Method for producing synthetic intermediates for monocyclic pyridine derivatives

Abstract

To provide a production method that enables synthesis of key intermediates for producing E7090, which is useful as an FGFR inhibitor, in higher yields and with higher working efficiency.SOLUTION: The present invention provides a production method for a compound (2i) or a salt thereof and a compound (1g).SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to a method for producing a synthetic intermediate for monocyclic pyridine derivatives useful as FGFR inhibitors. [Background technology]

[0002] The monocyclic pyridine derivative is 5-((2-(4-(1-(2-hydroxyethyl)piperidine-4-yl)benzamide)pyridine-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide butane dioate (2:3) [ka] (Hereinafter also referred to as "E7090") has a potent FGFR (fibroblast growth factor receptor) inhibitory effect and is useful as a therapeutic agent for intrahepatic cholangiocarcinoma, breast cancer, and other cancers in which FGFR kinase is involved (Patent Documents 1 and 2). [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] International Publication No. 2014 / 129477 [Patent Document 2] International Publication No. 2016 / 027781 [Overview of the project] [Problems that the invention aims to solve]

[0004] Methods for producing key intermediates of E7090 are described in Patent Document 1 (Examples 20, 22, etc.) and Patent Document 2 (Example 1, etc.).

[0005] In the synthesis of the compound (1g) described in Patent Document 1, 3,4-dihydroxybenzaldehyde (Compound (P 1-1)) is reacted with 1-bromo-3-methoxypropane. However, the selectivity of alkylation to the phenolic hydroxyl group is low. In the conversion from Compound (P 1-3) to Compound (P 1-4), nitromethane, which is highly toxic and dangerous, is used. The compound (P 1-5) obtained by nitrating Compound (P 1-4) has the problem of being an explosive compound. Furthermore, all the steps of converting Compound (P 1-3) to Compound (P 1-5) via Compound (P 1-4) are highly dangerous. Therefore, the construction of a new synthetic route with higher yield, safety, and efficiency has been desired.

Chemical formula

[0006] In the synthesis of the 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, allylation to the nitrogen atom of indole also proceeds, and in addition to the target compound (P 2-2), an N,O-diallyl compound is also generated, so the yield of Compound (P 2-2) is low. Also, since this reaction requires a high temperature of 150°C or higher, a method for constructing a heteroaryl skeleton under milder conditions has been demanded.

Chemical formula

[0007] The object of the present application is to provide a production method capable of synthesizing an important intermediate for producing E7090, which is useful as an FGFR inhibitor, with higher yield and working efficiency.

Means for Solving the Problems

[0008] In this specification, synthetic intermediates useful for the production of E7090, which is useful as an FGFR inhibitor, and methods for producing them are provided. That is, the present invention provides [1] to [7]. [1] Compound (2i) [ka] or a method for producing the salt thereof, 2-a) Compound (1g) [ka] By introducing a protecting group, Compound (2a) [ka] (In the formula, PG 1 (This refers to a protecting group for the nitrogen atom.) The process for manufacturing is 2a), 2-b) Compounds (2a) and (2b) obtained in step 2-a) [ka] (In the formula, X 1 (where represents a leaving group) is reacted with a base to form compound (2c). [ka] (In the formula, PG 1 The process 2-b) involves manufacturing the same base as described above, 2-c) Compound (2c) and compound (2d) obtained in step 2-b) [ka] (In the formula, R 1 Compound (2e) is formed by reacting a tert-pentyl group, tert-butyl group, tert-octyl group, or cumyl group with an activator. [ka] (In the formula, PG 1 and R 1Step 2-c) for producing (where each means the same group as described above), 2-d) Removing PG in the compound (2e) obtained in Step 2-c) to obtain compound (2f) 1

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0009] The present invention provides a manufacturing method that enables the synthesis of key intermediates for producing E7090 in higher yield and with greater work efficiency. [Modes for carrying out the invention]

[0010] Next, the meanings of symbols or terms used in this specification will be explained, and this specification will be described in detail.

[0011] In this specification, "C 1-6 An alkyl group is a monovalent group derived by removing one hydrogen atom from an aliphatic saturated hydrocarbon having 1 to 6 carbon atoms. It refers to a linear or branched substituent having 1 to 6 carbon atoms. 1-6 Examples of alkyl groups include methyl group, ethyl group, 1-propyl group, 2-propyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, 1-butyl group, 2-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, 1-hexyl group, 2-hexyl group, and 3-hexyl group, with methyl group and ethyl group being preferred.

[0012] In this specification, "C 6-10 An "aryl group" refers to an aromatic cyclic hydrocarbon group with 6 to 10 carbon atoms. 6-10 Examples of aryl groups include phenyl, 1-naphthyl, and 2-naphthyl groups, with phenyl being preferred.

[0013] In this specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and preferably a chlorine atom or a bromine atom.

[0014] In this specification, "base" can refer to, for example, inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium bicarbonate, potassium bicarbonate, and cesium carbonate; organometallic reagents such as butyllithium, methyllithium, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium bistrimethylsilylamide; 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.

[0015] In this specification, “compound” includes anhydrous, hydrate, and solvate compounds.

[0016] In this specification, "salt" refers to, for example, inorganic salts (sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorides, hydrochlorides, hydrobroms, and hydroiodides), organic carboxylates (acetates, oxalates, maleates, fumarates, succinates, tartrates, and citrates), organic sulfonates (methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, and camphorsulfonates), and salts with acidic amino acids (aspartates and glutamates).

[0017] The salt of compound (2i) is not particularly limited and may include, for example, salts with inorganic acids, salts with organic acids, or salts with acidic amino acids.

[0018] The manufacturing method according to the present invention is described in detail below.

[0019] Manufacturing method 1 Method for producing the compound (1g) [ka]

[0020] Step 1-a) is a step in which 1,2-(methylenedioxy)-4-nitrobenzene (compound (1a)) and 4-bromobenzyl alcohol (compound (1b)) are reacted in the presence of a base to obtain compound (1c). [ka]

[0021] 4-bromobenzyl alcohol may be used in an amount of 1.0 to 2.0 equivalents relative to compound (1a). Preferably, it is 1.1 to 1.3 equivalents.

[0022] The base may be potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, or sodium hydride. Sodium tert-butoxide is preferred. The base may be used in an amount of 1.0 to 5.0 equivalents relative to compound (1a). Preferably, it is 1.0 to 3.0 equivalents.

[0023] The solvent is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction. For example, it may be N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, tetrahydrofuran, or a mixture thereof. Preferably, it is a mixture of dimethyl sulfoxide and tetrahydrofuran.

[0024] The reaction temperature typically varies depending on the starting materials, solvent, and other reagents used in the reaction, and may range from 0°C to 30°C. Preferably, it is between 5°C and 20°C.

[0025] Step 1-b) is a step in which compound (1c) and a methoxyethylating agent are reacted in the presence of a base to obtain compound (1d). [ka]

[0026] Examples of methoxyethylating agents include 2-chloroethyl methyl ether, 2-bromoethyl methyl ether, and 2-iodoethyl methyl ether. Preferably, it is 2-bromoethyl methyl ether. The methoxyethylating agent may be used in an amount of 1.0 to 2.0 equivalents relative to compound (1c). Preferably, it is 1.0 to 1.2 equivalents.

[0027] The base may be potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, or sodium hydride. Potassium carbonate is preferred. The base may be used in an amount of 1.0 to 5.0 equivalents relative to compound (1d). Preferably, it is 1.1 to 1.3 equivalents.

[0028] The solvent is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction. For example, it may be N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, or 1,3-dimethyl-2-imidazolidinone. Preferably, it is N,N-dimethylformamide.

[0029] The reaction temperature typically varies depending on the starting materials, solvent, and other reagents used in the reaction, and can range from room temperature to 80°C. Preferably, it is between 40°C and 70°C.

[0030] Step 1-c) is a step in which compound (1d) and a cyanomethylating agent are reacted in the presence of a base to obtain compound (1f). [ka]

[0031] Examples of cyanomethylating agents include 4-chlorophenoxyacetonitrile, 4-bromophenoxyacetonitrile, phenoxyacetonitrile, 2-chloroacetonitrile, 2-bromoacetonitrile, 2-iodoacetonitrile, and (cyanomethyl)trimethylammonium iodide. Preferably, it is 4-chlorophenoxyacetonitrile. The cyanomethylating agent may be used in an amount of 1.0 to 2.0 equivalents relative to compound (1d). Preferably, it is 1.2 to 1.4 equivalents.

[0032] The base may be potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, or sodium hydride. Potassium tert-butoxide is preferred. The base may be used in an amount of 1.0 to 5.0 equivalents relative to compound (1d). Preferably, it is 2.0 to 4.0 equivalents.

[0033] The solvent is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction. For example, it may be N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, or 1,3-dimethyl-2-imidazolidinone. Preferably, it is N,N-dimethylformamide.

[0034] The reaction temperature usually varies depending on the starting materials, solvent, and other reagents used in the reaction, and may range from -70°C to room temperature. Preferably, it is between -70°C and -50°C.

[0035] Step 1-d) is a step to obtain compound (1g) by converting the nitro group in compound (1f) to an amino group, removing the 4-bromobenzyl group, and cyclizing with an acid catalyst. [ka]

[0036] For the conversion of nitro groups to amino groups and the removal of 4-bromobenzyl groups, a reduction catalyst under a hydrogen atmosphere may be used. Examples of reduction catalysts include palladium carbon, palladium black, and platinum oxide. Preferably, palladium carbon is used under a hydrogen atmosphere.

[0037] The reaction solvent is not particularly limited as long as it dissolves the starting materials and does not inhibit the reaction. For example, it may be tetrahydrofuran, methanol, ethanol, water, or a mixture thereof, tetrahydrofuran and water, tetrahydrofuran and methanol, or tetrahydrofuran and ethanol. Preferably, it is a mixture of tetrahydrofuran and water.

[0038] The acid catalyst may be hydrochloric acid, sulfuric acid, or acetic acid. Sulfuric acid is preferred. The concentration of the acid catalyst used may be 0.01N to 1.0N. Preferably, it is 0.01N to 0.2N. The reaction temperature usually varies depending on the starting materials, solvent, and other reagents used in the reaction, and may range from room temperature to 60°C. Preferably, it is 30°C to 50°C.

[0039] Manufacturing method 2 Method for producing compound (2i) [ka]

[0040] Step 2-a) is a step in which a protecting group is introduced to compound (1 g) to obtain compound (2a). [ka]

[0041] The protecting group to be introduced may be a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzoyl group, an acetyl group, or a trifluoroacetyl group. Preferably, it is a tert-butoxycarbonyl group. Di-tert-butyl dicarbonate or tert-butoxycarbonyl chloride may be used to introduce the tert-butoxycarbonyl group. Preferably, it is di-tert-butyl dicarbonate. Di-tert-butyl dicarbonate may be used in an amount of 1 to 5 equivalents per g of the compound. Preferably, it is 2.0 to 2.5 equivalents.

[0042] When using di-tert-butyl dicarbonate, triethylamine, N-methylimidazole, or N,N-dimethylaminopyridine (DMAP) may be used as the base. Preferably, N,N-dimethylaminopyridine (DMAP) is used. When using di-tert-butyl dicarbonate, N,N-dimethylaminopyridine (DMAP) may be used in an amount of 0.01 to 2.0 equivalents per g of the compound. Preferably, it is 0.05 to 0.2 equivalents.

[0043] The solvent is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction. For example, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, or ethyl acetate may be used. Tetrahydrofuran is preferred.

[0044] The reaction temperature typically varies depending on the starting materials, solvent, and other reagents used in the reaction, and may range from 0°C to 60°C. Preferably, it is between 20°C and 30°C.

[0045] In step 2-a), selective deprotection of the hydroxyl group may be performed, and deprotection can be carried out under appropriate conditions depending on the protecting group. For example, for the tert-butoxycarbonyl group and the benzyloxycarbonyl group, deprotection can be easily carried out under hydrolysis conditions. In particular, in the hydrolysis reaction of the di-tert-butoxycarbonyl compound, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate may be used as the base. Potassium carbonate is preferred. Potassium carbonate may be used in amounts of 0.7 to 1.2 equivalents per g of the compound. Preferably, it is 0.7 to 0.9 equivalents.

[0046] The solvent is not particularly limited as long as it dissolves the starting materials and does not inhibit the reaction, and may be, for example, methanol, ethanol, isopropyl alcohol, acetonitrile, water, or a mixture thereof. Methanol is preferred.

[0047] The reaction temperature typically varies depending on the starting materials, solvent, and other reagents used in the reaction, and may be between 25°C and 50°C. Preferably, it is between 30°C and 40°C.

[0048] Step 2-b) is a step in which compound (2a) and compound (2b) are reacted in the presence of a base to obtain compound (2c). [ka]

[0049] Compound (2b) may be 4-chloropyridine-1-ium-oleate, 4-bromopyridine-1-ium-oleate, or 4-nitropyridine-1-ium-oleate. Preferably, it is 4-nitropyridine-1-ium-oleate. Compound (2b) can be used in an amount of 1.0 to 1.4 equivalents relative to compound (2a). Preferably, it is 1.1 to 1.3 equivalents.

[0050] The base may be potassium carbonate, cesium carbonate, potassium tert-butoxide, or a 48% aqueous potassium hydroxide solution. Cesium carbonate is preferred. The base can be used in amounts of 1 to 3 equivalents relative to compound (2a). Preferably, it is 1.4 to 1.6 equivalents.

[0051] The solvent is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction, and may be, for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or 1,3-dimethyl-2-imidazolidinone. Dimethyl sulfoxide is preferred.

[0052] The reaction temperature typically varies depending on the starting materials, solvent, and other reagents used in the reaction, and may range from 0°C to 60°C. Preferably, it is between 30°C and 50°C.

[0053] Step 2-c) is a step in which compound (2c) and compound (2d) are reacted in the presence of an activator to obtain compound (2e). [ka]

[0054] Compound (2d) may be, for example, tert-butylamine, tert-pentylamine, cumylamine, or tert-octylamine. Preferably, it is tert-octylamine. Compound (2d) can be used in amounts of 1 to 15 equivalents relative to compound (2c). Preferably, it is 5 to 10 equivalents.

[0055] The activator may 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. Preferably, it is p-toluenesulfonyl chloride. The equivalent amount of the activator can be 1 to 5 equivalents relative to compound (2c). Preferably, it is 1.5 to 2.5 equivalents.

[0056] The solvent is not particularly limited as long as it dissolves the starting materials and does not inhibit the reaction, and may be, for example, trifluoromethylbenzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, dimethoxyethane, cyclopentyl methyl ether, 4-methyltetrahydropyran, water, or a mixture thereof. Preferably, it is a mixture of toluene, 4-methyltetrahydropyran, and water.

[0057] The reaction temperature typically varies depending on the starting materials, solvent, and other reagents used in the reaction, ranging from -50°C to room temperature, preferably from -20°C to 10°C.

[0058] Step 2-d) involves PG in compound (2e). 1 This is the step of removing the compound (2f) to obtain compound (2f). [ka]

[0059] In step 2-d), deprotection can be carried out under deprotection conditions corresponding to the protecting group. For example, in the case of a tert-butoxide carbonyl group or a benzyloxycarbonyl group, deprotection can be carried out under basic conditions. The base may be, for example, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, tert-butylamine, sodium methoxide, or sodium ethoxide. Sodium hydroxide is preferred. The amount of base is 1 to 10 equivalents, more preferably 2 to 4 equivalents, relative to compound (2e).

[0060] The solvent is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction, and may be, for example, ethanol, tetrahydrofuran, dimethyl sulfoxide, methanol, water, or a mixture thereof. For example, in the case of the tert-butoxide carbonyl group, 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 may be between 30°C and 70°C. Preferably, it is between 40°C and 60°C.

[0061] Step 2-e) is a step in which compound (2f) is reacted with compound (2g-1) or compound (2g-2) in the presence of a base to obtain compound (2h). [ka]

[0062] Compound (2g-1) or compound (2g-2) may be, for example, phenylmethyl carbamate, ethyl methyl carbamate, methylaminocarbonyl chloride, or methylaminocarbonyl bromide. Phenylmethyl carbamate is preferred. For example, 1.0 to 2.0 equivalents of phenylmethyl carbamate can be used relative to compound (2f). Preferably, 1.2 to 1.4 equivalents.

[0063] The base may be sodium hydroxide, potassium hydroxide, sodium tert-butoxide, or potassium tert-butoxide. Preferably, potassium tert-butoxide is used. The amount of base can be 0.1 to 3.0 equivalents relative to compound (2f). Preferably, it is 1.0 to 1.5 equivalents.

[0064] The solvent is not particularly limited as long as it dissolves the starting materials and does not inhibit the reaction, and may be, for example, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or a mixture thereof. Preferably, it is a mixture of tetrahydrofuran and dimethyl sulfoxide.

[0065] The reaction temperature typically varies depending on the starting materials, solvent, and other reagents used in the reaction, and can range from -10°C to room temperature. Preferably, it is 0°C.

[0066] Step 2-f) involves R in compound (2h). 1 This step involves removing the compound to obtain compound (2i), and then, if necessary, obtaining a salt of compound (2i). [ka]

[0067] In step 2-f), R 1 Depending on R 1 You can select conditions for removal. For example, R 1 However, in the case of cumyl or octyl groups, hydrochloric acid, sulfuric acid, formic acid, or methanesulfonic acid can be used as the acid. Methanesulfonic acid is preferred.

[0068] Compound (2i) can be converted to a salt by acid treatment. Examples of salts include inorganic acid salts (sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrofluorides, hydrochlorides, hydrobroms, and hydroiodides), organic carboxylate salts (acetates, oxalates, maleates, tartrates, fumarates, and citrates), organic sulfonates (methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, and camphorsulfonates), and amino acid salts (aspartates and glutamates). Methanesulfonates are preferred. Converting compound (2i) to a salt allows for long-term stable storage. Below, as an example, compound (2h) can be converted to R 1 A method for synthesizing the methanesulfonate of compound (2i) after the removal of [a certain component] is shown.

[0069] The amount of methanesulfonic acid may be 1 to 20 equivalents relative to the compound (2h). Preferably, it is 5 to 10 equivalents.

[0070] The reaction solvent is not particularly limited as long as it dissolves the starting materials and does not inhibit the reaction, and may be, for example, ethanol, methanol, dimethoxyethane, or a mixture thereof. Preferably, it is a mixture of ethanol and methanol. The reaction temperature usually varies depending on the starting materials, solvent, and other reagents used in the reaction, and may range from room temperature to 80°C. Preferably, it is between 20°C and 50°C. [Examples]

[0071] The present invention will be described in detail below with reference to examples. However, the present invention is not limited to these examples. Furthermore, the abbreviations used below are common abbreviations well known to those skilled in the art, and some of these abbreviations are listed below.

[0072] 11H-NMR spectra were measured using a BRUCKER AVANCE NEO 400 (400 MHz), BRUCKER AVANCE III 500 (500 MHz), BRUCKER AVANCE 600 (600 MHz), or BRUCKER AVANCE NEO 700 (700 MHz).

[0073] Proton nuclear magnetic resonance ( 1 The chemical shifts in the 1H-NMR spectrum are recorded in δ units (ppm) relative to tetramethylsilane, and the coupling constants are recorded in Hertz (Hz). The patterns are denoted as follows: s; singlet, d; doublet, br; broad, m; multiplet.

[0074] In the following examples, "room temperature" typically refers to a temperature range of approximately 10°C to 35°C. Unless otherwise specified, percentages are weight percentages.

[0075] Example 1: Preparation of 6-(2-methoxyethoxy)-1H-indol-5-ol (compound (1g)) [ka]

[0076] Manufacturing example 1: Preparation of 2-[(4-bromobenzyl)oxy]-5-nitrophenol (1c) [ka]

[0077] A solution of 4-bromobenzyl alcohol (120.6 kg, 645 mol, 1.2 eq.) and sodium tert-butoxide (103.3 kg, 1075 mol, 2.0 eq.) in dimethyl sulfoxide (450 L) and tetrahydrofuran (157 L) was brought to 13°C. To this solution, 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 at 10-15°C, followed by the addition of tetrahydrofuran (14 L), and 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 mixture. 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), and then with 9% saline solution (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 26-32°C, and after cooling to below 10°C, 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 of below 50°C to obtain 125 kg of the compound. 1 H NMR Spectrum(DMSO-d6)δ(ppm): 5.23(2H, s), 7.17(1H, d, J=9.1Hz), 7.44(2H, br d, J=8.3Hz), 7.60(2H, br d, J=8.3Hz), 7.63(1H, d, J=2.6Hz), 7.71(1H, dd, J=9.1, 2.6Hz)

[0078] Manufacturing Example 2-1: Preparation of 1-[(4-bromobenzyl)oxy]-2-(2-methoxyethoxy)-4-nitrobenzene (1d) (1) [ka]

[0079] To a solution of 2-[(4-bromobenzyl)oxy]-5-nitrophenol (351.4 g, 1084 mmol) in dimethylformamide (1750 mL), potassium carbonate (180 g, 1301 mmol, 1.2 eq.) was added and stirred. 2-bromoethyl methyl ether (166 g, 1193 mol, 1.1 eq.) was added and 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 then concentrated under reduced pressure at 50°C. The concentrated residue was suspended with heptane (1500 mL) and filtered to obtain crystals. The filtrate was concentrated under reduced pressure at 50°C, and the concentrated residue was suspended with heptane (1000 mL) and filtered to obtain crystals. The obtained crystals were combined and dried under reduced pressure at 50°C to obtain 408 g of the compound. 1 H NMR Spectrum (DMSO-d6)δ(ppm): 3.28(3H, s), 3.68(2H, t, J=4.5Hz), 4.23(2H, t, J=4.2Hz), 5.26(2H, s), 7.23(1H, d, J=9.1Hz), 7.41(2H, br d, J=7.9Hz), 7.60(2H, br d, J=7.9Hz), 7.79(1H, d, J=2.3Hz), 7.88(1H, dd, J=8.7, 1.9Hz)

[0080] Manufacturing Example 2-2: Preparation of 1-[(4-bromobenzyl)oxy]-2-(2-methoxyethoxy)-4-nitrobenzene (1d) (2) [ka]

[0081] To a solution of 2-bromoethyl methyl ether (29.5 kg, 212 mol, 1.1 eq.) in dimethylformamide (294 kg), 2-[(4-bromobenzyl)oxy]-5-nitrophenol (62.5 kg, 193 mol) and potassium carbonate (32.0 kg, 232 mol, 1.2 eq.) were added and the mixture was stirred at 56-60°C for 6 hours. After cooling, ethyl acetate (1252 L) and water (375 L) were added. After liquid-liquid extraction, the organic layer was washed with water (188 L), and ethyl acetate (83 L) and 5% sodium chloride aqueous solution (198 kg) were added to the organic layer and liquid-liquid extraction was performed. The organic layer was concentrated under reduced pressure to 737 L, and then a suspension of 1-[(4-bromobenzyl)oxy]-2-(2-methoxyethoxy)-4-nitrobenzene (22.2 g) in methanol (1.7 kg) was added. At 0 to -4°C, methanol (738 L) was added dropwise, and the precipitated crystals were collected by filtration. The crystals were washed with methanol (189 L), and the resulting crystals were dried under reduced pressure at an internal temperature of 50°C or less to obtain 66.0 kg of the compound in question.

[0082] Manufacturing example 3: Preparation of {5-[(4-bromobenzyl)oxy]-4-(2-methoxyethoxy)-2-nitrophenyl}acetonitrile (1f) [ka]

[0083] To a solution of potassium tert-butoxide (14.7 kg, 131 mol, 3 eq.) in dimethylformamide (168 L), 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 at -60 to -55°C. After adding dimethylformamide (21 L), the mixture was stirred at -63 to -58°C for 2 hours. A mixture of ethyl acetate (351 L) and acetic acid (8 L) was added dropwise to the reaction mixture. After adding 5% sodium chloride aqueous solution (168 kg), the organic layer was washed twice with 5% sodium chloride aqueous solution (84 kg, 85 kg). Ethyl acetate (34 L) was added to the organic layer, and then washed with a 5% sodium chloride aqueous solution (85 kg). The organic layer was concentrated under reduced pressure, and tert-butyl methyl ether (134 L) and methanol (13 L) were added to the concentration residue. The mixture was then cooled to 0-2°C, and the precipitated solid was filtered. The obtained crystals were washed with a mixture of tert-butyl methyl ether (30 L) / ethyl acetate (3 L) / methanol (3 L), and the resulting crystals were dried under reduced pressure at an internal temperature of 50°C or less to obtain 10.7 kg of the compound. 1 H-NMR Spectrum(CDCl3)δ(ppm):3.46(3H, s), 3.81(2H, t, J=4.8Hz), 4.19(2H, s), 4.25(2H, t, J=4.4Hz), 5.23(2H, s), 7.14(1H, s), 7.35(2H, d, J=8.0Hz), 7.54(2H, d, J=8.4Hz), 7.84(1H, s)

[0084] Manufacturing example 4: Manufacturing of 6-(2-methoxyethoxy)-1H-indole-5-ol (1g) [ka]

[0085] To a solution of {5-[(4-bromobenzyl)oxy]-4-(2-methoxyethoxy)-2-nitrophenyl}acetonitrile (28.2 kg, 66.9 mol) in tetrahydrofuran (282 L), 10% palladium / carbon (5.7 kg), water (28.2 L), and 98% purified concentrated sulfuric acid (0.21 kg) were added, and the mixture was stirred for 5 hours at 40-45°C and a hydrogen pressure of 0.02-0.15 MPa. After the reaction, the catalyst was filtered, and the catalyst residue was washed with ethyl acetate (284 L), after which the resulting filtrate was separated. A mixture of water (129 L) / hydrochloric acid (12.8 kg) was added dropwise to the organic layer, and the organic layer was separated. The organic layer was washed with 5% sodium bicarbonate solution (141 kg) and 3% saline solution (146 kg), and then the organic layer was concentrated under reduced pressure to 85 L. Ethyl acetate (144 L) and 10% sodium chloride aqueous solution (57 kg) were added to the concentrated residue, and the organic layer was washed. The organic layer was concentrated under reduced pressure to 85 L. Heptane (28 L) and sodium sulfate (14.1 kg) were added to the obtained concentrated residue and stirred. This mixture was purified by passing it through NH silica gel (28.2 kg) moistened with ethyl acetate (141 L). Then, the NH silica gel was 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, heptane (64 L) was added dropwise to the concentrated residue, and the mixture was concentrated under reduced pressure to 85 L at 50°C. Ethyl acetate (27 L) and heptane (60 L) were added, and after cooling to 0-10°C, 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 of 50°C or less to obtain 7.4 kg of the compound. 1 H NMR Spectrum(DMSO-d6)δ(ppm): 3.32(3H, s), 3.66-3.69(2H, m), 4.04-4.07(2H, m), 6.16(1H, t, J=2.1Hz), 6.88(2H, d, J=4.2Hz), 7.07(1H, dd, J=2.8, 2.5Hz), 8.08(1H, s), 10.57(1H, br s)

[0086] Manufacturing Example 4-2: Recrystallization of 6-(2-methoxyethoxy)-1H-indol-5-ol [ka]

[0087] A mixture of 6-(2-methoxyethoxy)-1H-indol-5-ol (21.2 kg, 102.3 mol) and ethyl acetate (97 L) was heated and stirred at an internal temperature of 50-60°C to confirm dissolution. The solution was filtered for clarity and washed with ethyl acetate (10 L). The mixture was cooled to an internal temperature of 40-45°C, and after confirming crystal precipitation, it was stirred at the same temperature for 1 hour. The suspension was cooled to an internal temperature of -10-0°C over 6 hours and then stirred for 14 hours. n-heptane (145 kg) was added dropwise over 1.5 hours and stirred at an internal temperature of -10-0°C for 3 hours. The suspension was filtered and washed with a mixture of ethyl acetate (5.7 kg) and n-heptane (8.7 kg). The obtained crystals were dried under reduced pressure at 40°C to obtain 20.2 kg of the compound.

[0088] Example 2: Preparation of 5-((2-aminopyridine-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide methanesulfonate (methanesulfonate of compound (2i)) [ka]

[0089] Manufacturing example 5: Preparation of tert-butyl-5-hydroxy-6-(2-methoxyethoxy)-1H-indole-1-carboxylate (2a-1) [ka]

[0090] To a suspension of 6-(2-methoxyethoxy)-1H-indole-5-ol (19.8 kg, 95.6 mol) and 4-(dimethylamino)pyridine (1.17 kg, 9.55 mol, 0.1 eq.) in tetrahydrofuran (70.4 kg), a solution of di-tert-butyl-dicarbonate (45.9 kg, 210 mol, 2.2 eq.) in tetrahydrofuran (26.4 kg) was added dropwise at a nitrogen atmosphere below 25°C, washed with tetrahydrofuran (8.8 kg), and stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to 90 L at a temperature below 40°C. Methanol (78.3 kg) and potassium carbonate (10.6 kg, 76.4 mol, 0.8 eq.) were added to the resulting concentrate under a nitrogen atmosphere, and the mixture was stirred at 34°C for 14 hours. After cooling the reaction mixture to 25°C, ethyl acetate (178.6 kg) and water (138.6 kg) were added, and 5N hydrochloric acid (15.2 kg of 35% hydrochloric acid, 16.3 kg of water) was added dropwise. After liquid-liquid separation, the organic layer was washed with 5% saline solution (3.0 kg of sodium chloride, 56.4 kg of water). The organic layer was concentrated under reduced pressure to 100 L at 50°C or below, and then azeotropically stirred twice with toluene (85.6 kg). Dimethyl sulfoxide (87.1 kg) was added to the resulting concentrate, and the mixture was concentrated under reduced pressure to 100 L to obtain the crude product of the labeled compound (content of 29.4 kg as 100%) as a dimethyl sulfoxide solution (100 L). 1 H 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=3.6Hz), 6.95(1H, s), 7.44(1H, d, J=3.6Hz), 7.59(1H, s), 8.75(1H, s)

[0091] Manufacturing example 6: tert-butyl-6-(2-methoxyethoxy)-5-[(1-oxo-1λ 5 Preparation of -pyridine-4-yl)oxy]-1H-indole-1-carboxylate (2c-1) [ka]

[0092] To a dimethyl sulfoxide solution (100 L) of tert-butyl-5-hydroxy-6-(2-methoxyethoxy)-1H-indole-1-carboxylate (29.4 kg, 95.6 mol), 4-nitropyridine-1-ium-oleate (16.1 kg, 115 mol, 1.2 eq.) and dimethyl sulfoxide (106.5 kg) were added. Under a nitrogen atmosphere, at 40°C, cesium carbonate (46.7 kg, 143 mol, 1.5 eq.) was added in seven portions every 30 minutes, and the mixture was stirred for 3 hours. After the reaction was complete, the reaction mixture was cooled to below 15°C, 2-methyltetrahydrofuran (252.5 kg) was added, water (293.6 kg) was added dropwise, and the mixture was separated. The aqueous layer was extracted with 2-methyltetrahydrofuran (126.3 kg), and the combined organic layers were washed with 10% saline solution (8.8 kg of sodium chloride, 79.2 kg of water). The resulting organic layer was concentrated under reduced pressure at 50°C or below to 130 L, and then azeotropically mixed three times with toluene (127.0 kg). Toluene (48.4 kg) was added to the concentrate, heated to 55°C, and the suspension was cooled to -15°C, filtered, and washed with toluene (51.0 kg). The resulting crystals were dried under reduced pressure at 50°C or below to obtain 28.61 kg of the compound. 1 H NMR Spectrum(DMSO-d6)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=3.8Hz), 6.83 -6.87(2H, m), 7.48(1H, s), 7.62(1H, d, J=3.6Hz), 7.82(1H, br s), 8.04-8.07(2H, m)

[0093] Manufacturing example 7: Preparation of 6-(2-methoxyethoxy)-N-methyl-5-({2-[(2,4,4-trimethylpentan-2-yl)amino]pyridine-4-yl}oxy)-1H-indole-1-carboxamide (2e-1) [ka]

[0094] To a suspension of tert-butyl-6-(2-methoxyethoxy)-5-[(1-oxo-1λ-pyridine-4-yl)oxy]-1H-indole-1-carboxylate (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.) were added, followed by washing with toluene (12.3 kg), and the mixture was stirred at -5°C or below. Under a nitrogen atmosphere, a mixed solution of p-toluenesulfonyl chloride (28.5 kg, 149 mol, 2.1 eq.) with 4-methyltetrahydropyran (6.1 kg) and toluene (98.6 kg) was added dropwise, followed by washing with toluene (24.7 kg), and the mixture was stirred at -10°C for 4 hours. After the reaction was complete, water (159.6 kg) was added dropwise to the reaction mixture and the mixture was separated. 5N hydrochloric acid (20.8 kg of 35% hydrochloric acid, 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, 0.5N aqueous sodium hydroxide solution (2.8 kg of caustic soda flakes, 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 resulting organic layer was concentrated under reduced pressure to 80 L at 50°C or below, then ethanol (67.5 kg) was added, and the mixture was concentrated under reduced pressure to 80 L. 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, washed with ethanol (67.8 kg), and the filtrate was concentrated under reduced pressure to 80 L. Ethanol (112.4 kg) was added to the obtained concentrate, and the mixture was concentrated under reduced pressure to 80 L to obtain the crude product of the indicated compound (content of 33.5 kg at 92%) as an ethanol solution (80 L).

[0095] Manufacturing example 8: Preparation of 4-{[6-(2-methoxyethoxy)-1H-indole-5-yl]oxy}-N-(2,4,4-trimethylpentan-2-yl)pyridine-2-amine (2f-1) [ka]

[0096] 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]pyridine-4-yl}oxy)-1H-indole-1-carboxamide (content 33.5 kg, 65.5 mol). Under a nitrogen atmosphere, a 5N sodium hydroxide aqueous solution (7.9 kg flake caustic soda, 197 mol, 3.0 eq., water 38.2 kg) 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 tert-butyl ether (173.8 kg), water (115.1 kg), and 5N hydrochloric acid (15.0 kg 35% hydrochloric acid, water 15.9 kg) were added and the mixture was separated. Tetrahydrofuran (59.5 kg) and 5% saline solution (16.8 kg sodium chloride, 150.6 kg water) were added to the organic layer and separated. The resulting organic layer was concentrated under reduced pressure at 50°C or below to 170 L, then n-propanol (188.1 kg) was added and the mixture was concentrated under reduced pressure to 160 L. Methyl tert-butyl ether (49.7 kg) was added to the concentrate and stirred at 48°C for 73 minutes. The suspension was cooled to 0°C, filtered, and washed with n-propanol (53.6 kg). The resulting crystals were dried under reduced pressure at 50°C or below to obtain 22.93 kg of the compound. 1 H NMR Spectrum(CD3OD)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=2.3Hz), 6.15(1H, dd, J=6.0, 2.3Hz), 6.36-6.39(1H, m), 7.11(1H, s), 7.17(1H, d, J=3.4Hz), 7.25(1H, s), 7.74(1H, d, J=6.0Hz)

[0097] Manufacturing example 9: Preparation of 6-(2-methoxyethoxy)-N-methyl-5-({2-[(2,4,4-trimethylpentan-2-yl)amino]pyridine-4-yl}oxy)-1H-indole-1-carboxamide (2h-1) [ka]

[0098] 4-{[6-(2-methoxyethoxy)-1H-indole-5-yl]oxy}-N-(2,4,4-trimethylpentan-2-yl)pyridine-2-amine (20.5 kg, 49.8 mol) was mixed with tetrahydrofuran (109.3 kg) and stirred at a temperature below 5°C. Under a nitrogen atmosphere, a solution of potassium tert-butoxide (5.9 kg, 52 mol, 1.05 eq.) in DMSO (22.6 kg) was added dropwise, washed with DMSO (2.3 kg), and stirred at 0°C for 30 minutes. A solution of phenylmethylcarbamate (9.0 kg, 60 mol, 1.30 eq.) in tetrahydrofuran (18.2 kg) was added dropwise, washed with tetrahydrofuran (9.1 kg), and stirred 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 stirred at 20°C, followed by liquid-liquid separation. A 1N sodium hydroxide aqueous solution (4.1 kg of caustic soda flakes, 102.5 kg of water) was added to the organic layer, followed by liquid-liquid separation. Then, a 10% ammonium chloride aqueous solution (10.3 kg of ammonium chloride, 92.3 kg of water) was added, and liquid-liquid separation was performed again. The organic layer was washed with 1% saline solution (1.0 kg of sodium chloride, 102.5 kg of water). The resulting organic layer was concentrated under reduced pressure to 80 L at 40°C or below, and then azeotropically boiled three times with ethanol (80.9 kg) to obtain the crude product of the labeled compound (content of 23.34 kg as 100%) as an ethanol solution (80 L). 1 H NMR Spectrum(CD3OD)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=2.3Hz), 6.18(1H, dd, J=5.9, 2.3Hz), 6.61(1H, d, J=3.2Hz), 7.32(1H, s), 7.58(1H, d, J=3.8Hz), 7.79(1H, d, J=5.9Hz), 8.08(1H, s)

[0099] Manufacturing example 10: Preparation of 5-((2-aminopyridine-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide methanesulfonate (methanesulfonate of (2i)) [ka]

[0100] A 90 L ethanol solution of 6-(2-methoxyethoxy)-N-methyl-5-({2-[(2,4,4-trimethylpentan-2-yl)amino]pyridine-4-yl}oxy)-1H-indole-1-carboxamide (content 26.0 kg, 55.5 mol) was concentrated to 75 L under reduced pressure at 40°C or below, and then methanol (37.0 kg) and ethanol (17.3 kg) were added. Under a nitrogen atmosphere, methanesulfonic acid (42.7 kg, 444 mol, 8.0 eq.) was added at 10°C, washed with methanol (4.2 kg), and stirred at 40°C for 28 hours. After confirming the completion of the reaction, it was cooled to 20°C, and methyl tert-butyl ether (385.8 kg) was added dropwise and stirred for 1 hour. After cooling to 0°C, the solution was filtered and washed with a mixture of methyl tert-butyl ether and ethanol (methyl tert-butyl ether / ethanol = 1.64 / 0.36 vol., 39.2 kg) and isopropyl acetate (45.5 kg). The resulting crystals were dried under reduced pressure at 50°C or below to obtain 22.89 kg of the compound. 1 H NMR Spectrum (DMSO-d6)δ(ppm): 2.32(3H, s), 2.84(3H, d, J=4.5Hz), 3.15(3H, s), 3.51-3.54(2H, m), 4.08-4.11(2H, m), 6.01(1H, d, J=2.3Hz), 6.63-6.66(2H, m), 7.50(1H, s), 7.61(2H, br s), 7.79(1H, d, J=3.8Hz), 7.90(1H, d, J=7.2Hz), 8.10(1H, s), 8.18(1H, q, J=4.2Hz), 12.82(1H, brs)

[0101] Manufacturing Example 10-2: Preparation of 5-((2-aminopyridine-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide methanesulfonate (methanesulfonate of (2i)) [ka]

[0102] To an ethanol solution (183 L) of 6-(2-methoxyethoxy)-N-methyl-5-({2-[(2,4,4-trimethylpentan-2-yl)amino]pyridine-4-yl}oxy)-1H-indole-1-carboxamide (content 47.8 kg, 102 mol, with the previous step as 100%), methanol (33.2 kg) was added under a nitrogen atmosphere. Methanesulfonic acid (117.7 kg, 1225 mol, 12.0 eq.) was added, washed with methanol (4.7 kg), stirred at 25-32°C for 21 hours, and 5-((2-aminopyridine-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide (46 g) was added. To the suspension from which the crystals had precipitated, methyl tert-butyl ether (355.3 kg) was added dropwise, and the mixture was cooled to 2-5°C. The precipitated solid was filtered and washed with a mixture of methyl tert-butyl ether (126.8 kg) and ethanol (54.0 kg) and isopropyl acetate (208.7 kg). The resulting crystals were dried under reduced pressure at 50°C or below to obtain 38.04 kg of the compound in question.

[0103] Manufacturing example 11: Preparation of 5-((2-aminopyridine-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide (2i) [ka]

[0104] To a suspension of 5-((2-aminopyridine-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide methanesulfonate (19.9 kg, 44.0 mol) in tetrahydrofuran (159.2 kg), a 1N sodium hydroxide aqueous solution (2.71 kg of flake caustic soda, 67.7 mol, 1.54 eq., water 67.7 kg) was added under a nitrogen atmosphere, and the mixture was stirred at 25°C for 30 minutes. Isopropyl acetate (156.2 kg) was added to the reaction solution, and after liquid-liquid extraction, the organic layer was washed with 5% saline solution (2.99 kg of sodium chloride, water 56.7 kg). The resulting organic layer was washed with water (59.7 kg), filtered for clarification, and washed with isopropyl acetate (8.7 kg). After concentrating under reduced pressure to 100 L at 40°C or below, the mixture was further azeotropically mixed 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 resulting crystals were dried under reduced pressure at 50°C or below to obtain 13.91 kg of the compound. 1 H NMR Spectrum (DMSO-d6)δ(ppm): 2.83(3H, d, J=4.4Hz), 3.18(3H, s), 3.50-3.54(2H, m), 4.04-4.08(2H, m), 5.69(1H, d, J=1.8Hz), 5.76(2H, s), 6.09(1H, dd, J=5.7, 2.2Hz), 6.59(1H, d, J=3.5Hz), 7.33(1H, s), 7.71-7.74(2H, m), 8.03(1H, s), 8.10-8.14(1H, m)

[0105] Manufacturing Example 11-2: Preparation of 5-((2-aminopyridine-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide (2i) [ka]

[0106] To a suspension of 5-((2-aminopyridine-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide methanesulfonate (36.6 kg, 80.9 mol) in tetrahydrofuran (292.5 kg), a 1N sodium hydroxide aqueous solution (5.5 kg flake caustic soda, 137.5 mol, 1.70 eq., water 138 kg) was added under a nitrogen atmosphere, and the mixture was stirred at 20°C for 30 minutes. Isopropyl acetate (287 kg) was added to the reaction solution, and after liquid-liquid extraction, the organic layer was washed with 5% saline solution (5.5 kg sodium chloride, water 104 kg). The resulting organic layer was washed with water (110 L), filtered for clarification, and washed with isopropyl acetate (47.9 kg). The solution was concentrated under reduced pressure to 184 L at 40°C or below, and then azeotropically stirred four times with acetonitrile (144 kg). Acetonitrile (28.8 kg) was added to the concentrate and the mixture was stirred at 45-46°C for 1 hour. The suspension was cooled to 2°C, filtered, and washed with acetonitrile (43.2 kg). The resulting crystals were dried under reduced pressure at 50°C or below to obtain 25.92 kg of the compound.

Claims

1. Compound (1g) 【Chemistry 1】 A method for manufacturing, 1-a) 1,2-(methylenedioxy)-4-nitrobenzene and 4-bromobenzyl alcohol are reacted in the presence of a base to form compound (1c). 【Chemistry 2】 Step 1) for manufacturing, 1-b) The compound (1c) obtained in step 1-a) is reacted with a methoxyethylating agent in the presence of a base to obtain compound (1d). 【Transformation 3】 The process 1-b) for manufacturing, 1-c) The compound (1d) obtained in step 1-b) is reacted with a cyanomethylating agent in the presence of a base to obtain compound (1f). 【Chemistry 4】 The process 1-c) for manufacturing, 1-d) In the presence of a reducing catalyst and an acid catalyst, the nitro group in compound (1f) obtained in step 1-c) is converted to an amino group, the 4-bromobenzyl group is removed, and the ring is closed in parallel to obtain compound (1g). 【Transformation 5】 A method comprising step 1-d) for manufacturing.

2. The manufacturing method according to claim 1, wherein in step 1-d), the reduction catalyst is a palladium catalyst and the acid catalyst is sulfuric acid.

Images