz), 6.61 (1H, d, J = 3.2 Hz), 7.32 (1H, s), 7.58 (1H, d, J = 3.8 Hz), 7.79 (1H, d, J = 5.9 Hz), 8.08 (1H, s)

[0100] Manufacturing Example 10: Manufacturing of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methanesulfonate ((2i) methanesulfonate) [Chemistry 45]

[0101] An ethanol solution (90 L) of 6-(2-methoxyethoxy)-N-methyl-5-({2-[(2,4,4-trimethylpentan-2-yl)amino]pyridin-4-yl}oxy)-1H-indole-1-methamide (26.0 kg, 55.5 mol)) was concentrated to 75 L under reduced pressure at below 40°C, followed by the addition of methanol (37.0 kg) and ethanol (17.3 kg). Under a nitrogen atmosphere, methanesulfonic acid (42.7 kg, 444 mol, 8.0 eq.) was added at 10°C, followed by washing with methanol (4.2 kg) and stirring at 40°C for 28 hours. After confirming the reaction was complete, the mixture was cooled to 20°C, and methyl tributyl ether (385.8 kg) was added dropwise, followed by stirring for 1 hour. After cooling to 0°C, the mixture was filtered and washed with a mixture of methyl tributyl ether and ethanol (methyl tributyl ether / ethanol = 1.64 / 0.36 vol., 39.2 kg) and isopropyl acetate (45.5 kg). The obtained crystals were dried under reduced pressure below 50°C to obtain 22.89 kg of the title compound. 1H NMR spectrum (DMSO-d 6) δ (ppm): 2.32 (3H, s), 2.84 (3H, d, J = 4.5 Hz), 3.15 (3H, s), 3.51-3.54 (2H, m), 4.08-4.11 (2H, m), 6.01 (1H, d, J = 2.3 Hz), 6.63-6.66 (2H, m), 7.50 (1H, s), 7.61 (2H, br s), 7.79 (1H, d, J = 3.8 Hz), 7.90 (1H, d, J = 7.2 Hz), 8.10 (1H, s), 8.18 (1H, q, J = 4.2 Hz), 12.82 (1H, brs)

[0102] Manufacturing Example 10-2: Manufacturing of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methanesulfonate ((2i) methanesulfonate) [Chemistry 46]

[0103] Under a nitrogen atmosphere, methanol (33.2 kg) was added to an ethanol solution (183 L) of 6-(2-methoxyethoxy)-N-methyl-5-({2-[(2,4,4-trimethylpentan-2-yl)amino]pyridin-4-yl}oxy)-1H-indole-1-methylamine (100% of the previous step, 47.8 kg, 102 mol). Methanesulfonic acid (117.7 kg, 1225 mol, 12.0 eq.) was added, followed by washing with methanol (4.7 kg). The mixture was stirred at 25°C–32°C for 21 hours, and then 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methylamine (46 g) was added. Methyl tributyl ether (355.3 kg) was added dropwise to the suspension of precipitated crystals, and the mixture was cooled to 2°C–5°C. The precipitated solid was filtered and washed with a mixture of methyl tributyl ether (126.8 kg) and ethanol (54.0 kg), and isopropyl acetate (208.7 kg). The obtained crystals were dried under reduced pressure below 50°C to give 38.04 kg of the title compound.

[0104] Manufacturing Example 11: Manufacturing of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide (2i) [Chemistry 47]

[0105] Under a nitrogen atmosphere, a 1 N sodium hydroxide aqueous solution (2.71 kg, 67.7 mol, 1.54 eq. of flake sodium hydroxide and 67.7 kg of 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 and 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 azeotropically treated four times with 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, filtered, and washed with acetonitrile (23.5 kg). The obtained crystals were dried under reduced pressure below 50°C to give 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)

[0106] Manufacturing Example 11-2: Manufacturing of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methamide (2i) [Chemistry 48]

[0107] Under a nitrogen atmosphere, a 1 N aqueous solution of sodium hydroxide (5.5 kg of flake sodium hydroxide, 137.5 mol of caustic soda flakes, 1.70 eq. of water and 5.5 kg of caustic soda flakes, 137.5 mol of water and 1.70 eq. of sodium hydroxide flakes, 138 kg of water) was added to a suspension of 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methylenediamine 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 and 104 kg of water). The obtained organic layer was washed with water (110 L), clarified, filtered, and washed with isopropyl acetate (47.9 kg). After concentration to 184 L under reduced pressure below 40°C, it was further azeotropically treated four times with 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 obtain 25.92 kg of the title compound.

Claims

1. A method for producing a compound (2i) or a salt thereof, [Chemical 1] comprising: 2-a) Step 2-a) to introduce a protecting group into compound (1g) to produce compound (2a), [Chemical 2] [Chemical 3] (wherein, PG1 represents the protecting group of the nitrogen atom); 2-b) Step 2-b) to react compound (2a) obtained in step 2-a) with compound (2b) in the presence of a base to produce compound (2c), [Chemical 4] (wherein, X1 represents the leaving group) [Chemical 5] (wherein, PG1 represents the same group as above); 2-c) Step 2-c) to react compound (2c) obtained in step 2-b) with compound (2d) in the presence of an activator to produce compound (2e), [Chemical 6] (wherein, R1 represents terpentyl, terbutyl, teroctyl or cumyl) [Chemical 7] (wherein, PG1 and R1 represent the same groups as above); 2-d) Step 2-d) to produce compound (2f) by removing PG1 from compound (2e) obtained in step 2-c) [Chemical 8] (where R1 represents the same group as above); 2-e) Step 2-e) to produce compound (2h) by reacting compound (2f) obtained in step 2-d) with compound (2g-1) or compound (2g-2) in the presence of a base [Chemical 9] (where R2 in formula (2g-1) is a C1-6 alkyl or C6-10 aryl, the C1-6 alkyl may have 1 to 3 substituents selected from the group consisting of halogen atoms and methoxy groups, which may be the same or different, the C6-10 aryl may have 1 to 3 substituents selected from halogen atoms, methyl, methoxy and nitro groups, which may be the same or different, X2 in formula (2g-2) represents a halogen atom) [Chemical 10] (where R1 represents the same group as above); 2-f) Step 2-f) involves removing R1 from the compound (2h) obtained in step 2-e) to produce compound (2i), [Chemistry 11]; And step 2-g, which, if necessary, converts the compound (2i) obtained in step 2-f) into its salt.

2. The manufacturing method of claim 1, wherein compound (2b) is 4-nitropyridine-1-onium-oleate.

3. The manufacturing method of claim 1, wherein compound (2d) is 1,1,3,3-tetramethylbutylamine.

4. The manufacturing method of claim 1, wherein compound (2d) is cumylamine.

5. The manufacturing method as claimed in claim 1, wherein the activator is p-toluenesulfonyl chloride.

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