Method for producing n-pyridylsulfonamide compound, pyridine compound, and crystal of n-pyridylsulfonamide compound

Abstract

Disclosed is a production method that involves synthesizing an N-pyridylsulfonamide compound (III) by means of a coupling reaction between a pyridine compound (I) and a sulfonamide compound (II).

Description

Method for producing N-pyridyl sulfonamide compound, pyridine compound, and crystal of N-pyridyl sulfonamide compound

[0001] The present disclosure relates to a method for producing N-pyridyl sulfonamide compounds, pyridine compounds, and crystals of N-pyridyl sulfonamide compounds.

[0002] 5-Fluoro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide (N-pyridylsulfonamide compound (III)) and its sodium salt have excellent tissue non-specific alkaline phosphatase (TNAP) inhibitory activity and are useful as pharmaceuticals (Patent Document 1). Patent Document 1 discloses a method for producing N-pyridylsulfonamide compound (III) represented by the following formula:

[0003] International Publication No. 2017 / 007943

[0004] The present disclosure relates to a novel method for stably producing N-pyridylsulfonamide compound (III) and its sodium salt with reduced by-products.

[0005] The present disclosure includes the following: [1] A compound of the following formula (I): and X represents a halogen atom, a benzenesulfonyloxy group, a toluenesulfonyloxy group, a nitrobenzenesulfonyloxy group, a methanesulfonyloxy group, an ethanesulfonyloxy group, or a trifluoromethanesulfonyloxy group; and By a coupling reaction with a sulfonamide compound represented by the following formula (III): [2] The method according to [1], wherein the N-pyridylsulfonamide compound is produced by the coupling reaction in a reaction solution containing copper(I) iodide and a carboxylic acid compound selected from pyridine-2-carboxylic acid and an N,N-dialkylamino acid. [3] The method according to [2], wherein the carboxylic acid compound is pyridine-2-carboxylic acid. [4] The method according to [2] or [3], further comprising adding an additional carboxylic acid compound to the reaction solution containing the N-pyridylsulfonamide compound, and then precipitating crystals containing the N-pyridylsulfonamide compound from the reaction solution. [5] The method according to [2] or [3], further comprising adding an additional carboxylic acid compound to the reaction solution containing the N-pyridylsulfonamide compound, and then precipitating crystals containing the N-pyridylsulfonamide compound from the reaction solution. [6] The method according to

[10] , further comprising adding an additional carboxylic acid compound to the reaction solution containing the N-pyridylsulfonamide compound, and then precipitating crystals containing the N-pyridylsulfonamide compound from the reaction solution. The method according to any one of [1] to [5], further comprising synthesizing a pyridine compound represented by formula (I) by an amidation reaction of a pyridine compound represented by formula (11): wherein in formula (11), R represents an alkyl group having 1 to 6 carbon atoms, and X has the same meaning as X in formula (I). [6] The method according to [5], wherein R is an alkyl group having 1 to 3 carbon atoms. [7] The method according to [5], wherein R is a methyl group. [8] The method according to the following formula (10): [9] The method according to any one of [5] to [7], further comprising synthesizing a pyridine compound represented by formula (11) from a pyridine compound represented by formula (10): The method according to any one of [1] to [8], further comprising synthesizing a sodium salt represented by the formula:

[10] The method according to [9], wherein synthesizing the sodium salt comprises: forming a solution containing the N-pyridylsulfonamide compound, sodium hydroxide, and water, wherein the N-pyridylsulfonamide compound and the sodium hydroxide are all dissolved in the water; and adding a poor solvent for the sodium salt to the solution to precipitate crystals containing the sodium salt.

[11] The method according to

[10] , wherein the solution further contains 1-propanol, and the N-pyridylsulfonamide compound and the sodium hydroxide are all dissolved in a mixed solvent containing water and 1-propanol.

[12] The method according to

[10] or

[11] above, wherein the poor solvent contains acetone, 1-propanol, or both.

[13] The method according to any one of [1] to

[12] , wherein X is a bromine atom.

[14] The method according to the formula (10):

[15] A pyridine compound represented by the following formula (11): wherein X represents a halogen atom, a benzenesulfonyloxy group, a toluenesulfonyloxy group, a nitrobenzenesulfonyloxy group, a methanesulfonyloxy group, an ethanesulfonyloxy group, or a trifluoromethanesulfonyloxy group, and R represents an alkyl group having 1 to 6 carbon atoms.

[17] The pyridine compound according to the above item

[16] , wherein X represents a bromine atom.

[18] The pyridine compound according to the above item

[16] or

[17] , wherein R represents a methyl group.

[19] A pyridine compound comprising sodium (5-fluoro-2-methoxyphenylsulfonyl)(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)azanide, and copper K αA powder X-ray diffraction pattern obtained by irradiation with x-rays shows peaks at diffraction angles 2θ of 8.1°±0.2°, 11.7°±0.2°, 12.1°±0.2°, 12.4°±0.2°, 12.8°±0.2°, 19.0°±0.2°, 20.0°±0.2°, 24.2°±0.2°, and 25.8°±0.2°.

[0006] According to the present disclosure, a novel production method for stably producing N-pyridylsulfonamide compound (III) and its sodium salt with reduced by-products can be provided. The method according to the present disclosure is also advantageous in that, when a catalyst is used, the catalyst can be easily removed.

[0007] 1 is a powder X-ray diffraction pattern of a crystal of the sodium salt of N-pyridylsulfonamide compound (IIIa).

[0008] The present invention is not limited to the following examples. For convenience, in this specification, a compound represented by formula (1) may be referred to as "compound (1)" or the like. Unless otherwise specified, the materials exemplified in this specification may be used alone or in combination of two or more. In the numerical ranges described in stages in this specification, the upper or lower limit of a certain numerical range may be replaced with the upper or lower limit of a numerical range of another stage. In the numerical ranges described in this specification, the upper or lower limit of the numerical range may be replaced with a value shown in the examples. In this specification, the term "crystal" refers to a structure in which specific molecules are arranged in a lattice in space so as to exhibit translational symmetry, and does not necessarily refer only to a structure consisting of a single compound.

[0009] An example of a method for producing the N-pyridylsulfonamide compound (III) includes a step A1 of synthesizing a pyridine compound (10) by reacting 2-aminoethanol (1) represented by the following formula with a pyridine compound (2): A step A2a of synthesizing a pyridine compound (11) from a pyridine compound (10) represented by the following formula: Step A2b: synthesizing pyridine compound (I) by an amidation reaction of pyridine compound (11) represented by the following formula: Step B: synthesizing a sulfonamide compound (II) from a sulfonic acid chloride (4) represented by the following formula; and Step C1 of synthesizing an N-pyridylsulfonamide compound (III) by coupling reaction of a pyridine compound (I) represented by the following formula with a sulfonamide compound (II).

[0010] The sodium salt can be produced by step C2 of synthesizing the sodium salt (IIIa) from the N-pyridylsulfonamide compound (III) represented by the following formula:

[0011] Step A1: Pyridine compound (10) is produced by reacting 2-aminoethanol (1) with pyridine compound (2). In pyridine compound (2), X is a halogen atom, a benzenesulfonyloxy group, a toluenesulfonyloxy group, a nitrobenzenesulfonyloxy group, a methanesulfonyloxy group, an ethanesulfonyloxy group, or a trifluoromethanesulfonyloxy group. Examples of halogen atoms include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. X may also be a bromine atom.

[0012] The amount of 2-aminoethanol (1) may be, for example, 1.0 mole or more and 2.0 moles or less per mole of the pyridine compound (2).

[0013] The reaction between 2-aminoethanol (1) and pyridine compound (2) can proceed efficiently in the presence of a base. The base may be, for example, an alkali metal alkoxide such as potassium tert-butoxide. The amount of the base may be, for example, 2.0 moles or more and 3.0 moles or less per mole of pyridine compound (2).

[0014] The reaction of 2-aminoethanol (1) with pyridine compound (2) may be carried out in a reaction solution containing these compounds, a base, and a solvent. The solvent may be, for example, an ether such as tetrahydrofuran. The reaction temperature of 2-aminoethanol (1) with pyridine compound (2) may be, for example, 30°C or higher and 80°C or lower.

[0015] The produced pyridine compound (10) can be isolated and purified by a combination of common methods such as neutralization, extraction, filtration, concentration, crystallization, recrystallization, washing, etc. The pyridine compound (10) may be used as is for synthesizing the pyridine compound (11) without isolation or purification.

[0016] Step A2a: Pyridine compound (10) is esterified to produce pyridine compound (11). In formula (11), R represents an alkyl group having 1 to 6 carbon atoms. R may be an alkyl group having 1 to 3 carbon atoms or a methyl group.

[0017] The esterification method of pyridine compound (10) may be any conventional method for producing an alkyl ester from a carboxylic acid. For example, a method can be used in which pyridine compound (10) and an alkyl alcohol are reacted in the presence of trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate. The amount of trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate may be, for example, 1.2 to 4.0 moles per mole of pyridine compound (10). Pyridine compound (10) may also be esterified in an excess amount of alkyl alcohol. The alkyl alcohol is a compound having an alkyl group having 1 to 6 carbon atoms and a hydroxyl group bonded thereto, and examples thereof include methanol. The reaction temperature for esterifying pyridine compound (10) may be, for example, 30°C to 80°C.

[0018] The produced pyridine compound (11) may be isolated and purified by a combination of common methods such as neutralization, extraction, filtration, concentration, crystallization, recrystallization, washing, etc. When the pyridine compound (11) is obtained as a solution, the solution may be used as is for synthesizing the pyridine compound (I) without isolation or purification.

[0019] Step A2b: Pyridine compound (11) is subjected to an amidation reaction accompanied by intramolecular cyclization to produce pyridine compound (I). This reaction can proceed while suppressing the by-production of a dimer due to an intermolecular reaction.

[0020] The amidation reaction of pyridine compound (11) may be carried out in a reaction solution containing a base and a solvent. The base may be, for example, an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The amount of the base may be, for example, 1.5 to 8.0 moles, or 3.0 to 8.0 moles, per mole of pyridine compound (10). The solvent may be, for example, an alcohol such as methanol. The reaction temperature for the amidation reaction of pyridine compound (11) may be, for example, 30 to 80°C.

[0021] The resulting pyridine compound (I) may be isolated and purified by a combination of common methods such as neutralization, extraction, filtration, concentration, crystallization, recrystallization, and washing.

[0022] Step B: Amidation of sulfonic acid chloride (4) produces sulfonamide compound (II). This reaction allows the introduction of an amino group that constitutes a sulfonamide group. As shown in the following formula, sulfonic acid chloride (4) may be formed from sulfonic acid compound (3), and then sulfonamide compound (II) may be produced by reacting sulfonic acid chloride (4) with ammonia.

[0023] Sulfonic acid chloride (4) is produced, for example, by the reaction of sulfonic acid compound (3) with oxalyl chloride in a reaction solution containing N,N-dimethylformamide. The amount of oxalyl chloride may be, for example, 1.0 mol to 2.0 mol per mole of sulfonic acid compound (3). The amount of N,N-dimethylformamide may be, for example, 0.3 mol to 1.0 mol per mole of sulfonic acid compound (3). The reaction solution may contain a solvent, such as an ether such as 1,2-dimethoxyethane. After completely dissolving sulfonic acid compound (3) in the solvent, the reaction solution may be concentrated. The reaction temperature for producing sulfonic acid chloride (4) may be, for example, 0°C to 60°C. The produced sulfonic acid chloride (4) may be used in solution for the synthesis of sulfonamide compound (II) without isolation or purification. Isolated sulfonic acid chloride (4) may be prepared and used for the synthesis of sulfonamide compound (II).

[0024] Ammonia water can be added to a reaction solution containing sulfonic acid chloride (4) to amidate the sulfonic acid chloride (4) to produce sulfonamide compound (II). The amount of ammonia may be, for example, 1.5 mol or more and 5.0 mol or less per mol of sulfonic acid chloride (4) (or sulfonic acid compound (3)). The reaction temperature for the amidation of sulfonic acid chloride (4) may be, for example, -10°C or more and 40°C or less.

[0025] The resulting sulfonamide compound (II) can be isolated and purified by a combination of common methods such as neutralization, extraction, filtration, concentration, crystallization, recrystallization, and washing.

[0026] Step C1: N-pyridyl sulfonamide compound (III) is produced by coupling reaction of pyridine compound (I) with sulfonamide compound (II). This reaction allows the synthesis of N-pyridyl sulfonamide compound (III) without the need to protect the nitrogen atom constituting the seven-membered ring of N-pyridyl sulfonamide compound (III) with a protecting group. Therefore, the use of a strong acid for deprotection can also be avoided.

[0027] The amount of the sulfonamide compound (II) may be, for example, 1.2 moles or more and 2.5 moles or less, or 1.5 moles or more and 2.2 moles or less, relative to 1 mole of the pyridine compound (I).

[0028] The N-pyridylsulfonamide compound (III) may be produced by a coupling reaction in a reaction solution containing a metal catalyst, a ligand, a base, and a solvent. The metal catalyst may be, for example, copper(I) iodide. The ligand may be, for example, a carboxylic acid compound selected from pyridine-2-carboxylic acid and an N,N-dialkylamino acid. The amount of the metal catalyst may be, for example, 0.2 to 0.6 mol, or 0.3 to 0.5 mol, relative to 1 mol of the pyridine compound (I). The amount of the ligand may be, for example, 0.4 to 1.2 mol, or 0.6 to 1.0 mol, relative to 1 mol of the pyridine compound (I). The base may be, for example, an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The amount of the base may be, for example, 2.5 to 4.5 mol, or 3.0 to 4.0 mol, relative to 1 mol of the pyridine compound (I). The solvent may be, for example, an alcohol such as tert-amyl alcohol. The reaction temperature for the coupling reaction may be, for example, 60°C or higher and 130°C or lower, or 80°C or higher and 120°C or lower.

[0029] The produced N-pyridylsulfonamide compound (III) can be isolated and purified by a combination of common methods such as neutralization, extraction, filtration, concentration, crystallization, recrystallization, and washing. When the reaction solution containing the produced N-pyridylsulfonamide compound (III) also contains a carboxylic acid compound selected from pyridine-2-carboxylic acid and an N,N-dialkylamino acid, an additional carboxylic acid compound may be added to the reaction solution, and then crystals containing N-pyridylsulfonamide compound (III) may be precipitated from the reaction solution. This method makes it possible to efficiently obtain crystals with little copper ion contamination. The amount of the additional carboxylic acid compound may be, for example, such that the pH of the reaction solution is 4.0 or more and 5.5 or less.

[0030] Step C2: The sodium salt (IIIa) of the N-pyridylsulfonamide compound (III) is produced by reacting the N-pyridylsulfonamide compound (III) with sodium hydroxide, for example, in a solution containing water. The amount of sodium hydroxide may be, for example, 1.0 mol or more and 1.1 mol or less per 1 mol of the N-pyridylsulfonamide compound (III). The solvent for the solution for producing the sodium salt (IIIa) may be a mixed solvent containing water and 1-propanol. In this case, the ratio of the volume of 1-propanol to the volume of water may be, for example, 0.5 or more and 1.5 or less. The temperature of the solution for producing the sodium salt (IIIa) may be, for example, −10° C. or more and 40° C. or less.

[0031] The resulting sodium salt (IIIa) can be isolated and purified by a combination of common methods such as neutralization, extraction, filtration, concentration, crystallization, recrystallization, and washing.

[0032] Step C2 of synthesizing the sodium salt (IIIa) may include forming a solution containing the N-pyridylsulfonamide compound (III), sodium hydroxide, and water, wherein the N-pyridylsulfonamide compound (III) and the sodium hydroxide are all dissolved in water, and adding a poor solvent for the sodium salt (IIIa) to the solution to precipitate crystals containing the sodium salt (IIIa). When the solution further contains 1-propanol, a solution may be formed in which the N-pyridylsulfonamide compound (III) and the sodium hydroxide are all dissolved in a mixed solvent containing water and 1-propanol. The poor solvent may include, for example, acetone, 1-propanol, or both. Seed crystals of the sodium salt (IIIa) may be added to the solution for crystal precipitation.

[0033] The crystals containing sodium salt (IIIa) are αIn the powder X-ray diffraction pattern obtained by irradiation with X-rays, peaks may be observed at diffraction angles 2θ of 8.1°±0.2°, 11.7°±0.2°, 12.1°±0.2°, 12.4°±0.2°, 12.8°±0.2°, 19.0°±0.2°, 20.0°±0.2°, 24.2°±0.2°, and 25.8°±0.2°. The X-ray diffraction pattern of the crystal can be measured, for example, using the method described in "General Test Methods," "2. Physical Test Methods," and "2.58 Powder X-ray Diffraction Measurement Method" in the 18th Edition of the Japanese Pharmacopoeia. The English version of the 18th Edition of the Japanese Pharmacopoeia has also been published. In this measurement method, the K of copper α In the measurement of many organic crystals using X-rays, it is usually adequate to record the diffraction pattern over the 2θ range from as close to 0° as possible to at least 40°. The 2θ diffraction angles between a sample and a reference material of the same crystal form will agree to within 0.2°.

[0034] The scope of the present invention is not limited to the following examples. 1 H NMR or 13 The δ values ​​(ppm) reported for the C NMR spectra are the chemical shift values ​​of the observed signals using tetramethylsilane as the standard. The splitting patterns of each signal are indicated as s for singlet, d for doublet, t for triplet, m for multiplet, and br for broad. Mass spectrometry (hereinafter referred to as MS) was performed by ESI (Electron Spray Ionization). In each step of the examples, the reaction solutions were prepared and the reactions were carried out at room temperature (1 to 30°C) unless otherwise specified.

[0035] Step A1: Synthesis of pyridine compound (10a) (2-(2-aminoethoxy)-5-bromopyridine-3-carboxylic acid)

[0036] Example A1-1 Under a nitrogen atmosphere, tetrahydrofuran (850.1 L) and 5-bromo-2-chloropyridine-3-carboxylic acid (2a) (170.0 kg, 719 mol) were placed in a reaction vessel. The mixture in the reaction vessel was stirred at 20 to 30°C for 3 hours. Next, insoluble matter in the mixture was filtered off, and the insoluble matter was washed with tetrahydrofuran (170.1 L). The solution (tetrahydrofuran solution containing 5-bromo-2-chloropyridine-3-carboxylic acid) obtained by combining the washings and the filtrate was stored in a container. Tetrahydrofuran (850.2 L), potassium tert-butoxide (177.49 kg, 1582 mol), and 2-aminoethanol (1) (52.70 kg, 863 mol) were placed in a separate reaction vessel, and the mixture in the reaction vessel was stirred at 15 to 35°C for 3 hours to form a reaction solution. To this reaction solution, a tetrahydrofuran solution containing 5-bromo-2-chloropyridine-3-carboxylic acid was added dropwise over 2 hours. After the addition, the reaction solution was stirred at 50 to 60°C for 2 hours. After stirring was completed, the reaction solution was cooled to 20°C or below. To this was added 5 mol / L hydrochloric acid (approximately 200 L) to adjust the pH of the reaction solution to 4.0 to 6.0. The reaction solution was stirred at 10 to 20°C for 1 hour or more, and the precipitated solid was collected by filtration. The obtained solid was washed with tetrahydrofuran (478 L) and then with methanol (515.6 L), yielding 323.74 kg of wet crystals of pyridine compound (10a).

[0037] The obtained wet crystals (322.10 kg) and water (85.7 L) were added to water (1479.1 L) in a reaction vessel cooled to 2 to 8°C under a nitrogen atmosphere to form an aqueous solution containing pyridine compound (10a). The aqueous solution was stirred for 18 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with water (528.5 L) and dried at 30°C to obtain 150.00 kg (yield 80.3%) of pyridine compound (10a). 1 H NMR (500 MHz, acetic acid-d4): δ= 8.47 (d, J = 2.6 Hz, 1H), 8.43 (d, J = 2.6 Hz, 1H), 4.76 (dt, J = 5.2, 2.6 Hz, 2H), 3.60 ppm (dt, J = 5.2, 2.6 Hz, 2H), 13C NMR (125 MHz, acetic acid-d4) δ= 169.1, 160.9, 151.7, 144.5, 119.9, 113.1, 64.1, 40.3 ppm; HRMS (ESI): calcd for C8H 10 BrN2O3 + [M + H] + 260.9875, found 260.9890.

[0038] Example A1-2 Under a nitrogen atmosphere, tetrahydrofuran (350.2 L) and 5-bromo-2-chloropyridine-3-carboxylic acid (2a) (70.0 kg, 296 mol) were placed in a reaction vessel. The mixture in the reaction vessel was stirred at 20 to 30°C for 3 hours. Next, insoluble matter in the mixture was filtered off, and the insoluble matter was washed with tetrahydrofuran (140.1 L). The solution (tetrahydrofuran solution containing 5-bromo-2-chloropyridine-3-carboxylic acid) obtained by combining the washing liquid and the filtrate was stored in a container. Tetrahydrofuran (350.1 L), potassium tert-butoxide (73.08 kg, 651 mol), and 2-aminoethanol (1) (21.70 kg, 355 mol) were placed in a separate reaction vessel, and the mixture in the reaction vessel was stirred at 15 to 35°C for 3 hours to form a reaction solution. To this reaction solution, a tetrahydrofuran solution containing 5-bromo-2-chloropyridine-3-carboxylic acid was added dropwise over 2 hours. After the addition, the reaction solution was stirred at 50 to 60°C for 2 hours. After stirring was completed, the reaction solution was cooled to 10°C or below. To this was added 5 mol / L hydrochloric acid (89.26 kg, 2266 mol) to adjust the pH of the reaction solution to 4.0 to 6.0. The reaction solution was stirred at 10 to 20°C for 1 hour or more, and the precipitated solid was collected by filtration. The obtained solid was washed with tetrahydrofuran (210.1 L) and then with methanol (210.3 L) to obtain wet crystals of pyridine compound (10a) (126.19 kg, dry mass: 72.56 kg).

[0039] The obtained wet crystals (125.19 kg, dry mass: 71.98 kg) and methanol (72 L) were added to a mixture of water (353 L) and methanol (79 L) in a reaction vessel cooled to 7-13°C under a nitrogen atmosphere to form a mixture containing pyridine compound (10a). The mixture was stirred for 5 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with 30% aqueous methanol solution (210.1 L) and dried at 35°C to obtain 67.46 kg of pyridine compound (10a) (yield: 87.3%).

[0040] Example A1-3: Under a nitrogen atmosphere, tetrahydrofuran (386.7 kg), potassium tert-butoxide (39.4 kg), and 2-aminoethanol (1) (10.5 kg) were placed in a reaction vessel. The mixture in the reaction vessel was stirred at 20-35°C for 0.5 hours. After stirring was completed, the mixture in the reaction vessel was cooled to 10-20°C, and 5-bromo-2-chloropyridine-3-carboxylic acid (2a) (39.5 kg) was added thereto in 10 portions. After the addition, the mixture was stirred at 50-60°C for 2 hours to form a reaction solution. After stirring, the reaction solution was concentrated under reduced pressure until the liquid volume was 210 L. Concentrated hydrochloric acid (7.25 kg), water (119.0 kg), and concentrated hydrochloric acid (13.09 kg) were added to the reaction solution in this order, and the pH of the reaction solution was adjusted to 6.0-6.5. The reaction solution was then concentrated under reduced pressure until the liquid volume was 130 L. After concentration, the reaction solution was stirred at 20 to 30°C for 0.5 hours. After stirring was completed, 24% aqueous sodium hydroxide solution (0.21 kg) was added to the reaction solution, and the pH of the reaction solution was adjusted to 6.0 to 6.5. The reaction solution was then stirred at 20 to 30°C for 2 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with water (79.1 kg) and dried under reduced pressure at 50°C, yielding 36.67 kg of pyridine compound (10a) (yield 84.1%).

[0041] Steps A2a and A2b: Synthesis of pyridine compound (Ia) (7-bromo-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one)

[0042] Example A2-1 Under a nitrogen atmosphere, the pyridine compound (10a) (130.00 kg, 498 mol) obtained in Example (A1-1), methanol (1,040 L), and trimethylsilyl trifluoromethanesulfonate (221.34 kg, 996 mol) were placed in a reaction vessel. The mixture in the reaction vessel was stirred under reflux conditions for 7 hours to form a reaction solution. After stirring was completed, the reaction solution was cooled to room temperature to obtain a methanol solution containing the pyridine compound (11a) (methyl 2-(2-aminoethoxy)-5-bromopyridine-3-carboxylate). 1 H NMR (500 MHz, DMSO-d6): δ= 8.53 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 2.6 Hz, 1H), 8.17 (br s, 2H), 4.55 (t, J = 5.4 Hz, 2H), 3.84 (s, 3H), 3.21 ppm (t, J = 5.4 Hz, 2H), 13 C NMR (125 MHz, DMSO-d6) δ= 163.6, 159.4, 150.9, 142.8, 116.0, 111.6, 63.2, 52.6, 37.8 ppm; HRMS (ESI): calcd for C9H 12 BrN2O3 + [M + H] + 275.0031, found 275.0043.

[0043] The methanol solution containing the pyridine compound (11a) was added dropwise over 4 hours to a mixture of methanol (2210 L) and 1,8-diazabicyclo[5.4.0]undec-7-ene (341.14 kg, 2241 mol) in a reaction vessel heated to an internal temperature of 50-60°C under a nitrogen atmosphere, while maintaining the internal temperature at 50-60°C, to form a reaction solution. After the dropwise addition, the reaction solution was washed with methanol (260 L) to obtain a wash solution, and the reaction solution was stirred for an additional 3 hours. After stirring was completed, the reaction solution was cooled to room temperature. Hydrochloric acid (268.52 kg) with a concentration of 5 mol / L was added dropwise to adjust the pH of the reaction solution to 6.5-7.5. Water (338 L) was added to the reaction solution, and the reaction solution was stirred for 0.5 hours at an internal temperature of 50-60°C. Next, the insoluble matter in the reaction solution was filtered off, and the insoluble matter was washed with methanol (260 L). The washings and filtrate were combined to form a mixture, and the mixture was stirred at 50 to 60°C for 0.5 hours and then cooled to 33°C. Pyridine compound (Ia) (130.00 g) was added to this mixture as seed crystals, and crystals of pyridine compound (Ia) were precipitated in the mixture. The mixture was stirred at 30 to 40°C for 17 hours, and then concentrated until the liquid volume was 742 L. Water (520 kg) was added to the mixture, and the mixture was stirred at 20 to 30°C for 0.5 hours, then at 2 to 8°C for 15 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with water (390 kg) and dried at 40°C, yielding 95.94 kg of pyridine compound (Ia) (yield 79.2%).

[0044] Example A2-2 Under a nitrogen atmosphere, the pyridine compound (10a) (53.60 kg, 205 mol) obtained in Example (A1-2), methanol (430.4 L), and trimethylsilyl chloride (49.1 kg, 452 mol) were placed in a reaction vessel. The mixture in the reaction vessel was stirred at 40°C for 16 hours to form a reaction solution. After stirring was completed, the reaction solution was cooled to 20 to 30°C to obtain a methanol solution containing the pyridine compound (11a).

[0045] The methanol solution containing the pyridine compound (11a) was added dropwise over 4.5 hours to a mixture of methanol (913.4 L) and 1,8-diazabicyclo[5.4.0]undec-7-ene (140.78 kg, 579 mol) in a reaction vessel heated to an internal temperature of 50 to 60°C under a nitrogen atmosphere, while maintaining the internal temperature at 50 to 60°C, to form a reaction solution. After the dropwise addition, the reaction solution was washed with methanol (107.0 L) to obtain a wash solution, and the reaction solution was stirred for an additional 3 hours. After stirring was completed, the reaction solution was cooled to room temperature. 5 mol / L hydrochloric acid (122.79 kg) was added dropwise to the reaction solution to adjust the pH of the reaction solution to 6.5 to 7.5. Water (139.8 L) was added to the reaction solution, and the reaction solution was stirred for 2 hours at an internal temperature of 45 to 55°C. Next, the insoluble matter in the reaction solution was filtered off, and the insoluble matter was washed with methanol (109.5 L). The washings and filtrate were combined to form a mixture, and the mixture was stirred at 30 to 40°C for 16 hours, then at 20 to 30°C for 1 hour, and then the mixture was concentrated until the liquid volume was 300 L. Water (215.0 L) was added to the mixture, and the mixture was stirred at 20 to 30°C for 17 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with water (160.9 L) and dried at 50°C, yielding 39.13 kg of pyridine compound (Ia) (yield 78.5%).

[0046] Example A2-3 Under a nitrogen atmosphere, the pyridine compound (10a) (36.00 kg, 138 mol) obtained in Example (A1-3), methanol (229.0 kg), and trimethylsilyl chloride (45.07 kg, 415 mol) were placed in a reaction vessel. The mixture in the reaction vessel was stirred at 40 to 50°C for 7 hours to form a reaction solution. After stirring was completed, the reaction solution was cooled to room temperature to obtain a methanol solution containing the pyridine compound (11a).

[0047] The methanol solution containing the pyridine compound (11a) was added dropwise over 4.5 hours to a mixture of methanol (421 kg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (136.1 kg, 894 mol) in a reaction vessel heated to an internal temperature of 50-60°C under a nitrogen atmosphere while maintaining the internal temperature at 50-60°C to form a reaction solution, which was then stirred for an additional 3 hours. After stirring was completed, the reaction solution was cooled to room temperature. 35% concentrated hydrochloric acid (52.2 kg) was added dropwise to adjust the pH of the reaction solution to 6.5-7.5. Water (93.7 kg) was added to the reaction solution, and the reaction solution was stirred for 1 hour at an internal temperature of 45-50°C. Next, insoluble matter in the reaction solution was filtered off. The insoluble matter was washed with methanol (57.2 kg), and the washings and filtrate were combined to form a mixture. The mixture was concentrated under reduced pressure until the liquid volume reached 225 L, and the walls of the reaction vessel were washed with methanol (14.2 kg). The mixture was stirred at room temperature for 0.5 hours and then at -2 to 7°C for 12 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with water (108.0 kg) and dried under reduced pressure at 50°C, yielding 25.74 kg of pyridine compound (Ia) (yield 76.8%).

[0048] Step B: Synthesis of sulfonamide compound (II) (5-fluoro-2-methoxybenzenesulfonamide) (Synthesis example from sulfonic acid compound) Example B-1 Under a nitrogen atmosphere, 1,2-dimethoxyethane (25.5 L) and crystals containing 5-fluoro-2-methoxybenzenesulfonic acid (3) (1.700 kg, containing water equivalent to a dihydrate, 5-fluoro-2-methoxybenzenesulfonic acid (3) content of 82.48% by qNMR measurement, pure amount 1.402 kg, 6.80 mol) were placed in a reaction vessel, and complete dissolution of the crystals in the mixture was confirmed. The mixture was concentrated at an internal temperature of 40°C under reduced pressure of 14 to 20 kPa until the liquid volume was 5 L. 1,2-Dimethoxyethane (20.4 L) was added to the mixture, and then the mixture was concentrated at an internal temperature of 40°C under reduced pressure of 14 to 20 kPa until the liquid volume was 5 L. This operation was repeated two more times. After concentration, the internal temperature of the mixture was cooled to room temperature. N,N-dimethylformamide (279 mL, 3.60 mol) was added thereto, and then oxalyl chloride (1.190 kg, 9.38 mol) was added dropwise over 1 hour at an internal temperature of 30°C or less to form a reaction solution. After the dropwise addition, the reaction vessel was washed with 1,2-dimethoxyethane (0.9 L), and the reaction solution was stirred at 20-30°C for 1 hour. The pressure inside the reaction vessel was reduced to 10 kPa, and the reaction solution was stirred for 3 minutes. Nitrogen was then added to the reaction vessel, and the pressure was returned to normal. This procedure was repeated two more times. The reaction solution was cooled to 0-10°C, and 10 wt% aqueous ammonia (4.906 kg, 28.8 mol) was added dropwise thereto over 5 hours. After the dropwise addition, the reaction solution was stirred at room temperature for 1 hour. 48 wt% aqueous potassium hydroxide solution (2845.6 g) was added to the reaction solution to adjust the pH of the reaction solution to 13 or higher. Water (10.54 L) was added to the reaction solution, and the reaction solution was stirred overnight at room temperature. After stirring was completed, 5 mol / L hydrochloric acid (6293.96 g) was added dropwise to the reaction solution to adjust the pH of the reaction solution to 1.0 to 2.0. The reaction solution was stirred overnight at 10°C or below, and the precipitated solid was collected by filtration. The obtained solid was washed with water (8.5 L) and dried at 40°C, yielding 1320.2 g (yield 94.6%) of sulfonamide compound (II).

[0049] (Synthesis example from sulfonic acid chloride) Example B-2: Tetrahydrofuran (1140.0 L) and 5-fluoro-2-methoxybenzenesulfonyl chloride (4) (190.0 kg, 846 mol) were placed in a reaction vessel. 10 wt% aqueous ammonia (423.65 kg, 2488 mol) was added dropwise to the mixture in the reaction vessel over 1 hour, followed by stirring at 20-30°C for 1 hour to form a reaction solution. A 2 mol / L aqueous potassium hydroxide solution (927.68 kg) and toluene (380 L) were added to the reaction solution, and the reaction solution was stirred for 1 hour. After stirring was completed, the reaction solution was allowed to stand overnight. After standing, the lower layer of the reaction solution in the reaction vessel was removed and stored. Water (570 L), a 2 mol / L aqueous potassium hydroxide solution (206.15 kg), and toluene (380 L) were added to the reaction vessel containing the upper layer of the reaction solution, and the reaction solution was stirred at 20-30°C for at least 15 minutes. After stirring was completed, the reaction solution was allowed to stand for 1.5 hours. After standing, the lower layer of the reaction solution in the reaction vessel was extracted and stored, and the upper layer of the reaction solution was discarded. The two stored lower layers of the reaction solution were placed in a reaction vessel and mixed. 5 mol / L hydrochloric acid (650.76 kg) was added dropwise to the mixed reaction solution to adjust the pH of the reaction solution to 1.0 to 2.0. The reaction solution was stirred for 1 hour or more, and the precipitated solid was collected by filtration. The obtained solid was washed with water (950.0 L) and dried at 40°C to obtain sulfonamide compound (II) (159.06 kg, yield 91.6%).

[0050] Example B-3 Tetrahydrofuran (450.0 L) and 5-fluoro-2-methoxybenzenesulfonyl chloride (4) (75.0 kg, 334 mol) were placed in a reaction vessel. 10 wt % aqueous ammonia (171.1 kg, 960 mol) was added dropwise to the mixture in the reaction vessel over 1.5 hours, and then the mixture was stirred at 20 to 30°C for 1 hour to form a reaction solution. The reaction solution was heated to 40°C, and a 2 mol / L aqueous potassium hydroxide solution (371.3 kg) and toluene (150.1 L) were added thereto, and the reaction solution was stirred for 1 hour. After stirring was completed, the reaction solution was allowed to stand overnight. After standing, the lower layer of the reaction solution in the reaction vessel was removed and stored. Water (225.1 L), a 2 mol / L aqueous potassium hydroxide solution (82.5 kg), and toluene (150.1 L) were added to the reaction vessel containing the upper layer of the reaction solution, and the reaction solution was stirred at 20-30°C for at least 15 minutes. After stirring was completed, the reaction solution was allowed to stand for 1.5 hours. After standing, the lower layer of the reaction solution in the reaction vessel was removed and stored, and the upper layer of the reaction solution was discarded. The two stored lower layers of the reaction solution were placed in a reaction vessel and mixed. 5 mol / L hydrochloric acid (260.0 kg) was added dropwise to the mixed reaction solution, and when half of the hydrochloric acid had been added, the reaction solution was cooled to below 10°C. The remaining hydrochloric acid was then added dropwise to the reaction solution to adjust the pH of the reaction solution to 1.0-2.0. The reaction solution was stirred for at least 1 hour, and the precipitated solid was collected by filtration. The obtained solid was washed with water (375.0 L) and dried at 40° C. to obtain 47.82 kg (yield 88.0%) of sulfonamide compound (II).

[0051] Example B-4 Under a nitrogen atmosphere, acetonitrile (93.0 kg) and 5-fluoro-2-methoxybenzenesulfonyl chloride (4) (59.51 kg, 265 mol) were placed in a reaction vessel. 27.1% aqueous ammonia (41.60 kg, 662 mol) was added dropwise to the mixture in the reaction vessel over 1.5 hours, followed by stirring for 1 hour to form a reaction solution. After stirring was completed, the reaction solution was cooled to 10°C or below. 35% concentrated hydrochloric acid (16.6 kg) was added dropwise thereto over 1 hour, and the pH of the reaction solution was adjusted to 2.0-3.0. Water (327.2 kg) was added to the reaction solution, and the reaction solution was stirred at 20-30°C for 1 hour, then at 0-5°C for 4 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with 13.5% aqueous acetonitrile solution (172.2 kg) cooled to 0 to 5°C and dried at 40°C to obtain 47.82 kg (yield 88.0%) of sulfonamide compound (II).

[0052] Step C1: Synthesis of N-pyridylsulfonamide compound (III) (5-fluoro-2-methoxy-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide)

[0053] Example C1-1 Under a nitrogen atmosphere, a reaction vessel was charged with pyridine compound (Ia) (93.00 kg, 382 mol), sulfonamide compound (II) (157.04 kg, 765 mol) obtained in Example B-1 or B-2, tert-amyl alcohol (558.0 L), 1,8-diazabicyclo[5.4.0]undec-7-ene (215.53 kg, 1416 mol), and pyridine-2-carboxylic acid (37.68 kg, 306 mol). The pressure inside the reaction vessel was reduced to 4 kPa or less, and the mixture was stirred for approximately 10 minutes until bubbling subsided. Nitrogen was then added to the reaction vessel to return to normal pressure. Copper (I) iodide (29.15 kg, 153 mol) was added to the mixture, and the mixture was stirred under reflux for 9 hours to form a reaction solution. The reaction solution was cooled to room temperature, and water (1674 L) was added and stirred. After the stirring was completed, the temperature of the reaction solution was adjusted to 45 to 55°C. A 40 wt% aqueous solution of pyridine-2-carboxylic acid (1674 L) was added thereto to adjust the pH of the reaction solution to 8 or less. N-pyridylsulfonamide compound (III) (93.00 g) was added as seed crystals to the reaction solution, and the reaction solution was stirred at 45 to 55°C for 22 hours. Next, a 40 wt% aqueous solution of pyridine-2-carboxylic acid (164.87 L) was added as a neutralizing agent to the reaction solution, and the pH of the reaction solution was adjusted to 4.0 to 5.5. The reaction solution was stirred at 45 to 55°C for 2 hours, and then stirred at 20 to 30°C for 15 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with water (1210 L) to obtain 239.84 kg of crude wet crystals of N-pyridylsulfonamide compound (III).

[0054] The obtained crude wet crystals of N-pyridylsulfonamide compound (III) (237.42 kg) were added to dimethyl sulfoxide (1,256.0 kg) in a reaction vessel under a nitrogen atmosphere, and the mixture was stirred for 18 hours to form a dimethyl sulfoxide solution containing N-pyridylsulfonamide compound (III). Activated carbon (15.81 kg) was added thereto, and the solution was stirred at 20 to 30°C for 1 hour. After stirring was completed, the activated carbon was removed by filtration. The activated carbon was washed with dimethyl sulfoxide (466.5 L), and the mixture of the washings and filtrate was stirred at 15 to 40°C for 0.5 hours. Next, water (1,581.4 L) was added dropwise to the mixture, and the mixture was stirred for 15 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with a 50% aqueous dimethyl sulfoxide solution (316.8 L) and water (789.4 L) and dried at 50°C to obtain 110.56 kg of N-pyridylsulfonamide compound (III) (pure content 108.82 kg, yield 77.4%). 1 H NMR (500 MHz, DMSO-d6) δ= 10.28 (s, 1H), 8.52 (br t, J = 5.2 Hz, 1H), 8.11-8.08 (m, 2H), 7.51-7.46 (m, 2H), 7.26-7.22 (m, 1H), 4.36 (t, J = 4.3 Hz, 2H), 3.86 (s, 3H), 3.40-3.30 (m, 2H), 13 C NMR (125 MHz, DMSO-d6) δ= 165.4, 157.5, 155.8, 153.9, 152.8, 144.5, 135.3, 129.3, 126.9, 121.8, 116.7, 114.7, 71.8, 56.7, 41.1ppm

[0055] Example C1-2 Under a nitrogen atmosphere, a reaction vessel was charged with pyridine compound (Ia) (30.00 kg, 123 mol), sulfonamide compound (II) (50.66 kg, 247 mol) obtained in Example B-3, tert-amyl alcohol (180 L), 1,8-diazabicyclo[5.4.0]undec-7-ene (69.52 kg, 457 mol), and pyridine-2-carboxylic acid (12.16 kg, 98.8 mol). The pressure inside the reaction vessel was reduced to 3 kPa or less, and the mixture was maintained for approximately 10 minutes until bubbling subsided. Nitrogen was then added to the reaction vessel to return to normal pressure. Copper (I) iodide (9.40 kg, 49.4 mol) was added to the mixture, and the mixture was stirred under reflux for 7 hours to form a reaction solution. The reaction solution was cooled to room temperature, water (420.1 L) was added, and the reaction solution was stirred. After stirring was completed, the temperature of the reaction solution was adjusted to 20 to 30°C. A 40 wt% aqueous solution of pyridine-2-carboxylic acid (95.3 L) was added thereto as a neutralizing agent to adjust the pH of the reaction solution to 4.0 to 5.5. The reaction solution was stirred at 20 to 30°C for 22 hours, and the precipitated solid was collected by filtration. The collected solid was washed with water (300.4 L) to obtain 78.80 kg (53.7 kg in terms of dry mass) of crude wet crystals of N-pyridylsulfonamide compound (III).

[0056] The obtained crude wet crystals of N-pyridylsulfonamide compound (III) (73.14 kg, dry mass: 50.00 kg) were added to a mixture of dimethyl sulfoxide (375.5 L) and activated carbon (5.00 kg) in a reaction vessel under a nitrogen atmosphere, and the mixture was stirred at 20 to 30°C for 1 hour. After stirring was completed, the activated carbon was removed by filtration. The activated carbon was washed with dimethyl sulfoxide (150.3 L), and a mixture of the washings and filtrate was stirred at 20 to 30°C for 1 hour. The temperature of the mixture was then adjusted to 15 to 40°C, and water (500.0 L) was added dropwise thereto. The mixture was stirred for 12 hours or more, and the precipitated solid was collected by filtration. The obtained solid was washed with 50% aqueous dimethyl sulfoxide solution (99.9 L) and water (250.2 L) and dried at 50°C to obtain 32.37 kg (yield 76.7%) of N-pyridylsulfonamide compound (III).

[0057] Example C1-3 Pyridine compound (Ia) (25.20 kg, 104 mol), sulfonamide compound (II) (40.50 kg, 197 mol) obtained in Example B-4, tripotassium phosphate (61.13 kg, 288 mol), and N,N-dimethylglycine (9.55 kg, 92.6 mol) were added to dimethyl sulfoxide (277.8 kg) in a reaction vessel heated to 45 to 55°C under a nitrogen atmosphere. The pressure in the reaction vessel was reduced to 2 kPa or less, and the mixture was maintained for 2 to 5 minutes. Nitrogen was then added to the reaction vessel to return to atmospheric pressure. This operation was repeated four more times. Copper (I) iodide (8.82 kg, 46.3 mol) was added to the mixture. The pressure in the reaction vessel was again reduced to 2 kPa or less, and the mixture was maintained for 2 to 5 minutes. Nitrogen was then added to the reaction vessel to return to atmospheric pressure. This operation was repeated four more times. The mixture in the reaction vessel was heated at 100-120°C for 4.5 hours to form a reaction solution. The reaction solution was cooled to room temperature, and water (252.1 kg) was added and the reaction solution was stirred. After stirring was completed, the reaction solution was allowed to stand, and then the lower layer of the reaction solution in the reaction vessel was removed and discarded. Water (252.3 kg) was added to the upper layer of the reaction solution, and the reaction solution was stirred. After stirring was completed, the reaction solution was allowed to stand, and then the lower layer of the reaction solution in the reaction vessel was removed and discarded. The pressure in the reaction vessel was reduced to 2 kPa or less, and the upper layer of the reaction solution was maintained for 2-5 minutes. Air was then added to the reaction vessel to return to normal pressure. This procedure was repeated four more times. While aerating the reaction solution, stirring was performed for 16 hours under an air atmosphere at 20-35°C. After stirring was completed, 35% concentrated hydrochloric acid (18.3 kg) was added to the reaction solution as a neutralizing agent over a period of 2 hours or more, and the pH of the reaction solution was adjusted to 3.8-4.3. The reaction mixture was stirred for 3 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with a cooled 35.5% aqueous dimethyl sulfoxide solution (78.3 kg) and water (126.8 kg), and dried at 50°C to obtain 49.34 kg of crude N-pyridylsulfonamide compound (III) (pure amount 29.80 kg, yield 78.0%).

[0058] The resulting crude N-pyridylsulfonamide compound (III) (48.80 kg, pure amount 29.47 kg, 80.2 mol), activated carbon (4.88 kg), and dimethyl sulfoxide (9.77 kg) were added to dimethyl sulfoxide (233.99 kg) in a reaction vessel under a nitrogen atmosphere, and the mixture was stirred at 20 to 30°C for 1.5 hours. After stirring was completed, the activated carbon was removed by filtration. The activated carbon was washed with dimethyl sulfoxide (107.0 kg), and the washings and filtrate were combined to form a mixture. Ethylenediamine (14.55 kg, 242 mol) was added thereto, and the mixture was stirred for 10 minutes. Water (293.0 kg) was then added, and the mixture was stirred for 15 minutes. After stirring was completed, 35% concentrated hydrochloric acid (50.2 kg) was added to the mixture, and the pH of the mixture was adjusted to 3.8 to 4.3. The mixture was stirred for 2.5 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with a cooled 35.5% aqueous dimethyl sulfoxide solution (101.0 kg) and water (146.0 kg), and dried at 50°C to obtain 26.39 kg of N-pyridylsulfonamide compound (III) (pure amount 25.70 kg, yield 87.2%).

[0059] Measurement of Residual Copper in Crude N-Pyridylsulfonamide Compound (III) In Examples C1-1, C1-2, and C1-3, the amount of residual copper in the crude N-pyridylsulfonamide compound (III) obtained by coupling reaction and subsequent neutralization was measured using an atomic absorption spectrophotometer. The protocol for measuring the amount of residual copper using an atomic absorption spectrophotometer was as follows: 1. A copper standard solution of atomic absorption spectrometry grade was diluted to prepare a standard solution. 2. Approximately 30 mg of crude N-pyridylsulfonamide compound (III) was dissolved in diluted nitric acid to prepare a sample solution. 3. The parameters of the atomic absorption spectrophotometer were set as follows, and measurements of the standard solution and sample solution were started. Lamp current: 4.5 mA Measurement wavelength: 324.8 nm Slit: 0.5 nm Cuvette: graphite cuvette Sample injection volume: 20 μL Background correction: Zeeman correction Signal calculation: peak height Heating control method: optical temperature control Number of repeated measurements: 3 Number of water washes: 3 Heating program: as shown in Table 1 4. Analyze the results.

[0060] Table 2 shows the amount of residual copper in the crude N-pyridylsulfonamide compound (III) in each example. It was confirmed that the amount of residual copper in the crude N-pyridylsulfonamide compound (III) can be further reduced by using a carboxylic acid compound as a neutralizing agent.

[0061] Step C2: Synthesis of sodium salt of N-pyridylsulfonamide compound (IIIa) (sodium = (5-fluoro-2-methoxyphenylsulfonyl)(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)azanide)

[0062] Example C2-1 Under a nitrogen atmosphere, the N-pyridylsulfonamide compound (III) (108.56 kg, pure content 106.86 kg, 291 mol) obtained in Example (C1-1), purified water (261 L), and 1-propanol (271 L) were placed in a reaction vessel. A 25 wt % aqueous sodium hydroxide solution (45.95 kg, 287 mol) and water (109 L) were added to the mixture in the reaction solution, and the mixture was stirred at 20 to 30°C to form a solution in which the entire amount of the N-pyridylsulfonamide compound and sodium hydroxide was dissolved in a mixed solvent of water and 1-propanol. Insoluble matter in the solution was filtered off, and the resulting filtrate was cooled to 0 to 5°C. Acetone (102.1 L) and seed crystals (1086 g) of the sodium salt of the N-pyridylsulfonamide compound (IIIa) were added to the solution, and the solution was stirred for 2 hours. Acetone (868.0 L) was added dropwise to the solution over 3 hours, and the solution was stirred for 12 hours. Next, 1-propanol (2497 L) was added dropwise over 5 hours, and the solution was stirred for an additional 19 hours, and the precipitated crystals were collected by filtration. The obtained crystals were washed with acetone (327 L) cooled to around 0°C and dried at 40°C, yielding 97.70 kg (yield 84.9%) of the sodium salt of N-pyridylsulfonamide compound (IIIa). 1H NMR (500 MHz, DMSO-d6) δ= 7.70 (d, J= 2.9 Hz, 1H), 7.60 (d, J= 2.9 Hz, 1H), 7.34 (dd, J= 8.3, 3.2 Hz, 1H), 7.10-7.06 (m, 1H), 6.92 (dd, J= 9.2, 4.0 Hz, 1H), 4.30 (t, J= 4.6 Hz, 2H), 3.59 (s, 3H), 3.33 (t, J= 4.6 Hz, 2H), 13 C NMR (125 MHz, DMSO-d6) δ= 170.7, 156.9, 154.5, 153.2, 146.3, 140.8, 134.9, 131.5, 120.0, 118.0, 116.7, 114.4, 73.7, 56.6, 41.3ppm

[0063] Example C2-2 Under a nitrogen atmosphere, a reaction vessel was charged with the N-pyridylsulfonamide compound (III) (29.00 kg, 78.9 mol) obtained in Example (C1-2), purified water (69.5 kg), and 1-propanol (72.4 L). Then, a 25 wt % aqueous sodium hydroxide solution (12.13 kg, 75.8 mol) and water (29.0 L) were added to the mixture, and the mixture was stirred at 20 to 30°C to form a solution in which the entire amount of N-pyridylsulfonamide compound (III) and sodium hydroxide was dissolved in a mixed solvent of water and 1-propanol. Insoluble matter in the solution was filtered off, and the resulting filtrate was cooled to 0 to 5°C. Acetone (29.8 L) and seed crystals (0.200 kg) of the sodium salt of the N-pyridylsulfonamide compound (IIIa) were added to the solution, and the solution was stirred for 2 hours. Acetone (232.6 L) was added dropwise to the solution over 3 hours, and the solution was stirred for 17 hours. Next, 1-propanol (666.9 L) was added dropwise over 4 hours, and the solution was stirred for an additional 22 hours, and the precipitated crystals were collected by filtration. The collected crystals were washed with acetone (87.7 L) cooled to around 0°C and dried at 40°C to obtain the sodium salt of N-pyridylsulfonamide compound (IIIa) (24.64 kg, yield 80.2%).

[0064] Example C2-3 Under a nitrogen atmosphere, N-pyridylsulfonamide compound (III) (25.70 kg, equivalent to a pure content of 25.02 kg, 68.1 mol) obtained in Example (C1-3) and purified water (180.2 kg) were placed in a reaction vessel. Next, 24 wt % aqueous sodium hydroxide solution (11.46 kg) was added to the mixture, and the pH of the solution was adjusted to 10.5 to 11.4, thereby forming a solution in which all of N-pyridylsulfonamide compound (III) and sodium hydroxide were dissolved in water. The solution was stirred at 20 to 30°C for 1 hour. Next, insoluble matter in the solution was filtered off, and the insoluble matter was washed with purified water (25.7 kg). The washing liquid and the filtrate were combined to form a mixture, which was then concentrated under reduced pressure at 25 to 35°C until the volume reached 50 L. After concentration, the mixture was stirred at 20 to 30°C for 13 hours. Next, acetone (20.5 kg) was added to the mixed solution, and the mixed solution was further stirred for 2 hours. The amount of water in the mixed solution was measured, and the shortage of water was added so that the amount of water became 44.5 L. Next, the mixed solution was heated to 35 to 45°C. Acetone (447.1 kg) was added dropwise thereto over 1 hour, and the mixed solution was stirred for 1 hour. The mixed solution was cooled to 20 to 30°C, stirred for 2 hours, and the precipitated crystals were collected by filtration. The obtained crystals were washed with 93.7% aqueous acetone solution (61.8 kg) and dried at 40°C, thereby obtaining 24.27 kg (yield 91.5%) of the sodium salt of N-pyridylsulfonamide compound (IIIa).

[0065] Powder X-ray diffraction pattern of sodium salt (IIIa) of N-pyridylsulfonamide compound (sodium = (5-fluoro-2-methoxyphenylsulfonyl)(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)azanide) The crystals of sodium salt (IIIa) of N-pyridylsulfonamide compound obtained in Example C2-2 were analyzed by powder X-ray diffraction. Figure 1 shows the powder X-ray diffraction pattern of the crystals of sodium salt (IIIa) of N-pyridylsulfonamide compound. Table 3 shows the diffraction angle (2θ), lattice plane spacing (d value), and relative intensity in the powder X-ray diffraction pattern.

[0066] The protocol for measuring the powder X-ray diffraction spectrum of the sodium salt (IIIa) of the N-pyridylsulfonamide compound was as follows: 1. Place 10 to 20 mg of crystals of the sodium salt (IIIa) of the N-pyridylsulfonamide compound on a rotating sample plate. 2. Set the parameters of the X-ray diffractometer as follows and start the measurement: Optical system: Parallel beam method Background measurement: None Scan axis: 2θ / θ Mode: Continuous Count unit: cps Scan start: 3.0 deg Scan end: 40.0 deg Scan step: 0.010 deg Scan speed: 2.0 deg / min Tube voltage: 40 kV Tube current: 40 mA Rotation: Yes X-ray source: Cu 3. Analyze the results.

[0067]

Claims

1. A compound represented by the following formula (I): and X represents a halogen atom, a benzenesulfonyloxy group, a toluenesulfonyloxy group, a nitrobenzenesulfonyloxy group, a methanesulfonyloxy group, an ethanesulfonyloxy group, or a trifluoromethanesulfonyloxy group; By a coupling reaction with a sulfonamide compound represented by the following formula (III): The method for producing an N-pyridylsulfonamide compound includes synthesizing an N-pyridylsulfonamide compound represented by the formula:

2. The method according to claim 1, wherein the N-pyridylsulfonamide compound is produced by the coupling reaction in a reaction solution containing copper(I) iodide and a carboxylic acid compound selected from pyridine-2-carboxylic acid and an N,N-dialkylamino acid.

3. The method of claim 2, wherein the carboxylic acid compound is pyridine-2-carboxylic acid.

4. The method according to claim 2, further comprising: adding an additional amount of the carboxylic acid compound to the reaction solution containing the N-pyridylsulfonamide compound; and then precipitating crystals containing the N-pyridylsulfonamide compound from the reaction solution.

5. The following formula (11): The method according to claim 1, further comprising synthesizing a pyridine compound represented by formula (I) by an amidation reaction of a pyridine compound represented by formula (11):

6. The method of claim 5, wherein R is an alkyl group having 1 to 3 carbon atoms.

7. The method of claim 5, wherein R is a methyl group.

8. The following formula (10): The method according to claim 5, further comprising synthesizing a pyridine compound represented by formula (11) from a pyridine compound represented by formula (10):

9. The N-pyridylsulfonamide compound is converted into the following formula (IIIa):

2. The method of claim 1, further comprising synthesizing a sodium salt of 10. The method according to claim 9, wherein synthesizing the sodium salt comprises: forming a solution containing the N-pyridylsulfonamide compound, sodium hydroxide, and water, wherein the N-pyridylsulfonamide compound and the sodium hydroxide are all dissolved in the water; and adding a poor solvent for the sodium salt to the solution to precipitate crystals containing the sodium salt.

11. The method of claim 10, wherein the solution further comprises 1-propanol, and wherein the entire amount of the N-pyridylsulfonamide compound and the sodium hydroxide are dissolved in a mixed solvent comprising water and 1-propanol, to form the solution.

12. The method of claim 10, wherein the anti-solvent comprises acetone, 1-propanol, or both.

13. The method according to any one of claims 1 to 12, wherein X is a bromine atom.

14. The following formula (10): wherein X represents a halogen atom, a benzenesulfonyloxy group, a toluenesulfonyloxy group, a nitrobenzenesulfonyloxy group, a methanesulfonyloxy group, an ethanesulfonyloxy group, or a trifluoromethanesulfonyloxy group.

15. The pyridine compound according to claim 14, wherein X is a bromine atom.

16. The following formula (11): wherein X represents a halogen atom, a benzenesulfonyloxy group, a toluenesulfonyloxy group, a nitrobenzenesulfonyloxy group, a methanesulfonyloxy group, an ethanesulfonyloxy group, or a trifluoromethanesulfonyloxy group, and R represents an alkyl group having 1 to 6 carbon atoms.

17. The pyridine compound according to claim 16, wherein X is a bromine atom.

18. The pyridine compound according to claim 16 or 17, wherein R is a methyl group.

19. Sodium (5-fluoro-2-methoxyphenylsulfonyl) (5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl) azanide, copper K α A powder X-ray diffraction pattern obtained by irradiation with x-rays shows peaks at diffraction angles 2θ of 8.1°±0.2°, 11.7°±0.2°, 12.1°±0.2°, 12.4°±0.2°, 12.8°±0.2°, 19.0°±0.2°, 20.0°±0.2°, 24.2°±0.2°, and 25.8°±0.2°.

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