WO2017056338A1 - Procédé pour produire un dérivé de pyrazole - Google Patents

Procédé pour produire un dérivé de pyrazole Download PDF

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Publication number
WO2017056338A1
WO2017056338A1 PCT/JP2015/080877 JP2015080877W WO2017056338A1 WO 2017056338 A1 WO2017056338 A1 WO 2017056338A1 JP 2015080877 W JP2015080877 W JP 2015080877W WO 2017056338 A1 WO2017056338 A1 WO 2017056338A1
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Prior art keywords
group
formula
methyl
acid
pyrazole
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PCT/JP2015/080877
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English (en)
Japanese (ja)
Inventor
佐藤　勉
ジーウェン リー
シャオゲン ヤン
ヨウチュ ワン
センフェイ マオ
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持田製薬株式会社
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Priority to JP2017542670A priority Critical patent/JP6592521B2/ja
Publication of WO2017056338A1 publication Critical patent/WO2017056338A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • the present invention relates to 4-heteroaryl-N- (2-phenyl- [1,2,4] triazolo [1,5] represented by the formula (I) having an inhibitory action on phosphodiesterase 10 (hereinafter referred to as “PDE10”).
  • PDE10 phosphodiesterase 10
  • Amide derivatives have excellent PDE10 inhibitory action, and are used in various psychiatric disorders involving PDE10 (eg, delusional, dismantled, strained, indistinguishable, or residual schizophrenia). It is expected to be useful for the treatment and / or prevention of symptoms and / or prevention, and as a therapeutic agent with reduced side effects.
  • Patent Document 1 A method for producing N-([1,2,4] triazolo [1,5-a] pyridin-7-yl) -1H-pyrazole-5-carboxylic acid amide derivative (formula (i)) is disclosed in International Publication No. 2012. / 076430 pamphlet, p26, scheme 1 (Patent Document 1). According to Patent Document 1, the compound of formula (i) is produced by a condensation reaction of a carboxylic acid derivative (formula (ii)) and an amine derivative (formula (iii)).
  • the compound of formula (iii) is prepared using a 2-aminopyridine derivative (formula (iv)) and O- (mesitylsulfonyl) hydroxylamine (formula (E-1)).
  • Patent Document 2 also discloses 4-heteroaryl-N- (2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl. ) -1H-pyrazole-5-carboxylic acid amide derivatives (formula (vi)) are disclosed.
  • the compound of formula (vi) is produced by a condensation reaction of a carboxylic acid derivative (formula (CA)) and an amine derivative (formula (AM)).
  • AM-4 7-amino- [1,2,4] triazolo [1,5-a] pyridine derivative
  • B-1 2-aminopyridine derivative
  • E-1 O- (mesitylsulfonyl) hydroxylamine
  • the derivative represented by the formula (I) in the present invention can be produced according to the method described in Patent Document 1 or Patent Document 2.
  • the compound of formula (iii) or the compound of formula (AM-4) used for the production is produced using the compound of formula (E-1).
  • the compound of the formula (E-1) is not suitable for use in mass synthesis or industrial production due to the stability and safety of the compound (Non-patent Document 1). ing. Accordingly, when considering mass synthesis or industrial production of the derivative represented by the formula (I), it is required to find a new production method different from the production methods disclosed in Patent Document 1 and Patent Document 2. It has been.
  • 2-phenyl- [1,2,4] triazolo [1,5-a] pyridine derivative can be produced by reacting an amidine derivative (AMD-1) with an oxidizing agent.
  • ADH-1 amidine derivative
  • ADP-1 oxidizing agent
  • Non-patent document 2 sodium hypochlorite
  • Non-patent document 3 lead tetraacetate
  • oxygen air
  • Non-patent document 4 iodine
  • PIFA iododo] benzene
  • the present invention is a method for producing a derivative represented by the above formula (I) having a PDE10 inhibitory action.
  • INDUSTRIAL APPLICABILITY The present invention can provide an industrially advantageous production method that is good in yield, high purity, easy and safe in a short process, and has high industrial utility.
  • the present invention relates to 4-heteroaryl-N- (2-phenyl- [1,2,4] triazolo [1,5-a] pyridin-7-yl represented by the formula (I) shown in the following embodiment ) -1H-pyrazole-5-carboxylic acid amide derivative production method, which will be described below.
  • a first aspect of the present invention is the following formula (I): [In the formula (I), p represents an integer of 0 to 3; q represents an integer of 0 to 2; and R 1 each independently represents a halogen atom, a cyano group, a C 1-6 alkyl group, C 3 ⁇ 8 cycloalkyl group, a halogenated C 1 ⁇ 6 alkyl group, C 2 ⁇ 6 alkenyl group, C 1 ⁇ 6 alkoxy group, C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkyl group, hydroxy C 1 ⁇ 6 alkyl group , and C 2 ⁇ 7 represents a group selected arbitrarily from alkanoyl group; R 2 represents a C 1 ⁇ 6 alkyl group; R 3 represents a hydrogen atom, and a group from the fluorine atoms optionally selected; R 4 are each independently a halogen atom, a C 1 ⁇ 6 alkyl group, and C 1 ⁇ 6 group selected from
  • a production method including a step of obtaining a compound represented by formula (I).
  • the ring represented by the above formula (I) [in the formula (I), p, R 1 , R 2 , R 4 and the formula (II) A group is the same as defined in the above embodiment [1-1]; q represents an integer of 0; R 3 represents a fluorine atom].
  • the step of obtaining a compound represented by formula [AD is the same as that in the embodiment [1]; the definition of the substituent in the formula (AD-3) of the starting material is as defined in the formula (1-1-1) It is the same as the definition of I)].
  • the equivalent amount of the oxidizing agent (PIFA) is 1.0 to 2.5 equivalents relative to the starting material.
  • the equivalent amount of the oxidizing agent (PIFA) is 1.2 to 2.0 equivalents relative to the starting material.
  • the base is present.
  • the base is cesium carbonate, sodium hydrogen carbonate, tripotassium phosphate, sodium acetate, DBU, triethylamine, cesium fluoride, or pyridine.
  • the base is sodium hydrogen carbonate, tripotassium phosphate, sodium acetate, DBU, triethylamine, cesium fluoride, or pyridine.
  • the equivalent amount of the base is 1.0 to 2.5 equivalents relative to the starting material.
  • the equivalent amount of the base is 1.2 to 2.0 equivalents relative to the starting material.
  • the solvent is 2-propanol, N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, water, or a solvent not involved in the reaction such as pyridine. Or a mixed solvent of solvents not involved in these reactions.
  • the solvent is a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine, and water. It is a mixed solvent.
  • the solvent is a mixed solvent of N, N-dimethylformamide and water.
  • the solvent is a mixed solvent of a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine and water.
  • a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine and water.
  • the volume ratio of a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine and water in the mixed solvent is 20: 1 to 1: 1.
  • the solvent is a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine, and water.
  • a volume ratio of a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine and water in the mixed solvent is 10: 1 to 3: 1. It is.
  • the solvent is a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine, and water.
  • the volume ratio of a solvent such as acetonitrile, 2-propanol, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, or pyridine and water in the mixed solvent is 8: 1.
  • reaction temperature is between 0 ° C. and about 50 ° C.
  • reaction temperature is between 0 ° C. and about 40 ° C.
  • reaction temperature is room temperature.
  • a second embodiment of the present invention is the following (Scheme 1): [(Scheme 1) wherein p, q, R 1 , R 2 , R 3 , R 4 , and the ring A group represented by the formula (II) Is the same as defined in the above embodiment [1]].
  • C 1-6 indicates that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, the total carbon of a linear, branched or cyclic group Represents the number of atoms.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Examples include hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • halogenated means that 1 to 5 of the “halogen atoms” may be contained as a substituent. “Halogenated” is also referred to as “optionally halogenated” or “halogeno”.
  • halogenated C 1-6 alkyl group means a group in which the “C 1-6 alkyl group” is optionally substituted with 1 to 5 halogen atoms. Meaning, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.
  • C 3 ⁇ 8 cycloalkyl group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C 2 ⁇ 6 alkenyl group for example, vinyl, allyl, isopropenyl, butenyl, pentenyl, and hexenyl, and the like.
  • examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclo Examples include butyloxy, cyclopentyloxy, and cyclohexyloxy.
  • the “C 1-6 alkoxy C 1-6 alkyl group” refers to a group in which the “C 1-6 alkoxy group” is substituted with the “C 1-6 alkyl group”. Means.
  • examples of the “C 1-6 alkoxy C 1-6 alkyl group” include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl.
  • hydroxy C 1-6 alkyl group means a group in which the “C 1-6 alkyl group” is optionally substituted with 1 to 5 hydroxyl groups. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methyl-ethyl and the like.
  • C 2 ⁇ 7 alkanoyl group for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl And cyclohexylcarbonyl.
  • C 7 ⁇ 20 aralkyl group for example, benzyl, phenethyl, diphenylmethyl, trityl, biphenyl methyl, naphthylmethyl, indanyl methyl, 1,2,3,4 -Tetrahydronaphthalen-1-ylmethyl and the like.
  • variable substituent when a cyclic substituent is substituted with a variable substituent, the variable substituent is bonded to a specific carbon atom of the cyclic group or a specific NH group in the cyclic group. It means not.
  • variable substituent R x in the following formula A can be substituted for any of the carbon atoms i, ii, iii, iv, or v in the formula A
  • variable substituent R y in the following formula B is represented by the formula A carbon atom vi in B or vii can be substituted
  • a variable substituent R z in the following formula C can be substituted with any of the carbon atoms viii, ix, x, or xi in formula C. It means you can do it.
  • the compound in the present invention may form an acid addition salt or a salt with a base depending on the type of substituent.
  • a salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basics, Or the salt with an acidic amino acid etc. are mentioned.
  • a salt may be formed from an inorganic or organic base.
  • a salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and represents a salt prepared from a pharmaceutically acceptable non-toxic base including an inorganic or organic base.
  • Salts obtained from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron (III) salts, iron (II) salts, lithium salts, magnesium salts, manganese (III) salts, manganese (II) salts. , Barium salt, potassium salt, sodium salt, cesium salt and zinc salt, etc.
  • Examples of the salt obtained from the organic base include methylamine, ethylamine, t-butylamine, t-octylamine, cyclohexylamine, ethanolamine, ethylenediamine, diethylamine, dicyclohexylamine, dibenzylamine, diethanolamine, N, N′-di Salts with benzylethylenediamine, trimethylamine, triethylamine, triethanolamine, piperidine, morpholine, pyridine, picoline, 2,6-lutidine, lysine, arginine, ornithine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, etc. Is mentioned.
  • a salt may be formed from an inorganic acid and an organic acid.
  • acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, mandelic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfone.
  • Acid ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid, camphorsulfonic acid, citric acid, gluconic acid, isethionic acid, mucoic acid, pamoic acid, pantothenic acid, hydroiodic acid, formic acid, trifluoroacetic acid , Propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, sorbic acid, oxalic acid, malonic acid, phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, aspartic acid and the like.
  • Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • the salt is formed by mixing the compound of the present invention with a solution containing an appropriate amount of acid or base to form the desired salt, and then collected by filtration, or the mixed solvent is distilled. It can be obtained by leaving.
  • the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol or glycerol.
  • solvate means a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.).
  • solvent molecules eg, water, ethanol, etc.
  • hydrate When the solvent molecule is water, it is particularly called “hydrate”.
  • any one isomerism And mixtures of isomers are also encompassed in the compounds of the present invention.
  • an optical isomer exists in the compound of the present invention, an optical isomer resolved from the racemate is also encompassed in the compound of the present invention.
  • tautomerism can occur.
  • tautomerism include proton tautomerism in compounds having an imino group, a keto group, or an oxime group.
  • the compound in the present invention is an optically active substance, it can be separated from the corresponding racemate into the (+) form or the ( ⁇ ) form [D form or L form] by ordinary optical resolution means.
  • each isomer is singly identified by a synthesis method or separation method known per se. It can obtain as a compound of.
  • the separation method include optical resolution methods such as a fractional recrystallization method, a diastereomer method, and a chiral column method.
  • Optical resolution agents include, for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, cinchonine , ( ⁇ )-Cinchonidine, brucine and the like.
  • Diastereomer method An optical resolution agent is covalently bonded to a racemic mixture to obtain a mixture of diastereomers, and then by a conventional separation means (for example, fractional recrystallization, silica gel column chromatography, HPLC, etc.) In this reaction, an optically pure optical isomer is obtained through separation into an optically pure diastereomer, followed by a step of removing an optical resolution agent by a chemical reaction (hydrolysis reaction or the like).
  • a conventional separation means for example, fractional recrystallization, silica gel column chromatography, HPLC, etc.
  • the compound of the present invention has a hydroxyl group or an amino group (primary or secondary), the compound and an optically active organic acid (for example, ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid, and ( A diastereomer of an ester form or an amide form is obtained from each by a condensation reaction with-)-menthoxyacetic acid or the like).
  • an optically active organic acid for example, ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid, and ( A diastereomer of an ester form or an amide form is obtained from each by a condensation reaction with-)-menthoxyacetic acid or the like.
  • the compound of this invention has a carboxy group
  • the diastereomer of an amide body or an ester body is obtained from each by the condensation reaction of the said compound, an optically active amine, or an optically active alcohol.
  • the diastereomers obtained by the condensation reaction are separated, and each diastere
  • Chiral column method A method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting to a chromatography using a chiral column (optical isomer separation column).
  • a mixture of optical isomers is added to a chiral column (for example, CHIRAL series manufactured by Daicel Corporation), and an elution solvent (water, various buffer solutions (for example, phosphate buffer) is added.
  • elution solvent water, various buffer solutions (for example, phosphate buffer)
  • Liquid and organic solvents eg, single solvents such as ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, and diethylamine, or mixed solvents thereof
  • chiral isomers for example, CP-Chirasil-DeX CB (manufactured by GL Sciences Inc.) can be used to separate optical isomers.
  • the compound in the present invention may be a crystal, and the compound of the present invention includes a single crystal form or a crystal form mixture.
  • the compound in the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • the compounds in the present invention include isotopes (eg, hydrogen isotopes, 2 H and 3 H, carbon isotopes, 11 C, 13 C, and 14 C, chlorine isotopes, 36 Cl, etc. Fluorine isotopes, 18 F, iodine isotopes, 123 I and 125 I, nitrogen isotopes, 13 N and 15 N, oxygen isotopes, 15 O, 17 O, 18 O, phosphorus, etc. Isotopes, 32 P, etc., as well as sulfur isotopes, 35 S, etc.).
  • isotopes eg, hydrogen isotopes, 2 H and 3 H, carbon isotopes, 11 C, 13 C, and 14 C, chlorine isotopes, 36 Cl, etc.
  • compounds labeled or substituted with certain isotopes can be obtained by, for example, positron emission tomography ( It can be used as a tracer (PET tracer) used in Positron Emission Tomography (PET), and is useful in fields such as medical diagnosis.
  • positron emitting isotopes such as 11 C, 18 F, 15 O, and 13 N
  • PET tracer Positron Emission Tomography
  • compounds labeled or substituted with certain isotopes are useful in drug and / or substrate tissue distribution studies.
  • 3 H and 14 C are useful for this research purpose because they are easy to label or displace with them and are easy to detect.
  • an isotope-labeled compound can be obtained by a common technique known to those skilled in the art or by a method similar to the synthesis method described in the examples described later.
  • the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.
  • the definition of X in the production method is a halogen atom unless otherwise specified.
  • the definition of W in the production method is boronic acid ester, boronic acid, trifluoroborate salt, or boronic acid N-methyliminodiacetic acid ester unless otherwise specified.
  • Definition of R A in the manufacturing method is a C 1 ⁇ 6 alkyl group, and C 7 ⁇ 20 aralkyl group.
  • Definition of R B in the manufacturing process, unless otherwise specified, is a C 1 ⁇ 6 alkyl group.
  • Defining R D in the manufacturing process is a C 1 ⁇ 6 alkyl group, C 6 ⁇ 14 aryl group, and C 7 ⁇ 20 groups selected arbitrarily from aralkyl groups.
  • Each formula in each step in the production method of the present invention may form a salt, and examples of the salt include the same salts as those of the formula (I) described above.
  • the raw material compound in each step in the production method of the present invention can be used in the next reaction as the reaction solution or as a crude product. It can also be isolated from the reaction mixture according to a conventional method, and easily purified by means known per se, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, and chromatography. Is possible.
  • Solvents used in the above recrystallization are, for example, water, methanol, ethanol, 2-propanol, butanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, n-hexane, cyclohexane, heptane, benzene, toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, chloroform, methylene chloride, 1,2-dichloroethane, acetonitrile, acetone, diphenyl ketone, methyl acetate, ethyl acetate, dimethyl sulfoxide , Acetic acid, trifluoroacetic acid, methanesulfonic acid, and the like.
  • solvents can be used alone, or two or more kinds of solvents can be mixed and used in an appropriate ratio, for example, a ratio of 1: 1 to 1:10.
  • the compound in a formula when marketed, it can also use a commercial item as it is, It is also possible to use what was manufactured by the method known per se, or a method according to it.
  • transformable functional group e.g., carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto group, C 1 ⁇ 6 alkoxycarbonyl group, C 6 ⁇ 14 aryloxy carbonyl group, C 7 ⁇ 20 aralkyloxycarbonyl group, a sulfo group, in the case containing a halogen atom, etc.
  • transformable functional group e.g., carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto group, C 1 ⁇ 6 alkoxycarbonyl group, C 6 ⁇ 14 aryloxy carbonyl group, C 7 ⁇ 20 aralkyloxycarbonyl group, a sulfo group, in the case containing a halogen atom, etc.
  • the compound when the compound is obtained in a free state, it may be converted into a salt according to a conventional method. When it is obtained as a salt, it is converted into a free form or other salt according to a conventional method. You can also.
  • each formula in each step in the production method of the present invention has a reactive group such as a hydroxyl group, an amino group, a carboxy group, and a thiol group as a substituent, these groups are appropriately protected in each reaction step, The protecting group can be removed at an appropriate stage.
  • the method of introducing and removing the protecting group is appropriately performed depending on the group to be protected or the type of protecting group.
  • Green, et al., “Protective Groups in Organic Synthesis”. ) 4th edition, 2007, can be performed by the method described in the book of John Wiley & Sons.
  • reaction temperature in each step in the production method of the present invention is not limited as long as it is in the range of the temperature at which the solvent is refluxed from ⁇ 78 ° C. unless otherwise specified.
  • reaction time is not limited as long as the reaction is sufficiently advanced unless otherwise specified.
  • range of the temperature at which the solvent is refluxed from ⁇ 78 ° C.” in the reaction temperature means a temperature within the range from ⁇ 78 ° C. to the temperature at which the solvent (or mixed solvent) used in the reaction is refluxed.
  • “at a temperature at which the solvent is refluxed from ⁇ 78 ° C.” means a temperature within a range from ⁇ 78 ° C. to a temperature at which the methanol is refluxed.
  • at a temperature at which the reaction solution is refluxed from ⁇ 78 ° C.” means a temperature within a range from ⁇ 78 ° C. to a temperature at which the reaction solution is refluxed.
  • room temperature means a temperature in a laboratory, a laboratory, etc., and means a temperature in the range of 1 to 30 ° C.
  • reaction in each step in the production method of the present invention can be performed without solvent or by dissolving or suspending the raw material compound in a solvent not involved in an appropriate reaction before the reaction.
  • solvent not involved in the reaction examples include water, cyclohexane, hexane, benzene, chlorobenzene, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, N, N-dimethylformamide ( DMF), N, N-dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1, 4-dioxane, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, butyl acetate, acetone, methyl ethyl ketone, dichloromethane, chloroform, carbon tetrachloride, 1,2-d
  • the solvent to be used may be a single solvent, or may be appropriately selected depending on the reaction conditions and used in two types. It means that the above solvents may be mixed and used at an appropriate ratio.
  • the base (or deoxidizing agent) used in each step in the production method of the present invention is, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate.
  • Examples of the acid or acid catalyst used in each step in the production method of the present invention include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, Tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, Etc. However, it is not necessarily limited to those described above.
  • W boronic acid N-methyliminodiacetic acid (MIDA) ester>
  • MIDA N-methyliminodiacetic acid
  • a solvent that does not participate in the reaction such as benzene, toluene, xylene or dimethyl sulfoxide, or a mixed solvent thereof
  • a solvent that does not participate in the reaction such as benzene, toluene, xylene or dimethyl sulfoxide, or a mixed solvent thereof
  • MIDA N-methyliminodiacetic acid
  • ⁇ Step 4> ⁇ Production Method A> Using the compound represented by the formula (CA-1) obtained in ⁇ Step 3>, a method known in the literature, for example, Synthesis, (12), p954-955, 1979, In the presence of a base such as N, N-diisopropylethylamine, triethylamine, pyridine, etc., a compound of ClCOOR A or di-tert-butyl dicarbonate (Boc 2 O) in the presence of a base such as N, N-diisopropylethylamine, triethylamine or pyridine Using an ether solvent such as 1,2-dimethoxyethane or a solvent not involved in the reaction, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C.
  • a base such as N, N-diisopropylethylamine, triethylamine, pyridine, etc.
  • an active ester Without isolating the active ester form, the method was subsequently published in a method known in the literature, for example, “Journal of the American Chemical Society, 75, p637-640, 1953”. According to the method described, a base such as N, N-diisopropylethylamine, triethylamine, pyridine, and ammonium carbonate were added to the above reaction solution, and the reaction was carried out at a temperature at which the solvent refluxed from 0 ° C. A compound represented by AD-1) can be produced.
  • a base such as N, N-diisopropylethylamine, triethylamine, pyridine, and ammonium carbonate
  • ⁇ Step 5> ⁇ Production Method A> Using the compound represented by the formula (ET-1) obtained in ⁇ Step 2>, a method known in the literature, for example, International Publication No. 2006/043145, P120, Example 43 (April 2006).
  • the compound represented by the formula (AD-1) can be produced by carrying out the reaction at a temperature at which the reaction solution is refluxed from 0 ° C. using an aqueous ammonia solution in accordance with the method described in the publication on May 27. .
  • ⁇ Production method B> Method for Producing Pyridine Acid Derivative (PY-1) [(PY-1-1): R 3 Fluorine Atom]: ⁇ Step 1> Methods known in the literature, for example, “Bioorganic & Medicinal Chemistry Letters, 22 (10), p3431-3436, 2012”, “International Publication No. 2011-073845 (June 2011) Published on the 23rd), p116, Example 56, step (A) ”, etc., in a solvent inert to the reaction such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, or a mixed solvent thereof.
  • a solvent inert to the reaction such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, or a mixed solvent thereof.
  • ⁇ Process 2> ⁇ Manufacturing method B> Using the compound of formula (B-2) obtained in ⁇ Step 1>, a method known in the literature, for example, Synthesis, 12, p905-908, 1989, etc. According to the method, a sealed tube reaction is carried out at 0 ° C. to 150 ° C. using a solvent inert to the reaction such as 1,4-dioxane in the presence of aqueous ammonia to produce the compound of formula (PY-1). be able to.
  • a solvent inert to the reaction such as 1,4-dioxane in the presence of aqueous ammonia to produce the compound of formula (PY-1).
  • ⁇ Manufacturing method C> Method for producing amidine acid derivative (AD-3): ⁇ Step 1> ⁇ Production method A> Using a compound of formula (AD-1) obtained in ⁇ Step 4> or ⁇ Step 5> and a compound of formula (PY-1) obtained in ⁇ Production method B> ⁇ Step2> In the presence of N, N-dimethyl-1,2-ethanediamine, copper iodide (CuI), and inorganic bases such as potassium carbonate and potassium phosphate, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • the compound of the formula (AD-2) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. in a solvent inert to the above reaction or a mixed solvent thereof.
  • ⁇ Process 2> ⁇ Production method C> Compounds of formula (AD-2) and formula (IM-1) obtained in ⁇ Step 1> or salts thereof (formula (IM-1) and salts thereof are commercially available compounds or commercially available compounds.
  • the reaction is carried out at a temperature at which the solvent refluxes from 0 ° C. in a solvent that does not participate in the reaction, such as dimethyl sulfoxide and pyridine. ) Can be produced.
  • Example 1 Synthesis of 5-fluoro-4-iodopyridin-2-amine ⁇ Step 1> Synthesis of 2,5-difluoro-4-iodopyridine Using 2,5-difluoropyridine, International Publication No. 20111 / The crude 2,5-difluoro-4-iodopyridine (96% crude yield) was obtained by a similar method described in pamphlet No. 073845 (published on June 23, 2011: p116, Example 56, step (A)). Obtained. The 1 H NMR data of the obtained 2,5-difluoro-4-iodopyridine was consistent with the data described in WO 2011/073845.
  • ⁇ Step 2> Synthesis of 5-fluoro-4-iodopyridin-2-amine (Example 1) Crude 2,5-difluoro-4-iodopyridine (2.26 g, 9.4) obtained in ⁇ Step 1> Mmol), 28% aqueous ammonia (6.8 mL) and 1,4-dioxane (2.3 mL) were added to a sealed tube reactor and heated in an oil bath at 135 ° C. for 53 hours. Water was added to the reaction mixture, and the mixture was extracted with methyl-tert-butyl ether (MTBE). The obtained organic layer was washed with water and concentrated under reduced pressure. Crude 5-fluoro-4-iodopyridin-2-amine (1.90 g, 85%) was obtained as a moss green solid.
  • MTBE methyl-tert-butyl ether
  • ⁇ Step 2> Synthesis of 4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (Example 2) Crude 4 synthesized in the same manner as in ⁇ Step 1> A mixture of-(2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (0.50 g, 1.9 mmol) and 25% aqueous ammonia (5 mL) at room temperature For 20 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • ⁇ Step 3> Synthesis of 4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (Example 2)
  • ⁇ Step 4> Synthesis of 4- (2,5-dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (Example 2) 4- synthesized in the same manner as in ⁇ Step 3> (2,5-Dimethylpyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (0.5 g, 2.2 mmol) and diisopropylethylamine (0.4 mL, 2.4 mmol) were added to tetrahydrofuran. (5 mL) and ethyl chloroformate (0.23 mL, 2.4 mmol) was added dropwise under ice cooling.
  • ⁇ Step 2> Synthesis of 1-methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxylic acid (Example 3) Methyl 1-methyl-obtained in ⁇ Step 1> Using 4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxylate (1.26 g), the same method as in (Example 2) ⁇ Step 3> or a method analogous thereto The title compound (682 mg) was obtained as a colorless solid.
  • ⁇ Step 3> Synthesis of 1-methyl-4- (2-methylpyrimidin-4-yl) -1H-pyrazole-5-carboxamide (Example 3) 1-methyl synthesized by the same method as in ⁇ Step 2> -4- (2-Methylpyrimidin-4-yl) -1H-pyrazole-5-carboxylic acid (2.0 g, 9.2 mmol) and diisopropylethylamine (1.8 mL, 10 mmol) in tetrahydrofuran (20 mL) And benzyl chloroformate (1.7 mL, 10 mmol) was added dropwise under ice cooling.
  • ⁇ Step 2> Synthesis of 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (Example 4) Methyl obtained in ⁇ Step 1> Using 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylate (1.6 g), similar to (Example 2) ⁇ Step 3> By the method or a method analogous thereto, 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (0.65 g) was obtained as a colorless solid.
  • ⁇ Step 3> Synthesis of 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxamide (Example 4) Synthesis was performed in the same manner as in ⁇ Step 2>. 4- (5-Fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5-carboxylic acid (0.50 g, 2.0 mmol), and ethyl chloroformate (0.21 mL) (Example 2) 4- (5-fluoro-2-methoxypyrimidin-4-yl) -1-methyl-1H-pyrazole-5 by the same method as in ⁇ Step 4>. Carboxamide (0.40 g, 80%) was obtained as a white solid.
  • ⁇ Step 2> Synthesis of methyl 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxylate (Example 5) Methyl-synthesized in ⁇ Step 1> 4- (5,5-dimethyl-1,3,2-dioxaborinan) -2-yl) -1 methyl-1H-pyrazole-5-carboxylate (300 mg, 1.19 mmol), and 2-bromo-4- (Trifluoromethyl) thiazole (291 mg) was used in the same manner as in (Example 2) ⁇ Step 1> or a method analogous thereto, but methyl 1-methyl-4- (4- (trifluoromethyl) thiazole- 2-yl) -1H-pyrazole-5-carboxylate (259 mg) was obtained as a light brown solid.
  • ⁇ Step 3> Synthesis of 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxylic acid (Example 5) Methyl obtained in ⁇ Step 2> 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxylate (210 mg) was used in the same manner as in (Example 2) ⁇ Step 3> or In a similar manner, 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxylic acid (173 mg) was obtained as a brown white solid.
  • ⁇ Step 4> Synthesis of 1-methyl-4- (4- (trifluoromethyl) thiazol-2-yl) -1H-pyrazole-5-carboxamide (Example 5) Synthesis was performed in the same manner as in ⁇ Step 3>.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé pour produire un composé représenté par la formule (I). L'invention permet d'obtenir un dérivé amide d'acide 4-hétéroaryl-N-(2-phényl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylique.
PCT/JP2015/080877 2015-09-30 2015-11-02 Procédé pour produire un dérivé de pyrazole WO2017056338A1 (fr)

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Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
JAVIER MENDIOLA ET AL.: "Preparation, Use, and Safety of O-Mesitylenesulfonylhydroxylamine", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 13, no. 2, 14 January 2009 (2009-01-14), pages 263 - 267, XP055376391 *
K. T. POTTS ET AL.: "1,2,4-Triazoles. XIII. Derivatives of the s-Triazolo[1,5-a]pyridine Ring System", J. ORG. CHEM., vol. 31, no. 1, January 1966 (1966-01-01), pages 260 - 265, XP002239504 *
SONG,L. ET AL.: "I2/KI-Mediated Oxidative N-N Bond Formation for the Synthesis of 1,5-Fused 1,2,4-Triazoles from N-Aryl Amidines", JOURNAL OF ORGANIC CHEMISTRY, vol. 80, no. 14, 26 June 2015 (2015-06-26), pages 7219 - 7225, XP055376388 *
UEDA,S. ET AL.: "Facile Synthesis of 1,2,4- Triazoles via a Copper-Catalyzed Tandem Addition-Oxidative Cyclization", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 131, no. 42, pages 15080 - 15081, XP055055624 *
VICTOR J. GRENDA ET AL.: "Novel Preparation of Benzimidazoles from N-Arylamidines. New Synthesis of Thiabendazole", J. ORG. CHEM., vol. 30, no. 1, January 1965 (1965-01-01), pages 259 - 261, XP055092396 *
ZHENG,Z. ET AL.: "PhI(OCOCF3)2-Mediated Intramolecular Oxidative N-N Bond Formation: Metal-Free Synthesis of 1,2,4-Triazolo[1,5-a] pyridines", JOURNAL OF ORGANIC CHEMISTRY, vol. 79, no. 10, 18 April 2014 (2014-04-18), pages 4687 - 4693, XP055376389 *

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