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WO2025070390A1 - Procédé de production d'un composé de n-pyridylsulfonamide, d'un composé de pyridine et d'un cristal de composé de n-pyridylsulfonamide - Google Patents

Procédé de production d'un composé de n-pyridylsulfonamide, d'un composé de pyridine et d'un cristal de composé de n-pyridylsulfonamide Download PDF

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Publication number
WO2025070390A1
WO2025070390A1 PCT/JP2024/033932 JP2024033932W WO2025070390A1 WO 2025070390 A1 WO2025070390 A1 WO 2025070390A1 JP 2024033932 W JP2024033932 W JP 2024033932W WO 2025070390 A1 WO2025070390 A1 WO 2025070390A1
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compound
group
pyridylsulfonamide
reaction
solution
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Japanese (ja)
Inventor
祐一 安藝
貴久 内田
稔 萩澤
泰夫 木谷
義史 梅原
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present disclosure relates to a method for producing an N-pyridylsulfonamide compound, a pyridine compound, and a crystal of the N-pyridylsulfonamide compound.
  • Patent Document 1 discloses a method for producing N-pyridylsulfonamide compound (III) represented by the following formula:
  • This disclosure relates to a novel method for stably producing N-pyridylsulfonamide compound (III) and its sodium salt with reduced by-products.
  • the present disclosure includes the following.
  • the method includes synthesizing an N-pyridylsulfonamide compound represented by the formula: A method for producing an N-pyridyl sulfonamide compound.
  • the N-pyridylsulfonamide compound is converted into the following formula (IIIa):
  • the synthesis of the sodium salt comprises: forming a solution comprising the N-pyridylsulfonamide compound, sodium hydroxide, and water, wherein the entire amount of the N-pyridylsulfonamide compound and the sodium hydroxide are dissolved in the water; adding a poor solvent for the sodium salt to the solution to precipitate crystals containing the sodium salt;
  • the present disclosure provides a novel method for stably producing N-pyridylsulfonamide compound (III) and its sodium salt with reduced by-products.
  • the method disclosed herein is also advantageous in that, when a catalyst is used, the catalyst can be easily removed.
  • the present invention is not limited to the following examples.
  • the compound represented by formula (1) may be referred to as "compound (1)”.
  • the materials exemplified in this specification may be used alone or in combination of two or more.
  • the upper or lower limit of a certain numerical range may be replaced by the upper or lower limit of the numerical range of another stage.
  • the upper or lower limit of the numerical range may be replaced by the values shown in the examples.
  • 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.
  • 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: A step A2b of synthesizing a pyridine compound (I) by an amidation reaction of a pyridine compound (11) represented by the following formula: Step B is for synthesizing a sulfonamide compound (II) from a sulfonic acid chloride (4) represented by the following formula: and a step C1 of synthesizing an N-pyridylsulfonamide compound (III) by a coupling reaction between a pyridine compound (I) represented by the following formula and a sulfonamide compound (II).
  • the sodium salt can be produced by the step C2 of synthesizing the sodium salt (IIIa) from the N-pyridylsulfonamide compound (III) represented by the following formula.
  • Step A1 The reaction of 2-aminoethanol (1) with pyridine compound (2) produces pyridine compound (10).
  • X is a halogen atom, a benzenesulfonyloxy group, a toluenesulfonyloxy group, a nitrobenzenesulfonyloxy group, a methanesulfonyloxy group, an ethanesulfonyloxy group, or a trifluoromethanesulfonyloxy group.
  • the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • X may be a bromine atom.
  • the amount of 2-aminoethanol (1) may be, for example, 1.0 mole or more and 2.0 moles or less per mole of pyridine compound (2).
  • 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).
  • the reaction between 2-aminoethanol (1) and pyridine compound (2) may be carried out in a reaction liquid containing these compounds, a base, and a solvent.
  • the solvent may be, for example, an ether such as tetrahydrofuran.
  • the reaction temperature between 2-aminoethanol (1) and pyridine compound (2) may be, for example, 30°C or higher and 80°C or lower.
  • the pyridine compound (10) thus produced can be isolated and purified by combining common methods such as neutralization, extraction, filtration, concentration, crystallization, recrystallization, and washing.
  • the pyridine compound (10) may be used as is for the synthesis of the pyridine compound (11) without isolation or purification.
  • Step A2a The pyridine compound (10) is esterified to produce a pyridine compound (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.
  • the method for esterifying the pyridine compound (10) may be a normal method for producing an alkyl ester from a carboxylic acid.
  • a method of reacting the pyridine compound (10) with an alkyl alcohol in the presence of trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate can be adopted.
  • the amount of trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate may be, for example, 1.2 moles or more and 4.0 moles or less per mole of the pyridine compound (10).
  • the pyridine compound (10) may 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 the pyridine compound (10) may be, for example, 30°C or more and 80°C or less.
  • the pyridine compound (11) thus produced may be isolated and purified by a combination of common methods such as neutralization, extraction, filtration, concentration, crystallization, recrystallization, and washing.
  • the pyridine compound (11) is obtained as a solution, the solution may be used as is for the synthesis of the pyridine compound (I) without isolation or purification.
  • Step A2b The pyridine compound (I) is produced by an amidation reaction accompanied by intramolecular cyclization of the pyridine compound (11). This reaction can proceed while suppressing the by-production of a dimer due to an intermolecular reaction.
  • the amidation reaction of the 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 the pyridine compound (10).
  • the solvent may be, for example, an alcohol such as methanol.
  • the reaction temperature for the amidation reaction of the pyridine compound (11) may be, for example, 30°C to 80°C.
  • 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.
  • Process B Amidation of sulfonyl 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, sulfonyl chloride (4) may be formed from sulfonic acid compound (3), and then the sulfonamide compound (II) may be produced by reacting sulfonyl chloride (4) with ammonia.
  • the sulfonic acid chloride (4) is produced, for example, by the reaction of the 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 mol of the sulfonic acid compound (3).
  • the amount of N,N-dimethylformamide may be, for example, 0.3 mol to 1.0 mol per mol of the sulfonic acid compound (3).
  • the reaction solution may contain a solvent, examples of which include ethers such as 1,2-dimethoxyethane. After the sulfonic acid compound (3) is completely dissolved in the solvent, the reaction solution may be concentrated.
  • the reaction temperature for producing the 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 the sulfonamide compound (II) without isolation or purification.
  • the isolated sulfonic acid chloride (4) may be prepared and used for the synthesis of the sulfonamide compound (II).
  • the sulfonic acid chloride (4) can be amidated to produce sulfonamide compound (II).
  • the amount of ammonia may be, for example, 1.5 moles or more and 5.0 moles or less per mole 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.
  • the resulting sulfonamide compound (II) can be isolated and purified by combining common methods such as neutralization, extraction, filtration, concentration, crystallization, recrystallization, and washing.
  • Step C1 The coupling reaction between pyridine compound (I) and sulfonamide compound (II) produces N-pyridylsulfonamide compound (III).
  • This reaction makes it possible to synthesize N-pyridylsulfonamide compound (III) without the need to protect the nitrogen atom constituting the seven-membered ring of N-pyridylsulfonamide compound (III) with a protecting group. Therefore, the use of a strong acid for deprotection can also be avoided.
  • the amount of 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, per mole of pyridine compound (I).
  • 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 N,N-dialkylamino acid.
  • the amount of the metal catalyst may be, for example, 0.2 mol to 0.6 mol, or 0.3 mol to 0.5 mol, relative to 1 mol of the pyridine compound (I).
  • the amount of the ligand may be, for example, 0.4 mol to 1.2 mol, or 0.6 mol 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 mol to 4.5 mol, or 3.0 mol 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 of the coupling reaction may be, for example, from 60°C to 130°C, or from 80°C to 120°C.
  • the produced N-pyridylsulfonamide compound (III) can be isolated and purified by combining common methods such as neutralization, extraction, filtration, concentration, crystallization, recrystallization, and washing.
  • the reaction solution containing the produced N-pyridylsulfonamide compound (III) contains a carboxylic acid compound selected from pyridine-2-carboxylic acid and N,N-dialkylamino acid
  • an additional carboxylic acid compound may be further added to the reaction solution, and then crystals containing N-pyridylsulfonamide compound (III) may be precipitated from the reaction solution.
  • 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.
  • Step C2 The sodium salt (IIIa) of the N-pyridylsulfonamide compound (III) is produced by reacting the N-pyridylsulfonamide compound (III) with sodium hydroxide in a solution containing water.
  • the amount of sodium hydroxide may be, for example, 1.0 mole or more and 1.1 mole or less per mole of the N-pyridylsulfonamide compound (III).
  • the solvent of the solution for producing the sodium salt (IIIa) may be a mixed solvent containing water and 1-propanol. In that 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.
  • 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.
  • the step C2 of synthesizing the sodium salt (IIIa) may include forming a solution containing the N-pyridylsulfonamide compound (III), sodium hydroxide, and water, in which the N-pyridylsulfonamide compound (III) and the sodium hydroxide are all dissolved in water, and precipitating crystals containing the sodium salt (IIIa) by adding a poor solvent for the sodium salt (IIIa) to the solution.
  • 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 precipitating the crystals.
  • the crystals containing sodium salt (IIIa) may show peaks at diffraction angles 2 ⁇ 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° in a powder X-ray diffraction pattern obtained by irradiating with copper K ⁇ rays.
  • the X-ray diffraction pattern of the crystals 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 Revised Japanese Pharmacopoeia.
  • the scope of the present invention is not limited to the following examples.
  • the ⁇ values (ppm) described for the nuclear magnetic resonance ( 1 H NMR or 13 C NMR) spectra of the synthesized compounds 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, MS was performed by ESI (Electron Spray Ionization) method. In each step of the examples, the preparation of the reaction solution and the reaction were carried out at room temperature (1 to 30° C.) unless otherwise specified regarding the temperature.
  • Step A1 Synthesis of pyridine compound (10a) (2-(2-aminoethoxy)-5-bromopyridine-3-carboxylic acid)
  • 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. Then, the 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 washing liquid 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 another reaction vessel, and the mixture in the reaction vessel was stirred at 15 to 35° C. for 3 hours to form a reaction liquid.
  • a tetrahydrofuran solution containing 5-bromo-2-chloropyridine-3-carboxylic acid was added dropwise to the reaction solution over 2 hours. After the addition, the reaction solution was stirred at 50 to 60°C for 2 hours. After the stirring was completed, the reaction solution was cooled to 20°C or lower.
  • 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. Then, 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 another reaction vessel, and the mixture in the reaction vessel was stirred at 15 to 35° C. for 3 hours to form a reaction solution.
  • a tetrahydrofuran solution containing 5-bromo-2-chloropyridine-3-carboxylic acid was added dropwise to the reaction solution over 2 hours. After the addition, the reaction solution was stirred at 50 to 60° C. for 2 hours. After the stirring was completed, the reaction solution was cooled to 10° C. or lower.
  • 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 the 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.
  • Steps A2a and A2b Synthesis of pyridine compound (Ia) (7-bromo-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one)
  • Example A2-1 In a nitrogen atmosphere, the pyridine compound (10a) (130.00 kg, 498 mol) obtained in Example (A1-1), methanol (1040 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).
  • a 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 liquid.
  • the reaction liquid was added with a wash obtained by washing the inside of the reaction vessel from which the reaction liquid was transferred with methanol (260 L), and the reaction liquid was stirred for another 3 hours. After stirring was completed, the reaction liquid was cooled to room temperature.
  • Example A2-2 In 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 the stirring was completed, the reaction solution was cooled to 20 to 30° C. to obtain a methanol solution containing the pyridine compound (11a).
  • a methanol solution containing 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 50-60°C under a nitrogen atmosphere while maintaining the internal temperature at 50-60°C to form a reaction liquid.
  • the reaction liquid was added with a wash obtained by washing the inside of the reaction vessel from which the reaction liquid was transferred with methanol (107.0 L), and the reaction liquid was stirred for another 3 hours. After stirring, the reaction liquid was cooled to room temperature.
  • Example A2-3 In 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 the stirring was completed, the reaction solution was cooled to room temperature to obtain a methanol solution containing the pyridine compound (11a).
  • a methanol solution containing the pyridine compound (11a) was added dropwise 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 over 4.5 hours while maintaining the internal temperature at 50-60°C to form a reaction liquid, which was then stirred for another 3 hours. After stirring was completed, the reaction liquid was cooled to room temperature. 35% concentrated hydrochloric acid (52.2 kg) was added dropwise thereto to adjust the pH of the reaction liquid to 6.5-7.5.
  • 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 dihydrate, 5-fluoro-2-methoxybenzenesulfonic acid (3) content 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.
  • reaction solution was stirred at 20 to 30°C for 1 hour.
  • the reaction vessel was depressurized to 10 kPa, and the reaction solution was stirred for 3 minutes. Next, nitrogen was added to the reaction vessel to return to normal pressure. This operation was repeated two more times.
  • the reaction solution was cooled to 0 to 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.
  • a 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 more.
  • Water (10.54 L) was added to the reaction solution, and the reaction solution was stirred at room temperature overnight.
  • 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 less, and the precipitated solid was collected by filtration.
  • the obtained solid was washed with water (8.5 L) and dried at 40° C. to obtain 1320.2 g (yield 94.6%) of sulfonamide compound (II).
  • 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, and then the mixture was stirred 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, the reaction solution was left to stand overnight.
  • 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 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, the reaction solution was left to stand overnight.
  • Example B-4 Acetonitrile (93.0 kg) and 5-fluoro-2-methoxybenzenesulfonyl chloride (4) (59.51 kg, 265 mol) were placed in a reaction vessel under a nitrogen atmosphere. 27.1% aqueous ammonia (41.60 kg, 662 mol) was added dropwise to the mixture in the reaction vessel over 1.5 hours, and then the mixture was stirred for 1 hour to form a reaction solution. After stirring was completed, the reaction solution was cooled to 10°C or less. 35% concentrated hydrochloric acid (16.6 kg) was added dropwise thereto over 1 hour to adjust the pH of the reaction solution to 2.0-3.0.
  • 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)
  • Example C1-1 In a nitrogen atmosphere, 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) were placed in a reaction vessel. The pressure in the reaction vessel was reduced to 4 kPa or less, and the mixture was stirred for about 10 minutes until foaming subsided. Nitrogen was then added to the reaction vessel to return to normal pressure.
  • the obtained crude wet crystals of N-pyridylsulfonamide compound (III) (237.42 kg) were added to dimethylsulfoxide (1256.0 kg) in a reaction vessel under a nitrogen atmosphere, and the mixture was stirred for 18 hours to form a dimethylsulfoxide 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 the stirring was completed, the activated carbon was removed by filtration. The activated carbon was washed with dimethylsulfoxide (466.5 L), and the mixture of the washing liquid and the filtrate was stirred at 15 to 40°C for 0.5 hours.
  • Example C1-2 In a nitrogen atmosphere, 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) were placed in a reaction vessel. The pressure in the reaction vessel was reduced to 3 kPa or less, and the mixture was held for about 10 minutes until foaming subsided. Nitrogen was then added to the reaction vessel to return to normal pressure.
  • 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 45-55° C. under a nitrogen atmosphere. The pressure in the reaction vessel was reduced to 2 kPa or less, and the mixture was held for 2-5 minutes. Nitrogen was then added to the reaction vessel to return to normal pressure. This operation was repeated four more times.
  • reaction liquid was allowed to stand, and then the lower layer of the reaction liquid in the reaction vessel was extracted and discarded.
  • the pressure in the reaction vessel was reduced to 2 kPa or less, and the upper layer of the reaction liquid was held for 2-5 minutes. Air was then added to the reaction vessel to return to normal pressure. This operation was repeated four more times.
  • the reaction liquid was stirred for 16 hours at 20-35°C under an air atmosphere while aerating the reaction liquid.
  • 35% concentrated hydrochloric acid (18.3 kg) was added to the reaction liquid as a neutralizing agent over a period of 2 hours or more, and the pH of the reaction liquid was adjusted to 3.8-4.3.
  • the reaction solution was stirred for 3 hours, and the precipitated solid was collected by filtration.
  • Lamp current 4.5mA Measurement wavelength: 324.8nm Slit: 0.5 nm Cuvette: Graphite cuvette Sample injection volume: 20 ⁇ L 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.
  • 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 could be further reduced by using a carboxylic acid compound as a neutralizing agent.
  • 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.
  • Example C2-2 Under a nitrogen atmosphere, 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) were placed in a reaction vessel. Then, 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 the N-pyridylsulfonamide compound (III) and sodium hydroxide was dissolved in a mixed solvent of water and 1-propanol.
  • Example C2-3 Under a nitrogen atmosphere, the 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. Then, a 24 wt % aqueous sodium hydroxide solution (11.46 kg) was added to the mixture to adjust the pH of the solution to 10.5 to 11.4, thereby forming a solution in which the entire amount of the N-pyridylsulfonamide compound (III) and sodium hydroxide was dissolved in water. The solution was stirred at 20 to 30° C. for 1 hour.
  • the 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 mixed liquid, and the mixed liquid was concentrated under reduced pressure at 25 to 35° C. until the liquid volume reached 50 L. After completion of the concentration, the mixed liquid was stirred at 20 to 30° C. for 13 hours.
  • acetone (20.5 kg) was added to the mixed liquid, and the mixed liquid was further stirred for 2 hours. The amount of water in the mixture was measured, and the shortage of water was added so that the amount of water became 44.5 L.
  • the mixture was then heated to 35-45°C.
  • Acetone (447.1 kg) was added dropwise thereto over 1 hour, and the mixture was stirred for 1 hour.
  • 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 (2 ⁇ ), lattice spacing (d value), and relative intensity in the powder X-ray diffraction pattern.
  • the protocol for powder X-ray diffraction spectrum measurement of the sodium salt of N-pyridylsulfonamide compound (IIIa) was as follows. 1. 10 to 20 mg of crystals of the sodium salt of the N-pyridylsulfonamide compound (IIIa) is placed on a rotating sample plate. 2. Set the parameters of the X-ray diffraction device as follows and start the measurement.
  • Optical system Parallel beam method Background measurement: None Scan axis: 2 ⁇ / ⁇ Mode: Continuous Counting 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: 40mA Rotation: Yes X-ray source: Cu 3. Analyze the results.

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Abstract

L'invention concerne un procédé de production qui consiste à synthétiser un composé de N-pyridylsulfonamide (III) au moyen d'une réaction de couplage entre un composé de pyridine (I) et un composé de sulfonamide (II).
PCT/JP2024/033932 2023-09-25 2024-09-24 Procédé de production d'un composé de n-pyridylsulfonamide, d'un composé de pyridine et d'un cristal de composé de n-pyridylsulfonamide Pending WO2025070390A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6178789A (ja) * 1984-09-19 1986-04-22 エイ・エツチ・ロビンス・カンパニー・インコーポレーテツド 芳香族１，４‐オキサゼピノンおよび‐チオンの製法
WO2010038081A2 (fr) * 2008-10-03 2010-04-08 Astrazeneca Ab Dérivés hétérocycliques et procédés d’utilisation associés
WO2011151652A1 (fr) * 2010-06-03 2011-12-08 Arrow Therapeutics Limited Composés de benzodiazépine utiles pour le traitement de l'hépatite c
JP2018522814A (ja) * 2015-07-08 2018-08-16 第一三共株式会社 ピリジン化合物
JP2021514401A (ja) * 2018-03-09 2021-06-10 南京薬石科技股▲フン▼有限公司Ｐｈａｒｍａｂｌｏｃｋ Ｓｃｉｅｎｃｅｓ （Ｎａｎｊｉｎ）， Ｉｎｃ． タンパク質アルギニンメチルトランスフェラーゼ５（ｐｒｍｔ５）の阻害剤、その医薬品及びその方法
CN114085911A (zh) * 2022-01-19 2022-02-25 珠海圣美生物诊断技术有限公司 一种检测肿瘤细胞或肿瘤细胞碎片的方法
CN114457159A (zh) * 2022-02-24 2022-05-10 珠海圣美生物诊断技术有限公司 一种检测肿瘤细胞或肿瘤细胞碎片的方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6178789A (ja) * 1984-09-19 1986-04-22 エイ・エツチ・ロビンス・カンパニー・インコーポレーテツド 芳香族１，４‐オキサゼピノンおよび‐チオンの製法
WO2010038081A2 (fr) * 2008-10-03 2010-04-08 Astrazeneca Ab Dérivés hétérocycliques et procédés d’utilisation associés
WO2011151652A1 (fr) * 2010-06-03 2011-12-08 Arrow Therapeutics Limited Composés de benzodiazépine utiles pour le traitement de l'hépatite c
JP2018522814A (ja) * 2015-07-08 2018-08-16 第一三共株式会社 ピリジン化合物
JP2021514401A (ja) * 2018-03-09 2021-06-10 南京薬石科技股▲フン▼有限公司Ｐｈａｒｍａｂｌｏｃｋ Ｓｃｉｅｎｃｅｓ （Ｎａｎｊｉｎ）， Ｉｎｃ． タンパク質アルギニンメチルトランスフェラーゼ５（ｐｒｍｔ５）の阻害剤、その医薬品及びその方法
CN114085911A (zh) * 2022-01-19 2022-02-25 珠海圣美生物诊断技术有限公司 一种检测肿瘤细胞或肿瘤细胞碎片的方法
CN114457159A (zh) * 2022-02-24 2022-05-10 珠海圣美生物诊断技术有限公司 一种检测肿瘤细胞或肿瘤细胞碎片的方法

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