US20170253577A1 - Method for producing indole compound - Google Patents

Method for producing indole compound Download PDF

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US20170253577A1
US20170253577A1 US15/323,851 US201515323851A US2017253577A1 US 20170253577 A1 US20170253577 A1 US 20170253577A1 US 201515323851 A US201515323851 A US 201515323851A US 2017253577 A1 US2017253577 A1 US 2017253577A1
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compound
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dimethyl
tetrahydro
indazol
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Teruhiko Inoue
Koji Matsumura
Shinichi Kikuchi
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Japan Tobacco Inc
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Japan Tobacco Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present invention relates to a new method for producing an indole compound or a salt thereof, which is useful as an inducible T cell kinase (ITK) inhibitor, and an intermediate thereof.
  • ITK inducible T cell kinase
  • Patent Document 1 discloses a compound useful as an ITK inhibitor, and a method for producing the same.
  • the present invention aims to provide a new method for producing an indole compound or a salt thereof, which is useful for the prophylaxis or treatment of inflammatory disease, and the like.
  • Embodiments of the present invention are shown in the following (1) to (16).
  • R 1 and R 2 are each independently hydrogen, C 1-6 alkyl or C 1-6 alkoxy, to a reduction reaction to give N-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine (formula [V]
  • R 2 is as defined above, which comprises a step of subjecting a compound of the formula [XII]
  • R 2 is as defined above.
  • an indole compound having an ITK inhibitory action which is useful for the prophylaxis or treatment of inflammatory disease, and the like, can be produced via compound considered to be free from safety concerns, in a few steps and in good yield.
  • a new intermediate for producing the indole compound can also be provided by the method.
  • FIG. 1 shows multi record of powder X-ray diffraction pattern of N-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine.
  • the axis of ordinate shows diffraction strength (cps: counts per second), and the axis of abscissas shows diffraction angle 2 ⁇ °.
  • C 1-6 alkyl means straight chain or branched chain alkyl having 1 to 6 carbon atoms, preferably straight chain or branched chain alkyl having 1 to 4 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, 1-ethylpropyl, neo-pentyl, hexyl, 2-ethylbutyl, 3,3-dimethylbutyl and the like. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferable, and methyl is particularly preferable.
  • C 1-6 alkoxy means alkyl-oxy wherein the alkyl moiety is the above-defined “C 1-6 alkyl”. Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, tert-pentoxy, 1-ethylpropoxy, neopentoxy, hexoxy, 2-ethylbutoxy, 3,3-dimethylbutoxy and the like. Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy are preferable, and methoxy is particularly preferable.
  • Compounds [III], [V], [VI] and [VII] of the present invention have tetrahydropyranyl as a protecting group at the 1-position on the 4,5,6,7-tetrahydro-1H-indazole moiety.
  • the compounds may have methoxymethyl instead of tetrahydropyranyl.
  • the protecting group at the 1-position on the 4,5,6,7-tetrahydro-1H-indazole moiety in the compound of the present invention is preferably tetrahydropyranyl.
  • the “reactive derivative” of the carboxylic acid may be any carboxylic acid derivative as long as it can form an amide bond. Examples thereof include acid halides, anhydrides and the like. Acid halides are preferable.
  • the “salt” of the compound may be any salt as long as it forms a salt with the compound of the present invention.
  • Examples thereof include salts with inorganic acid, salts with organic acid, salts with inorganic base, salts with organic base, salts with amino acid, and the like.
  • salts with inorganic acid examples include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
  • salts with organic acid examples include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • salts with inorganic base examples include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.
  • salts with organic base examples include salts with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine and the like.
  • salts with amino acid examples include salts with lysine, arginine, aspartic acid, glutamic acid and the like.
  • the salt of compound [IV] is preferably hydrochloride, particularly preferably monohydrochloride.
  • halogen means fluorine, chlorine, bromine, iodine or the like. Chlorine and bromine are preferable, and chlorine is particularly preferable.
  • the “methylating agent” means a reagent capable of introducing methyl into a reactive functional group such as —NH— and the like. Examples thereof include methyl iodide, dimethylsulfuric acid and the like. Methyl iodide is preferable.
  • R 1 and R 2 are each independently hydrogen, C 1-6 alkyl or C 1-6 alkoxy, is preferably the formula [VI-1] (benzyl 2-[4-(N-benzyloxycarbonyl-N-methylamino)-2-nitrophenyl]-3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate)
  • R 1 is as defined above
  • R 1 is as defined above, is preferably formula [VIII-1] (benzyl 3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-oxopropanoate)
  • R 2 is as defined above, is preferably formula [X-1] (monobenzyl potassium malonate)
  • the compound of the present invention may exist as a tautomer.
  • the compound of the present invention may exist as a single tautomer or a mixture thereof.
  • the compound of the present invention may contain one or more asymmetric carbons.
  • the compound of the present invention may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers or a mixture of diastereomers.
  • the compound of the present invention may exist as an atropisomer.
  • the compound of the present invention may exist as a single atropisomer or a mixture thereof.
  • the compound of the present invention may simultaneously contain plural structural characteristics that produce the above-mentioned isomers. Moreover, the compound of the present invention may contain the above-mentioned isomers at any ratio.
  • a diastereomeric mixture can be separated into each diastereomer by a conventional method such as chromatography, crystallization and the like.
  • each diastereomer can also be produced by using a stereochemically single starting material, or by a synthetic method employing a stereoselective reaction.
  • An enantiomeric mixture can be separated into each single enantiomer by a method well known in the art.
  • a diastereomic mixture can be prepared by reacting an enantiomeric mixture with a substantially pure enantiomer that is known as a chiral auxiliary, and the diastereomeric mixture can be separated into single diastereomer having a high isomer ratio or substantially pure single diastereomer by a standard method such as fractional crystallization and chromatography.
  • the separated diastereomer can be converted to a desired enantiomer by removing the added chiral auxiliary by cleavage.
  • an enantiomeric mixture can also be directly separated by a chromatography method using a chiral solid phase well known in the art.
  • one of enantiomers can also be obtained by using a substantially pure optically active starting material or by employing stereoselective synthesis (asymmetric induction) of a prochiral intermediate using a chiral auxiliary and an asymmetric catalyst.
  • the absolute steric configuration can be determined based on the X-ray crystal analysis of the crystalline product or intermediate.
  • a crystalline product or intermediate derivatized with a reagent having an asymmetric center with a known steric configuration may be used if necessary.
  • the treatment after reaction can be performed by a general method, and the product can be purified by appropriately selecting or combining a conventional method such as distillation, crystallization, recrystallization, column chromatography, preparative HPLC, slurry washing and the like.
  • the product may be directly used in the next step without isolation or purification.
  • R 2 is hydrogen, C 1-6 alkyl or C 1-6 alkoxy, and Hal is halogen.
  • Compound [XII] can be obtained by reacting 4-fluoro-3-nitroaniline (compound [XIII]) with compound [XIV] in an ester solvent (ethyl acetate, etc.), an ether solvent (tetrahydrofuran, dimethyl ether, diethyl ether, etc.), a polar solvent (dimethyl sulfoxide, N,N-dimethylformamide, etc.) or the like or in a mixed solvent thereof, in the presence of an inorganic base (sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate) or an organic base (triethylamine, N,N-diisopropylethylamine, pyridine, etc.).
  • an ester solvent ethyl acetate, etc.
  • an ether solvent tetrahydrofuran, dimethyl ether, diethyl ether, etc.
  • a polar solvent dimethyl sulfoxide, N,N-dimethylform
  • water may be mixed with an inorganic base.
  • the amount of compound [XIV] is 1.05 equivalent to 1.5 equivalent, preferably 1.1 equivalent, relative to 4-fluoro-3-nitroaniline.
  • the amount of the base is 1.5 equivalent to 1.1 equivalent, preferably 1.3 equivalent, relative to 4-fluoro-3-nitroaniline.
  • the reaction temperature is 0° C. to 50° C., preferably room temperature.
  • the reaction time is 1 hr to 10 hr, preferably 2 hr to 4 hr, particularly preferably 3 hr.
  • Compound [XIV] may be a commercially available product, or can be prepared by a known method from a benzyl alcohol having a desired substituent and a carbonyldihalogen such as phosgene and the like.
  • R 2 is as defined above.
  • Compound [XI] can be obtained by reacting compound [XII] with a methylating agent such as methyl iodide, dimethylsulfuric acid and the like, in a solvent such as a polar solvent (dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, etc.), an ether solvent (tetrahydrofuran, dimethyl ether, diethyl ether, etc.) and the like, in the presence of an inorganic base (cesium carbonate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride, sodium tert-butoxide, etc.).
  • a methylating agent such as methyl iodide, dimethylsulfuric acid and the like
  • a solvent such as a polar solvent (dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, etc.), an ether solvent (te
  • the amount of the methylating agent is 1.1 equivalent to 1.5 equivalent, preferably 1.2 equivalent, relative to compound [XII].
  • the amount of the inorganic base is 1.1 equivalent to 1.5 equivalent, preferably 1.2 equivalent, relative to compound [XII].
  • the reaction temperature is 0° C. to 40° C., preferably 20° C. to 10° C.
  • the reaction time is 1 hr to 10 hr, preferably 2 hr to 4 hr, particularly preferably 3 hr.
  • R 1 is hydrogen, C 1-6 alkyl or C 1-6 alkoxy, and M is sodium or potassium.
  • a condensing agent such as 1,1′-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide and the like, in a polar solvent (dimethyl sulfoxide, N,N-dimethylformamide, etc.), an aromatic hydrocarbon (benzene, toluene, etc.), an ether solvent (tetrahydrofuran, dimethyl ether, diethyl ether, etc.) or the like or in a mixed solvent thereof, for 1 hr to 3 hr, preferably for 2 hr or more.
  • a condensing agent such as 1,1′-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclo
  • compound [X] is reacted with magnesium chloride in a polar solvent (dimethyl sulfoxide, N,N-dimethylformamide, etc.), an aromatic hydrocarbon (benzene, toluene, etc.), an ether solvent (tetrahydrofuran, dimethyl ether, diethyl ether, etc.) or the like or in a mixed solvent thereof, and the resulting product is mixed with the mixture obtained in (1), and the mixture is reacted for 1 hr to 3 hr, preferably for 3 hr, to give compound [VIII].
  • a polar solvent dimethyl sulfoxide, N,N-dimethylformamide, etc.
  • an aromatic hydrocarbon benzene, toluene, etc.
  • an ether solvent tetrahydrofuran, dimethyl ether, diethyl ether, etc.
  • the reaction rate can be increased and the yield can be improved, by addition of a tertiary amine (triethylamine, diisopropylethylamine, etc.).
  • the amount of compound [X] is 1.5 equivalent or more, preferably 2 equivalent, relative to compound [IX].
  • the amount of the condensing agent is 1.0 equivalent to 1.5 equivalent, preferably 1.1 equivalent, relative to compound [IX].
  • the amount of the magnesium chloride is 1.1 equivalent to 1.5 equivalent, preferably 1.25 equivalent, relative to compound [X].
  • solvent amount thereof may be added 2 hr after reaction initiation, or later.
  • the reaction temperature is 0° C. to 100° C., preferably 45° C. to 55° C.
  • the reaction mixture is preferably warmed to 65° C. to 75° C. depending on the reaction progress.
  • the reaction time is 1 hr to 10 hr, preferably 2 hr to 6 hr.
  • Compound [X] may be a commercially available product, or can be prepared by a known method from a benzyl alcohol having a desired substituent and malonic acid.
  • R 1 is as defined above.
  • Compound [VII] can be obtained by reacting compound [VIII] with 3,4-dihydro-2H-pyran in a solvent such as an ester solvent (ethyl acetate, etc.), a polar solvent (N,N-dimethylformamide, etc.), an ether solvent (tetrahydrofuran, etc.), an aromatic hydrocarbon (toluene, etc.) and the like, in the presence of an organic acid (p-toluenesulfonic acid, methanesulfonic acid, etc.).
  • the amount of the 3,4-dihydro-2H-pyran is 1.1 equivalent to 2 equivalent, preferably 1.5 equivalent, relative to compound [VIII].
  • the amount of the organic acid is a catalyst amount (for example 0.05 equivalent).
  • the reaction temperature is 0° C. to 50° C., preferably 15° C. to 30° C.
  • the reaction temperature is 1 hr to 5 hr, preferably 2 hr.
  • the solvent to be used for this reaction is preferably ethyl acetate, since the production of impurities can be suppressed, compared with N,N-dimethylformamide, tetrahydrofuran or toluene.
  • R 1 and R 2 are as defined above.
  • Compound [VI] can be obtained by reacting compound [VII] with compound [XI] in an ether solvent (tetrahydrofuran, dimethyl ether, diethyl ether, etc.), a polar solvent (dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, etc.) or a mixed solvent thereof, in the presence of an inorganic base (tripotassium phosphate, cesium carbonate, sodium carbonate, potassium carbonate, etc.).
  • the molar ratio of compound [VII] and compound [XI] is preferably about 1:1.
  • the amount of the inorganic base is 2 equivalent to 3 equivalent, preferably 2.5 equivalent, relative to compound [VII].
  • the reaction temperature is 30° C. to 100° C., preferably 50° C. to 60° C.
  • the reaction time is 2 hr to 30 hr, preferably 20 hr.
  • R 1 and R 2 are as defined above.
  • N-[2-[6,6-Dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine (compound [V]) can be obtained by subjecting compound [VI] to a reduction reaction by hydrogenation in an alcohol (methanol, ethanol, 1-propanol, 2-propanol, etc.) alone, or in a mixed solvent of an alcohol with an aromatic hydrocarbon (toluene, benzene, etc.), an ether solvent (tetrahydrofuran, dimethyl ether, diethyl ether, etc.), an ester solvent (ethyl acetate, etc.) or the like, in the presence of a palladium catalyst (palladium on carbon (preferably PE type), palladium black, palladium hydroxide carbon or the like, preferably palladium on carbon PE type).
  • an alcohol methanol, ethanol, 1-
  • the hydrogen pressure is 1 atm to 10 atm, preferably 3 atm to 4 atm.
  • the reaction temperature is 0° C. to 50° C., preferably 15° C. to 30° C.
  • the reaction time is 5 hr to 40 hr, preferably 20 hr.
  • compound [V] Since compound [V] is crystallized, it can be purified. In particular, the color substance produced in the reaction can be removed.
  • purification is performed by recrystallization or slurry washing, a mixed solvent of toluene and 2-propanol is preferably used.
  • a base sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc.
  • the reaction temperature is 0° C. to 50° C., preferably 20° C. to 35° C.
  • the reaction time is 3 hr to 7 hr, preferably 5 hr.
  • the molar ratio of compound [V] and compound [IV] or a salt thereof is 1:1 to 1:1.2, preferably 1:1.1.
  • the amount of the condensing agent is 1.1 equivalent to 1.3 equivalent, preferably 1.2 equivalent, relative to compound [V].
  • the amount of the reaction accelerator is 0.1 equivalent to 1.0 equivalent, preferably 0.2 equivalent, relative to compound [V].
  • the amount thereof is preferably 1 equivalent relative to the salt of compound [IV].
  • N-[2-(6,6-Dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide (compound [I]) can be obtained by reacting compound [III] in the presence of an inorganic acid (hydrogen chloride, hydrogen bromide, etc.), in an ether solvent (cyclopentyl methyl ether, tetrahydrofuran, dimethyl ether, diethyl ether, etc.) or in a mixed solvent of an ester solvent (ethyl acetate, etc.) and an alcohol (methanol, ethanol, 1-propanol, 2-propanol, etc.), or in an alcohol (methanol, ethanol, 1-propanol, 2-propanol, etc.) alone.
  • an inorganic acid hydrogen chloride, hydrogen bromide, etc.
  • an ether solvent cyclopentyl
  • the reaction temperature is 40° C. to 70° C., preferably 50° C. to 60° C.
  • the reaction time is 30 min to 4 hr, preferably 3.5 hr.
  • the amount of the inorganic acid is 2 to 4 equivalent, preferably 3 equivalent, relative to compound [III].
  • the solvent for extraction on neutralization with aqueous sodium hydroxide solution and on washing is preferably cyclopentyl methyl ether.
  • N-[2-(6,6-Dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide monohydrochloride (compound [II]) can be obtained by reacting compound [I] with hydrogen chloride in an alcohol (methanol, ethanol, 1-propanol, 2-propanol, etc.), an ester solvent (ethyl acetate, etc.) or a mixed solvent thereof.
  • the amount of the hydrogen chloride is 0.9 equivalent to 1.2 equivalent, preferably 1.05 equivalent, relative to compound [I].
  • the reaction temperature is 40° C. to 70° C., preferably 50° C. to 60° C.
  • the reaction time is 30 min to 2 hr, preferably 1.5 hr.
  • Compound [II] can be precipitated as a crystal by lowering the reaction temperature to 0° C. to 30° C.
  • the purification of compound [II] is performed using an alcohol (ethanol, 1-propanol, 2-propanol, etc.) alone, a mixed solvent of an alcohol (ethanol, 1-propanol, 2-propanol, etc.) and an ether solvent (cyclopentyl methyl ether, tetrahydrofuran, etc.), or a mixed solvent of an alcohol (ethanol, 1-propanol, 2-propanol, etc.) and an ester solvent (ethyl acetate, etc.), preferably 1-propanol.
  • an alcohol ethanol, 1-propanol, 2-propanol, etc.
  • a mixed solvent of an alcohol ethanol, 1-propanol, 2-propanol, etc.
  • an ether solvent cyclopentyl methyl ether, tetrahydrofuran, etc.
  • an ester solvent ethyl acetate, etc.
  • the purified compound [II] can be obtained by suspending the obtained crystals of compound [II] in a solvent, and then by continuously stirring at the temperature of 90° C. to 100° C. for 6 hr or more, subsequently at 0° C. to 30° C. for 1 hr or more.
  • Compound [V] can be obtained from compound [VI] by the progress of the following five reactions due one reduction reaction: (1) removal of benzyloxycarbonyl bonding to amino at the 4-position on the phenyl, (2) reduction of nitro at the 2-position on the phenyl, (3) removal of benzyl from the benzyl 3-oxopropanoate moiety, (4) formation of the indole ring by condensation and cyclization reaction of the amino formed by the reduction in (2) and the oxo group of the 3-oxopropanoic acid moiety formed in (3), and (5) decarboxylation reaction after the formation of the indole ring.
  • the amount of compound [IV] can be reduced to 1 to 1.2 equivalent, preferably 1.1 equivalent, relative to compound [V].
  • compound [XI], compound [VIII], compound [VII], compound [VI], compound [V] and compound [III] used for the production method of the present invention are useful compounds in order to obtain compound [I].
  • benzyl 4-fluoro-3-nitrophenylcarbamate (20.0 g, 68.9 mmol) was dissolved in N,N-dimethylformamide (120 mL), and cesium carbonate (26.9 g, 82.7 mmol) was added thereto.
  • Methyl iodide (11.7 g, 82.7 mmol) was added dropwise thereto at the internal temperature of 25° C. or lower, and the mixture was stirred at the internal temperature of 20° C. to 30° C. for 3 hr. After the completion of the reaction, toluene (200 mL) was added thereto, and water (100 mL) was added thereto at the internal temperature of 35° C. or lower.
  • DSC Differential scanning calorimetry
  • Step 1 Under nitrogen atmosphere, 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (10.0 g, 51.5 mmol) and 1,1′-carbonyldiimidazole (9.19 g, 56.7 mmol) were suspended in tetrahydrofuran (60 mL), to the suspension was added dropwise N,N-dimethylformamide (20 mL), and the mixture was stirred at the internal temperature of 20° C. to 30° C. for 1 hr (solution (1)).
  • Step 2 Under nitrogen atmosphere, magnesium chloride (19.6 g, 206 mmol) and monobenzyl potassium malonate (23.9 g, 103 mmol) were suspended in tetrahydrofuran (80 mL) in another reaction container, and to the suspension was added dropwise N,N-dimethylformamide (80 mL) at the internal temperature of 20° C. to 50° C. The mixture was stirred at the internal temperature of 60° C. for 30 min, the solution (1) was added thereto, and the mixture was stirred at the internal temperature of 60 to 65° C. for 3 hr.
  • benzyl 3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-oxopropanoate (10.0 g, 30.6 mmol) was dissolved in ethyl acetate (80 mL), to this solution were successively added p-toluenesulfonic acid (0.29 g, 1.53 mmol) and 3,4-dihydro-2H-pyran (3.86 g, 45.9 mmol), and the mixture was stirred at the internal temperature of 15° C. to 25° C. for 4 hr.
  • the obtained compound in this step is deduced to be a mixture of R-form and S-form, but its ratio is not measured.
  • benzyl 3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-oxopropanoate (20.0 g, 61.3 mmol) was dissolved in ethyl acetate (150 mL), and to this solution were successively added p-toluenesulfonic acid (1.17 g, 6.13 mmol) and dihydropyran (7.73 g, 92.0 mmol).
  • the used container was washed with ethyl acetate (10 mL), and the washings were also added thereto. The mixture was stirred at the internal temperature of 15° C. to 30° C.
  • the obtained compound in this step is deduced to be a mixture of R-form and S-form, but its ratio is not measured.
  • reaction solution was cooled to room temperature, and poured into 5 w/w % aqueous citric acid solution. Then, the mixture was extracted with ethyl acetate, and separated, and the obtained organic layer was washed successively with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the obtained compound in this step is deduced to be a mixture of diastereomers and/or tautomers, but its ratio is not measured.
  • the obtained compound in this step is deduced to be a mixture of diastereomers and/or tautomers, but its ratio is not measured.
  • the obtained compound in this step is deduced to be a mixture of R-form and S-form, but its ratio is not measured.
  • the sample was fixed on an aluminium cell, and powder X-ray diffraction was measured using powder X-ray diffraction apparatus (PANalytical X′ pert Pro) under the condition of X-ray source: Cu, tube voltage: 45 kV, tube current: 40 mA, scan speed: 0.418°/sec, step width: 0.0334° and diffraction angle: 3° to 25° to give a diffraction pattern.
  • the obtained diffraction pattern is shown in FIG. 1 .
  • N-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine (1.50 g, 3.96 mmol) was dissolved in N,N-dimethylformamide (7.5 mL), and (S)-2-(morpholin-4-yl)propanoic acid (694 mg, 4.36 mmol), 1-hydroxybenzotriazole monohydrate (606 mg, 3.96 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (836 mg, 4.36 mmol) were successively added thereto at room temperature, and the mixture was stirred at room temperature for 5 hr.
  • the obtained compound in this step is deduced to be a mixture of SR-form and SS-form, but its ratio is not measured.
  • N-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine (10.0 g, 26.4 mmol) was dissolved in N,N-dimethylformamide (50 mL), and (S)-2-(morpholin-4-yl)propanoic acid monohydrochloride (5.67 g, 29.0 mmol), sodium hydrogencarbonate (2.44 g, 29.0 mmol), 1-hydroxybenzotriazole monohydrate (0.81 g, 5.28 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.08 g, 31.7 mmol) were successively added thereto at room temperature, and the mixture was stirred at the internal temperature of 20° C.
  • the obtained compound in this step is deduced to be a mixture of SR-form and SS-form, but its ratio is not measured.
  • N-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide (1.88 g, 3.62 mmol) was dissolved in methanol (18.8 mL), and 2N hydrochloric acid (5.43 mL) was added thereto. The mixture was stirred for 2 hr and 10 min in an oil bath of 60° C. After the completion of the reaction, the mixture was cooled to room temperature, and concentrated under reduced pressure.
  • this solution was added dropwise to a mixed solution of 1N aqueous sodium hydroxide solution (84.5 mL) and cyclopentyl methyl ether (350 mL) at the internal temperature of 0° C. to 60° C., the used container was washed with ethanol (20 mL), and the washings were also added thereto. After confirming that the pH of the aqueous layer was 9 or more, the mixture was separated at the internal temperature of 40° C. to 50° C., and the obtained organic layer was washed three times with water (100 mL) at the same temperature, and concentrated under reduced pressure until the volume became about 30 mL.
  • N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide monohydrochloride (4.0 g) was suspended in 1-propanol (18 mL), and the suspension was stirred at the internal temperature of 90° C. to 100° C. for 7.5 hr, and then overnight at room temperature. The crystals were collected by filtration, and the obtained wet crystals were washed with 1-propanol (8 mL). The wet crystals were dried under reduced pressure at the external temperature of 65° C.
  • KH 2 PO 4 (4.08 g) and K 2 HPO 4 (5.23 g) are exactly weighed, and dissolved in water (3 L). This solution are filtered through a filter (0.45 ⁇ m), and the filtrate is degassed well, and then used for LC analysis.
  • the compound of the present invention is useful as a synthetic intermediate for producing a compound of the formula [II].
  • the present invention can provide a method for producing a compound of the formula [II] in good yield.
  • the production method of the present invention can be performed in a few steps without a reagent that needs careful handling due to danger and toxicity, and therefore it is useful as an industrial large-scale synthetic method.

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US11104667B2 (en) 2014-07-04 2021-08-31 Japan Tobacco Inc. Method for producing indole compound
US11464782B2 (en) 2018-05-25 2022-10-11 Japan Tobacco Inc. Method of treating pain or interstitial cystitis using indole compound

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EP3804727B1 (fr) * 2018-05-25 2023-10-11 Japan Tobacco Inc. Compose contenant de l'indol a utiliser dans le traitement du syndrome nephrotique
EP3804726A4 (fr) * 2018-05-25 2022-03-16 Japan Tobacco Inc. Agent thérapeutique ou prophylactique de la sclérose en plaques contenant un composé indole
CR20220299A (es) 2019-12-20 2022-08-05 Pfizer Derivados de becimidazol

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US8299070B2 (en) 2009-11-25 2012-10-30 Japan Tobacco Inc. Indole compounds and pharmaceutical use thereof
JP5886310B2 (ja) 2010-12-06 2016-03-16 グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ Ｌｐ−ＰＬＡ２により媒介される疾患または状態の処置における使用のためのピリミジノン化合物
AR086665A1 (es) * 2011-06-14 2014-01-15 Lilly Co Eli Inhibidor de aldosterona sintasa y composiciones farmaceuticas
ES2748324T3 (es) 2014-07-04 2020-03-16 Japan Tobacco Inc Método para producir un compuesto de indol

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US11104667B2 (en) 2014-07-04 2021-08-31 Japan Tobacco Inc. Method for producing indole compound
US11464782B2 (en) 2018-05-25 2022-10-11 Japan Tobacco Inc. Method of treating pain or interstitial cystitis using indole compound

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