WO2012063931A1 - ピラジノ〔2,3-d〕イソオキサゾール誘導体 - Google Patents
ピラジノ〔2,3-d〕イソオキサゾール誘導体 Download PDFInfo
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- WO2012063931A1 WO2012063931A1 PCT/JP2011/076029 JP2011076029W WO2012063931A1 WO 2012063931 A1 WO2012063931 A1 WO 2012063931A1 JP 2011076029 W JP2011076029 W JP 2011076029W WO 2012063931 A1 WO2012063931 A1 WO 2012063931A1
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- 0 *c1n[o]c2c1nc(*)cn2 Chemical compound *c1n[o]c2c1nc(*)cn2 0.000 description 3
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- 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
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07—ORGANIC CHEMISTRY
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- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/18—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C251/36—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/38—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C07C255/29—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups and acylated amino groups bound to the carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/18—Oxygen or sulfur atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
Definitions
- the present invention relates to a pyrazino useful as an intermediate for the production of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (hereinafter referred to as T-705) effective for treatment such as prevention and treatment of influenza virus infection.
- T-705 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
- the present invention relates to a [2,3-d] isoxazole derivative and a production method thereof.
- the present invention also relates to a method for producing a pyrazinecarbonitrile derivative and a pyrazinecarboxamide derivative using a pyrazino [2,3-d] isoxazole derivative.
- T-705 is a compound useful for the treatment such as prevention and treatment of viral infections, particularly influenza virus infections.
- T-705 is known to be produced from, for example, 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile (hereinafter referred to as T-705A) (Patent Documents 1 and 2).
- Patent Document 2 describes that T-705A can be efficiently isolated as a salt with various amines.
- T-705A As a method for producing T-705A, for example, (1) a method of reacting 3,6-difluoro-2-pyrazinecarbonitrile with benzyl alcohol and then debenzylating, (2) 3,6-difluoro-2- A method of subjecting pyrazinecarbonitrile to a reaction with water, (3) a method of reacting 3,6-difluoro-2-pyrazinecarbonitrile with a carboxylate, and then generating it by hydrolysis are known (patents) References 1, 2).
- An object of the present invention is to provide a production intermediate such as T-705 and a production method thereof, which are excellent in safety and easy to handle, and further provide a safe and simple production method such as T-705. is there.
- X represents a halogen atom, a hydroxyl group or a sulfamoyloxy group
- Y represents —C ( ⁇ O) R or —CN
- R represents a hydrogen atom, an alkoxy group, an aryloxy group, an alkyl
- a sulfamoyloxy group, an alkoxy group, an aryloxy group, an alkyl group, an aryl group and an amino group may have a substituent.
- Pyrazino [2,3-d] isoxazole derivatives.
- X is a fluorine atom or a chlorine atom
- Y is —C ( ⁇ O) R
- R is a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, or an n-butoxy group.
- the pyrazino [2,3-d] isoxazole derivative according to [1].
- X represents a halogen atom, a hydroxyl group or a sulfamoyloxy group
- Y represents —C ( ⁇ O) R or —CN; wherein R represents a hydrogen atom, an alkoxy group, an aryloxy group, an alkyl
- R represents a hydrogen atom, an alkoxy group, an aryloxy group, an alkyl
- a sulfamoyloxy group, an alkoxy group, an aryloxy group, an alkyl group, an aryl group and an amino group may have a substituent.
- a pyrazino [2,3-d] isoxazole derivative obtained by treating with a base is represented by the following general formula (III)
- X represents a halogen atom, a hydroxyl group or a sulfamoyloxy group
- Y represents —C ( ⁇ O) R or —CN
- R represents a hydrogen atom, an alkoxy group, an aryloxy group, an alkyl
- a sulfamoyloxy group, an alkoxy group, an aryloxy group, an alkyl group, an aryl group and an amino group may have a substituent.
- the pyrazino [2,3-d] isoxazole derivative is treated with a base to give the following general formula (III)
- the method includes the steps of producing a compound represented by “wherein X has the same meaning as described above”, and adding water to the compound represented by the general formula (III): Formula (IV)
- X is a fluorine atom
- Y is —C ( ⁇ O) R (R is an alkoxy group, and the alkoxy group may have a substituent) [7] or [7] 8].
- X is a fluorine atom
- Y is —C ( ⁇ O) R (R is a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, or an n-butoxy group). 7] or the production method according to [8].
- R 1 represents an alkyl group
- R 3 represents —CH 2 CN
- R represents an alkoxy group
- M represents H, Li, K, or Na
- the alkoxy group and the alkyl group may have a substituent ”.
- R 2 represents an alkyl group or an aryl group; the alkyl group or aryl group may have a substituent, and is represented by pyrazino [2,3-d] isoxazo-
- J-5 is characterized by reacting a sulfur derivative with a fluorinating agent in the presence of 2,4-dinitrochlorobenzene or 2,4-dinitrofluorobenzene:
- R 2 represents an alkyl group or an aryl group; the alkyl group or aryl group may have a substituent, and is represented by pyrazino [2,3-d] isoxazo- A method for producing a ruline derivative.
- J-1 The following general formula (J-1)
- R 2 represents an alkyl group or an aryl group; and the alkyl group or aryl group may have a substituent.
- the compound of general formula (I-1), the compound of general formula (III), the compound of general formula (IV), the compound of general formula (J-2), and the compound of general formula (J-3) there are tautomers.
- the present invention encompasses these tautomers.
- the present invention can use hydrates, solvates, and all crystal forms.
- the compound described in this specification may form the salt.
- the salt in that case include a salt that is generally known in a basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group.
- salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
- salts in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
- preferred salts include pharmacologically acceptable salts.
- T-705 and the like can be produced safely and easily.
- X represents a halogen atom, a hydroxyl group or a sulfamoyloxy group.
- X represents a halogen atom
- examples include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- X represents a sulfamoyloxy group
- the nitrogen atom of the sulfamoyloxy group is substituted with a hydroxyl group, an amino group, an alkyl group, an aryl group, a heterocyclic group or an alkylene group which may be via a hetero atom. May be.
- the number of carbon atoms of the substituent on the nitrogen atom is preferably 0 to 10, more preferably 2 to 8, and most preferably 2 to 6. These may further have one or more substituents, and preferred substituents are those listed in Substituent Group A described later.
- substituents are those listed in Substituent Group A described later.
- the sulfamoyloxy group which may have a substituent include sulfamoyloxy group, N, N-dimethylsulfamoyloxy group, N, N-diethylsulfamoyloxy group, morpholinosulfonyloxy Groups and the like.
- X is preferably a fluorine atom, a chlorine atom, a bromine atom, or a hydroxyl group, more preferably a fluorine atom, a chlorine atom, or a hydroxyl group, and most preferably a fluorine atom.
- Y represents —C ( ⁇ O) R or —CN.
- R represents a hydrogen atom, an alkoxy group, an aryloxy group, an alkyl group, an aryl group or an amino group.
- R represents an alkoxy group, a linear, branched, or cyclic alkoxy group having 1 to 10 carbon atoms is preferable.
- the number of carbon atoms is more preferably 1-8, and most preferably 1-6.
- These groups may further have one or more substituents, and the substituents listed in Substituent Group A are preferable.
- examples thereof include an oxy group, an n-amyloxy group, a neopentyloxy group, an n-hexyloxy group, a cyclohexyloxy group, a benzyloxy group, and a 2-ethylhexyloxy group.
- R represents an aryloxy group
- an aryloxy group having 6 to 12 carbon atoms is preferable, 6 to 10 is more preferable, and 6 to 8 is most preferable.
- These groups may further have one or more substituents, and the substituents listed in Substituent Group A are preferable.
- the aryloxy group which may have a substituent include phenoxy group, 4-methoxyphenoxy group, 4-dimethylaminophenoxy group, 3-methylphenoxy group, 2,6-dimethylphenoxy group, 4-t -Amylphenoxy group etc. are mentioned.
- R represents an alkyl group
- a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms is preferable.
- the number of carbon atoms is more preferably 1-8, and most preferably 1-6.
- These groups may further have one or more substituents, and the substituents listed in Substituent Group A are preferable.
- alkyl groups include methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, n-butyl, n-pentyl, cyclopentyl, cyclohexyl, 1-ethylpropyl, etc. Is mentioned.
- R represents an aryl group
- the carbon number is preferably 6 to 12, more preferably 6 to 10, and most preferably 6 to 8.
- These groups may further have one or more substituents, and the substituents listed in Substituent Group A are preferable.
- the aryl group which may have a substituent include a phenyl group, a 4-chlorophenyl group, a 4-methoxyphenyl group, a 3,4-dimethylphenyl group, and a 4-fluorophenyl group.
- R represents an amino group
- the amino group may be substituted with a hydroxyl group, an amino group, an alkyl group, an aryl group, a heterocyclic group, or an alkylene group which may be interposed via a hetero atom.
- the number of carbon atoms of the substituent on the amino group is preferably 0 to 10, more preferably 2 to 8, and most preferably 2 to 6.
- These substituents may further have one or more substituents, and the substituents listed in the substituent group A are preferable.
- amino group which may have a substituent examples include an amino group, N, N-dimethylamino group, N, N-diethylamino group, N, N-diisopropylamino group, N, N-dipropylamino group, Examples thereof include a morpholino group, a piperidino group, a 4-methylpiperazino group, a pyrrolidino group, and an N-methyl-N-phenylamino group.
- Y is preferably —C ( ⁇ O) R (R is an alkoxy group).
- Substituent group A alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms, alkynyl group having 2 to 10 carbon atoms, alkoxy group having 1 to 10 carbon atoms, aryloxy having 6 to 10 carbon atoms A group, a halogen atom, an aryl group having 6 to 10 carbon atoms, a hydroxyl group, an amino group, an acylamino group having 1 to 10 carbon atoms, an alkylsulfonylamino group having 1 to 10 carbon atoms, a carbamoyl group having 1 to 10 carbon atoms, A sulfamoyl group having 0 to 10 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 10 carbon atoms, an acyloxy group having 2 to 12 carbon atoms, a heterocyclic group, a cyano group, and a nitro group.
- alkenyl groups having 2 to 10 carbon atoms include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl, hexenyl, heptenyl and octenyl. Etc.
- alkynyl group having 2 to 10 carbon atoms include ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, and octynyl group.
- Examples of the acylamino group having 1 to 12 carbon atoms include acetylamino group, propionylamino group, benzoylamino group, and naphthoylamino group.
- Examples of the alkylsulfonylamino group having 1 to 10 carbon atoms include a methanesulfonylamino group, a benzenesulfonylamino group, and a toluenesulfonylamino group.
- Examples of the carbamoyl group having 1 to 10 carbon atoms include carbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group and morpholinocarbonyl group.
- Examples of the sulfamoyl group having 0 to 10 carbon atoms include a sulfamoyl group, an N, N-dimethylsulfamoyl group, an N, N-diethylsulfamoyl group and a morpholinosulfonyl group.
- alkoxycarbonyl group having 2 to 10 carbon atoms examples include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, 2-methoxyethoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group And t-butoxycarbonyl group.
- Examples of the acyloxy group having 2 to 12 carbon atoms include acetyloxy group, propionyloxy group, benzoyloxy group and naphthoyloxy group.
- Examples of heterocyclic groups include pyrrolyl, pyrrolinyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl, imidazolinyl , Imidazolidinyl group, pyrazolinyl group, pyrazolidinyl group, furyl group, pyranyl group, thienyl group, oxazolyl group, oxadiazolyl group, isoxazolyl group, morpholinyl group, thiazolyl group, isothiazolyl group, thiadia
- alkyl groups having 1 to 10 carbon atoms examples include What was mentioned about this substituent by description of general formula (I) is mentioned.
- the substituent of the substituent group A may be further substituted with one or more substituents selected from the substituent group A.
- X in the general formula (I) is a fluorine atom, a chlorine atom or a hydroxyl group, and Y is —C ( ⁇ O) R (R is an alkoxy group or An amino group, an alkoxy group and an amino group may have a substituent), X is a fluorine atom, a chlorine atom or a hydroxyl group, and Y is —C ( ⁇ O) R (R is an alkoxy group).
- Group and an alkoxy group may have a substituent
- X is a fluorine atom
- Y is —C ( ⁇ O) R (where R is an alkoxy group, and an alkoxy group is a substituent).
- X may be a fluorine atom
- Y may be —C ( ⁇ O) R (where R is a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, or an n— Most preferred is a butoxy group.
- R 1 represents a hydrogen atom or an alkyl group; the alkyl group may have a substituent.
- R 1 represents an alkyl group, a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms is preferable. The number of carbon atoms is more preferably 1-8, and most preferably 1-6.
- R 1 is preferably a methyl group or an ethyl group.
- the compound of general formula (I) and the compound of general formula (II) can be synthesized, for example, by the following scheme.
- the definitions and preferred ranges of R and R 1 are the same as those described for general formula (I) or general formula (II), respectively, and M represents H, Li, K, or Na.
- Acetate ester (A) is hydrolyzed to obtain carboxylic acid (B).
- various solvents can be used as the solvent, but usually a mixed solvent of water or an organic solvent miscible with water can be used.
- various inorganic bases and organic bases can be used as the base, metal hydroxides such as sodium hydroxide, lithium hydroxide, and potassium hydroxide are preferable.
- the reaction temperature is preferably ⁇ 20 to 100 ° C., more preferably 0 to 80 ° C.
- carboxylic acid (B) is reacted with aminoacetonitrile in the basic to neutral range to convert it to amide (C).
- condensing agent carbodiimides such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, N, N'-disuccinimidyl carbonate and the like Agent, 2-chloro-1-methylpyridinium iodide, 2-chloro-1,3-dimethylimidazolinium chloride, chloro-N, N, N ′, N′-tetramethylformamidinium hexafluorophospho A cationic dehydration condensing agent such as a gate can be used.
- reaction temperature varies depending on the condensing agent used, it is generally preferably from ⁇ 20 ° C. to room temperature.
- the solvent used is not particularly limited as long as it does not affect the reaction.
- nitriles such as acetonitrile, aromatic hydrocarbons such as benzene, toluene and xylene, chloroform, methylene chloride, 1,2- Halogenated hydrocarbons such as dichloroethane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and N-ethylpyrrolidone, esters such as ethyl acetate, isopropyl acetate and butyl acetate, Examples thereof include sulfoxides such as dimethyl sulfoxide, sulfolane, tetrahydrofuran and the like, and these may be used as a mixture.
- a reaction in a two-phase system of an organic solvent and water is also preferably used.
- the condensation reaction from amide (C) to amide (D) can be carried out by reaction with oxalic acid diester or the like in a solvent such as tetrahydrofuran or toluene using a metal alkoxide as a base.
- the reaction temperature is preferably 0 to 60 ° C, more preferably 10 to 40 ° C.
- the product usually precipitates from within the reaction system as a salt.
- the salt may be collected by filtration and used in the next reaction, or may be used as it is in the next reaction without any special operation. Further, the crystal collected by filtration may be neutralized and used for the next reaction.
- Conversion of amide (D) to isoxazole is achieved by first forming an oxime by reaction with hydroxylamine and then carrying out a ring-closing reaction with an acid or base catalyst.
- hydroxylamine a 50% aqueous solution of hydroxylamine can be used, or hydroxylamine hydrochloride, hydroxylamine sulfate, etc. can be used.
- solvent dimethyl sulfoxide, methanol, ethanol, water and the like are preferably used.
- the reaction temperature is preferably 0 to 100 ° C, more preferably room temperature to 80 ° C.
- 5-hydroxypyrazino [2,3-d] isoxazole (general formula (I-1a)) can be produced by treating the compound of general formula (II-1) with an acid.
- the acid used include protonic acids such as hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, camphor-sulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and Lewis acids such as aluminum chloride, zinc chloride, and iron chloride.
- Protonic acid is preferable, hydrogen chloride, sulfuric acid and p-toluenesulfonic acid are more preferable, and p-toluenesulfonic acid is particularly preferable.
- the amount of the acid used as the catalyst is preferably 0.0001 to 1000 times mol of the compound of the general formula (II-1), more preferably 0.001 to 100 times mol, and most preferably 0.01 to 10 times mol. .
- the solvent used is not particularly limited as long as it does not affect the reaction.
- nitriles such as acetonitrile, aromatic hydrocarbons such as benzene, toluene and xylene, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether Ethers such as tellurium, ketones such as acetone, 2-butanone, alcohols such as methanol, ethanol, 2-propanol, N, N-dimethylformamide, N, N-dimethyl
- amides such as acetamide, carboxylic acids such as acetic acid, propionic acid, and trifluoroacetic acid, esters such as ethyl acetate and isopropyl acetate, and sulfoxides such as dimethyl sulfoxide.
- Preferred solvents include aromatic hydrocarbons, ethers, alcohols, carboxylic acids, esters, sulfoxides, carboxylic acids, alcohols, esters are more preferred, and acetic acid is further preferred. preferable.
- the solvent may also serve as the acid catalyst.
- the amount of the solvent to be used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) relative to the compound of general formula (II-1).
- the reaction temperature varies depending on the acid catalyst and solvent used, but is preferably 200 ° C. or lower, more preferably 0 to 150 ° C.
- the reaction time is not particularly limited, but is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and particularly preferably 5 minutes to 5 hours. In this reaction, it is particularly preferred that R of the compound of the general formula (II-1) is an alkoxy group.
- Conversion of the compound of general formula (I-1a) to 5-chloropyrazino [2,3-d] isoxazole can be carried out in various ways with or without the use of a solvent.
- the chlorinating agent can be selected from phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride and the like.
- N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, sulfolane, N-methylpyrrolidone, ethyl acetate or a mixed solvent thereof is preferable, and triethylamine, pyridine, triethylamine hydrochloride, etc. if necessary May be added.
- the reaction temperature is preferably from room temperature to 130 ° C, and more preferably from 50 to 110 ° C.
- fluorinating agents In the reaction of converting the compound of general formula (I-2) to 5-fluoropyrazino [2,3-d] isoxazole (general formula (I-3)), various fluorinations are used as fluorinating agents.
- Reagents can be used. Preferred examples include potassium fluoride, cesium fluoride, tetra-n-butylammonium fluoride, tetramethylammonium fluoride, and tetraphenylphosphonium fluoride. Of these, potassium fluoride and cesium fluoride are preferred, and the spray-dried one is particularly preferred for potassium fluoride.
- the addition amount of the fluorinating agent is preferably 1 to 10 times mol, more preferably 1.1 to 5 times mol, most preferably 1.1 to 3 times mol based on the reaction substrate.
- a dehydrating fluorinating agent such as 2,2-difluoro-1,3-dimethylimidazoline (DFI) or 1,1,2,3,3,3-hexafluoro-1-diethylaminopropane (Ishikawa reagent) You can also.
- aprotic solvents such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, sulfolane, dimethyl sulfoxide, N-methylpyrrolidone, N-ethylpyrrolidone and tetrahydrofuran are preferable, and acetonitrile, N, N- Dimethylformamide, N, N-dimethylacetamide, sulfolane, and dimethylsulfoxide are more preferable, and acetonitrile, N, N-dimethylformamide, and dimethylsulfoxide are more preferable.
- the amount of solvent used is not particularly limited, but is preferably 0.5 to 20 times (v / w), more preferably 1 to 10 times (v / w) relative to the compound of general formula (I-2) IV.
- the most preferable amount is 1 to 3 times (v / w).
- the upper limit of the reaction temperature varies depending on the boiling point of the solvent, it is usually preferably 0 to 130 ° C, more preferably room temperature to 110 ° C, and most preferably 50 to 100 ° C.
- the concentration of water in the reaction system is preferably low, more preferably 0.01 to 1000 ppm, still more preferably 0.01 to 500 ppm, and most preferably 0.01 to 300 ppm.
- various dehydration operations may be performed before the reaction.
- a high boiling point solvent dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N, N-dimethylformamide, etc.
- azeotropic dehydration using toluene or xylene is also preferably used.
- it is also preferably used to reduce the water content in the system by distilling off the high-boiling solvent under reduced pressure.
- molecular sieves or the like can be added for the purpose of reducing moisture in the system.
- the molecular sieve is preferably dehydrated and dried at a high temperature.
- cationic systems such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetraphenylphosphonium chloride, tetramethylammonium chloride, trimethylbenzylammonium bromide, 18-crown-6,
- Nonionic phase transfer catalysts such as polyethylene glycol 400, polyethylene glycol 1000, and tris (2- (2-methoxyethoxy) ethyl) amine can also be preferably used.
- the reaction time is preferably 5 minutes to 50 hours, more preferably 10 minutes to 10 hours, and most preferably 15 minutes to 5 hours.
- the addition amount of 2,4-dinitrochlorobenzene and 2,4-dinitrofluorobenzene is preferably 0.001 to 10 times mol, more preferably 0.01 to 1 times mol of the compound of the general formula (J-4), 0 A molar ratio of 0.01 to 0.2 times is most preferable.
- a fluorine anion source is obtained. It is also possible to convert to a compound of the general formula (I-3) by substituting with potassium bromide or tetrabutylammonium fluoride. That is, a pyrazino [2,3-d] isoxazole derivative having a group that can be substituted by a fluorine atom at the 5-position or a group that can be easily derived into such a group is also important as an intermediate for the production of T-705A. .
- nitriles such as acetonitrile, aromatic hydrocarbons such as benzene, toluene and xylene, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether Ethers such as tellurium, ketones such as acetone, 2-butanone, alcohols such as methanol, ethanol, 2-propanol, N, N-dimethylformamide, N, N-dimethyl
- amides such as acetamide, esters such as ethyl acetate and isopropyl acetate, sulfoxides such as dimethyl sulfoxide, and the like.
- Preferable solvents include aromatic hydrocarbons, ethers, alcohols, esters and sulfoxides.
- the amount of the solvent to be used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) relative to the compound of general formula (I).
- the reaction temperature is preferably 200 ° C. or lower, more preferably 0 to 150 ° C.
- the reaction time is not particularly limited, but is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and particularly preferably 5 minutes to 5 hours.
- R 2 represents an alkyl group or an aryl group; the alkyl group and the aryl group may have a substituent.
- R 2 in the compound of the general formula (J-5) When R 2 represents an alkyl group, a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms is preferable. The number of carbon atoms is more preferably 1-8, and most preferably 1-6. These groups may further have a substituent, and as the substituent, those listed in Substituent Group A are preferable.
- R 2 represents an aryl group
- the carbon number is preferably 6 to 12, more preferably 6 to 10, and most preferably 6 to 8.
- These groups may further have a substituent, and as the substituent, those listed in Substituent Group A are preferable.
- the aryl group which may have a substituent include phenyl group, 4-methoxyphenyl group, 4-dimethylaminophenyl group, 3-methylphenyl group, 2,6-dimethylphenyl group, 4-t -Amylphenyl group and the like can be mentioned.
- R 2 in the compounds of the general formulas (J-0) to (J-4) is preferably an alkyl group having 1 to 6 carbon atoms, and is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Particularly preferred are n-butyl group, isobutyl group, sec-butyl group and t-butyl group.
- the hydroxyl group of the oxime can take an isomeric structure of anti and syn, but in the present invention, either one may be a mixture.
- the compound of the general formula (J-0) can be synthesized by a known method.
- maleic anhydride and alcohol can be reacted to synthesize a maleic acid monoester, followed by derivatization into an acid chloride using a chlorinating agent such as thionyl chloride, and then reaction with ammonia to convert it to an amide.
- the maleic acid monoester can be reacted with, for example, methanesulfonyl chloride or chloroformic acid ester to be converted into a mixed acid anhydride, and subsequently reacted with ammonia to be converted into an amide form.
- a salt such as ammonium carbonate or ammonium acetate may be used.
- maleic anhydride is reacted with ammonia to synthesize maleic acid monoamide, which is then reacted with alcohol in the presence of an acid catalyst such as concentrated sulfuric acid for esterification to obtain a compound of the general formula (J-0).
- an acid catalyst such as concentrated sulfuric acid for esterification to obtain a compound of the general formula (J-0).
- the compound of the general formula (J-0) may be any cis-trans isomer.
- Conversion of the compound of general formula (J-0) to the compound of general formula (J-1) can be achieved by conjugate addition of hydroxylamine.
- hydroxylamine a 50% aqueous solution of hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate or the like can be used.
- hydroxylamine hydrochloride or sulfate it is preferable to add various organic bases or inorganic bases.
- the base that can be used include triethylamine, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, sodium phosphate and the like.
- the amount of the base used is preferably 0.1 to 10 times mol of hydroxylamine, more preferably 0.5 to 2 times mol, and most preferably 1 to 1.2 times mol.
- the amount of hydroxylamine used is preferably 1 to 10 moles, more preferably 1 to 2 moles, and most preferably 1 to 1.2 moles of the compound of general formula (J-0).
- the solvent used is not particularly limited as long as it does not affect the reaction.
- nitriles such as water and acetonitrile, aromatic hydrocarbons such as benzene, toluene and xylene, dioxane, tetrahydrofuran, ethylene glycol Ethers such as rudimethyl ether, ketones such as acetone, 2-butanone, alcohols such as methanol, ethanol, 2-propanol, N, N-dimethylformamide, N, N -Amides such as dimethylacetamide, esters such as ethyl acetate and isopropyl acetate, sulfoxides such as dimethyl sulfoxide, and the like may be used as a mixture.
- Preferable solvents include aromatic hydrocarbons, ethers, alcohols, esters, and sulfoxides, and aromatic hydrocarbons, alcohols, and esters are more preferable.
- the amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 10 times (v / w) relative to the compound of general formula (J-0), The amount of 1 to 3 times (v / w) is most preferable.
- the reaction temperature varies depending on the solvent used, it is preferably 0 to 130 ° C, more preferably room temperature to 100 ° C, and particularly preferably room temperature to 50 ° C.
- the reaction time is not particularly limited, but is preferably 5 minutes to 10 hours, more preferably 10 minutes to 5 hours, and particularly preferably 10 minutes to 1 hour.
- the compound of the general formula (J-1) may be isolated and subjected to the next step, or may be directly subjected to the next step without isolation.
- Conversion of the compound of general formula (J-1) to the compound of general formula (J-2) can be achieved by reacting with glyoxal in the presence of an acid or a base.
- glyoxal an inexpensive 40% aqueous solution is preferably used, but as the glyoxal equivalent, for example, an acetal form or an adduct of sulfite ion can be used.
- the amount of glyoxal used is preferably 1 to 10 times mol, more preferably 1 to 5 times mol, and most preferably 1 to 3 times mol of the compound of general formula (J-1).
- the solvent used is not particularly limited as long as it does not affect the reaction.
- nitriles such as water and acetonitrile, aromatic hydrocarbons such as benzene, toluene and xylene, dioxane, tetrahydrofuran, ethylene glycol Ethers such as rudimethyl ether, ketones such as acetone, 2-butanone, alcohols such as methanol, ethanol, 2-propanol, N, N-dimethylformamide, N, N -Amides such as dimethylacetamide, esters such as ethyl acetate and isopropyl acetate, sulfoxides such as dimethyl sulfoxide, and the like may be used as a mixture.
- Preferred solvents include water, nitriles, ethers, ketones, alcohols and amides, with water, ethers and alcohols being more preferred and water being most preferred.
- the amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 20 times (v / w) relative to the compound of general formula (J-1), The amount of 1 to 10 times (v / w) is most preferable.
- an acid or a base for the purpose of improving the yield.
- acids used include proton acids such as hydrogen chloride, sulfuric acid, acetic acid, p-toluenesulfonic acid, camphor-sulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and Lewis acids such as aluminum chloride, zinc chloride, and iron chloride.
- proton acids such as hydrogen chloride, sulfuric acid, acetic acid, p-toluenesulfonic acid, camphor-sulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid
- Lewis acids such as aluminum chloride, zinc chloride, and iron chloride.
- Protic acid is preferable, and hydrogen chloride, sulfuric acid, and acetic acid are more preferable.
- inorganic bases or organic bases can be used as the base to be used.
- inorganic base sodium hydrogen carbonate, potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, sodium monohydrogen phosphate and the like are preferable.
- organic base triethylamine, N, N-diisopropyl Ethylamine, pyridine, picoline and the like are preferable.
- the amount of the acid or base used is preferably 0.01 to 100 times mol, more preferably 0.1 to 10 times mol, and most preferably 1 to 5 times mol of the compound of general formula (J-1).
- the reaction temperature varies depending on the solvent used, it is preferably 0 to 130 ° C, more preferably room temperature to 100 ° C, and particularly preferably 40 to 80 ° C.
- the reaction time is not particularly limited, but is preferably 5 minutes to 10 hours, more preferably 10 minutes to 5 hours, and particularly preferably 30 minutes to 2 hours.
- Conversion of the compound of general formula (J-2) to the compound of general formula (J-3) can be achieved by reacting with a nitrite in the presence of an acid.
- a nitrite ethyl nitrite, n-propyl nitrite, isopropyl nitrite, n-butyl nitrite, isobutyl nitrite, t-butyl nitrite, isoamyl nitrite and the like can be used.
- isoamyl nitrite is preferable from the viewpoint of availability.
- the compound of the general formula (J-3) can also be obtained by adding an aqueous sodium nitrite solution to the mixture of the compound of the general formula (J-2) and the acid.
- the amount of nitrite or sodium nitrite to be used is preferably 1 to 10 times mol, more preferably 1 to 5 times mol, and most preferably 1 to 3 times mol of the compound of general formula (J-2).
- acids used include proton acids such as hydrogen chloride, sulfuric acid, acetic acid, p-toluenesulfonic acid, camphor-sulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and Lewis acids such as aluminum chloride, zinc chloride, and iron chloride.
- proton acids more preferred are hydrogen chloride, sulfuric acid and acetic acid, and most preferred is hydrogen chloride.
- hydrogen chloride can be generated in the system by adding an acid chloride such as acetyl chloride to alcohols such as ethanol.
- the amount of the acid used is preferably 0.01 to 100 times mol, more preferably 0.1 to 10 times mol, and most preferably 1 to 5 times mol of the compound of general formula (J-2).
- the solvent used is not particularly limited as long as it does not affect the reaction.
- water nitriles such as acetonitrile, aromatic hydrocarbons such as benzene, toluene, xylene, dioxane, tetrahydrofuran, ethylene glyco- Ethers such as rudimethyl ether, ketones such as acetone, 2-butanone, alcohols such as methanol, ethanol, 2-propanol, N, N-dimethylformamide, N, N -Examples include amides such as dimethylacetamide, carboxylic acids such as acetic acid, propionic acid and trifluoroacetic acid, esters such as ethyl acetate and isopropyl acetate, and sulfoxides such as dimethyl sulfoxide. Also good.
- Preferable solvents include water, ethers, alcohols, amides and carboxylic acids. Ethers, alcohols and carboxylic acids are more preferable
- the amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 10 times (v / w) with respect to the compound of general formula (J-2), The amount of 1 to 5 times (v / w) is most preferable.
- the reaction temperature varies depending on the solvent used, it is preferably 0 to 130 ° C, more preferably room temperature to 100 ° C, particularly preferably room temperature to 70 ° C.
- the reaction time is not particularly limited, but is preferably 5 minutes to 10 hours, more preferably 10 minutes to 5 hours, and particularly preferably 30 minutes to 3 hours.
- chlorination and isoxazole cyclization of the pyrazine ring may be performed simultaneously, or these two reactions are stepwise performed. You may go to In this reaction, phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, phosphorus trichloride, pyrocatealkylphosphotrichloride, dichlorotriphenylphosphorane, oxalyl chloride, etc. can be used alone or in combination of two or more as reagents. .
- phosphorus oxychloride and thionyl chloride are more preferable in terms of yield and cost, and phosphorus oxychloride is particularly preferable.
- the amount of these reagents to be used is preferably 1 to 20-fold mol, more preferably 2 to 10-fold mol, and most preferably 2 to 5-fold mol of the compound of general formula (J-3).
- the solvent used is not particularly limited as long as it does not affect the reaction.
- nitriles such as acetonitrile, aromatic hydrocarbons such as benzene, toluene and xylene, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether Ethers such as tellurium, ketones such as acetone and 2-butanone, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, 1,3-dimethyl-2-imidazo Examples include ureas such as lizinone, esters such as ethyl acetate and isopropyl acetate, and these may be used in combination.
- Preferable solvents include nitriles, aromatic hydrocarbons, ethers, amides, ureas and esters, and aromatic hydrocarbons and amides are more preferable. In order to increase the reaction rate, it is preferable to add dimethylformamide.
- the amount of the solvent used is not particularly limited, but it is preferably 1 to 50 times (v / w), more preferably 1 to 10 times (v / w) relative to the compound of general formula (J-3), The amount of 1 to 5 times (v / w) is most preferable.
- the reaction temperature varies depending on the solvent used, it is preferably 0 to 130 ° C, more preferably room temperature to 100 ° C, and particularly preferably 50 to 80 ° C.
- the reaction time is not particularly limited, but is preferably 5 minutes to 20 hours, more preferably 30 minutes to 10 hours, and particularly preferably 1 to 5 hours.
- inorganic bases include potassium fluoride, cesium fluoride, sodium bicarbonate, potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, boric acid Sodium and the like are preferable.
- organic base triethylamine, ethyl (diisopropyl) amine, pyridine, picoline and the like are preferable.
- Sodium hydrogen carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, and sodium monohydrogen phosphate are more preferable.
- the amount of the base used is preferably 0.1 to 100 times mol, more preferably 0.5 to 30 times mol, and most preferably 1 to 10 times mol of the compound of general formula (I).
- the solvent used is not particularly limited as long as it does not affect the reaction.
- water nitriles such as acetonitrile, aromatic hydrocarbons such as benzene, toluene, xylene, dioxane, tetrahydrofuran, ethylene glycol Ethers such as dimethyl ether, acetone, ketones such as 2-butanone, alcohols such as methanol, ethanol, 2-propanol, N, N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide, esters such as ethyl acetate and isopropyl acetate, sulfoxides such as dimethyl sulfoxide, and the like.
- aromatic hydrocarbons such as benzene, toluene, xylene, dioxane, tetrahydrofuran
- ethylene glycol Ethers such as dimethyl ether
- acetone ketones
- ketones such as 2-butanone
- alcohols such as methanol, ethanol, 2-propanol
- the solvent water alone or a mixed solution of water and an organic solvent (alcohols, nitriles, ethers, sulfoxides) miscible with water is preferably used. It is also preferable to react in a two-phase system with water using a solvent that is not miscible with water, such as aromatic hydrocarbons, esters, ethers, etc., and a solvent that is immiscible with water is mixed. It can also be used. More preferable solvents include aromatic hydrocarbons, ethers, alcohols, esters, and water, and a two-layer system of aromatic hydrocarbons and water is more preferable.
- the amount of the solvent to be used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) relative to the compound of general formula (I).
- the reaction temperature is preferably 200 ° C. or lower, more preferably 0 to 150 ° C.
- the reaction time is not particularly limited, but is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and particularly preferably 5 minutes to 5 hours.
- the above-mentioned cationic phase transfer catalyst and nonionic phase transfer catalyst can be used.
- X in the compound of the general formula (I) is a fluorine atom
- Y is —C ( ⁇ O) R (R is an alkoxy group, and the alkoxy group may have a substituent). Is particularly preferred.
- T-705A and T-705 can be produced safely and simply by using the compound of the general formula (I) of the present invention as an intermediate.
- s is a single line
- d is a double line
- t is a triple line
- q is a quadruple line
- quint is 5 lines
- sep is 7 lines
- h is 9 lines
- dd is 4 lines which are not evenly spaced
- m is a multiple line
- “br” is a wide line.
- Synthesis Example 1 Synthesis of (B-1) 11.3 L of water and 1090 g of sodium hydroxide were added to and dissolved in a 30 L glass reaction vessel. To this, 4000 g of (A-1) (Tokyo Kasei Reagent) was added and stirred at an internal temperature of 70 ° C. for 30 minutes. To the reaction solution, 2270 g of sodium chloride was added and dissolved, and the reaction mixture was cooled to 0 ° C. or lower. After 2270 mL of concentrated hydrochloric acid was added little by little, 11.3 L of ethyl acetate was added, and the aqueous layer was discarded after liquid separation.
- A-1 Tokyo Kasei Reagent
- Synthesis Example 2 Synthesis of (C-1) (B-1) 1.48 kg (10.0 mol) was dissolved in 7.40 L of acetonitrile, and 1.10 kg (5.25 mol) of aminoacetonitrile sulfate was added. While maintaining the internal temperature at 5 ° C. or lower, 1.91 kg (10.0 mol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added. While maintaining the internal temperature at 0 to 6 ° C., 2.07 kg (20.0 mol) of triethylamine was added dropwise over 90 minutes. The resulting reaction mixture was left overnight at room temperature. After adding 3.00 L of water to the reaction mixture, the solvent was distilled off under reduced pressure.
- Synthesis Example 4 Synthesis of (F-1) 1.51 kg (5.40 mol) of (E-1) was dissolved in 3.90 L of acetic acid, and 213 g (1.12 mol) of p-toluenesulfonic acid monohydrate was added. The reaction was carried out at an internal temperature of 77-80 ° C. for 2 hours. The resulting reaction mixture was cooled to room temperature, and 8.00 L of water was added and stirred for 20 minutes. The precipitate was collected by filtration, washed with water until the pH of the filtrate reached 5 or higher, and dried at 40 ° C. overnight to obtain 615 g of (F-1) pale yellow solid. Yield 58.4%.
- Synthesis Example 7 Synthesis of (H-1) After mixing 1.80 g (31.0 mmol) of potassium fluoride and 22.0 mL of dimethyl sulfoxide, 15.0 mL of toluene was added and stirred. Toluene was distilled off under reduced pressure at an external temperature of 80 ° C. and 70 mmHg, 1.07 g (5.00 mmol) of (G-1) was added, and the mixture was reacted at an internal temperature of 80 ° C. for 3 hours. After cooling to room temperature, the operation of adding 300 mL of ethyl acetate and 200 mL of water, stirring and allowing to stand to remove the aqueous layer was repeated twice.
- Synthesis Example 8 Synthesis of T-705A (H-1) To 200 mg (1.01 mmol), tetrahydrofuran (3.00 mL), water (3.00 mL), and sodium hydroxide (55.0 mg, 1.38 mmol) were added. Heated at 80 ° C. for 3 hours. After cooling to room temperature, ion exchange resin DOWEX (registered trademark) 50W ⁇ 2-200 (H) was added, and filtration and concentration were performed to obtain 126 mg of T-705A as a yellow solid. Yield 89.7%.
- DOWEX registered trademark
- T-705 can be produced using T-705A synthesized by the method of the present invention by the method of treating with the basic aqueous solution described in Patent Document 1 Production Example 4 or Patent Document 2 Production Example 1. is there.
- Synthesis Example 15 Synthesis of (A-7) (G-1) 2.14 g (10.0 mmol) and cyclohexyl alcohol 10.0 g were mixed, and diisopropylethylamine 2.00 mL (10.0 mmol), 4-dimethyl 0.210 g of aminopyridine was added and reacted at an internal temperature of 100 ° C. for 1 hour. After cooling to room temperature, 100 mL of ethyl acetate and 50.0 mL of hydrochloric acid (1 mol / L) were added, and the operation of stirring and allowing to stand to remove the aqueous layer was repeated twice.
- Synthesis Example 20 Synthesis of (A-12) 0.630 g (10.8 mmol) of potassium fluoride and 14.4 mL of dimethyl sulfoxide were mixed, and the solvent was distilled off under reduced pressure at an external temperature of 80 ° C. and 3 to 5 hPa. 15.0 mL of dry dimethyl sulfoxide and 0.820 g (3.60 mmol) of (A-1a) were added and reacted at an internal temperature of 90 ° C. for 4 hours. According to high performance liquid chromatography-analysis, the production rate was 97.0%. (Diphenyl ether was used as an internal standard.)
- Synthesis Example 21 Synthesis of (A-13) After mixing 3.50 g (60.0 mmol) of potassium fluoride and 250 mL of dimethyl sulfoxide, the solvent was distilled off under reduced pressure at an external temperature of 130 ° C and 21 mmHg. 80.0 mL of dry dimethyl sulfoxide and 4.83 g (20.0 mmol) of (A-2) were added and reacted at an internal temperature of 90 ° C. for 4 hours. After cooling to room temperature, the operation of adding 100 mL of toluene and 100 mL of water, stirring and allowing to stand to remove the aqueous layer was repeated twice.
- Synthesis Example 22 Synthesis of (A-14) 0.360 g (6.20 mmol) of potassium fluoride and 8.00 mL of dimethyl sulfoxide were mixed, and then 14.0 mL of toluene was added and stirred. Toluene was distilled off under reduced pressure at an external temperature of 80 ° C. and 70 mmHg, 0.510 g (2.00 mmol) of (A-3) was added, and the mixture was reacted at an internal temperature of 80 ° C. for 2 hours and at an internal temperature of 90 ° C. for 1.5 hours. .
- Synthesis Example 23 Synthesis of (A-15) In a nitrogen atmosphere, 4.68 mL of dimethyl sulfoxide and 10.0 mL of toluene were added to 203 mg (3.51 mmol) of potassium fluoride, heated to 70 ° C., and toluene was added under reduced pressure. Was distilled off. Furthermore, 0.300 g (1.17 mmol) of (A-4) was added and reacted at 80 ° C. for 2 hours with stirring. As a result of HPLC analysis of the reaction solution, the production rate was 84.0%. (Diphenyl ether was used as an internal standard.)
- Synthesis Example 24 Synthesis of (A-16) In the same manner as in Synthesis Example 22, potassium fluoride 0.230 g (4.00 mmol), dimethyl sulfoxide 6.00 mL, (A-5) 0.400 g (1.50 mmol) ) To obtain 0.190 g of a white solid (A-16). Yield 50.1%.
- Synthesis Example 25 Synthesis of (A-17) After mixing 0.620 g (10.7 mmol) of potassium fluoride and 14.4 mL of dimethyl sulfoxide, 14.0 mL of toluene was added and stirred. Toluene was distilled off under reduced pressure at an external temperature of 80 ° C. and 70 mmHg, 0.510 g of (A-6) was added, and the mixture was reacted at an internal temperature of 80 ° C. for 2 hours and at an internal temperature of 90 ° C. for 2 hours. According to high performance liquid chromatography-analysis, the production rate was 89.0%. (Diphenyl ether was used as an internal standard.)
- Synthesis Example 27 Synthesis of (A-19) In the same manner as in Synthesis Example 25, 0.590 g (10.0 mmol) of potassium fluoride, 12.0 mL of dimethyl sulfoxide, 0.760 g (3.00 mmol) of (A-10) ) For 4 hours at 80 ° C., the yield was 65.0%.
- Synthesis Example 28 Synthesis of (A-20) In the same manner as in Synthesis Example 25, 0.520 g (9.00 mmol) of potassium fluoride, 12.0 mL of dimethyl sulfoxide, 0.76 g (3.00 mmol) of (A-11) ) For 4 hours at 80 ° C., the yield was 81.0%.
- Synthesis Example 30 Synthesis of T-705A (A-15) To 0.500 g (2.22 mmol), 2.00 mL of toluene, 1.00 mL of water, and 0.224 g (2.66 mmol) of sodium bicarbonate were added and stirred. The reaction was carried out at 80 ° C. for 3 hours and at 100 ° C. for 5 hours. When the reaction solution was analyzed by high performance liquid chromatography, the yield was 92.0%.
- Synthesis Example 32 Synthesis of (A-23) (F-1) 6.66 g (34.0 mmol), acetonitrile 50.0 mL, diisopropylethylamine 6.80 mL (41.0 mmol) mixed, ice-cooled, diethyl 5.10 mL (41.0 mmol) of carbamic acid chloride and 0.370 g (3.00 mmol) of 4-dimethylaminopyridine were added and allowed to react at room temperature overnight. After concentration, 100 mL of ethyl acetate and 100 mL of hydrochloric acid (1 mol / L) were added, and the operation of stirring and allowing to stand to remove the aqueous layer was repeated twice.
- Synthesis Example 35 Synthesis of (A-21) to 0.510 g (2.00 mmol) of (A-10), 2.00 mL of toluene, 1.00 mL of water, 0.340 g (4.00 mmol) of sodium bicarbonate, tetrabutyl 0.130 g (0.400 mmol) of ammonium bromide was added, and the mixture was reacted at 100 ° C. for 2 hours with stirring. When the reaction solution was analyzed by high performance liquid chromatography, the production rate was 13.0%.
- Synthesis Example 39 Synthesis of (T-705A) Under a nitrogen atmosphere, dimethylsulfoxide (10.0 mL) and N, N-dimethylformamide (15.0 mL) were added to potassium fluoride (460 mg, 7.91 mmol). , N-dimethylformamide was distilled off. Further, 0.460 g (2.61 mmol) of (A-22) was added and reacted at 80 ° C. for 3 hours with stirring. After cooling to room temperature, 50.0 mL of ethyl acetate and 30.0 mL of water were added and stirred and allowed to stand.
- Synthesis Example 42 Synthesis of (A-29) 40% glyoxal aqueous solution 56.0 g (0.386 mol), tetrahydrofuran 125 mL, water 125 mL, potassium carbonate 13.3 g (0.0955 mol) were added and cooled to 12 ° C. . (A-27) 33.7 g (0.191 mol) was added, and the mixture was stirred at 20 ° C. for 3 hours. After adding 11.6 g of acetic acid, the reaction solution was concentrated to 80.0 g, and 30.0 mL of saturated brine was added and stirred.
- Synthesis Example 43 Synthesis of (A-31) (A-29) To a mixture of 5.00 g (0.0252 mol) and ethanol 65.0 mL, ethanol 30.0 mL, acetyl chloride 1.60 mL (22. 5 mmol) was added and stirred. After adding 3.70 mL (27.5 mmol) of isoamyl nitrite and stirring at room temperature for 4 hours, 0.500 mL (3.72 mmol) of isoamyl nitrite was added, and the mixture was further stirred at room temperature for 3.5 hours.
- Synthesis Example 45 Synthesis of isopropyl- (Z) -4-amino-4-oxo-2-butenoate 196 g (2.00 mol) of maleic anhydride was added to 123 g (2.05 mol) of 2-propanol and 800 mL of ethyl acetate. Dissolved in. Triethylamine 300 mL (2.15 mol) was added dropwise at an internal temperature of 10 ° C. or less over 1.5 hours, followed by stirring for 1 hour. To the reaction mixture, 193 mL (2.03 mol) of ethyl chloroformate was added dropwise over 2 hours at an internal temperature of ⁇ 5 ° C. or lower.
- Synthesis Example 46 Synthesis of (A-28) 13.9 g (0.210 mol) of a 50% aqueous hydroxylamine solution was dissolved in 200 mL of 2-propanol. While maintaining the internal temperature at 3.5 to 6 ° C. in an ice bath, 31.4 g (0.200 mol) of isopropyl- (Z) -4-amino-4-oxo-2-butenoate was added over 15 minutes. 20.0 mL of 2-propanol was added. The resulting reaction solution was stirred at room temperature for 3 hours and then allowed to stand in a refrigerator. The precipitated solid was separated by filtration, washed with cold 2-propanol, and then dried under reduced pressure at room temperature.
- Synthesis Example 47 Synthesis of (A-28) 9.43 g (60.0 mmol) of isopropyl- (E) -4-amino-4-oxo-2-butenoate was dissolved in 28.3 mL of tetrahydrofuran, and the mixture was heated to 42 ° C. Warmed in the set water bath. 4.16 g (63.0 mmol) of 50% hydroxylamine aqueous solution was added dropwise over 20 minutes, and the resulting reaction solution was stirred at 42 ° C. for 1 hour. After adding 9.40 mL of water, tetrahydrofuran was distilled off under reduced pressure. It was confirmed by 1 H-NMR that the raw material disappeared and (A-28) was contained in the obtained solution.
- Synthesis Example 48 Synthesis of (A-30) 3.72 g (25.0 mmol) of 39% glyoxal aqueous solution was dissolved in 30.0 mL of 2-propanol. The internal temperature was set to 41 ° C. in a hot water bath, and 2.38 g (12.5 mmol) of (A-28) was dissolved in 2.00 mL of water and 4.00 mL of 2-propanol and added dropwise. At this time, the reaction solution was added dropwise together with a 1 mol / L sodium carbonate aqueous solution so as to maintain the pH of the reaction solution at 8.9 to 9.1. The obtained reaction mixture was reacted at an internal temperature of 41 ° C. for 2 hours.
- Synthesis Example 49 Synthesis of (A-30) 12.22 g (77.8 mmol) of isopropyl- (E) -4-amino-4-oxo-2-butenoate was dissolved in 19.8 mL of THF, and the temperature was 15 to 20 ° C. Cooled in a water bath. 5.14 g (77.8 mmol) of 50% hydroxylamine aqueous solution was added dropwise over 1 minute, and the resulting reaction solution was stirred at 27-30 ° C. for 3 hours. It was confirmed by 1 H-NMR that the raw material disappeared and (A-28) was contained in the obtained solution. Sodium hydrogen carbonate 0.118 g was dissolved in water 18.3 mL.
- a 40% aqueous solution of glyoxal (20.31 g, 140.0 mmol) and the above THF solution of (A-28) were added dropwise over 60 minutes.
- the reaction solution was added dropwise together with a 50% aqueous sodium hydroxide solution so that the pH of the reaction solution was maintained at 8.2 to 8.4 (simultaneous addition of three solutions).
- the obtained reaction mixture was reacted at an internal temperature of 50 ° C. for 1 hour.
- a 50% aqueous sodium hydroxide solution was added dropwise so as to maintain the pH of the reaction solution at 8.4.
- THF was distilled off under reduced pressure, and 5.0 g of sodium chloride was added.
- Synthesis Example 50 Synthesis of (A-32) Under a nitrogen atmosphere, 20.0 mL of isopropyl alcohol was added to 4.60 g (21.7 mmol) of (A-30), and the mixture was cooled to 5 ° C while stirring. Further, 2.86 mL (40.3 mmol) of acetyl chloride was added dropwise while maintaining the internal temperature at 10 ° C. or lower. The temperature was raised to 40 ° C., and 5.41 mL (40.3 mmol) of isoamyl nitrite was added dropwise. After completion of dropping, the mixture was stirred at 25 ° C. for 1 hour 30 minutes, and then cooled to ⁇ 10 ° C.
- Synthesis Example 51 Synthesis of (A-2) In a nitrogen atmosphere, a mixture of (A-32) 25.0 g (0.104 mol), N, N-dimethylformamide 62.5 mL, and toluene 62.5 mL was stirred. The internal temperature was kept at 15 ° C. or lower, and 47.3 mL (0.510 mol) of phosphorus oxychloride was added dropwise. After completion of dropping, the temperature was raised to 70 ° C. and stirred for 7 hours. The mixture was allowed to cool to room temperature, and this reaction mixture was slowly added dropwise to a mixed solution of 62.5 mL of toluene and 300 mL of 10% brine at an internal temperature of 10 ° C. or lower.
- the organic layer was washed twice with 100 mL of 10% brine, and further with 100 mL of 10% aqueous sodium bicarbonate and 100 mL of 10% brine.
- the organic layer was concentrated, and 7.50 mL of isopropyl alcohol and 150 mL of hexane were added to the residue.
- Synthesis Example 52 Synthesis of (A-13) 0.219 g (2.00 mmol) of tetramethylammonium chloride, 2.32 g (40.0 mmol) of potassium fluoride, 9.70 mL of dry dimethyl sulfoxide, and 38.6 mL of dry toluene were mixed. After that, toluene was distilled off under reduced pressure at an external temperature of 120 ° C. After cooling to room temperature, 0.203 g (1.00 mmol) of 2,4-dinitrochlorobenzene and 4.83 g (20.0 mmol) of (A-2) were added and reacted at an internal temperature of 90 ° C. for 2 hours.
- Synthesis Example 53 Synthesis of T-705A dicyclohexylamine salt To the solution of (A-13) obtained in Synthesis Example 52, 14.5 mL of water and 3.36 g (40.0 mmol) of sodium bicarbonate were added, and the external temperature was 100 ° C. The reaction was performed for 4 hours. The organic layer was removed, 3.43 mL (60.0 mmol) of acetic acid was added to the aqueous layer, and the mixture was refluxed under reduced pressure at an external temperature of 70 ° C. and 100 mmHg for 1.5 hours. After cooling to room temperature, 5.00 mL of water, 9.60 mL of acetone, and 3.30 mL of 28% aqueous ammonia were added.
- Synthesis Example 54 Synthesis of T-705 10.0-mL (15.6 mmol) of T-705A dicyclohexylamine salt in 10.0 mL of toluene and an aqueous sodium hydroxide solution (0.656 g of sodium hydroxide dissolved in 20.0 mL of water) And stirred at room temperature for 30 minutes. After standing for 10 minutes, the upper layer was removed. Toluene 10.0 mL was added to the lower layer, and the upper layer was removed by stirring and leaving for 10 minutes.
- the solid on Nutsche was washed with 5.00 mL of water, and hydrochloric acid was added to the mixed solution of the filtrate and the washing solution at an internal temperature of 35 to 45 ° C. to adjust the pH to 3 to 4. After cooling to 0-5 ° C. and stirring for 1 hour, the precipitated solid was filtered and washed with 5.00 mL of water and 5.00 mL of isopropyl alcohol to obtain 2.06 g of a white solid (T-705). Yield 84.0%.
- the present invention is useful for the production of T-705 useful for treatment such as prevention and treatment of influenza virus infection.
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Abstract
Description
T-705Aの製造方法として、例えば、(1)3,6-ジフルオロ-2-ピラジンカルボニトリルをベンジルアルコールと反応させた後、脱ベンジル化する方法、(2)3,6-ジフルオロ-2-ピラジンカルボニトリルを水との反応に付す方法、(3)3,6-ジフルオロ-2-ピラジンカルボニトリルとカルボン酸塩を反応させたのち、加水分解により生成させる方法などが知られている(特許文献1、2)。
また、3位にカルボニル基を有するピラジノ〔2,3-d〕イソオキサゾールの合成に関しては非特許文献1、2に記載された例が知られているが、本発明のピラジノ〔2,3-d〕イソオキサゾールは同様の方法で合成することはできない。
[1]下記一般式(I)
[2]Yが-C(=O)R(Rはアルコキシ基またはアミノ基、アルコキシ基およびアミノ基は置換基を有していてもよい)であることを特徴とする[1]に記載のピラジノ〔2,3-d〕イソオキサゾ-ル誘導体。
[4]Xがフッ素原子または塩素原子であり、Yが-C(=O)R(Rはアルコキシ基、アルコキシ基は置換基を有していてもよい)であることを特徴とする[1]に記載のピラジノ〔2,3-d〕イソオキサゾ-ル誘導体。
[5]Xがフッ素原子または塩素原子であり、Yが-C(=O)R(Rはメトキシ基、エトキシ基、n-プロポキシ基、イソプロポキシ基またはn-ブトキシ基)であることを特徴とする[1]に記載のピラジノ〔2,3-d〕イソオキサゾ-ル誘導体。
[6]下記一般式(II)
で表されるピラジノ〔2,3-d〕イソオキサゾ-ル誘導体の製造方法。
[7]下記一般式(I)
[8]下記一般式(I)
[9]Xがフッ素原子であり、Yが-C(=O)R(Rはアルコキシ基、アルコキシ基は置換基を有していてもよい)であることを特徴とする[7]または[8]に記載の製造方法。
[10]Xがフッ素原子であり、Yが-C(=O)R(Rはメトキシ基、エトキシ基、n-プロポキシ基、イソプロポキシ基またはn-ブトキシ基)であることを特徴とする[7]または[8]に記載の製造方法。
[11]下記一般式(C-2)
[12]下記一般式(J-3)
で表されるピラジノ〔2,3-d〕イソオキサゾ-ル誘導体の製造方法。
[13]下記一般式(J-4)
[14]下記一般式(J-1)
[15]下記一般式(J-2a)
その場合の塩としては、通常知られているアミノ基などの塩基性基またはヒドロキシルもしくはカルボキシル基などの酸性基における塩を挙げることができる。
塩基性基における塩としては、たとえば、塩酸、臭化水素酸、硝酸および硫酸などの鉱酸との塩;ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸およびトリフルオロ酢酸などの有機カルボン酸との塩;ならびにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩が挙げられる。
上記した塩の中で、好ましい塩としては、薬理学的に許容される塩が挙げられる。
一般式(I)で表される化合物において、Xはハロゲン原子、水酸基またはスルファモイルオキシ基を表す。Xがハロゲン原子を表す場合、例としてはフッ素原子、塩素原子、臭素原子またはヨウ素原子が挙げられる。Xがスルファモイルオキシ基を表す場合、スルファモイルオキシ基の窒素原子は、水酸基、アミノ基、アルキル基、アリ-ル基、複素環基またはヘテロ原子を介していてもよいアルキレン基で置換されていてもよい。窒素原子上の置換基の炭素数は0~10が好ましく、2~8がより好ましく、2~6が最も好ましい。これらはさらに1つ以上の置換基を有していてもよく、置換基としては、後述する置換基群Aに挙げたものが好ましい。置換基を有していてもよいスルファモイルオキシ基の例としては、スルファモイルオキシ基、N,N-ジメチルスルファモイルオキシ基、N,N-ジエチルスルファモイルオキシ基、モルホリノスルホニルオキシ基などが挙げられる。
Yが-C(=O)R(Rはアルコキシ基)であることが好ましい。
炭素数2~10のアルキニル基の例としては、エチニル基、プロピニル基、ブチニル基、ペンチニル基、ヘキシニル基、ヘプチニル基およびオクチニル基などが挙げられる。
炭素数1~12のアシルアミノ基の例としては、アセチルアミノ基、プロピオニルアミノ基、ベンゾイルアミノ基およびナフトイルアミノ基などが挙げられる。
炭素数1~10のアルキルスルホニルアミノ基の例としてはメタンスルホニルアミノ基、ベンゼンスルホニルアミノ基およびトルエンスルホニルアミノ基などが挙げられる。
炭素数0~10のスルファモイル基の例としては、スルファモイル基、N,N-ジメチルスルファモイル基、N,N-ジエチルスルファモイル基およびモルホリノスルホニル基などが挙げられる。
炭素数2~10のアルコキシカルボニル基の例としては、メトキシカルボニル基、エトキシカルボニル基、n-プロポキシカルボニル基、イソプロポキシカルボニル基、2-メトキシエトキシカルボニル基、n-ブトキシカルボニル基、イソブトキシカルボニル基およびt-ブトキシカルボニル基などが挙げられる。
複素環基の例としては、ピロリル基、ピロリニル基、ピロリジニル基、ピペリジル基、ピペラジニル基、イミダゾリル基、ピラゾリル基、ピリジル基、テトラヒドロピリジル基、ピリダジニル基、ピラジニル基、ピリミジニル基、テトラゾリル基、イミダゾリニル基、イミダゾリジニル基、ピラゾリニル基、ピラゾリジニル基、フリル基、ピラニル基、チエニル基、オキサゾリル基、オキサジアゾリル基、イソオキサゾリル基、モルホリニル基、チアゾリル基、イソチアゾリル基、チアジアゾリル基、チオモルホリニル基、チオキサニル基、ピロ-ル-1-イル基、ピロリン-1-イル基、ピロリジン-1-イル基、ピペリジン-1-イル基、ピペラジン-1-イル基、イミダゾ-ル-1-イル基、ピラゾ-ル-1-イル基、テトラゾ-ル-1-イル基、イミダゾリン-1-イル基、イミダゾリジン-1-イル基、ピラゾリン-1-イル基、ピラゾリジン-1-イル基、モルホリン-4-イル基、チオモルホリン-4-イル基、インドリル基、インドリニル基、2-オキソインドリニル基、イソインドリル基、インドリジニル基、ベンズイミダゾリル基、ベンゾトリアゾリル基、インダゾリル基、キノリル基、テトラヒドロキノリニル基、テトラヒドロイソキノリニル基、キノリジニル基、イソキノリル基、フタラジニル基、ナフチリジニル基、キノキサリニル基、ジヒドロキノキサリニル基、キナゾリニル基、シンノリニル基、キヌクリジニル基、ピロロピリジル基、2,3-ジヒドロベンゾピロリル基、ベンゾフラニル基、イソベンゾフラニル基、クロメニル基、クロマニル基、イソクロマニル基、ベンゾ-1,3-ジオキソリル基、ベンゾ-1,4-ジオキサニル基、2,3-ジヒドロベンゾフラニル基、ベンゾチエニル基、2,3-ジヒドロベンゾチエニル基、ベンゾモルホリニル基、ベンゾモルホロニル基、ベンゾチアゾリル基、ベンゾチアジアゾリル基、インド-ル-1-イル基、インドリン-1-イル基、イソインド-ル-2-イル基、ベンズイミダゾ-ル-1-イル基、ベンゾトリアゾ-ル-1-イル基、ベンゾトリアゾ-ル-2-イル基、インダゾ-ル-1-イル基、ベンゾモルホリン-4-イル基、チアントレニル基、キサンテニル基、フェノキサチイニル基、カルバゾリル基、β-カルボリニル基、フェナントリジニル基、アクリジニル基、ペリミジニル基、フェナントロリニル基、フェナジニル基、フェノチアジニル基およびフェノキサジニル基などが挙げられる。
置換基群Aの置換基は更に置換基群Aから選ばれる1つ以上の置換基で置換されていてもよい。
一般式(II)、一般式(I-1)、一般式(III)および一般式(IV)においてXおよびYの定義および好ましい範囲は一般式(I)について述べたものと同じである。
一般式(II)において、R1は水素原子またはアルキル基を表す;アルキル基は置換基を有していてもよい。R1がアルキル基を表す場合、炭素数が1~10の、直鎖、分岐、または環状のアルキル基が好ましい。炭素数は1~8がより好ましく、1~6が最も好ましい。これらの基はさらに1つ以上の置換基を有していてもよく、置換基としては置換基群Aに挙げたものが好ましい。アルキル基の例としてはメチル基、エチル基、n-プロピル基、イソプロピル基、t-ブチル基、イソブチル基、n-ブチル基、n-ペンチル基、シクロペンチル基、シクロヘキシル基、1-エチルプロピル基などが挙げられる。R1としてはメチル基およびエチル基が好ましい。
反応温度は用いる酸触媒や溶媒によって異なるが、200℃以下が好ましく、0~150℃がより好ましい。反応時間は特に限定されないが、5分間~50時間が好ましく、5分間~24時間がより好ましく、5分間~5時間が特に好ましい。
この反応においては、一般式(II-1)の化合物のRがアルコキシ基であることが特に好ましい。
すなわち、5位にフッ素原子によって置換可能な基またはそのような基へと容易に誘導できる基を有するピラジノ〔2,3-d〕イソオキサゾ-ル誘導体もT-705A製造の中間体として重要である。
R2がアルキル基を表す場合、炭素数が1~10の、直鎖、分岐、または環状のアルキル基が好ましい。炭素数は1~8がより好ましく、1~6が最も好ましい。これらの基はさらに置換基を有していてもよく、置換基としては置換基群Aに挙げたものが好ましい。置換基を有していてもよいアルキル基の例としてはメチル基、エチル基、n-プロピル基、イソプロピル基、2-メトキシエチル基、t-ブチル基、イソブチル基、n-ブチル基、イソアミル基、n-アミル基、ネオペンチル基、n-ヘキシル基、シクロヘキシル基、ベンジル基、2-エチルヘキシル基などが挙げられる。
一般式(J-3)の化合物において、オキシムの水酸基はアンチとシンの異性体構造を取りうるが本発明ではどちらか一方でも、混合物であってもよい。
本発明において、一般式(J-0)の化合物はシス-トランスのいずれの異性体でもよい。
使用するヒドロキシルアミンはヒドロキシルアミンの50%水溶液やヒドロキシルアミン塩酸塩、ヒドロキシルアミン硫酸塩などを用いることができる。
ヒドロキシルアミンの塩酸塩や硫酸塩を用いる際には各種有機塩基または無機塩基を添加することが好ましい。塩基としては例えばトリエチルアミン、ピリジン、水酸化ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素ナトリウム、リン酸ナトリウム等が使用できる。塩基の使用量はヒドロキシルアミンの0.1~10倍モルが好ましく、0.5~2倍モルがより好ましく、1~1.2倍モルが最も好ましい。
使用される溶媒としては反応に影響を及ぼさないものであれば特に限定されないが、例えば水、アセトニトリルなどのニトリル類、ベンゼン、トルエン、キシレンなどの芳香族炭化水素類、ジオキサン、テトラヒドロフラン、エチレングリコ-ルジメチルエ-テルなどのエ-テル類、アセトン、2-ブタノンなどのケトン類、メタノ-ル、エタノ-ル、2-プロパノ-ルなどのアルコ-ル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、酢酸エチル、酢酸イソプロピルなどのエステル類、ジメチルスルホキシドなどのスルホキシド類などが挙げられ、これらは混合して使用してもよい。好ましい溶媒としては、芳香族炭化水素類、エ-テル類、アルコ-ル類、エステル類、スルホキシド類が挙げられ、芳香族炭化水素類、アルコ-ル類、エステル類がより好ましい。
反応温度は用いる溶媒によって異なるが、0~130℃が好ましく、室温~100℃がより好ましく、室温~50℃が特に好ましい。
反応時間は特に限定されないが、5分間~10時間が好ましく、10分間~5時間がより好ましく、10分間~1時間が特に好ましい。
一般式(J-1)の化合物は単離して次工程に供してもよいし、単離することなく、そのまま次工程に供してもよい。
グリオキサ-ルの使用量は一般式(J-1)の化合物の1~10倍モルが好ましく、1~5倍モルがより好ましく、1~3倍モルが最も好ましい。
溶媒の使用量は特に限定されないが、一般式(J-1)の化合物に対して、1~50倍量(v/w)が好ましく、1~20倍量(v/w)がより好ましく、1~10倍量(v/w)が最も好ましい。
反応温度は用いる溶媒によって異なるが、0~130℃が好ましく、室温~100℃がより好ましく、40~80℃が特に好ましい。
反応時間は特に限定されないが、5分間~10時間が好ましく、10分間~5時間がより好ましく、30分間~2時間が特に好ましい。
また、一般式(J-2)の化合物と酸の混合物に亜硝酸ナトリウム水溶液を添加することによっても一般式(J-3)の化合物を得ることができる。
亜硝酸エステルまたは亜硝酸ナトリウムの使用量は一般式(J-2)の化合物の1~10倍モルが好ましく、1~5倍モルがより好ましく、1~3倍モルが最も好ましい。
反応温度は用いる溶媒によって異なるが、0~130℃が好ましく、室温~100℃がより好ましく、室温~70℃が特に好ましい。
反応時間は特に限定されないが、5分間~10時間が好ましく、10分間~5時間がより好ましく、30分間~3時間が特に好ましい。
本反応には試薬としてオキシ塩化リン、塩化チオニル、五塩化リン、三塩化リン、ピロカテキルホスホ三塩化物、ジクロロトリフェニルホスホラン、塩化オキサリルなどを単独または2種以上組み合わせて用いることができる。このうち、オキシ塩化リン、塩化チオニルが収率およびコストの点でより好ましく、オキシ塩化リンが特に好ましい。これらの試薬の使用量は一般式(J-3)の化合物の1~20倍モルが好ましく、2~10倍モルがより好ましく、2~5倍モルが最も好ましい。
反応温度は用いる溶媒によって異なるが、0~130℃が好ましく、室温~100℃がより好ましく、50~80℃が特に好ましい。反応時間は特に限定されないが、5分間~20時間が好ましく、30分間~10時間がより好ましく、1~5時間が特に好ましい。
使用される溶媒としては反応に影響を及ぼさないものであれば特に限定されないが、例えば、水、アセトニトリルなどのニトリル類、ベンゼン、トルエン、キシレンなどの芳香族炭化水素類、ジオキサン、テトラヒドロフラン、エチレングリコ-ルジメチルエ-テルなどのエ-テル類、アセトン、2-ブタノンなどのケトン類、メタノ-ル、エタノ-ル、2-プロパノ-ルなどのアルコ-ル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、酢酸エチル、酢酸イソプロピルなどのエステル類、ジメチルスルホキシドなどのスルホキシド類などが挙げられ、これらは混合して使用してもよい。溶媒は水単独または水と混和しうる有機溶媒(アルコ-ル類、ニトリル類、エ-テル類、スルホキシド類)と水の混合液を用いることが好ましい。また、芳香族炭化水素類、エステル類、エ-テル類など水と自由に混和しない溶媒を用いて水との二相系で反応することも好ましく、水と混和する溶媒と混和しない溶媒を混合して用いることもできる。より好ましい溶媒としては、芳香族炭化水素類、エ-テル類、アルコ-ル類、エステル類、水が挙げられ、芳香族炭化水素類と水の2層系がさらに好ましい。溶媒の使用量は特に限定されないが、一般式(I)の化合物に対して、1~50倍量(v/w)が好ましく、1~15倍量(v/w)がより好ましい。
これらの反応においては前述のカチオン系相間移動触媒、ノニオン系相間移動触媒を用いることもできる。
この反応においては一般式(I)の化合物のXがフッ素原子であり、Yが-C(=O)R(Rはアルコキシ基、アルコキシ基は置換基を有していてもよい)であることが特に好ましい。
30Lガラス製反応容器に水11.3Lと水酸化ナトリウム1090gを添加、溶解した。これに(A-1)(東京化成試薬)4000gを添加、内温70℃で30分間撹拌した。反応液に塩化ナトリウム2270gを添加、溶解して、反応混合物を0℃以下に冷却した。濃塩酸2270mLを少しずつ加えた後、酢酸エチル11.3Lを添加、分液後に水層を廃棄した。得られた有機層に飽和食塩水11.3Lを添加、分液後に水層を廃棄した。得られた有機層を減圧濃縮した。得られた残渣にトルエン5.00Lを加え、トルエン溶液を減圧濃縮した。再度トルエン5.00Lを添加して減圧濃縮した結果、淡黄色のオイル(B-1)3200gを得た。収率95.1%。
1H-NMR(400MHz,CDCl3) δ値:9.09(br,1H), 4.97(s,1H), 3.64-3.77(m,4H), 1.28(t,J=7.1Hz,6H)
(B-1)1.48kg(10.0mol)をアセトニトリル7.40Lに溶解し、アミノアセトニトリル硫酸塩1.10kg(5.25mol)を添加した。内温を5℃以下に維持しながら1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩1.91kg(10.0mol)を添加した。内温を0~6℃に維持しながらトリエチルアミン2.07kg(20.0mol)を90分かけて滴下した。得られた反応混合物を室温で一晩放置した。反応混合物に水3.00Lを加えた後、溶媒を減圧留去した。酢酸エチル7.40Lを加えて10分間撹拌した後で静置して、水層を除去した。有機層を冷却した後、内温を6℃以下に維持しながら1.00mol/L塩酸約2.00Lを加えて水層のpHを5に調整した。さらに水1.00Lを加えて撹拌した後で静置して、水層を除去した。有機層に飽和食塩水3.00Lを加えて撹拌した後で静置して、水層を除去した。得られた有機層は溶媒を減圧留去して、トルエン2.00Lを加えて減圧留去し、さらにトルエン1.00Lを加えて減圧留去することで、薄褐色オイル(C-1)1.11kgを得た。収率59.7%。
1H-NMR(CDCl3) δ値:1.27(6H, t, J=7.2Hz), 3.65(2H, q, J=7.2Hz), 3.69(2H, q, J=7.2Hz), 4.22(1H, s), 4.23(1H, s), 4.86(1H, s), 6.80-7.10(1H, br)
窒素雰囲気下、テトラヒドロフラン10.4Lにtert-ブトキシカリウム1.44kg(12.8mol)を溶解した後、内温を10℃以下に保ったまま、(C-1) 2.08kg(11.2mol)をテトラヒドロフラン2.08Lに溶解した溶液を1時間かけて滴下した。続いてシュウ酸ジメチル 1.58kg(13.4mol)を加えて、40℃で2時間撹拌した。更にメタノ-ル16.0Lを加えてから、濃縮し、(D-1)のメタノ-ル溶液を得た。そのまま次の反応に使用した。
1H-NMR(DMSO-d6)δ値:1.15(6H,t,J=7.2Hz), 3.52-3.58(4H,m), 3.60(3H,s), 4.75(1H,s), 7.88(1H,br)
1H-NMR(CDCl3) δ値:1.32(6H,t,J=6.8Hz), 3.50-3.80(m,4H), 3.98(3H,s), 4.93(1H,s), 5.82(2H,br), 9.29(1H,br)
(E-1)1.55kg(5.40mol)を酢酸3.90Lに溶解し、p-トルエンスルホン酸一水和物213g(1.12mol)を加えて、内温77~80℃で2時間反応させた。得られた反応混合物を室温に冷却して、水8.00Lを添加して20分間撹拌した。析出物を濾取して、ろ液のpHが5以上になるまで水洗した後、40℃で一晩乾燥させることで、(F-1)の淡黄色固体615gを得た。収率58.4%。
1H-NMR(DMSO-d6) δ値:3.99(3H, s), 8.26(1H, s), 12.75-13.00(1H, br)
なお、(F-1)は固体であり、揮発性、皮膚刺激性ともに低いため、安全かつ簡便に次の反応に使用できた。
(F-1)156g(0.800mol)とオキシ塩化リン373mL(4.00mol)を混合し、トリエチルアミン塩酸塩110g(0.800mol)を加えて、内温85℃で4時間反応させた後、室温まで冷却した。トルエン800mLと水1600mLの混合液を氷冷して、これに反応混合物を1時間かけて内温25~30℃を維持しながら添加した。さらに内温22~23℃で1時間撹拌した後で静置した。水層を除去し、有機層に飽和食塩水800mLを加えて撹拌・静置して水層を除去する操作を4回繰り返した。この4回目の水層のpHは6であった。得られた有機層に無水硫酸ナトリウムを加えて撹拌し、硫酸ナトリウムを除去してから溶媒を減圧留去することで、薄褐色固体(G-1)152gを得た。収率88.9%。
1H-NMR(CDCl3) δ値:4.14(3H, s), 8.65(1H, s)
なお、(G-1)は固体であり、揮発性、皮膚刺激性ともに低いため、安全かつ簡便に次の反応に使用できた。
窒素雰囲気下、(F-1)2.00g(10.3mmol)とアセトニトリル40.0mLの混合液を撹拌し、2,2-ジフルオロ-1,3-ジメチルイミダゾリジン1.88mL(15.4mmol)を滴下した。滴下終了後、80~90℃で3時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィ-(溶離液:ヘキサン/酢酸エチル=2/1(体積比))にて、分離精製した。この結果、白色固体(H-1)0.900gを得た。収率44.4%。
1H-NMR(CDCl3) δ値:8.53(1H, d, J=6.6Hz), 4.14(3H, s)
19F-NMR(CDCl3) δ値:-78.74 (1F, d, J=6.6Hz)
なお、(H-1)は固体であり、揮発性、皮膚刺激性ともに低いため、安全かつ簡便に次の反応に使用できた。
フッ化カリウム1.80g(31.0mmol)とジメチルスルホキシド22.0mLを混合した後、トルエン15.0mLを加えて撹拌した。外温80℃、70mmHgでトルエンを減圧留去し、(G-1)1.07g(5.00mmol)を加えて内温80℃で3時間反応させた。室温まで冷却した後、酢酸エチル300mLと水200mLを加えて撹拌・静置して水層を除去する操作を2回繰り返した。有機層に飽和食塩水50.0mLを加え、撹拌・静置して水層を除去し、硫酸マグネシウムで乾燥させてろ過した。ろ液を濃縮後、褐色固体(H-1)0.830gと(G-1)0.03gの混合物を得た。収率84.0 %。
(混合物の成分比はNMRスペクトル積分値より計算した)
(H-1)200mg(1.01mmol)へ、テトラヒドロフラン3.00mL、水3.00mL、水酸化ナトリウム55.0mg(1.38mmol)を加え、撹拌しながら、80℃で3時間加熱した。室温まで冷却した後に、イオン交換樹脂DOWEX(登録商標) 50W×2-200(H)を加え、ろ過、濃縮を行い、T-705A 126mgを黄色固体として得た。収率89.7%。
1H-NMR(DMSO-d6) δ値:8.22(1H, d, J=8.1Hz), 13.85(1H,br)
19F-NMR(DMSO-d6) δ値:-94.13(1H, br)
(G-1)10.7g(50.0mmol)とエチルアルコ-ル50.0mLを混合し、ジイソプロピルエチルアミン17.4mL(100mmol)、4-ジメチルアミノピリジン0.610g(5.00mmol)を加えて、内温80℃で2.5時間反応させた後、室温まで冷却した。濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、白色固体(A-1a)7.39gを得た。収率64.8%。
1H-NMR(CDCl3)δ値:8.62(1H, s), 4.60(2H, q, J=7.0Hz), 1.51(3H, t, J=7.0Hz)
(G-1)42.7g(0.200mol)とイソプロピルアルコ-ル500mLを混合し、トリエチルアミン42.0mL(0.300mol)を加えて、内温80℃で2時間反応させた後、室温まで冷却した。濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、白色固体(A-2)41.6gを得た。収率86.0%。
1H-NMR(CDCl3)δ値:8.63(1H, s), 5.45(1H, quint, J=6.0Hz), 1.49(6H, s)
(G-1)32.0g(150mmol)と1-ブチルアルコ-ル150mLを混合し、ジイソプロピルエチルアミン52.3mL(300mmol)、4-ジメチルアミノピリジン1.83g(15.0mmol)を加えて、内温90℃で2時間反応させた後、室温まで冷却した。濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、白色固体(A-3)25.1gを得た。収率65.4%。
1H-NMR(CDCl3)δ値:8.63(1H, s), 4.55(2H, t, J=6.8Hz), 1.81-1.89(2H, m), 1.47-1.57(2H, m), 1.00(3H, t, J=7.2Hz)
(A-1a)1.00g(4.39mmol)をイソブチルアルコ-ル10.0mLに溶解し、4-ジメチルアミノピリジン 107mg(0.878mmol)を加え、100℃で5時間加熱撹拌した。室温まで冷却後、濃縮を行い、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)にて精製を行い、淡黄色オイルとして、(A-4)0.780gを得た。収率69.4%。
1H-NMR(CDCl3) δ値:1.07(6H,d,J=6.8Hz), 2.19(1H,h,J=6.7Hz), 4.32(2H,d,J=6.6Hz), 8.63(1H,s)
(G-1)1.07g(5.00mmol)とネオペンチルアルコ-ル5.00gを混合し、ジイソプロピルエチルアミン1.70mL(10.0mmol)を加えて、内温100℃で5時間反応させた。室温まで冷却した後、酢酸エチル30.0mLと水20.0mLを加えて撹拌・静置して水層を除去する操作を2回繰り返した。有機層を濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、白色固体(A-5)0.750gを得た。収率55.6%。
1H-NMR(CDCl3) δ値:8.63(1H, d, J=6.6Hz), 4.23(2H, s), 1.09(9H, s)
(A-1a)2.28g(10.0mmol)と1-ヘキシルアルコ-ル10.0gを混合し、ジイソプロピルエチルアミン3.48mL(20.0mmol)、4-ジメチルアミノピリジン0.120gを加えて、内温80℃で3.5時間反応させた後、室温まで冷却した。濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、白色固体(A-6)2.30gを得た。収率81.0%。
1H-NMR(CDCl3) δ値:8.63(1H, s), 4.54(2H, t, J=6.8Hz), 1.81-1.90(2H, m), 1.31-1.53(6H, m), 0.91(3H, t, J=7.2Hz)
(G-1)2.14g(10.0mmol)とシクロヘキシルアルコ-ル10.0gを混合し、ジイソプロピルエチルアミン2.00mL(10.0mmol)、4-ジメチルアミノピリジン0.210gを加えて、内温100℃で1時間反応させた。室温まで冷却した後、酢酸エチル100mLと塩酸(1mol/L)50.0mLを加えて撹拌・静置して水層を除去する操作を2回繰り返した。有機層に飽和食塩水20.0mLを加え、撹拌・静置して水層を除去し、硫酸マグネシウムで乾燥させ、ろ過した。ろ液を濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、白色固体(A-7)1.30gを得た。収率46.1%。
1H-NMR(CDCl3)δ値:8.62(1H, s), 5.19-5.28(1H, m), 1.31-2.08(10H, m)
(A-1a)2.28g(10.0mmol)とベンジルアルコ-ル2.08mL(20.0mmol)を混合し、ジイソプロピルエチルアミン20.0mLを加えて、内温80℃で1時間反応させた後、室温まで冷却した。濃縮後、残渣を再結晶(ヘキサン/酢酸エチル)することで、白色固体(A-8)0.780gを得た。収率26.9%。
1H-NMR(CDCl3)δ値:8.62(1H, s), 7.32-7.57(5H, m), 5.57(2H, s)
(G-1)0.430g(2.00mmol)とエチルアルコ-ル4.00mLを混合し、ベンジルアミン0.220mL(2.00mmol)を加えて、室温で1時間反応させた。濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、黄色固体(A-9)0.490gを得た。収率84.8%。
1H-NMR(CDCl3)δ値:8.64(1H, s), 7.31-7.42(5H, m), 4.77(2H, d, J=6.0Hz)
(G-1)6.41g(30.0mmol)とジエチルアミン16.0mL(150mmol)を混合し、50℃で45分間反応させた。濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、黄色固体(A-10)6.33gを得た。収率82.7%。
1H-NMR(CDCl3)δ値:8.60(1H, s), 3.67(2H, t, J=7.2Hz), 3.47(2H, t, J=7.2Hz), 1.34(3H, t, J=7.2Hz), 1.26(3H, t, J=7.2Hz)
(G-1) 2.14g(10.0mmol)とメチルアルコ-ル15.0mLを混合し、ピロリジン0.860mL(10.5mmol)を加えて、室温で40分間反応させた。濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、黄色固体(A-11)2.27gを得た。収率89.7%。
1H-NMR(CDCl3)δ値:8.61(1H, s), 3.72-3.81(4H, m), 1.98-2.05(4H, m)
フッ化カリウム0.630g(10.8mmol)とジメチルスルホキシド14.4mLを混合した後、外温80℃、3~5hPaで溶媒を減圧留去した。乾燥ジメチルスルホキシド15.0mL、(A-1a)0.820g(3.60mmol)を加えて内温90℃で4時間反応させた。高速液体クロマトグラフィ-分析によれば、生成率は97.0%であった。(内部標準としてジフェニルエ-テルを使用した。)
フッ化カリウム3.50g(60.0mmol)とジメチルスルホキシド250mLを混合した後、外温130℃、21mmHgで溶媒を減圧留去した。乾燥ジメチルスルホキシド80.0mL、(A-2)4.83g(20.0mmol)を加えて内温90℃で4時間反応させた。室温まで冷却した後、トルエン100mLと水100mLを加えて撹拌・静置して水層を除去する操作を2回繰り返した。有機層に飽和食塩水100mLを加え、撹拌・静置して水層を除去し、硫酸マグネシウムで乾燥させてろ過した。ろ液を濃縮後、固体3.97g(A-13)を得た。収率88.2%。
1H-NMR(CDCl3)δ値:8.50(1H, d, J=6.4Hz), 5.46(1H, quintet, J=6.4Hz), 1.49(6H, d, J=6.4Hz)
19F-NMR(CDCl3)δ値:-79.16 (1F, d, J=6.4Hz)
フッ化カリウム0.360g(6.20mmol)とジメチルスルホキシド8.00mLを混合した後、トルエン14.0mLを加えて撹拌した。外温80℃、70mmHgでトルエンを減圧留去し、(A-3)0.510g(2.00mmol)を加えて内温80℃で2時間、内温90℃で1.5時間反応させた。室温まで冷却した後、トルエン30.0mLと水20.0mLを加えて撹拌・静置して水層を除去する操作を3回繰り返した。有機層に飽和食塩水20.0mLを加え、撹拌・静置して水層を除去し、硫酸マグネシウムで乾燥させてろ過した。ろ液を濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、白色固体(A-14)0.400gを得た。収率83.7%。
1H-NMR(CDCl3)δ値:8.51(1H, d, J=6.4Hz), 4.54(2H, t, J=6.8Hz), 1.81-1.89(2H, m), 1.47-1.57(2H, m), 1.00(3H, t, J=7.2Hz)
19F-NMR(CDCl3)δ値:-79.02(1F, d, J=6.4Hz)
窒素雰囲気下、フッ化カリウム203mg(3.51mmol)に、ジメチルスルホキシド4.68mL、トルエン10.0mLを加え、70℃まで加熱して、減圧下でトルエンを留去した。更に(A-4) 0.300g(1.17mmol)を加えて、撹拌しながら80℃で2時間反応させた。反応溶液のHPLC分析の結果、生成率は84.0%であった。(内部標準としてジフェニルエ-テルを使用した。)
合成例22と同様の操作により、フッ化カリウム0.230g(4.00mmol)、ジメチルスルホキシド6.00mL、(A-5)0.400g(1.50mmol)から白色固体(A-16)0.190gを得た。収率50.1%。
1H-NMR(CDCl3)δ値:8.51(1H, d, J=6.6Hz), 4.22(2H, s), 1.09(9H, s)
19F-NMR(CDCl3)δ値:-79.11(1F, d, J=6.6Hz)
フッ化カリウム0.620g(10.7mmol)とジメチルスルホキシド14.4mLを混合した後、トルエン14.0mLを加えて撹拌した。外温80℃、70mmHgでトルエンを減圧留去し、(A-6)0.510gを加えて内温80℃で2時間、内温90℃で2時間反応させた。高速液体クロマトグラフィ-分析によれば、生成率は89.0%であった。(内部標準としてジフェニルエ-テルを使用した。)
合成例22と同様の操作により、フッ化カリウム0.470g(8.10mmol)、ジメチルスルホキシド11.0mL、(A-7)0.760g(2.70mmol)から白色固体(A-18)0.310gを得た。収率43.4%。
1H-NMR(CDCl3)δ値:8.49(1H, d, J=6.6Hz), 5.20-5.27(1H, m), 1.99-2.07(2H, m), 1.33-1.90(8H, m)
19F-NMR(CDCl3)δ値:-79.21(1F, d, J=6.6Hz)
合成例25と同様の操作により、フッ化カリウム0.590g(10.0mmol)、ジメチルスルホキシド12.0mL、(A-10)0.760g(3.00mmol)を80℃で4時間反応させたところ、生成率は65.0%であった。
合成例25と同様の操作により、フッ化カリウム0.520g(9.00mmol)、ジメチルスルホキシド12.0mL、(A-11)0.76g(3.00mmol)を80℃で4時間反応させたところ、生成率は81.0%であった。
(G-1)100mg(0.468mmol)へ、テトラヒドロフラン1.00mL、水1.00mL、水酸化ナトリウム20.0mg(0.491mmol)を加え、撹拌しながら、80℃で1時間加熱した。室温まで冷却した後に、イオン交換樹脂DOWEX(登録商標)50W×2-200(H)を加え、ろ過、濃縮を行い、(A-21)70.0mgを黄色固体として得た。収率95.9%。
1H-NMR(DMSO-d6) δ値:8.44(1H,s), 13.85(1H,br)
(A-15)0.500g(2.22mmol)へ、トルエン2.00mL、水1.00mL、炭酸水素ナトリウム0.224g(2.66mmol)を加え、撹拌しながら、80℃で3時間、100℃で5時間反応させた。反応液を高速液体クロマトグラフィ-分析すると、生成率は92.0%であった。
(F-1)1.36g(7.00mmol)とアセトニトリル20.0mL、ジイソプロピルエチルアミン1.49mL(9.00mmol)を混合した溶液を氷冷し、ジメチルカルバミン酸クロライド0.860mL(8.00mmol)を加え、室温で1時間反応させた。酢酸エチル100mLと水100mLを加えて撹拌・静置して水層を除去する操作を2回繰り返した。有機層を硫酸マグネシウムで乾燥後、濃縮し、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、白色固体(A-22)0.740gを得た。収率35.1%。
1H-NMR(CDCl3)δ値:8.57(1H, s), 4.10(3H, s), 3.17(6H, s)
(F-1)6.66g(34.0mmol)とアセトニトリル50.0mL、ジイソプロピルエチルアミン6.80mL(41.0mmol)を混合した溶液を氷冷し、ジエチルカルバミン酸クロライド5.10mL(41.0mmol)、4-ジメチルアミノピリジン0.370g(3.00mmol)を加え、室温で終夜反応させた。濃縮した後、酢酸エチル100mLと塩酸(1mol/L)100mLを加えて撹拌・静置して水層を除去する操作を2回繰り返した。有機層を硫酸マグネシウムで乾燥後、濃縮し、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、黄色液体(A-23)9.97gを得た。収率88.4%。
1H-NMR(CDCl3)δ値:8.56(1H, s), 4.11(3H, s), 3.59(4H, q, J=7.2Hz), 1.31(6H, t, J=7.2Hz)
(A-23)1.65g(5.00mmol)と1-ブチルアルコ-ル5.00mLを混合し、ジイソプロピルエチルアミン1.70mL(10.0mmol)を加えて、内温80℃で2時間反応させた後、室温まで冷却した。濃縮後、残渣をシリカゲルクロマトグラフィ-(ヘキサン:酢酸エチル=4:1)することで、黄色液体(A-24)1.47gを得た。収率79.0%。
1H-NMR(CDCl3)δ値:8.55(1H, s), 4.52(2H, t, J=6.8Hz), 3.57(4H, q, J=7.2Hz), 1.80-1.88(2H, m), 1.48-1.57(2H, m), 1.30(6H, t, J=7.2Hz), 1.00(3H, t, J=7.2Hz)
(A-22)1.51g(5.00mmol)へ、テトラヒドロフラン10.0mL、水10.0mL、水酸化ナトリウム0.270g(6.75mmol)を加え、撹拌しながら、80℃で40分間加熱した。室温まで冷却した後に、イオン交換樹脂DOWEX(登録商標)50W×2-200(H)を加え、ろ過、濃縮を行い、(A-25)0.610gを黄色固体として得た。収率50.0%。
1H-NMR(DMSO-d6)δ値:8.04(1H, s), 2.88(3H, s)
(A-10)0.510g(2.00mmol)へ、トルエン2.00mL、水1.00mL、炭酸水素ナトリウム0.340g(4.00mmol)、テトラブチルアンモニウムブロミド0.130g(0.400mmol)を加え、撹拌しながら、100℃で2時間反応させた。反応液を高速液体クロマトグラフィ-分析すると、生成率は13.0%であった。
(A-14)185mg(0.773mmol)へN,N-ジメチルホルムアミド0.750mL、水0.120mL、酢酸カリウム114mg(1.16mmol)を加え、撹拌しながら、80℃で3時間加熱後、室温まで冷却した。反応混合物の高速液体クロマトグラフィ-分析によると生成率は57.0%であった。
(A-14)185mg(0.773mmol)へ、テトラヒドロフラン2.00mL、水1.00mL、水酸化ナトリウム37.0mg(0.930mmol)を加え、撹拌しながら、80℃で1時間加熱後、室温まで冷却した。反応混合物の高速液体クロマトグラフィ-分析によると生成率は94.9%であった。
(A-14)185mg(0.773mmol)へ、イソプロピルアルコ-ル2.00mL、水1.00mL、水酸化ナトリウム37.0mg(0.930mmol)を加え、撹拌しながら、80℃で1時間加熱後、室温まで冷却した。反応混合物の高速液体クロマトグラフィ-分析によると生成率は85.6%であった。
窒素雰囲気下、フッ化カリウム460mg(7.91mmol)に、ジメチルスルホキシド10.0mL、N,N-ジメチルホルムアミド15.0mLを加え、80℃、80mmHgでN,N-ジメチルホルムアミドを留去した。更に(A-22) 0.460g(2.61mmol)を加えて、攪拌しながら80℃で3時間反応させた。室温まで冷却後、酢酸エチル50.0mL、水30.0mLを加えて攪拌し、静置した。分液後、得られた有機層を水30.0mL、更に飽和食塩水30.0mLで洗浄し、溶媒をエバポレ-タ-で留去した。残渣にジメチルスルホキシド2.0mL、水1.0mL、水酸化ナトリウム0.120g(3.00mmol)を加えて、攪拌しながら、80℃で30分反応させた。室温まで冷却後、ジシクロヘキシルアミン0.48mL(2.41mmol)を加え、更に濃塩酸で、pH=9にしてから、アセトン2.0mL,水3.0mLを加えた。析出した結晶をろ過し、T-705Aジシクロヘキシルアミン塩を淡褐色固体として0.25g得た。
(G-1) 5.00g(23.4mmol)と1-プロパノ-ル23.0mLを混合し、ジイソプロピルエチルアミン8.00mL(46.8mmol)、4-ジメチルアミノピリジン0.250g(2.00mmol)を加えて、80℃で70分間および90℃で110分間反応させた。濃縮後、残渣をシリカゲルクロマトグラフィ-することで、淡黄色固体(A-26)3.50gを得た。収率61.8%。
1H-NMR(CDCl3)δ値:8.64(1H, s), 4.51(2H, q, J=6.8Hz), 1.85-1.94(2H, m) , 1.08(3H, t, J=7.2Hz)
窒素雰囲気下、エタノ-ル300mLにエチル-(Z)-4-アミノ-4-オキソ-2-ブテノエ-ト54g(0.377mol)を溶解し、内温を15~25℃に保ちながら、50%ヒドロキシルアミン水溶液26.2g(0.396mol)を滴下した。20℃で4時間30分撹拌した後に、反応液を-20℃まで冷却し、析出した固体をろ過した。得られた固体を冷却した酢酸エチル50.0mLで洗浄し、白色固体(A-27)42.4gを得た。収率63.8%。
1H- NMR(DMSO-d6)δ値:1.18(3H,t,J=7.2Hz), 2.40(1H,dd,J=7.6,15.6Hz), 2.59(1H,dd,J=6.0,16.0Hz), 3.63(1H,dd,J=6.0,7.6Hz), 4.05(2H,q,J=6.8Hz), 5.80(1H,br),7.12(1H,br),7.31(1H,br),7.51(1H,br)
40%グリオキサ-ル水溶液56.0g(0.386mol)、テトラヒドロフラン125mL、水 125mL、炭酸カリウム13.3g(0.0955mol)を加え、12℃まで冷却した。(A-27)33.7g(0.191mol)を加え、20℃で3時間撹拌した。酢酸11.6gを加えた後、反応液を80.0gまで濃縮し、飽和食塩水30.0mLを加えて撹拌した。析出した固体をろ過し、飽和食塩水30mLで洗浄、乾燥を行い、淡桃色固体(A-29)14.0gを得た。収率36.7%。
1H- NMR(DMSO-d6)δ値: 1.16(3H,t,J=6.8Hz), 3.69(2H,s), 4.06(2H,q,J=7.2Hz), 7.24(1H,d,J=6.0Hz), 7.54(1H,d,J=5.6Hz), 12.3(1H,br)
(A-29)5.00g(0.0252mol)とエタノ-ル65.0mLの混合物に、エタノ-ル30.0mLに塩化アセチル1.60mL(22.5mmol)を加えた溶液を添加し撹拌した。亜硝酸イソアミル3.70mL(27.5mmol)を加え室温で4時間撹拌した後に、亜硝酸イソアミルを0.500mL(3.72mmol)添加し、さらに室温で3.5時間撹拌した。該反応液に、エタノ-ル5.00mLに塩化アセチル0.500mL(7.04mmol)を加えた溶液と亜硝酸イソアミル0.500mL(3.72mmol)を添加し、一晩放置した。続けてエタノ-ル20.0mLに塩化アセチル1.60mL(22.5mmol)を加えた溶液と亜硝酸イソアミル1.50mL(11.1mmol)を添加し、35℃で撹拌した後、溶媒を減圧濃縮した。アセトニトリルを加え氷冷し、析出した固体をろ過した。白色固体(A-31)4.10gを得た。収率71.5%。
1H-NMR(DMSO-d6)δ値:13.0(1H,br),12.4(1H,br),7.66(1H,d,J=6.0Hz),7.29(1H,d,J=6.0Hz), 4.20(2H,q,J=7.0Hz),1.21(3H,t,J=7.0Hz)
トルエン12.0ml、ジメチルホルムアミド12.0mLを氷冷し、オキシ塩化リン4.60mL(49.3mmol)を加えた後、(A-31)2.27g(10.0mmol)を添加し、70℃で4.5時間撹拌した。室温に冷却して酢酸エチルと水を加えて撹拌後静置した。水層を除去し、有機層を減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィ-(溶離液:ヘキサン/酢酸エチル=9/1)で分離した結果、白色固体(A-1a)1.60gを得た。収率70.3%。
無水マレイン酸 196g(2.00mol)を2-プロパノ-ル123g(2.05mol)、酢酸エチル800mLに溶解した。内温10℃以下でトリエチルアミン300mL(2.15mol)を1.5時間かけて滴下し後、1時間撹拌した。反応混合物に内温-5℃以下でクロロギ酸エチル193mL(2.03mol)を2時間かけて滴下した。30分撹拌した後、得られた反応混合物を28%アンモニア水300mL(2.16mol)、氷250gの水溶液に滴下した。得られた反応混合物を室温で一晩放置した。酢酸エチル400mLを加えて撹拌後、分液操作を行って、水層を除去した。これを三回繰り返した。得られた有機層を合わせて濃縮し、ヘキサン/酢酸エチルで再結晶した結果、白色固体としてイソプロピル-(Z)-4-アミノ-4-オキソ-2-ブテノエ-ト50.5gを得た。収率16.1%。
1H-NMR(DMSO-d6)δ値:1.20(6H,d,J=6.0Hz), 4.94(1H,sep,J=6.4Hz), 6.15(1H,d,J=11.6Hz), 6.26(1H,d,J=12.0Hz), 7.18(1H,br), 7.57(1H,br)
50%ヒドロキシルアミン水溶液13.9g(0.210mol)を2-プロパノ-ル200mLに溶解した。氷浴で内温を3.5~6℃に維持しながら15分かけてイソプロピル-(Z)-4-アミノ-4-オキソ-2-ブテノエ-ト31.4g(0.200mol)を添加し、2-プロパノ-ル20.0mLを添加した。得られた反応液を室温で3時間撹拌した後、冷蔵庫で静置した。析出した固体を濾別し、固体を冷2-プロパノ-ルで洗浄した後、室温で減圧乾燥した。白色固体(A-28)22.3gを得た。収率58.6%
1H-NMR(DMSO-d6) δ値:1.18(6H, d, J=6.4Hz), 2.36(1H, dd, J=8.0, 16.0Hz), 2.55(1H, dd, J=6.0, 16.0Hz), 3.61(1H, t, J=6.8Hz), 4.87(1H, sep, J=6.4, 6.4Hz), 5.70-5.90(1H, br), 7.00-7.18(1H, br), 7.20-7.35(1H, br), 7.46(1H, s)
イソプロピル-(E)-4-アミノ-4-オキソ-2-ブテノエ-ト9.43g(60.0mmol)をテトラヒドロフラン28.3mLに溶解し、42℃に設定した水浴で加温した。50%ヒドロキシルアミン水溶液4.16g(63.0mmol)を20分かけて滴下し、得られた反応液を42℃で1時間撹拌した。水9.40mLを加えた後、テトラヒドロフランを減圧留去した。得られた溶液中には原料が消失し(A-28)が含まれていることを1H-NMRで確認した。
1H-NMR(D2O) δ値:1.26(6H, d, J=6.4Hz), 2.68(1H, dd, J=6.8, 16.4Hz), 2.77(1H, dd, J=7.2, 16.0Hz), 3.96(1H, t, J=6.8Hz), 5.01(1H, sep, J=6.4, 6.4Hz)
39%グリオキサ-ル水溶液3.72g(25.0mmol)を2-プロパノ-ル30.0mLに溶解した。湯浴で内温41℃に設定し、(A-28)2.38g(12.5mmol)を水2.00mLと2-プロパノ-ル4.00mLに溶解して滴下した。この際、反応液のpHを8.9~9.1に維持するように1mol/L炭酸ナトリウム水溶液と合わせて滴下した。得られた反応混合物を内温41℃で2時間反応させた。内温20℃に冷却した後、酢酸を添加してpHを6.0に調整した。溶媒を減圧留去してから飽和食塩水を加え、生じた固体を濾別し、冷飽和食塩水で洗浄した後、乾燥した。薄褐色固体(A-30)2.89gを得た。収率62.3%(純度57.2%)
1H-NMR(DMSO-d6) δ値:1.17(6H, d, J=6.0Hz), 3.66(2H, s), 4.87(1H, sep, J=6.4, 6.4Hz), 7.24(1H, d, J=5.6Hz), 7.53(1H, d, J=5.6Hz), 12.00-12.50(1H, br)
イソプロピル-(E)-4-アミノ-4-オキソ-2-ブテノエ-ト12.22g(77.8mmol)をTHF19.8mLに溶解し、15~20℃に水浴で冷却した。50%ヒドロキシルアミン水溶液5.14g(77.8mmol)を1分かけて滴下し、得られた反応液を27~30℃で3時間攪拌した。得られた溶液中には原料が消失し(A-28)が含まれていることを1H-NMRで確認した。
炭酸水素ナトリウム0.118gを水18.3mLに溶解させた。40%グリオキサ-ル水溶液20.31g(140.0mmol)、前記の(A-28)のTHF溶液を60分かけて滴下した。この際、反応液のpHを8.2~8.4に維持するように50%水酸化ナトリウム水溶液と合わせて滴下した(3液同時滴下)。得られた反応混合物を内温50℃で1時間反応させた。この際、反応液のpHを8.4に維持するように50%水酸化ナトリウム水溶液を滴下した。THFを減圧下留去し、食塩5.0gを加えた。内温40~50℃で濃塩酸を滴下し、pHを3.0に調整した。1時間かけて5℃に冷却し、ろ過した。ヌッチェ上の固体を5℃以下の水10mLで2回洗浄した。乾燥し、薄褐色固体(A-30)10.80gを得た(純度90%)。A-28からの収率58.9%
窒素雰囲気下、(A-30)4.60g(21.7mmol)に、イソプロピルアルコ-ル20.0mLを加え、撹拌しながら、5℃まで冷却した。更に塩化アセチル 2.86mL(40.3mmol)を内温10℃以下に保ちながら滴下した。40℃まで昇温し、亜硝酸イソアミル 5.41mL(40.3mmol)を滴下した。滴下終了後、25℃で1時間30分撹拌を行った後に、-10℃まで冷却した。析出した固体をろ過し、トルエン5.00mLで2回洗浄し乾燥した。薄黄色固体(A-32)4.59gを得た。収率87.9%。
1H-NMR(DMSO-d6) δ値:1.22(6H,d,J=6.0Hz), 5.01(1H,sep,J=6.4Hz), 7.28(1H,d,J=5.6Hz), 7.65(1H,d,J=5.6Hz), 12.4(1H,br), 13.0(1H,br)
窒素雰囲気下、(A-32)25.0g(0.104mol)、N,N-ジメチルホルムアミド62.5mL、トルエン62.5mLの混合液を撹拌しながら、内温を15℃以下に保ち、オキシ塩化リン 47.3mL(0.510mol)を滴下した。滴下終了後、70℃まで昇温し、7時間撹拌した。室温まで放冷し、この反応混合物をトルエン62.5mL、10%食塩水300mLの混合液中に内温10℃以下で、ゆっくりと滴下した。分液操作後、有機層を10%食塩水100mLで2回、更に10%重曹水100mL、10%食塩水100mLで洗浄した。この有機層を濃縮し、残渣にイソプロピルアルコ-ル7.50mL、ヘキサン150mLを加えた。析出した固体をろ過し、更にイソプロピルアルコ-ル/ヘキサン=5/95(体積比)の混合溶媒 15.0mLで2回洗浄し、淡桃色固体(A-2)12.6g(純度98.3%)を得た。収率49.3%。
テトラメチルアンモニウムクロリド0.219g(2.00mmol)、フッ化カリウム2.32g(40.0mmol)、乾燥ジメチルスルホキシド9.70mL、乾燥トルエン38.6mLを混合した後、外温120℃でトルエンを減圧留去した。室温に冷却してから2,4-ジニトロクロロベンゼン0.203g(1.00mmol)、(A-2)4.83g(20.0mmol)を加えて内温90℃で2時間反応させた。室温まで冷却した後、水0.180mLを加えて2.5時間撹拌し、さらに水0.180mLを加えて1時間撹拌した。反応液にトルエン14.5mL、水14.2mLを加え、撹拌・静置して水層を除去し、有機層に飽和重曹水14.5mLを加え、撹拌・静置して水層を除去した。(A-13)の淡黄色溶液が得られ、黒色のタ-ル成分は見られなかった。この溶液をこのまま次の工程に使用した。
前記合成例52で得られた(A-13)の溶液に水14.5mL、重曹3.36g(40.0mmol)を加え、外温100℃で4時間反応させた。有機層を除去し、水層へ酢酸3.43mL(60.0mmol)を加え、外温70℃、100mmHgで減圧還流を1.5時間行った。室温に冷却した後、水5.00mL、アセトン9.60mL、28%アンモニア水3.30mLを加えた。ジシクロヘキシルアミン3.78mL(19.0mmol)を10分かけて滴下し、室温で1時間撹拌した。水9.60mLを加え、内温5℃で1時間撹拌し、固体をろ過した。ヌッチェ上の固体を、水10.0mL、アセトン5.00mLと水5.00mLの混合液、10℃以下のアセトン10.0mLで順に洗浄した。乾燥後、淡褐色固体のT-705Aジシクロヘキシルアミン塩5.37gを得た。収率83.0%、HPLC純度99.0%。
T-705Aジシクロヘキシルアミン塩5.00g(15.6mmol)にトルエン10.0mL、水酸化ナトリウム水溶液(水酸化ナトリウム0.656gを水20.0mLに溶かしたもの)を加え、室温で30分間撹拌した。10分間静置した後、上層を除去した。下層にトルエン10.0mLを加えて10分間撹拌・静置して上層を除去した。下層に水酸化ナトリウム水溶液(水酸化ナトリウム0.593gを水5.00mLに溶かしたもの)を加えた後、内温15~20℃を保ちながら40.0%v/w過酸化水素2.68mL(31.5mmol)を滴下した。25℃で30分撹拌した後、塩酸でpHを6.5~8.0にし、40℃に加温して固体を完溶させた。活性炭素(白鷺A)0.250gを加え、40℃で30分撹拌した後、ろ過した。ヌッチェ上の固体を水5.00mLで洗い、ろ液と洗浄液を混合した溶液へ内温35~45℃で塩酸を加え、pHを3~4に調整した。0~5℃に冷やして1時間撹拌した後、析出した固体をろ過し、水5.00mL、イソプロピルアルコ-ル5.00mLで洗浄し、白色固体(T-705)2.06gを得た。収率84.0%。
Claims (15)
- Yが-C(=O)R(Rはアルコキシ基またはアミノ基、アルコキシ基およびアミノ基は置換基を有していてもよい)であることを特徴とする請求項1に記載のピラジノ〔2,3-d〕イソオキサゾ-ル誘導体。
- Xが水酸基、塩素原子またはフッ素原子であることを特徴とする請求項1または2に記載のピラジノ〔2,3-d〕イソオキサゾ-ル誘導体。
- Xがフッ素原子または塩素原子であり、Yが-C(=O)R(Rはアルコキシ基、アルコキシ基は置換基を有していてもよい)であることを特徴とする請求項1に記載のピラジノ〔2,3-d〕イソオキサゾ-ル誘導体。
- Xがフッ素原子または塩素原子であり、Yが-C(=O)R(Rはメトキシ基、エトキシ基、n-プロポキシ基、イソプロポキシ基またはn-ブトキシ基)であることを特徴とする請求項1に記載のピラジノ〔2,3-d〕イソオキサゾ-ル誘導体。
- 下記一般式(I)
- Xがフッ素原子であり、Yが-C(=O)R(Rはアルコキシ基、アルコキシ基は置換基を有していてもよい)であることを特徴とする請求項7または8に記載の製造方法。
- Xがフッ素原子であり、Yが-C(=O)R(Rはメトキシ基、エトキシ基、n-プロポキシ基、イソプロポキシ基またはn-ブトキシ基)であることを特徴とする請求項7または8に記載の製造方法。
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AU2011327111A AU2011327111B2 (en) | 2010-11-12 | 2011-11-11 | Pyrazino[2,3-d]isoxazole Derivative |
NZ611498A NZ611498A (en) | 2010-11-12 | 2011-11-11 | Pyrazino[2,3-d]isoxazole derivative |
SG2013034541A SG190772A1 (en) | 2010-11-12 | 2011-11-11 | Pyrazino[2,3-d]isooxazole derivative |
RU2013126415/04A RU2570802C2 (ru) | 2010-11-12 | 2011-11-11 | ПРОИЗВОДНОЕ ПИРАЗИНО[2,3-d]ИЗОКСАЗОЛА |
ES11839720.7T ES2535341T3 (es) | 2010-11-12 | 2011-11-11 | Derivado de pirazino[2,3-d]isoxazol |
EP11839720.7A EP2639235B1 (en) | 2010-11-12 | 2011-11-11 | Pyrazino[2,3-d]isooxazole derivative |
KR1020137013626A KR101902857B1 (ko) | 2010-11-12 | 2011-11-11 | 피라지노〔2,3-d〕이소옥사졸 유도체 |
BR112013011418-5A BR112013011418B1 (pt) | 2010-11-12 | 2011-11-11 | Derivado de pirazino[2,3-d]isoxazol, métodos para a produção de um derivado de pirazino [2,3-d]isoxazol e compostos |
CN201180053816.5A CN103347884B (zh) | 2010-11-12 | 2011-11-11 | 吡嗪并[2,3-d]异*唑衍生物 |
MX2013005179A MX2013005179A (es) | 2010-11-12 | 2011-11-11 | Derivado de pirazino[2,3-d]isoxazol. |
CA2816687A CA2816687C (en) | 2010-11-12 | 2011-11-11 | Pyrazino[2,3-d]isoxazole derivative |
US13/886,483 US8901302B2 (en) | 2010-11-12 | 2013-05-03 | Pyrazino[2,3-D]isoxazole derivative which is useful as a production intermediate of pyrazine carboxamide derivative |
IL226228A IL226228A (en) | 2010-11-12 | 2013-05-08 | The history of pyrazino [3,2 – d] isoxazole and its process for preparation |
ZA2013/04074A ZA201304074B (en) | 2010-11-12 | 2013-06-04 | Pyrazino[2,3-d]isoxazole derivative |
HK13113416.4A HK1185882A1 (en) | 2010-11-12 | 2013-12-02 | Pyrazino[2,3-d]isoxazole derivative [23-d] |
US14/527,174 US9181203B2 (en) | 2010-11-12 | 2014-10-29 | Substituted pyrazino[2,3-d]isooxazoles as intermediates for the synthesis of substituted pyrazinecarbonitriles and substituted pyrazinecarboxamides |
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JPH07112970A (ja) * | 1993-09-07 | 1995-05-02 | F Hoffmann La Roche Ag | カルボキサミド類 |
WO2001060834A1 (fr) * | 2000-02-16 | 2001-08-23 | Toyama Chemical Co., Ltd. | Nouveaux derives de pyrazine ou leurs sels, compositions pharmaceutiques contenant ces derives ou leurs sels et intermediaires utilises dans leur preparation |
WO2009041473A1 (ja) * | 2007-09-27 | 2009-04-02 | Toyama Chemical Co., Ltd. | 6-フルオロ-3-ヒドロキシ-2-ピラジンカルボニトリルの有機アミン塩およびその製造法 |
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CZ282939B6 (cs) * | 1992-03-04 | 1997-11-12 | Lonza A.G. | Mikrobiologický způsob hydroxylace dusíkatých heterocyklických karboxylových kyselin |
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JPH07112970A (ja) * | 1993-09-07 | 1995-05-02 | F Hoffmann La Roche Ag | カルボキサミド類 |
WO2001060834A1 (fr) * | 2000-02-16 | 2001-08-23 | Toyama Chemical Co., Ltd. | Nouveaux derives de pyrazine ou leurs sels, compositions pharmaceutiques contenant ces derives ou leurs sels et intermediaires utilises dans leur preparation |
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BR112013011418A2 (pt) | 2016-07-19 |
US20150051396A1 (en) | 2015-02-19 |
KR20140082588A (ko) | 2014-07-02 |
CN103347884A (zh) | 2013-10-09 |
MX2013005179A (es) | 2013-07-05 |
BR112013011418B1 (pt) | 2021-03-16 |
US20130245264A1 (en) | 2013-09-19 |
EP2639235A1 (en) | 2013-09-18 |
CA2816687C (en) | 2018-11-27 |
HK1185882A1 (en) | 2014-02-28 |
KR101902857B1 (ko) | 2018-10-01 |
NZ611498A (en) | 2014-05-30 |
EP2639235A4 (en) | 2014-07-30 |
CN103347884B (zh) | 2015-12-02 |
IL226228A0 (en) | 2013-07-31 |
ZA201304074B (en) | 2014-08-27 |
ES2535341T3 (es) | 2015-05-08 |
TW201226412A (en) | 2012-07-01 |
BR112013011418A8 (pt) | 2018-08-14 |
US8901302B2 (en) | 2014-12-02 |
JP2012180336A (ja) | 2012-09-20 |
CA2816687A1 (en) | 2012-05-18 |
RU2570802C2 (ru) | 2015-12-10 |
IL226228A (en) | 2017-11-30 |
SG190772A1 (en) | 2013-08-30 |
RU2013126415A (ru) | 2014-12-20 |
AU2011327111B2 (en) | 2015-04-23 |
AU2011327111A1 (en) | 2013-05-02 |
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