Isoxazole derivatives

专利摘要:
The isoxazole derivative represented by the following formula (I) has an excellent monoamine oxidase inhibitory activity and is useful for the treatment or prevention of neurological diseases such as manic-depressive diseases: [Formula I] Wherein R 1 represents optionally substituted aryl or optionally substituted aromatic heterocyclic group; R 2 represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an alkoxy group, a cyano group, a carboxyl group, an alkanoyl group, an alkoxycarbonyl group or an optionally substituted carbamoyl group ; R 3 represents an optionally substituted amino group or a saturated heterocyclic group, X represents an oxygen atom or a sulfur atom, and n represents an integer of 2 to 6.
公开号:KR19990087339A
申请号:KR1019980706748
申请日:1997-02-27
公开日:1999-12-27
发明作者:고이찌 고지마；주니찌 사까이；나오즈미 사마따；마사오 고즈까；겐지 요시미；쓰기오 가네꼬
申请人:가와무라 요시부미；상꾜 가부시키가이샤；
IPC主号:

专利说明:

Isoxazole derivatives
Manic-depressive disorder is a disorder in which mood is the main disease during mood disorder, and it is thought to be one of the causes due to dysfunction of serotonin and noradrenaline nervous system in the brain. Serotonin and noradrenaline are mainly metabolized into monoamine oxidase in type A monoamine oxidase to lose bioactivity. Type A monoamine oxidase inhibitors are considered to be useful as antidepressant drugs, and their research and development have been actively conducted. Recently, moclobemide as a selective type A monoamine oxidase inhibitor has been provided for clinical use.
The present invention relates to an isoxazole derivative having a good A-type monoamine oxidase inhibitor or a pharmacologically acceptable salt thereof, manic-depressive disease, Parkinson's disease, Alzheimer's dementia (such as cognitive impairment based on Alzheimer's disease) or cerebrovascular disease Compositions for the treatment or prevention of neurological diseases (especially manic-depressive diseases), such as dementia (cognitive impairment based on cerebrovascular dementia), their use for the manufacture of a medicament for the treatment or prevention of said diseases, or their pharmacologically effective amounts The present invention relates to a method of treating or preventing the above-mentioned disease to be administered to an animal.
The present inventors have conducted long-term studies on the synthesis and pharmacological action of isoxazole derivatives for the purpose of developing an excellent manic-depressive medicine and the like. As a result, the isoxazole derivative having a specific structure has a strong type A monoamine oxidase inhibitory activity. Therapeutic or prophylactic effects of neurological disorders (particularly manic-depressive disorders) such as coordination, Parkinson's, Alzheimer's dementia (such as Alzheimer's dementia) or cerebrovascular dementia (such as dementia based on cerebrovascular dementia) In particular, the present invention was found to have a therapeutic effect.
The present invention relates to isoxazole derivatives having excellent type A monoamine oxidase inhibitory activity, or pharmacologically acceptable salts thereof, to orchestrated diseases, Parkinson's disease, Alzheimer's type dementia (such as cognitive impairment based on Alzheimer's disease), or brain. Compositions for the treatment or prevention of neurological diseases (especially manic-depressive diseases) such as vascular dementia (cognitive impairment based on cerebrovascular dementia), their use for the manufacture of a medicament for the treatment or prevention of such diseases, or their pharmacologically effective amounts It provides a method for the treatment or prevention of the disease to be administered to warm blooded animals.
The isoxazole derivatives of the present invention have formula (I).
Wherein R ¹ may have the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent groups, or 1 to 3 said substituents, and may be a nitrogen atom, an oxygen atom, and A 5 to 6 membered aromatic heterocyclic group having 1 to 2 heteroatoms identically or differently selected from the group consisting of sulfur atoms (wherein the substituent group is halogen; C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl, C ₇ -C ₁₈ aralkyl, C ₆ -C ₁₄ aryloxy or C ₇ -C ₁₈ aralkyloxy which may have the same or different substituents selected from the following groups: The substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Cyano; Nitro; Hydroxyl group; C ₁ -C ₇ alkanoyl; C ₁ -C ₇ alkanoyloxy; C ₂ -C ₇ alkoxycarbonyl; Amino; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl and monoC ₇ -C ₁₅ arylcarbonylamino which may have 1 to 3 substituents, identically or differently selected from the following group (the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy)
R ² is a hydrogen atom; Halogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkyl groups substituted with halogen or C ₁ -C ₆ alkoxy; C ₂ -C ₆ alkenyl group; C ₂ -C ₆ alkynyl group; C ₃ -C ₁₀ cycloalkyl group; C ₃ -C ₁₀ cycloalkenyl group; C ₁ -C ₆ alkoxy group; Cyano group; Carboxyl group; C ₁ -C ₇ alkanoyl group; C ₂ -C ₇ alkoxycarbonyl group; Carbamoyl group; Mono (C ₁ -C ₆ alkyl) carbamoyl group or di (C ₁ -C ₆ alkyl) carbamoyl group,
R ³ is an amino group, a mono C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group, a mono C ₁ -C ₇ alkanoylamino group, a mono C ₂ -C ₇ alkoxycarbonylamino group, the same or differently Mono C ₇ -C ₁₅ arylcarbonylamino group which may have 1 to 3 substituents selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy), or 1 A 5- to 6-membered saturated heterocyclic group containing a nitrogen atom, which may further contain one nitrogen atom or an oxygen atom, provided that the group is bonded on a nitrogen atom,
X represents an oxygen atom or a sulfur atom
n represents the integer of 2-6.
In addition, the active ingredient of the monoamine oxidase inhibitor of the present invention is an isoxazole derivative having the formula (I).
"Halogen atom" in the definition of the substituent groups, and R ² contained in R ¹ in the formula Ⅰ, for example, a fluorine atom, can be a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, more Preferably it is a chlorine atom.
In the above, the "C ₁ -C ₆ alkyl group" in the definitions of substituents and the like contained in R ¹ and R ² is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl Group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group , 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3 It may be a linear or branched alkyl group having 1 to 6 carbon atoms such as -dimethylbutyl group or 2-ethylbutyl group, the substituent contained in R ¹ is preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or It is an ethyl group, Especially preferably, it is a methyl group. R ² is preferably a C ₁ -C ₄ alkyl group, more preferably an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a t-butyl group, and particularly preferably an isopropyl group.
In the definition of R ² , the “C ₂ -C ₆ alkenyl group” is, for example, a vinyl group, 1-propenyl group, allyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, or 2- Methyl-1-propenyl group, isopropenyl group, allenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, isoprenyl group, 5-hexenyl group or 1,4-hexadiee It may be a linear or branched alkenyl group having 2 to 6 carbon atoms having 1 to 2 double bonds, such as a silyl group, preferably a vinyl group, 1-propenyl group, aryl group, 1-methyl-1-propenyl group, iso It is a propenyl group, 2-butenyl group, or 3-butenyl group, More preferably, it is an allyl group, an isopropenyl group, or 2-butenyl group, Especially preferably, it is an allyl group.
In the definition of R ² , the “C ₂ -C ₆ alkynyl group” is, for example, an ethynyl group, 1-propynyl group, propargyl group, 1-methyl-2-propynyl group, 2-methyl-2-propynyl group, 2 -Ethyl-2-propynyl group, 2-butynyl group, 1-methyl-2-butynyl group, 2-methyl-2-butynyl group, 3-butynyl group, 2-pentynyl group, 5-hexynyl group or 2-methyl- It may be a straight or branched chain alkynyl group having 2 to 6 carbon atoms such as a 4-pentynyl group, preferably an ethynyl group, propargyl group, 2-butynyl group or 3-butynyl group, more preferably propargyl group .
In the definition of R ² , the “C ₃ -C ₁₀ cycloalkyl group” is, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a norbornyl group, or an adamantyl group ( Iii) It may be a 3 to 10 membered saturated cyclic hydrocarbon group, preferably a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, more preferably a cyclopropyl group.
In the above, "C ₃ -C ₁₀ cycloalkenyl group" in the definition of R ² is, for example, a 2-cyclopropenyl group, 2-cyclobutenyl group, 1-cyclopentenyl group, 2-cyclopentenyl group, or 3-cyclopentenyl group. , 1-cyclohexenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, 2-cycloheptenyl group, 3-norborenyl group or 3-adamantenyl group having one double bond and can be condensed It may be a 3 to 10 membered unsaturated ring hydrocarbon group, preferably 2-cyclopentenyl group, 3-cyclopentenyl group, 2-cyclohexenyl group or 3-cyclohexenyl group, more preferably 2-cyclo Pentenyl group.
In the above, the substituent contained in R ¹ and "C ₁ -C ₆ alkyl group substituted with halogen or C ₁ -C ₆ alkoxy" in the definition of R ² include 1 to 5 of the "halogen atom" described above. _Group bonded to _1- C ₆ alkyl group or later "C ₁ -C ₆ alkoxy" represents a group bonded to the C ₁ -C ₆ alkyl group, and as a group where halogen is bonded to a C ₁ -C ₆ alkyl group, for example, Romethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, 3-fluoropropyl group, 3-chloropropyl group, 3- Promopropyl group, 4-fluorobutyl group or 6-iodine hexyl group, C ₁ -C ₆ alkoxy is a group bonded to a C ₁ -C ₆ alkyl group, for example, methoxymethyl group, ethoxymethyl group, propoxy Methyl group, butoxymethyl group, methoxyethyl group, ethoxyethyl group, propoxyethyl group, butoxyethyl group, propoxypropyl group, butoxy part Hexyl group or hexyloxy may be a group, the substituent contained in R ¹ is preferably a C ₁ -C ₆ alkyl group substituted by halogens or 1 to 3 C ₁ -C ₄ alkoxy, more preferably fluoro Chloromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, methoxymethyl group or methoxyethyl group, even more preferably Fluoromethyl group, 2,2,2-trifluoroethyl group or methoxymethyl group, and particularly preferably trifluoromethyl group. R ² is preferably a fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, It is a methoxymethyl group or a methoxyethyl group, More preferably, it is a trifluoromethyl group, 2-fluoroethyl group, 1-chloroethyl group, or 2-chloroethyl group, Especially preferably, it is 1-chloroethyl group.
In the above, the "C ₁ -C ₆ alkoxy group" in the definition of the substituents contained in R ² and R ² , such as the substituents contained in R ¹ , means that the "C ₁ -C ₆ alkyl group" is bonded to an oxygen atom. Group, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, s-butoxy group, t-butoxy group, pentoxy group, isopentoxy group, 2-methylbutoxy group, neo Pentoxy group, 1-ethylpropoxy group, hexyloxy group, 4-methylpentoxy group, 3-methylpentoxy group, 2-methylpentoxy group, 1-methylpentoxy group, 3,3-dimethylbutoxy group, 2,2- Dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group or 2-ethylbutoxy group, preferably C ₁ -C ₄ alkoxy group, more preferably a methoxy group or an ethoxy group, and particularly preferably a methoxy group.
In the above, in the definition of the substituents contained in R ¹ "C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents identically or differently selected from the following group (the substituent group is halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ alkoxy) ”refers to an aromatic hydrocarbon group having 6 to 14 carbon atoms which may have 1 to 3 substituents which are the same or differently selected from the above substituent group, for example, a phenyl group, a fluorophenyl group, a chlorophenyl group , Dichlorophenyl group, methylphenyl group, trimethylphenyl group, methoxyphenyl group, indenyl group, methylindenyl group, naphthyl group, dichloronaphthyl group, phenanthrenyl group, hexylphenanthrenyl group, anthracenyl group, dimethylanthracenyl group or hexyloxyanthra And may have 1 to 2 substituents, which are preferably the same or differently selected from the group consisting of fluorine, chlorine, methyl and methoxy. It is a phenyl group, more preferably a phenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 2,4-dichlorophenyl group, 4-methylphenyl group or a 4-ethoxy group, particularly preferably a phenyl group.
In the above, in the definition of the substituents contained in R ¹ "C ₇ -C ₁₈ aralkyl group which may have 1 to 3 substituents identically or differently selected from the following group (the substituent group is halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ alkoxy) ”means that one or two phenyl groups or one naphthyl group which may have 1 to 3 substituents which are the same or differently selected from the above substituents is selected from the above“ C ₁ -C ₆ Alkyl ", such as benzyl, fluorobenzyl, difluorobenzyl, trifluorobenzyl, chlorobenzyl, dichlorobenzyl, trichlorobenzyl, bromobenzyl, methylbenzyl, dimethylbenzyl , Trimethylbenzyl group, ethylbenzyl group, propylbenzyl group, methoxybenzyl group, dimethoxybenzyl group, ethoxybenzyl group, hexyloxybenzyl group, diphenylmethyl group, naphthylmethyl group, fluoronaphthylmethyl group, difluoro Naphthylmethyl Group, chloronaphthylmethyl group, dichloronaphthylmethyl group, methylnaphthylmethyl group, dimethylnaphthylmethyl group, ethylnaphthylmethyl group, phenethyl group, fluorophenethyl group, difluorophenethyl group, chlorophenethyl group, dichlorophenethyl group, methyl Phenethyl group, trimethylphenethyl group, naphthylethyl group, fluoronaphthylethyl group, chloronaphthylethyl group, phenylpropyl group, fluorophenylpropyl group, chlorophenylpropyl group, dichlorophenylpropyl group, methylphenylpropyl group, dimethylphenylpropyl group , Trimethylphenylpropyl group, naphthylpropyl group, iodine naphthylpropyl group, hexylnaphthylpropyl group, methoxynaphthylpropyl group, hexyloxynaphthylpropyl group, phenylbutyl group, fluorophenylbutyl group, difluoro Phenylbutyl group, chlorophenylbutyl group, dichlorophenylbutyl group, trimethylphenylbutyl group or naphthylbutyl group, preferably halogen, C ₁ -C ₄ alkyl and C _1- A benzyl group or a phenethyl group which may have 1 to 3 substituents identically or differently selected from the group consisting of C ₄ alkoxy, more preferably fluorine, chlorine, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy Benzyl group which may have one substituent selected from the group consisting of, more preferably benzyl group, fluorobenzyl group, chlorobenzyl group, difluorobenzyl group, dichlorobenzyl group, methylbenzyl group, dimethylbenzyl group or It is a methoxy benzyl group, Especially preferably, it is a benzyl group.
In the above, in the definition of the substituents contained in R ¹ "C ₆ -C ₁₄ aryloxy group which may have 1 to 3 substituents identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy ”refers to a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents, which may be identically or differently selected from the following group (the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy) "represents a group bonded to an oxygen atom, for example, phenoxy group, fluorophenoxy group, chlorophenoxy group, dichlorophenoxy group, methylphenoxy group, trimethylphenoxy group, methoxy It may be a phenoxy group, indenyloxy group, methyl indenyloxy group, naphthyloxy group, dichloronaphthyloxy group, phenanthrenyloxy group, hexylphenanthrenyloxy group, anthracenyloxy group, dimethyl anthracenyloxy group or hexyloxy anthracenyloxy group There , Preferably a phenoxy group which may have 1 to 2 substituents identically or differently selected from the group consisting of fluorine, chlorine, methyl and methoxy, more preferably phenoxy group, 4-fluorophenoxy group, 4 -Chlorophenoxy group, 2,4-dichlorophenoxy group, 4-methylphenoxy group or 4-methoxyphenoxy group, and particularly preferably a phenoxy group.
In the above, in the definition of the substituent contained in R ¹ "C ₇ -C ₁₈ aralkyloxy group which may have 1 to 3 substituents identically or differently selected from the following group (the substituent group is halogen, C _1- C ₆ alkyl or C ₁ -C ₆ alkoxy ”refers to a C ₇ -C ₁₈ aralkyl group which may have 1 to 3 substituents, which may be identically or differently selected from the following group (the substituent group being halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy) "represents a group bonded to an oxygen atom, for example benzyloxy group, fluorobenzyloxy group, difluorobenzyloxy group, trifluorobenzyloxy group, chloro Benzyloxy group, dichlorobenzyloxy group, trichlorobenzyloxy group, bromobenzyloxy group, methylbenzyloxy group, dimethylbenzyloxy group, trimethylbenzyloxy group, ethylbenzyloxy group, propylbenzyloxy group, methoxybenzyl jade Period, dimethoxybenzyloxy group, ethoxy Nitrogen group, hexyloxybenzyloxy group, diphenylmethoxy group, naphthylmethoxy group, fluoronaphthylmethoxy group, difluoronaphthylmethoxy group, chloronaphthylmethoxy group, dichloronaphthylmethoxy group, methylnaphthyl methoxy Period, dimethylnaphthylmethoxy group, ethylnaphthylmethoxy group, phenylethoxy group, fluorophenylethoxy group, difluorophenylethoxy group, chlorophenylethoxy group, dichlorophenylethoxy group, methylphenylethoxy group , Trimethylphenylethoxy group, naphthylethoxy group, fluoronaphthylethoxy group, chloronaphthylethoxy group, phenylpropoxy group, fluorophenylpropoxy group, chlorophenylpropoxy group, dichlorophenylpropoxy Time period, methylphenyl propoxy group, dimethylphenyl propoxy group, trimethylphenyl propoxy group, naphthyl propoxy group, iodine naphthyl propoxy group, hexyl naphthyl propoxy group, methoxy naphthyl propoxy group, hexyloxy naph Tilpropoxy , Phenyl-butoxy group, a phenyl-butoxy, fluoro, phenyl-butoxy-difluoro, chloro-phenyl-butoxy group, dichlorophenyl butoxy group, and a butoxy group can trimethylphenyl or naphthyl tilbu ethoxy group, preferably a halogen, C ₁ -C ₄ A benzyloxy group or a phenylethoxy group which may have 1 to 3 substituents identically or differently selected from the group consisting of alkyl and C ₁ -C ₄ alkoxy, more preferably fluorine, chlorine, C ₁ -C ₄ Benzyloxy group which may have one substituent selected from the group consisting of alkyl and C ₁ -C ₄ alkoxy, even more preferably benzyloxy group, 4-fluorobenzyloxy group, 4-chlorobenzyloxy group, 2,4-difluorobenzyloxy group, 2,4-dichlorobenzyloxy group, 4-methylbenzyloxy group, 2,4-dimethylbenzyloxy group or 4-methoxybenzyloxy group, particularly preferably benzyl It's oxygen.
In the above, "C ₁ -C ₇ alkanoyl group" in the definition of a substituent contained in R ¹ and R ² represents a group in which a hydrogen atom or the "C ₁ -C ₆ alkyl" is bonded to a carbonyl group, for example, a formyl group , Acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group or heptanoyl group, preferably formyl group or acetyl group, particularly preferably acetyl It is.
In the above, in the definition of the substituent contained in R ¹ , "C ₁ -C ₇ alkanoyloxy group" refers to a group in which the "C ₁ -C ₇ alkanoyl group" is bonded to an oxygen atom, for example, a formyloxy group, It may be an acetoxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group, hexanoyloxy group or heptanoyloxy group, preferably formyloxy group or It is an acetoxy group, Especially preferably, it is an acetoxy group.
In the above, "C ₂ -C ₇ alkoxycarbonyl group" in the definition of a substituent contained in R ¹ and R ² represents a group in which the "C ₁ -C ₆ alkoxy group" is bonded to a carbonyl group, for example, a methoxycarbonyl group, Ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, pentoxycarbonyl group, isopentoxycarbonyl group, 2-methylbutoxycarbonyl group, neo Pentoxycarbonyl group, 1-ethylpropoxycarbonyl group, hexyloxycarbonyl group, 4-methylpentoxycarbonyl group, 3-methylpentoxycarbonyl group, 2-methylpentoxycarbonyl group, 1-methylpentoxycarbonyl group, 3,3-dimethylbutoxy Carbonyl group, 2,2-dimethylbutoxycarbonyl group, 1,1-dimethylbutoxycarbonyl group, 1,2-dimethylbutoxycarbonyl group, 1,3-dimethylbutoxycarbonyl group, 2,3-dimethylbutoxycarbonyl group Or 2-ethylbutoxycarbonyl group, preferably a C ₂ -C ₅ alkoxycarbonyl group, more preferably a methoxycarbonyl group or an ethoxycarbonyl group, and particularly preferably a methoxycarbonyl group.
In the above, in the definition of R ³ , the "mono C ₁ -C ₆ alkylamino group" refers to a group in which the "C ₁ -C ₆ alkyl group" is bonded to an amino group, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group. , Butylamino group, isobutylamino group, s-butylamino group, t-butylamino group, pentylamino group or hexylamino group, preferably mono C ₁ -C ₄ alkylamino group, more preferably methylamino group or ethylamino group And particularly preferably methylamino group.
In the above, in the definition of R ³ , "di (C ₁ -C ₆ alkyl) amino group" is, for example, N, N-dimethylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N- Isopropyl-N-methylamino group, N-butyl-N-methylamino group, N-isobutyl-N-methylamino group, Ns-butyl-N-methylamino group, Nt-butyl-N-methylamino group, N, N-di Ethylamino group, N-ethyl-N-propylamino group, N-ethyl-N-isobutylamino group, N, N-dipropylamino group, N, N-dibutylamino group, N, N-dipentylamino group or N, N- It may be a dihexylamino group, preferably a di (C ₁ -C ₄ alkyl) amino group, more preferably an N, N-dimethylamino group or N, N-diethylamino group, particularly preferably N, N- It is a dimethylamino group.
In the above, in the definition of R ³ "C ₁ -C ₇ alkanoylamino group" is represents an above-described "C ₁ -C ₇ alkanoyl group" is bonded to an amino group, such as formyl group, acetyl group, propionyl group , Butyrylamino group, isobutyrylamino group, valerylamino group, isovalerylamino group, fivaloylamino group, hexanoylamino group or heptanoylamino group, preferably formylamino group or acetylamino group, particularly preferably It is an acetylamino group.
In the above, R ³ in the definition of "C ₂ -C ₇ alkoxycarbonylamino group", a "C ₂ -C ₇ alkoxycarbonyl group" represents a group bonded to the amino group, for example methoxycarbonyl group, ethoxycarbonyl group , Propoxycarbonylamino group, isopropoxycarbonylamino group, butoxycarbonylamino group, isobutoxycarbonylamino group, s-butoxycarbonylamino group, t-butoxycarbonylamino group, pentoxycarbonylamino group, isopen Methoxycarbonylamino group, 2-methylbutoxycarbonylamino group, neopentoxycarbonylamino group, 1-ethylpropoxycarbonylamino group, hexyloxycarbonylamino group, 4-methylpentoxycarbonylamino group, 3-methylphene Oxycarbonylamino group, 2-methylpentoxycarbonylamino group, 1-methylpentoxycarbonylamino group, 3,3-dimethylbutoxycarbonylamino group, 2,2-dimethylbutoxycarbonylamino group , 1,1-dimethylbutoxycarbonylamino group, 1,2-dimethylbutoxycarbonylamino group, 1,3-dimethylbutoxycarbonylamino group, 2,3-dimethylbutoxycarbonylamino group or 2-ethylbutoxy It may be a carbonylamino group, preferably a C ₂ -C ₅ alkoxycarbonylamino group, more preferably a methoxycarbonylamino group or an ethoxycarbonylamino group, particularly preferably a methoxycarbonylamino group.
In the above, the "mono (C ₁ -C ₆ alkyl) carbamoyl group" in the definition of the substituent contained in R ¹ and R ² is, for example, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropyl Carbamoyl group, butyl carbamoyl group, isobutyl carbamoyl group, s-butyl carbamoyl group, t-butyl carbamoyl group, pentyl carbamoyl group or hexyl carbamoyl group, preferably mono (C _1- C ₄ alkyl) carbamoyl group, more preferably methyl carbamoyl group or ethyl carbamoyl group.
In the above, the substituent contained in R ¹ and the "di (C ₁ -C ₆ alkyl) carbamoyl group" in the definition of R ² are, for example, N, N-dimethylcarbamoyl group and N-ethyl-N-methylcarba. Barmoyl group, N, N-diethylcarbamoyl group, N, N-dipropylcarbamoyl group, N, N-diisopropylcarbamoyl group, N, N-dibutylcarbamoyl group, N, N-diiso Butylcarbamoyl group, N, N-di-s-butylcarbamoyl group, N, N-di-t-butylcarbamoyl group, N, N-dipentylcarbamoyl group or N, N-dihexylcarbamoyl Group, preferably a di (C ₁ -C ₄ alkyl) carbamoyl group, more preferably an N, N-dimethylcarbamoyl group or a N, N-diethylcarbamoyl group, particularly preferably N And N-dimethylcarbamoyl group.
In the above, the substituents contained in R ¹ and in the definition of R ³ "a mono C ₇ -C ₁₅ arylcarbonylamino group which may have 1 to 3 substituents selected from the same or differently from the following group (the substituent group is Halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy) refers to a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents, which may be identically or differently selected from the following: Is halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy) "is a group bonded to a carbonylamino group, for example, benzoylamino group, fluorobenzoylamino group, chlorobenzoylamino group, dichlorobenzoylamino group, toluoylamino group, Trimethylbenzoylamino group, anisoylamino group, indenoylamino group, methylindenoylamino group, naphthylamino group, dichloronaphthylamino group, phenanthrenoylamino group, hexylphenant Noylamino group, anthracenoylamino group, dimethylanthracenoylamino group or hexyloxyanthracenylamino group, preferably 1 to 2 substituents selected identically or differently from the group consisting of fluorine, chlorine, methyl and methoxy Benzoylamino group, more preferably a benzoylamino group, 4-fluorobenzoylamino group, 4-chlorobenzoylamino group, 2,4-dichlorobenzoylamino group, 4-toluoylamino group or 4-anisoylamino group, particularly Preferably it is a benzoylamino group.
In the above, in the definition of R ³ "5 to 6 membered saturated heterocyclic group which contains one nitrogen atom and may further contain one nitrogen atom or oxygen atom, provided that the group is bonded on a nitrogen atom. May be, for example, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidyl group, a piperazinyl group or a morpholinyl group, and is preferably a piperidyl group or a morpholinyl group.
In the above, in the definition of R ¹ "C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the same or different substituent groups" is, for example, a phenyl group, which may be substituted by the substituent It may be a silyl group, a naphthyl group, a phenanthrenyl group or an anthracenyl group, preferably a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the same or different substituents (wherein the substituent group is halogen ; C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl; Phenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy; Benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy, 2,4-difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-methylbenzyloxy, 2,4-dimethylbenzyloxy, 4- Methoxybenzyloxy; Cyano; Nitro; Hydroxyl group; Acetoxy; C ₂ -C ₇ alkoxycarbonyl; Amino; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; Di (C ₁ -C ₆ alkyl) carbamoyl; Benzoylamino, 4-fluorobenzoylamino, 4-chlorobenzoylamino, 2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino], more preferably the same or different And a C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected. C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Cyano; C ₂ -C ₇ alkoxycarbonyl; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; And di (C ₁ -C ₆ alkyl) carbamoyl], more preferably a C ₆ -C ₁₄ aryl group which may have from 1 to 3 substituents selected from the same or different substituent groups [the substituents The group is halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, Carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl], even more preferably the same or different A phenyl group which may have 1 to 3 substituents [the substituent group is halogen, methyl, ethyl, trifluoromethyl, methoxy, Yl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarbamoyl], and even more preferably the same or different from the following substituent groups And a phenyl group which may have 1 to 2 substituents (wherein the substituent group is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy), particularly preferably a phenyl group, a fluorophenyl group, a chlorophenyl group and a difluorine group. It is a phenyl group, a dichlorophenyl group, or a methylphenyl group, More preferably, they are a phenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2, 4- difluorophenyl group, or 2, 4- dichlorophenyl group. The number of substituents on the aryl group is preferably 1 to 3, more preferably 1 to 2, and particularly preferably 2.
In the above definition, in the definition of R ¹ "5 to 6 membered having 1 to 3 said substituents and having 1 to 2 heteroatoms identically or differently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Aromatic heterocyclic group ”includes, for example, a pyrrolyl group, imidazolyl group, pyrazolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, It may be a pyridyl group, a pyrazinyl group, a pyrimidinyl group or a pyridazinyl group, and may preferably have 1 to 3 substituents selected from the same or different substituent groups, and a group consisting of nitrogen atom, oxygen atom and sulfur atom Is a 5 to 6 membered aromatic heterocyclic group having 1 to 2 heteroatoms identically or differently selected from [The substituent group is halogen; C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl; Phenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy; Benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy, 2,4-difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-methylbenzyloxy, 2,4-dimethylbenzyloxy, 4- Methoxybenzyloxy; Cyano; Nitro; Hydroxyl group; Acetoxy; C ₂ -C ₇ alkoxycarbonyl; Amino; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; Di (C ₁ -C ₆ alkyl) carbamoyl; Benzoylamino, 4-fluorobenzoylamino, 4-chlorobenzoylamino, 2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino], more preferably the same or different It is a 5 to 6 membered aromatic heterocyclic group which may have 1 to 3 substituents selected and has 1 to 2 heteroatoms identically or differently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. Silver halogen; C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Cyano; C ₂ -C ₇ alkoxycarbonyl; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; And di (C ₁ -C ₆ alkyl) carbamoyl], more preferably the same or different, and may have 1 to 2 substituents selected from the group of substituents and are selected from the group consisting of nitrogen, oxygen and sulfur A 5- to 6-membered aromatic heterocyclic group having 1 to 2 heteroatoms, identically or differently selected, wherein the substituent group is halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoro Methyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4 Dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl], more preferably the same or different It is a furyl group, thienyl group or pyridyl group which may have 1 to 2 substituents selected from the group group [the substituent group is halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl , Carbamoyl, methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarbamoyl], and more preferably, a furyl group and thienyl group which may have one substituent selected from the following substituent groups Or a pyridyl group [the relevant substituent groups are fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy], particularly preferably 2-furyl group, 3-furyl group, 2-thienyl group or 3-thienyl group More preferably 2-furyl group or 2-thienyl group. The number of substituents on the aromatic heterocyclic group is preferably 1 to 3, more preferably 1 to 2, and particularly preferably 1. Moreover, it is preferable that the bond of an aromatic heterocyclic group and a isoxazole ring couple | bonds with the carbon atom of the said aromatic heterocyclic ring between them.
X in the above is preferably an oxygen atom.
In the above, n is preferably an integer of 2 to 4, particularly preferably 2.
Compound (I) of the present invention can be used as an acid addition salt according to a conventional method. For example, compound (I) may be obtained by treating with a corresponding acid in a solvent (such as ethers, esters or alcohols, in particular ethers), corresponding acid at room temperature for 5 to 30 minutes to filter the precipitated crystals or removing the solvent under reduced pressure distillation. Can be. Such salts include, for example, inorganic acid salts such as hydrofluoric acid salts, hydrochloride salts, hydrobromide salts, iodide salts, nitrate salts, perchlorates, sulfates and phosphates; Sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate or p-toluene sulfonate; Carboxylates such as fumarate, succinate, citrate, tartarate, oxalate or maleate; Or an amino acid salt such as glutamate or aspartate, preferably an inorganic acid salt (particularly hydrochloride).
Compound (I) of the present invention may have a subsidiary carbon in a molecule, and stereoisomers each having an R configuration and an S configuration may exist, but each or a mixture of any of them is included in the present invention.
The compound (I) or salts thereof of the present invention may absorb water and become watery or hydrated by being left in the air or recrystallized. Compound salts containing such water are also included in the present invention.
In the compound having the above formula (I), preferably
(1) R ¹ may have the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 said substituents selected from the following substituent group or 1 to 3 said substituents, and may be nitrogen atom, oxygen atom and Compounds which are 5- to 6-membered aromatic heterocyclic groups having 1 to 2 heteroatoms identically or differently selected from the group consisting of sulfur atoms [The substituent group is halogen, C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent groups are halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy); Benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl; Phenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy; Benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy, 2,4-difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-methylbenzyloxy, 2,4-dimethylbenzyloxy, 4- Methoxybenzyloxy; Cyano; Nitro; Hydroxyl group; Acetoxy; C ₂ -C ₇ alkoxycarbonyl; Amino; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; Di (C ₁ -C ₆ alkyl) carbamoyl; Benzoylamino, 4-fluorobenzoylamino, 4-chlorobenzoylamino, 2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino],
(2) R ¹ may be the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 of the above substituents selected from the following substituent group, or may have 1 to 3 of the above substituents, nitrogen atom, oxygen atom And a 5 to 6 membered aromatic heterocyclic group having 1 to 2 heteroatoms identically or differently selected from the group consisting of sulfur atoms [the substituent group is halogen, C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Cyano; C ₂ -C ₇ alkoxycarbonyl; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; And di (C ₁ -C ₆ alkyl) carbamoyl],
(3) R ¹ may be the same or different, a C ₆ -C ₁₄ aryl group which may have 1 to 3 of the above substituents selected from the following substituent group, or may have 1 to 2 of the above substituents, nitrogen atom, oxygen atom And a 5 to 6 membered aromatic heterocyclic group having 1 to 2 heteroatoms identically or differently selected from the group consisting of sulfur atoms [the substituent group is halogen, C ₁ -C ₄ alkyl, fluoromethyl, di Fluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4 -Chlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl],
(4) A compound in which R ¹ is the same or different, is a phenyl group which may have 1 to 3 substituents selected from the following substituent groups, or a furyl group, thienyl group or pyridyl group which may have 1 to 2 substituents described above. Substituent groups are halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarbamoyl ],
(5) A compound in which R ¹ is the same or different and is a phenyl group which may have 1 to 2 substituents selected from the following substituent groups, or a furyl group, thienyl group or pyridyl group which may have one of the above substituents Is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy],
(6) a compound in which R ¹ is phenyl group, fluorophenyl group, chlorophenyl group, difluorophenyl group, dichlorophenyl group, methylphenyl group, 2-furyl group, 3-furyl group, 2-thienyl group, or 3-thienyl group,
(7) a compound in which R ¹ is a phenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2-furyl group or 2-thienyl group,
(8) R ² is hydrogen atom, halogen atom, C ₁ -C ₆ alkyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group, 2 , 2,2-trifluoroethyl group, methoxymethyl group, methoxyethyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, 2-cyclopente Nyl group, 3-cyclopentenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, methoxy group, ethoxy group, cyano group, carboxyl group, formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group , A methyl carbamoyl group, an ethyl carbamoyl group, or a N, N-dimethylcarbamoyl group,
(9) a compound in which R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group,
(10) a compound in which R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, an allyl group, isopropenyl group, 2-butenyl group, or propargyl group,
(11) a compound in which R ² is a hydrogen atom, a chlorine atom, an ethyl group, a propyl group, isopropyl group, an isobutyl group or a t-butyl group,
(12) a compound in which R ² is a hydrogen atom or an isopropyl group,
(13) R ³ may contain an amino group, a mono C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group or one nitrogen atom, and may further contain one nitrogen atom or oxygen atom 5- to 6-membered saturated heterocyclic group, provided that the group is bonded on a nitrogen atom,
(14) A compound in which R ³ is an amino group, methylamino group, ethylamino group, N, N-dimethylamino group, piperidyl group or morpholinyl group,
(15) a compound in which R ³ is an amino group,
(16) a compound in which X is an oxygen atom,
(17) A compound in which n is 2 may be mentioned, with respect to R ¹ , the preferred rank is increased in the order (1) to (7), and the preferred rank is increased in the order of (8) to (12) with respect to R ² . , R ³ is preferred in order of (13) to (15).
In addition, as the compound having the formula (I), 2 to 5 in the group consisting of (1)-(7), (8)-(12), (13)-(15), (16) and (17) And those which are arbitrarily combined with these may be cited. As preferable compounds in the combination, for example,
(18) R ⁶ may have the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent groups, or may have 1 to 3 such substituents, and include nitrogen atom, oxygen atom and And a 5-6 membered aromatic heterocyclic group having 1 to 2 heteroatoms identically or differently selected from the group consisting of sulfur atoms [The substituent group is halogen; C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Cyano; C ₂ -C ₇ alkoxycarbonyl; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; And di (C ₁ -C ₆ alkyl) carbamoyl],
R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group,
R ³ contains an amino group, a mono C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group or one nitrogen atom, and may further contain one nitrogen atom or oxygen atom to five to one member A 6-membered saturated heterocyclic group, provided that the group is bonded on a nitrogen atom,
(19) R ¹ may have the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent groups, or may have 1 to 3 such substituents, and may include a nitrogen atom, an oxygen atom, and And a 5-6 membered aromatic heterocyclic group having 1 to 2 heteroatoms identically or differently selected from the group consisting of sulfur atoms [The substituent group is halogen; C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Cyano; C ₂ -C ₇ alkoxycarbonyl; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; And di (C ₁ -C ₆ alkyl) carbamoyl],
R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group,
R ³ is an amino group,
X is an oxygen atom,
n is 2,
(20) R ¹ may have the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent group, or may have 1 to 2 such substituents, and include nitrogen atom, oxygen atom and A 5-6 membered aromatic heterocyclic group having 1 to 2 heteroatoms identically or differently selected from the group consisting of sulfur atoms [the substituent group is halogen; C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, Methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl],
R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, an allyl group, isopropenyl group, 2-butenyl group or propargyl group,
R ³ is an amino group,
X is an oxygen atom,
n is 2,
(21) R ¹ is the same or different and is a phenyl group which may have 1 to 3 substituents selected from the following substituent groups, or a phenyl group or a furyl group, thienyl group or pyridyl group which may have 1 to 2 said substituents [ The substituent group is halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcarba Gather together;
R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, an allyl group, isopropenyl group, 2-butenyl group or propargyl group,
R ³ is an amino group,
X is an oxygen atom,
n is 2,
(22) R ¹ is the same or different, a phenyl group which may have 1 to 2 substituents selected from the following substituent groups, or a furyl group, thienyl group or pyridyl group which may have one of the above substituents. , Fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy]
R ² is a hydrogen atom, a chlorine atom, an ethyl group, a propyl group, isopropyl group, isobutyl group or t-butyl group,
R ³ is an amino group,
X is an oxygen atom,
n is 2,
(23) R ¹ is a fluorophenyl group, chlorophenyl group, difluorophenyl group, dichlorophenyl group, methylphenyl group, 2-furyl group, 3-furyl group, 2-thiethyl group or 3-thienyl group,
R ² is a hydrogen atom, a chlorine atom, an ethyl group, a propyl group, isopropyl group, isobutyl group or t-butyl group,
R ³ is an amino group,
X is an oxygen atom,
n is 2,
(24) R ¹ is a phenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2-furyl group or 2-thienyl group,
R ² is a hydrogen atom or an isopropyl group,
R ³ is an amino group,
X is an oxygen atom,
The compound whose n is 2 is mentioned and a preferable rank rises in order from (18) to (24) regarding the above.
As the representative compound of the present invention, for example, the compounds listed in the following table may be mentioned, but the present invention is not limited to these compounds.
The abbreviations in the table are as follows.
Ac: Acetyl
All: Allyl
Bn: Benzyl
Bu: Butyl
Bu ⁱ : Isobutyl
Bu ^s : sec-butyl
Bu ^t : tert-butyl
Bun (2): 2-butenyl
Bz: Benzoyl
Et: ethyl
Fur (2): 2-furyl
Hex: Hexyl
Imid (2): 2-imidazolyl
Inde (1): 1-indenyl
Isothiz (3): 3-isothiazolyl
Isox (3): 3-isoxazolyl
Me: Methyl
Moc: methoxycarbonyl
Mor (4): 4-morpholinyl
Np (1): 1-naphthyl
Np (2): 2-naphthyl
Oxa (2): 2-oxazolyl
Pen ^c (2): 2-cyclopentenyl
Ph: Phenyl
Pip (1): 1-piperidyl
Piz (1): 1-piperazinyl
Pn: pentyl
Pn ^c : cyclopentyl
Pn ⁱ : isopentyl
Pr: Profile
Pr ^c : cyclopropyl
Pr ⁱ : Isopropyl
Pre ⁱ : Isopropenyl
Prg: Propargyl
Pym (2): 2-pyrimidinyl
Pyr (2): 2-pyridyl
Pyr (3): 3-pyridyl
Pyr (4): 4-pyridyl
Pyrd (1): 1-pyrrolidinyl
Pyrr (3): 3-pyrrolyl
Pyz (2): 2-pyrazinyl
Pyza (1): 1-pyrazolyl
Pyzn (3): 3-pyridazinyl
Thi (2): 2-thienyl
Thi (3): 3-thienyl
Thiz (2): 2-thiazolyl
[Formula I]
















In the isoxazole derivatives having formula I of the present invention, preferred compounds include 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 25, 27, 28, 29, 30, 32, 36, 48, 50, 54, 66, 70, 74, 93, 95, 96, 111, 112, 113, 114, 115, 116, 117, 125, 127, 131, 143, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 188, 190, 194, 206, 208, 212, 224, 226, 230, 242, 244, 248, 260, 262, 263, 264, 266, 278, 296, 298, 314, 316, 332, 334, 350, 357, 363, 368, 379, 386, 397, 408, 469, 475, 481, 505, 510, 511, 517, 523, 535, 538, 539, 540, 541, 542, 543, 544, 545, 546, 562, 568, 574, 580, 586, 592, 598, 604, 610, 616, 622, 628, 724, 728, 729, 730, 731, 732, 733, 752, 764, 776, 788, 794, 800, 806, 812, 818, 824, 1056, 1061, 1347, 1348, 1349, 1350, 1351, 1357, 1359, 1386, 1388, 1390, 1392, 1394, 1396, 1398, 1400, 1402, 1404, 1406, 1408, 1410, 1412, 1414, 1416, 1459, 1495, 1499, 1500, 1526, 1545, 1549, 1550, 1576, 1590, 1604, 1618, 1632, 1646, 1660 , 1674, 1688, 1702, 1716, 1809 or 1811.
More preferred compounds include 1, 4, 5, 6, 7, 8, 9, 11, 13, 14, 15, 30, 32, 36, 48, 50, 54, 66, 70, 74, 93, 95, 99 , 111, 113, 117, 125, 127, 131, 143, 147, 149, 150, 151, 170, 172, 176, 188, 190, 194, 206, 208, 212, 224, 226, 230, 242, 244 , 248, 260, 262, 263, 264, 266, 278, 296, 298, 314, 316, 332, 334, 350, 357, 363, 368, 379, 386, 397, 408, 469, 475, 481, 505 , 510, 511, 517, 523, 535, 538, 539, 540, 541, 542, 543, 544, 545, 546, 562, 568, 574, 580, 586, 592, 598, 604, 610, 616, 622 , 628, 724, 728, 729, 730, 731, 732, 733, 752, 764, 776, 788, 794, 800, 806, 812, 818, 824, 1056, 1061, 1392, 1394, 1398, 1809 or 1811 Can be mentioned.
Even more preferred compounds include 1, 4, 5, 6, 7, 8, 9, 11, 13, 14, 15, 30, 48, 66, 74, 93, 111, 117, 125, 143, 149, 150 , 151, 170, 176, 188, 206, 224, 242, 260, 296, 314, 332, 350, 368, 386, 408, 469, 475, 481, 505, 510, 511, 517, 523, 535, 538 , 539, 543, 568, 586, 598, 604, 622, 724, 733, 1392, 1394 or 1398.
Particularly preferred compounds include 1, 4, 5, 6, 7, 8, 9, 11, 13, 66, 93, 111, 117, 125, 143, 149, 150, 151, 170, 176, 224, 260, 332, 386, 510, 535, 539, 543, 604, 1392, 1394 or 1398.
As the most preferable compound,
Exemplary Compound No-1: 3- (2-Aminoethoxy) -5-phenylisoxazole,
Exemplary Compound No.-5: 3- (2-Aminoethoxy) -4-chloro-5-phenylisoxazole,
Exemplary Compound No-7: 3- (2-Aminoethoxy) -4-ethyl-5-phenylisoxazole,
Exemplary Compound No.-8: 3- (2-Aminoethoxy) -5-phenyl-4-propylisoxazole,
Exemplary Compound No-9: 3- (2-Aminoethoxy) -4-isopropyl-5-phenylisoxazole,
Exemplary Compound No-11: 3- (2-Aminoethoxy) -4-isobutyl-5-phenylisoxazole,
Exemplary Compound No.-117: 3- (2-Aminoethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole,
Exemplified compound No.-143: 3- (2-aminoethoxy) -5- (4-chlorophenyl) isoxazole,
Exemplary Compound No.-151: 3- (2-Aminoethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole,
Exemplary Compound No.-176: 3- (2-Aminoethoxy) -5- (2,4-dichlorophenyl) -4-isopropylisoxazole,
Exemplary Compound No.-510: 3- (2-Aminoethoxy) -5- (2-furyl) -4-isopropylisoxazole,
Exemplified Compound No.-535: 3- (2-Aminoethoxy) -5- (2-thienyl) isoxazole,
Exemplary Compound No.-539: 3- (2-Aminoethoxy) -4-chloro-5- (2-thienyl) isoxazole,
Exemplary Compound No.-543: 3- (2-Aminoethoxy) -4-isopropyl-5- (2-thienyl) isoxazole,
Exemplary compound No. -1392: 4-allyl-3- (2-aminoethoxy) -5-phenylisoxazole.
The manufacturing method of the compound of this invention is shown next.
In the above formula, R ¹ , R ² , R ³ , X and n represent the same significance as described above, R ³ a represents an amino group in which the amino group or monoC ₁ -C ₆ alkylamino group contained in R ³ is protected, Except for being a protected monoC ₁ -C ₆ alkylamino group, it represents the same meaning as R ³ , Y represents a hydroxyl group or a leaving group, and Z represents a halogen atom.
The protecting group of the amino group or monoC ₁ -C ₆ alkylamino group of R ³ a can be used without particular limitation as long as it is a group generally used as a protecting group of an amino group. For example, formyl group, acetyl group, propionyl group, butyryl group, C ₁ -C ₆ alkanoyl groups such as isobutyryl group, pentanoyl group, pivaloyl group, valeryl group, isovaleryl group or hexanoyl group; Chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, 3-fluoro propionyl group, 4,4-dichlorobutyryl group, methoxyacetyl group, butoxyacetyl group, ethoxy propionyl group Or a C ₁ -C ₄ alkanoyl group substituted with halogen or C ₁ -C ₄ alkoxy, such as propoxybutyryl group; Unsaturated C ₁ -C ₄ alkanoyl groups such as acryloyl group, propioloyl group, methacryloyl group, crotonoyl group or isocrotonoyl group; Benzoyl group, α-naphthoyl group, β-naphthoyl group, 2-fluorobenzoyl group, 2-bromobenzoyl group, 2,4-dichlorobenzoyl group, 6-chloro-α-naphthoyl group, 4-tol Luoyl group, 4-propylbenzoyl group, 4-t-butylbenzoyl group, 2,4,6-trimethylbenzoyl group, 6-ethyl-α-naphthoyl group, 4-anisoyl group, 4-propoxybenzoyl group, 4-t-butoxybenzoyl group, 6-ethoxy-α-naphthoyl group, 2-ethoxycarbonylbenzoyl group, 4-t-butoxycarbonylbenzoyl group, 6-methoxycarbonyl-α-naph Toyl group, 4-phenylbenzoyl group, 4-phenyl-α-naphthoyl group, 6-α-naphthylbenzoyl group, 4-nitrobenzoyl group, 2-nitrobenzoyl group or 6-nitro-α-naphthoyl group such as halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl, C ₆ C ₆ -C ₁₀ aryl group which may be substituted with -C ₁₀ aryl or nitro; Methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, chloromethoxycarbonyl group, 2,2,2-trichloro Ethoxycarbonyl group, 2-fluoropropoxycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibromo-t-butoxycarbonyl group, triethylsilylmethoxycarbonyl group, 2-trimethylsilylethoxy C ₁ -C ₄ alkoxycarbonyl group which may be substituted with halogen or tri C ₁ -C ₄ alkylsilyl such as carbonyl group, 4-tripropylsilylbutoxycarbonyl group or t-butyldimethylsilylpropoxycarbonyl group; C ₂ -C ₅ alkenyloxycarbonyl groups such as vinyloxycarbonyl group, allyloxycarbonyl group, 1,3-butadienyloxycarbonyl group or 2-pentenyloxycarbonyl group; Aryldicarbonyl groups such as phthaloyl group; Benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl or 9-anthrylmethyl Aralkyl groups such as; Or benzyloxycarbonyl group, (1-phenyl) benzyloxycarbonyl group, α-naphthylmethyloxycarbonyl group, β-naphthylmethyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyl A C ₇ -C ₁₅ aralkyloxycarbonyl group which may be substituted with methoxy or nitro, such as an oxycarbonyl group, preferably a C ₁ -C ₄ alkanoyl group; Trifluoroacetyl group; Methoxyacetyl group; Benzoyl group; α-naphthoyl group; β-naphthoyl group; Anisoyl group; Nitrobenzoyl group; C ₁ -C ₄ alkoxycarbonyl group; Methoxycarbonyl group; Ethoxycarbonyl group; t-butoxycarbonyl group; 2,2,2-trichloroethoxycarbonyl group; Triethylsilyl methoxycarbonyl group; 2-trimethylsilylethoxycarbonyl group; Vinyloxycarbonyl group; Allyloxycarbonyl group; Phthaloyl group; Benzyl group; Benzyloxycarbonyl group; Or a nitrobenzyloxycarbonyl group, more preferably formyl group, acetyl group, benzoyl group, 4-anisoyl group, 4-nitrobenzoyl group, methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, It is a phthaloyl group, benzyl group, benzyloxycarbonyl group, or p-nitrobenzyloxycarbonyl group, Especially preferably, it is t-butoxycarbonyl group.
The leaving group of Y is not particularly limited as long as it is a group leaving normally as a nucleophilic moiety, but for example a halogen atom such as a chlorine atom, bromine atom or iodine atom; C ₁ -C ₄ alkanesulfonyloxy groups such as methanesulfonyloxy group, ethanesulfonyloxy group, propanesulfonyloxy group or butanesulfonyloxy group; Such as trifluoromethanesulfonyloxy group, 2,2,2-trichloroethanesulfonyloxy group, 3,3,3-tribromopropanesulfonyloxy group or 4,4,4-trifluorobutanesulfonyloxy group Halogen C ₁ -C ₄ alkanesulfonyloxy group; Or a benzenesulfonyloxy group, α-naphthylsulfonyloxy group, β-naphthylsulfonyloxy group, p-toluenesulfonyloxy group, 4-t-butylbenzenesulfonyloxy group, mesitylenesulfonyloxy group or 6-ethyl-α C ₆ -C ₁₀ arylsulfonyloxy group which may have 1 to 3 C ₁ -C ₄ alkyl, such as -naphthylsulfonyloxy group, preferably a chlorine atom, bromine atom, iodine atom; Methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group, 2,2,2-trichloroethanesulfonyloxy group; Benzenesulfonyloxy group, toluenesulfonyloxy group or mesitylenesulfonyloxy group, more preferably chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, p- Toluenesulfonyloxy group or mesitylenesulfonyloxy group.
The halogen atom of Z may be, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom.
Method A (Scheme A) is a method for producing compound (I).
Step A1 is carried out by reacting a compound (II) with a halogenating agent in the presence of an inert solvent or in the absence of a solvent (preferably in an inert solvent), with or without a base (preferably with a base). It is a process of manufacturing the compound which has III).
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably halogenated hydrocarbons (especially methylene chloride) or ethers (especially Tetrahydrofuran or dioxane).
Bases to be used include, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; Alkali metal hydrogen carbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; Triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1 , 5-diazabicyclo [4.3.0] nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] Organic amines such as deck-7-ene (DBU), preferably alkali metal carbonates or organic amines, more preferably organic amines (especially triethylamine or pyridine).
The halogenating agent used may be, for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus iodine or phosphorus pentachloride or mixtures thereof, preferably phosphorus oxychloride, phosphorus pentachloride or mixtures thereof.
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually 0 ° C to 150 ° C, preferably 10 ° C to 100 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 30 minutes to 10 hours, preferably 1 hour to 5 hours.
After completion of the reaction, the target compound of the process is taken from the reaction mixture according to conventional methods. For example, the solvent is distilled and poured into the reaction solution to extract a solvent (e.g., benzene, ether, ethyl acetate, etc.) that are not miscible with water. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is removed. The target compound can be obtained by distilling off. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
The second step A2 is a step of preparing a compound having the formula (V) by reacting the compound having the formula (III) with the compound having the formula (IV) in an inert solvent.
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide; Or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers, amides or sulfoxides, more preferably ethers (especially diethyl ether, tetrahydrofuran or dioxane) or Amides (especially dimethylformamide).
Bases to be used include, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; Alkali metal hydrogen carbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1 , 5-diazabicyclo [4.3.0] nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] Organic amines such as deck-7-ene (DBU); Alkyllithiums such as methyllithium, ethyllithium or butyllithium; Or lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal carbonates or alkali metal hydrides or organic amines, and more preferably alkali metal carbonates (especially sodium carbonate). Or potassium carbonate) or alkali metal hydrides (especially sodium hydride).
In addition, crown ethers such as dibenzo-18-crown-6 and the like may be added to effectively carry out the reaction.
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 150 ° C, preferably 0 ° C to 80 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 30 minutes to 30 hours, preferably 1 hour to 10 hours.
After completion of the reaction, the target compound of the process is taken from the reaction mixture according to conventional methods. For example, the reaction solution is neutralized appropriately, and if an insoluble matter is present, the solvent is filtered off if necessary, the solvent is distilled off, and water is poured into the reaction solution so as not to be mixed with water (for example, benzene, ether, ethyl acetate, etc.). ), Followed by extraction, washing with water, drying the organic layer containing the target compound with anhydrous magnesium sulfate or the like, and then distilling off the solvent, the target compound can be obtained. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
Step A3 is a step for producing compound (I) by removing the protecting group of an amino group or an alkylamino group as desired.
The removal of the protecting group of the amino group depends on the kind thereof, but is generally carried out as follows by a method well known in the organic synthetic chemistry technique.
The protecting group of the amino group is C ₁ -C ₆ alkanoyl group (preferably formyl group or acetyl group); C ₆ -C ₁₀ arylcarbonyl group (preferably benzoyl group); C ₁ -C ₄ alkoxycarbonyl groups which may be substituted with halogen or triC ₁ -C ₄ alkylsilyl (preferably methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2- Bromo-t-butoxycarbonyl group or 2,2-dibromo-t-butoxycarbonyl group); C ₂ -C ₅ alkenyloxycarbonyl group (preferably vinyloxycarbonyl group); Or a C ₇ -C ₁₅ aralkyloxycarbonyl group which may be substituted with methoxy or nitro (preferably benzyloxycarbonyl group, (1-phenyl) benzyloxycarbonyl group, 9-anthrylmethyloxycarbonyl group, p-methoxybenzyloxy Carbonyl group or p-nitrobenzyloxycarbonyl group) can be removed by treatment with an acid in an inert solvent or an aqueous solvent. At this time, the target compound can also be obtained as a salt. The acid used may be, for example, an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or trifluoroacetic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid or trifluoroacetic acid.
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Esters such as methyl acetate or ethyl acetate; Alcohols such as methanol, ethanol, propanol, isopropanol or butanol; Amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide; Sulfoxides such as dimethyl sulfoxide or sulfolane; Fatty acids such as formic acid or acetic acid; Or water or a mixed solvent of water and the solvent, preferably halogenated hydrocarbons, ethers, alcohols, fatty acids or a mixed solvent of water and the solvent, more preferably halogenated hydrocarbons (particularly methylene chloride) ), Ethers (particularly tetrahydrofuran or dioxane), fatty acids (particularly acetic acid) or water or a mixed solvent of water and the solvent.
The reaction temperature varies depending on the starting compound, the solvent or the acid used, and is usually -10 ° C to 150 ° C, preferably 0 ° C to 60 ° C.
The reaction time varies depending on the starting compound, the solvent or the acid used, and is usually 5 minutes to 20 hours, preferably 10 minutes to 5 hours.
After completion of the reaction, the target compound of the process is taken from the reaction mixture according to conventional methods. For example, the target compound precipitated in the reaction solution is collected by filtration or neutralized, the solvent is distilled off, and water is added to the reaction solution to add a solvent (eg, benzene, ether, ethyl acetate, etc.) that is not miscible with water. After extraction, the organic layer containing the target compound is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
When the protecting group of the amino group is alkanoyls, arylcarbonyls, alkoxycarbonyls, alkenyloxycarbonyls, aryldicarbonyls, aralkyls or aralkyloxycarbonyls, the base is in an inert solvent or an aqueous solvent. It can be removed by treatment with.
Bases to be used include, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; Alkali metal hydrogen carbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; It may be a mercaptan alkali metal such as methyl mercaptan sodium or ethyl mercaptan sodium, preferably alkali metal carbonates (particularly sodium carbonate or potassium carbonate), alkali metal hydroxides (particularly sodium hydroxide or potassium hydroxide), alkali metal alkoxy Drews (particularly sodium methoxide, sodium ethoxide or potassium-t-butoxide) or organic amines (particularly hydrazine or methylamine).
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Alcohols such as methanol, ethanol, propanol, isopropanol or butanol; Amides such as dimethylacetamide or hexanemethyl phosphate triamide; Sulfoxides such as dimethyl sulfoxide or sulfolane; Or a mixed solvent of water and the solvent, preferably halogenated hydrocarbons, ethers, alcohols, or a mixed solvent of water and the solvent, more preferably ethers (especially tetrahydrofuran or dioxane), Alcohols (especially methanol, ethanol) or a mixed solvent of water and the solvent.
The reaction temperature is changed depending on the raw material compound, the solvent or the base used, and is usually -10 ° C to 150 ° C, preferably 0 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the solvent or the base used, and is usually 30 minutes to 20 hours, preferably 1 hour to 5 hours.
After completion of the reaction, the target compound of this process is taken from the reaction mixture according to a conventional method. For example, the target compound precipitated in the reaction solution is collected by filtration, or the solvent is distilled off and water is poured into the reaction solution to filter the precipitate, or a solvent (eg, benzene, ether, ethyl acetate, etc.) which is not mixed with water is added The target compound can be obtained by extracting, washing the organic layer containing the target compound with water, drying with anhydrous magnesium sulfate, and distilling off the solvent. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
In the case where the protecting group of the amino group is a tert-butoxycarbonyl group, it can also be removed by treatment with a silyl compound or an acid, especially in an inert solvent.
The silyl compound used may be, for example, trimethylsilyl chloride, trimethylsilyl iodide or trimethylsilyltrifluoromethanesulfonate, and the acid used is, for example, aluminum chloride, hydrochloric acid or trifluoroacetic acid.
The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Nitriles such as acetonitrile, and are preferably halogenated hydrocarbons (particularly methylene chloride, chloroform) or nitriles (particularly acetonitrile).
The reaction temperature varies depending on the starting compound, the reagent or the solvent, and is usually -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the reagent, the solvent or the reaction temperature, and is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours.
After completion of the reaction, the target compound of the process is taken from the reaction mixture according to conventional methods. For example, the solvent is distilled off and the precipitated target compound is collected by filtration, or water is added to the reaction solution to make the aqueous layer alkaline, and the precipitate is collected by filtration, or a solvent (eg, benzene, ether, ethyl acetate, etc.) that is not miscible with water. The target compound can be obtained by adding and extracting, washing the organic layer containing the target compound with water, drying with anhydrous magnesium sulfate, and distilling off the solvent. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
When the protecting group of the amino group is an allyloxycarbonyl group, the same solvent, reaction temperature, and reaction time as those of the removal method by contact reduction reaction in the case of an aralkyl group using palladium and triphenylphosphine or nickel tetracarbonyl are used. It can be removed using the reaction conditions.
When the protecting group of an amino group is an aralkyl group or a C ₇ -C ₁₁ aralkyloxycarbonyl group, it is usually removed by contacting with a reducing agent (preferably by catalytic reduction in the presence of a catalyst) in an inert solvent or by using an oxidizing agent. Preferably the protecting group can be removed.
The solvent used in the case of the reaction for removing the protecting group by catalytic reduction is not particularly limited as long as it is not involved in the present reaction, for example, aliphatic hydrocarbons such as hexane or cyclohexane; Aromatic hydrocarbons such as toluene, benzene or xylene; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Esters such as ethyl acetate or propyl acetate; Alcohols such as methanol, ethanol or isopropanol; Fatty acids such as formic acid or acetic acid; Or a mixed solvent of these organic solvents and water, preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols, fatty acids, or a mixed solvent of these organic solvents and water, and more preferably alcohols ( Methanol or ethanol), fatty acids (particularly formic acid or acetic acid), or a mixed solvent of these organic solvents and water.
The catalyst used is not particularly limited as long as it is used in a conventional catalytic reduction reaction, and may be, for example, palladium black, palladium-carbon, Raney nickel, rhodium-aluminum oxide or palladium-barium sulfate, preferably palladium-carbon or Raney Nickel.
Although the pressure of hydrogen is not specifically limited, Usually, it is 1-10 atmospheres, Preferably it is 1 atmosphere.
The reaction temperature is changed depending on the raw material compound, the solvent or the reducing agent used, and is usually 0 ° C to 100 ° C, preferably 10 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the solvent, the reducing agent used or the reaction temperature, and is usually 15 minutes to 10 hours, preferably 30 minutes to 3 hours.
After completion of the reaction, the target compound of the process is taken from the reaction mixture according to conventional methods. For example, after the catalyst is filtered off, the solvent is distilled off, water is added to the reaction solution to make the aqueous layer alkaline, and the precipitates are collected by filtration or extracted by adding a solvent (for example, benzene, ether, ethyl acetate, etc.) that is not mixed with water. The desired compound can be obtained by washing the organic layer containing the target compound with water, drying with anhydrous magnesium sulfate, and distilling off the solvent. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
The solvent used in the removal method by oxidation is not particularly limited as long as it is not involved in the present reaction. Examples thereof include ketones such as acetone; Halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; Nitriles such as acetonitrile; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Amides such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; Sulfoxides such as dimethyl sulfoxide; Or a mixed solvent of these organic solvents and water, preferably ketones, halogenated hydrocarbons, nitriles, ethers, amides, sulfoxides, or a mixed solvent of these organic solvents and water, and more preferably ketones (especially Acetone), halogenated hydrocarbons (particularly methylene chloride), nitriles (particularly acetonitrile), amides (particularly hexamethylphosphorotriamide), sulfoxides (particularly dimethyl sulfoxide) or a mixed solvent of these organic solvents and water to be.
The oxidizing agent used may be, for example, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), preferably ammonium cerium nitrate Rate (CAN) or 2,3, -dichloro-5,6-dicyano-p-benzoquinone (DDQ).
The reaction temperature is changed depending on the raw material compound, the solvent, or the oxidizing agent used, and is usually 0 ° C to 150 ° C, preferably 10 ° C to 50 ° C.
The reaction time varies depending on the compound, the solvent or the oxidizing agent or the reaction temperature used, and is usually 15 minutes to 24 hours, preferably 30 minutes to 5 hours.
After completion of the reaction, the target compound of the process is taken from the reaction mixture according to conventional methods. For example, the oxidant is filtered off, and then the solvent is distilled off, water is added to the reaction solution to make the aqueous layer alkaline, and the precipitate is collected by filtration or extracted by adding a solvent (for example, benzene, ether, ethyl acetate, etc.) which is not mixed with water. The desired compound can be obtained by washing the organic layer containing the target compound with water, drying with anhydrous magnesium sulfate, and distilling off the solvent. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
When the protecting group of the amino group is removed using an acid, the target compound is usually obtained in the form of a salt. Generally, the amino group of the target compound can be used as a free base by removing the acid used by a method well known in the art of organic chemistry. .
Method B (Scheme B) is a method for separately preparing compound (Va) in which X is an oxygen atom in intermediate (V) of method A.
Step B1 is a step of producing compound (Va) by reacting compound (II) with a compound having formula (IVa).
If Y is hydroxyl, then basically Bull. Chem. Soc. According to the optical reaction described in Jap., 40. 2380 (1967), it is carried out by the dehydration condensation reaction of compound (IVa) corresponding to compound (II) in the presence of phosphines and azo compounds in an inert solvent.
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, preferably aliphatic hydrocarbons, aromatic hydrocarbons or ethers, more preferably Ethers, in particular diethyl ether or tetrahydrofuran.
Examples of the phosphine used include triC ₁ -C ₆ alkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine or trihexylphosphine; TriC ₆ -C ₁₀ arylphosphine such as triphenylphosphine, triindenylphosphine or trinaphthylphosphine; Or a C ₁ -C ₄ alkyl such as triylphenylphosphine, tritrisylphosphine, trimesitylphosphine, tributylphenylphosphine or tri-6-ethyl-2-naphthylphosphine as a substituent. TriC ₆ -C ₁₀ arylphosphine, preferably triC ₁ -C ₆ alkylphosphines (particularly trimethylphosphine, triethylphosphine, tripropylphosphine or tributylphosphine) or triC _6- C ₁₀ arylphosphine (particularly triphenylphosphine, triindenylphosphine or trinaphthylphosphine), more preferably triC ₆ -C ₁₀ arylphosphine (particularly triphenylphosphine).
The azo compound to be used is not particularly limited as long as it is a known azodicarboxylic acid derivative. Examples thereof include dimethyl azodicarboxylic acid, azodicarboxylic acid diethyl, azodicarboxylic acid dipropyl or azodicarboxylic acid dibutyl. And azodicarboxylic acid di-C ₁ -C ₄ alkyl, such as dimethyl azodicarboxylic acid or diethyl azodicarboxylic acid.
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature. The reaction time is usually 15 minutes to 48 hours, preferably 30 minutes to 24 hours.
After completion of the reaction, the target compound of the process is taken from the reaction mixture according to conventional methods. For example, if an insoluble matter is present, it is filtered off and distilled off the solvent, if necessary, or a solvent (eg, benzene, ether, ethyl acetate, etc.) which is not miscible with water by pouring water into the residue from which the solvent is distilled off. After adding and extracting, washing with water, drying with anhydrous magnesium sulfate and the like, and then distilling off the solvent, the target compound can be obtained. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
When Y is a leaving group, compound (Va) can be obtained by making compound (IVa) correspond to compound (II) in presence of a base in an inert solvent.
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide; Or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably amides or sulfoxides, more preferably amides (particularly dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide). .
Bases to be used include, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; Alkali metal hydrogen carbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; Mercaptan alkali metals such as methyl mercaptan sodium or ethyl mercaptan sodium; Triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1 , 5-diazabicyclo [4.3.0] nona-5-ene, 1,4, -diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec- Organic amines such as 7-ene (DBU); Alkyllithiums such as methyllithium, ethyllithium or butyllithium; Lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably alkali metal carbonates, alkali metal hydrides or alkali metal hydroxides, and more preferably alkali metal hydrides (especially Sodium hydroxide).
And in order to perform reaction effectively, you may add crown ethers, such as dibenzo-18-crown-6, etc.
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 30 minutes to 20 hours, preferably 1 hour to 5 hours.
After completion of the reaction, the target compound of the process is taken from the reaction mixture according to conventional methods. For example, if the reaction solution is neutralized appropriately and insoluble matter is present, the solvent is filtered off, the solvent is distilled off, and water is added to the reaction solution to add a solvent (eg benzene, ether, ethyl acetate, etc.) that is not miscible with water. The target compound can be obtained by extracting, washing the organic layer containing the target compound with water, drying with anhydrous magnesium sulfate, and distilling off the solvent. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
Method C (Scheme C) is a method for separately preparing compound (I) in method A.
Step C1 is a step to be carried out as desired.
Reaction (a): reaction which introduce | transduces an alkyl group, an alkoxy group, or a carboxyl group into the isoxazole ring or the aromatic ring contained in R <^1> ,
Reaction (b): reaction which introduce | transduces a hydroxyalkyl group into the isoxazole ring or the aromatic ring contained in R <^1> ,
Reaction (c): reaction which converts the hydroxy group contained in the hydroxyalkyl group produced by reaction (b) to a halogen atom,
Reaction (d): The reaction which makes the hydroxy group contained in the hydroxyalkyl group produced by reaction (b) 1,2-leaving ((beta) leaving),
Reaction (e): reaction which converts the hydroxyalkyl group produced by reaction (b) to a carbonyl group,
Reaction (f): reaction for esterifying a carboxyl group,
Reaction (g): reaction which converts alkoxycarbonyl group into carbamoyl group,
Reaction (h): a reaction for converting a carboxyl group to a carbamoyl group,
Reaction (i): reaction which converts carbamoyl group into a cyano group,
Reaction (j): reaction which converts an aromatic alkoxy group into a hydroxyl group,
Reaction (k): reaction to acylate a hydroxyl group or an amino group,
Reaction (l): reaction for aralkylating a hydroxyl group or an amino group,
Reaction (m): reaction for converting a nitro group to an amino group, and
Reaction (n): It carries out by changing order suitably including reaction which removes the protecting group of the amino group contained in R <^3a> etc.
Reaction (a):
Reaction which introduce | transduces an alkyl group, an alkoxy group, or a carboxyl group into the isoxazole ring in reaction (a), the aromatic ring contained in R <^1> , etc. is performed by the method well known by organic synthetic chemistry. For example, in the presence of a base, in the presence of a base, halogenoC ₁ -C ₆ alkanes, diC ₁ -C ₆ alkyl carbonates or carbon dioxide (preferably halogenoC ₁ -C ₆ alkanes or carbon dioxide) are reacted. By doing so.
The halogenoC ₁ -C ₆ alkanes used may be, for example, methyl chloride, methyl bromide, methyl iodide, methyl chloride, ethyl iodide, propyl bromide, butyl iodide, pentyl iodide or hexyl iodide, preferably methyl bromide or iodide Methyl, more preferably methyl iodide.
The diC ₁ -C ₆ alkylcarbonates used are, for example, dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, di-sec-butyl Carbonate, di-tert-butyl carbonate, dipentyl carbonate or dihexyl carbonate, preferably dimethyl carbonate or diethyl carbonate.
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Diamines such as N, N, N ', N'-tetramethylethylenediamine; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethyl phosphate triamide or hexamethyl phosphite triamide; Or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers, amides or sulfoxides, more preferably ethers (particularly tetrahydrofuran).
Bases to be used include, for example, alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; Alkyllithiums such as methyllithium, ethyllithium, butyllithium or sec-butyllithium; Lithium alkylamides such as lithium diisopropylamide, lithium dicyclohexylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide, preferably alkyllithium And lithium alkylamides (particularly lithium diisopropylamide).
The reaction temperature varies depending on the starting compound, the reagent and the like, and is usually -100 ° C to 30 ° C, preferably -70 ° C to 0 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off or water is poured into the residue from which the solvent is distilled off to make the aqueous layer acidic as desired, and then a solvent (e.g., benzene, ether, ethyl acetate, etc.) that is not miscible with water is removed. The target compound can be added by extracting the target compound, washing the extracted organic layer with water, drying with anhydrous magnesium sulfate, etc., and distilling off the solvent. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
Reaction (b):
Reaction which introduce | transduces a hydroxyalkyl group into the isoxazole ring in reaction (b), the aromatic ring contained in R <^1> , etc. is performed by the method well known in organic synthetic chemistry. For example, it is carried out by reacting with aldehydes or ketones in the presence of a base in an inert solvent.
The aldehydes may be, for example, straight or branched chain carbon atoms having 2 to 6 carbon atoms, such as acetaldehyde, propionaldehyde, butylaldehyde, isobutylaldehyde, barrelaldehyde, isobarrelaldehyde or hexaaldehyde, preferably C ₂ -C ₄ Alkanal, more preferably acetaldehyde.
Ketones are, for example, acetone, 2-butanone, 2-pentanone, 3-pentanone, 3-methyl-2-butanone, 2-hexanone, 3-hexanone, 3-methyl-2-pentanone, 4- Linear or branched alkanones having 3 to 6 carbon atoms, such as methyl-2-pentanone or 3,3-dimethyl-2-butanone, preferably acetone, 2-butanone or 3-butanone, More preferably acetone.
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Diamines such as N, N, N ', N'-tetramethylethylenediamine; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethyl phosphate triamide or hexamethyl phosphite triamide; Or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers, amides or sulfoxides, more preferably ethers (particularly tetrahydrofuran).
Bases to be used include, for example, alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; Alkyllithiums such as methyllithium, ethyllithium, butyllithium or sec-butyllithium; Lithium alkylamides such as lithium diisopropylamide, lithium dicyclohexylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide, preferably alkyllithium And lithium alkylamides (particularly lithium diisopropylamide).
The reaction temperature varies depending on the starting compound, the reagent and the like, and is usually -100 ° C to 30 ° C, preferably -70 ° C to 0 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off or water is poured into the residue from which the solvent is distilled to remove a target compound by adding a solvent (eg, benzene, ether, ethyl acetate, etc.) that is not mixed with water, and the extracted organic layer. The resulting compound was washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent was distilled off to obtain the target compound. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
Reaction (c):
The reaction for converting the hydroxy group contained in the hydroxyalkyl group produced by the reaction (b) in the reaction (c) into a halogen atom is carried out by a method well known in organic synthetic chemistry. For example, the reaction is carried out by reacting with hydrochloric acid in an inert solvent.
The hydrofluoric acid used may, for example, be hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, preferably hydrochloric acid.
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Esters such as methyl acetate or ethyl acetate; Or water or a mixed solvent of water and the solvent, preferably ethers (particularly dioxane) or a mixed solvent of ethers and water.
The reaction temperature varies depending on the starting compound, the reagent and the like, and is usually -50 ° C to 80 ° C, preferably 0 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off or water is poured into the residue from which the solvent is distilled to remove a target compound by adding a solvent (eg, benzene, ether, ethyl acetate, etc.) that is not mixed with water, and the extracted organic layer. The resulting compound was washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent was distilled off to obtain the target compound. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
Reaction (d):
In the reaction (d), the reaction of 1,2-leaving (β-releasing) the hydroxy group contained in the hydroxyalkyl group produced by the reaction (b) is carried out by a method well known in organic synthetic chemistry. For example, it is carried out by reacting with an acid in an inert solvent.
The acids used are, for example, inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; Sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; Or carboxylic acids such as trifluoroacetic acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably inorganic acids (particularly hydrochloric acid).
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Or esters such as methyl acetate or ethyl acetate, preferably ethers or esters, more preferably ethers (especially dioxane).
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually 0 ° C to 150 ° C, preferably 50 ° C to 130 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 5 minutes to 10 hours, preferably 10 minutes to 5 hours.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off or water is poured into the residue from which the solvent is distilled to remove a target compound by adding a solvent (eg, benzene, ether, ethyl acetate, etc.) that is not mixed with water, and the extracted organic layer. The resulting compound was washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent was distilled off to obtain the target compound. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
Reaction (e):
The reaction which converts the hydroxyalkyl group produced by reaction (b) in reaction (e) into a carbonyl group is performed by the method well known in organic synthetic chemistry. For example, it is performed by reacting with an oxidizing agent in an inert solvent.
The oxidizing agent to be used is not particularly limited as long as it is usually used in an oxidation reaction, for example, manganese oxides such as potassium permanganate and manganese dioxide; Ruthenium oxides such as ruthenium tetraoxide; Silver compounds such as silver oxide; Inorganic metal oxidizing agents such as chromic acid compounds such as potassium chromate, chromic acid-sulfuric acid complex, chromic acid-pyridine complex, and cerium compounds such as ammonium cerium nitrate (CAN); Reagents used for DMSO oxidation (complexes of dimethyl sulfoxide and cyclohexylcarbodiimide, oxaryl chloride, acetic anhydride or phosphorus pentoxide or pyridine-sulfuric anhydride); Succinimides such as N-bromosuccinimide; Or an organic oxidant such as a quinone compound such as 2,3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ), preferably an inorganic metal oxidant or reagents used for oxidizing DMSO, and more preferably. Inorganic metal oxidants (particularly chromic acid-pyridine complexes).
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Ketones such as acetone; Esters such as methyl acetate or ethyl acetate; Nitriles such as acetonitrile; Amides such as dimethylformamide, dimethylacetamide or hexamethylphosphorotriamide; Sulfoxides such as dimethyl sulfoxide; Or a mixed solvent of these organic solvents and water, preferably halogenated hydrocarbons, ethers, ketones, nitriles, amides or sulfoxides, and more preferably halogenated hydrocarbons (particularly methylene chloride).
The reaction temperature varies depending on the starting compound, the reagent and the like, and is usually 0 ° C to 100 ° C, preferably 20 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 30 minutes to 48 hours, preferably 1 hour to 30 hours.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after removing the oxidizing agent, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled, and a solvent (for example, benzene, ether, ethyl acetate, etc.) which is not miscible with water is added to extract the target compound and extracted. The organic compound is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain the target compound. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
Reaction (f):
The reaction for esterifying the carboxyl group in the reaction (f) is carried out by a method well known in organic synthetic chemistry. for example,
(1) react with an esterifying agent in an inert solvent, or
(2) react with an active esterification agent in an inert solvent to produce an active ester, and then react with an alcohol in an inert solvent, or
(3) An acid halide is prepared by reacting with a halogenating agent in an inert solvent, followed by reacting with an alcohol in an inert solvent.
The esterifying agent used in the reaction (f1) is not particularly limited as long as it is generally used in organic synthetic chemistry techniques, and may be, for example, diazoalkanes or trialkylsilyldiazoalkanes, preferably diazomethane, diaza C ₁ -C ₆ diazoalkanes or trimethylsilyldiazomethanes, such as, for example, ethane, diazopropane, diazobutane, diazopentane or diazohexane, more preferably C ₁ -C ₄ diazoalkanes Or trimethylsilyldiazomethane, and particularly preferably diazomethane.
The solvent used in the reaction using diazoC ₁ -C ₆ alkanes is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Esters such as methyl acetate or ethyl acetate; Or a mixed solvent of the solvent, preferably halogenated hydrocarbons, ethers, esters or a mixed solvent of the solvent, more preferably ethers (especially diethyl ether) and esters (especially ethyl acetate) Or a mixed solvent of the solvent.
The solvent used in the reaction using trimethylsilyldiazomethane is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. For example, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, Alcohols such as pentanol or hexanol; Or aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; And a solvent selected from the group consisting of esters such as methyl acetate or ethyl acetate and the above alcohols, preferably alcohols (particularly methanol) or aromatic hydrocarbons (particularly benzene) and alcohols (particularly methanol) It is a mixed solvent.
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 100 ° C, preferably 10 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 10 minutes to 10 hours, preferably 15 minutes to 2 hours.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, the target compound can be obtained by distilling a solvent off after completion | finish of reaction. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
The active esterifying agent used in the reaction (f2) is not particularly limited as long as it is generally used in organic synthetic chemistry techniques, such as ethyl chloroformate, N-hydroxysuccinimide, 1-hydroxybenzotriazole or N- N-hydroxy compounds such as hydroxy-5-norbornene-2,3-dicarboxyimide or disulfide compounds such as dipyridyldisulfide, and the active esterification reaction is dicyclohexylcarbodiimide, It is preferably done in the presence of a condensing agent such as carbonyldiimidazole or triphenylphosphine.
The solvent used in the two reactions is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide; Or nitriles such as acetonitrile, preferably ethers (particularly tetrahydrofuran) or amides (particularly dimethylformamide).
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -70 ° C to 150 ° C (preferably -10 ° C to 100 ° C) in the active esterification reaction, and -20 ° C to 100 ° C in the reaction of the active ester compound and alcohols. ° C (preferably 0 ° C to 50 ° C).
The time required for the reaction varies depending on the starting compound, the reagent, and the reaction temperature, and both reactions are usually 30 minutes to 80 hours (preferably 1 hour to 48 hours).
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off or water is poured into the residue from which the solvent is distilled to remove a target compound by adding a solvent (eg, benzene, ether, ethyl acetate, etc.) that is not mixed with water, and the extracted organic layer. The resulting compound was washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent was distilled off to obtain the target compound. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
The halogenating agent used in the reaction (f3) is not particularly limited as long as it is generally used in organic synthetic chemistry techniques, and may be, for example, oxaryl chloride, thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, preferably Thionyl chloride.
The solvent used in the two reactions is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, and preferably (particularly tetrahydrofuran).
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -70 ° C to 150 ° C (preferably -10 ° C to 100 ° C) in the acid halide reaction, and -20 ° C to 100 ° C in the reaction of the acid halide and alcohol. (Preferably 0 ° C to 50 ° C).
The time required for the reaction varies depending on the starting compound, the reagent, and the reaction temperature, and both reactions are usually 30 minutes to 80 hours (preferably 1 hour to 48 hours).
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off or water is poured into the residue from which the solvent is distilled to remove a target compound by adding a solvent (eg, benzene, ether, ethyl acetate, etc.) that is not mixed with water, and the extracted organic layer. The resulting compound was washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent was distilled off to obtain the target compound. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
Reaction (g):
The reaction which converts the alkoxycarbonyl group in reaction (g) into a carbamoyl group is performed by the method well known in organic synthetic chemistry. For example, it is carried out by reacting ammonia gas or concentrated ammonia water in an inert solvent.
The solvent used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; Diamines such as N, N, N ', N'-tetramethylethylenediamine; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethyl phosphate triamide or hexamethyl phosphite triamide; Or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers or alcohols, more preferably ethers (particularly tetrahydrofuran).
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off or water is poured into the residue from which the solvent is distilled to remove a target compound by adding a solvent (eg, benzene, ether, ethyl acetate, etc.) that is not mixed with water, and the extracted organic layer. The resulting compound was washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent was distilled off to obtain the target compound. The desired compound obtained can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography if necessary.
Reaction (h):
The reaction for converting the carboxyl group in the reaction (h) to a carbamoyl group is carried out by a method well known in organic synthetic chemistry. For example, it is performed by condensation with ammonia in an inert solvent according to a conventional method in the peptide synthesis method, such as the azide method, active ester method, mixed acid anhydride method or condensation method (preferably mixed acid anhydride method).
In the above method, the azide method is an inert solvent (for example, amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide, preferably dimethylformamide), hydrazine, -10 The amino acid hydrazide obtained by reacting at a temperature of from 100 ° C. to 100 ° C. (preferably 0 ° C. to 50 ° C.) is reacted with a nitrite compound to be converted into an azide compound and then treated with ammonia.
The nitrite compounds used are, for example, alkali metal nitrites such as sodium nitrite or alkyl nitrites such as isoamyl nitrite.
The reaction is preferably performed in an inert solvent, and the solvent used is, for example, amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide; Sulfoxides such as dimethyl sulfoxide or sulfolane; Or pyrrolidones such as N-methylpyrrolidone, and preferred are amides (especially dimethylformamide).
In addition, the two processes of the present reaction (azidation and reaction with ammonia) are usually performed in one reaction liquid.
The reaction temperature varies depending on the starting compound, the reagent, and the like. Usually, the azide process is -70 ° C to 50 ° C (preferably -50 ° C to 0 ° C), and the reaction with ammonia is -70 ° C to 50 ° C ( Preferably -10 ° C to 10 ° C).
The time required for the reaction varies depending on the raw material, the reagent, and the reaction temperature. Typically, the azide process is 5 minutes to 3 hours (preferably 10 minutes to 1 hour), and the reaction with ammonia is 5 hours to 7 days (preferably between 10 hours and 5 days).
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off, or water is poured into the residue from which the solvent is distilled, thereby adding a solvent (eg, benzene, ether, ethyl acetate, etc.) that is not miscible with water to extract the target compound. The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
The active ester method is carried out by reacting with an active esterification agent in an inert solvent to produce an active ester, and then reacting with ammonia in an inert solvent.
The solvent used in both reactions is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene ; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Amides such as formamide, dimethylformamide, dimethylacetamide, or hexamethyl phosphate triamide; Or nitriles such as acetonitrile, preferably ethers (particularly tetrahydrofuran) or amides (particularly dimethylformamide).
The active esterification agent used is, for example, N-hydroxy, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxyimide. It may be a compound or a disulfide compound such as dipyridyl disulfide, and the active etherification reaction is appropriately carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine.
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -70 ° C to 150 ° C (preferably -10 ° C to 100 ° C) in the active esterification reaction, and -20 ° C to 100 ° C in the reaction of the active ester compound and ammonia. ° C (preferably 0 ° C to 50 ° C).
The time required for the reaction varies depending on the starting compound, the reagent, and the reaction temperature, and both reactions are typically 30 minutes to 80 hours (preferably 1 hour to 48 hours).
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent may be distilled off or a solvent (eg, benzene, ether, ethyl acetate, etc.) which is not mixed with water by pouring water into the residue from which the solvent is distilled off may be added. After extraction, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain a target compound. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
The mixed acid anhydride method is performed by reacting a mixed acid anhydride in the inert solvent in the presence of a base to produce a mixed acid anhydride, and then reacting the mixed acid anhydride with ammonia in an inert solvent.
The solvent used in the reaction for preparing the mixed acid anhydride is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. For example, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene Halogenated hydrocarbons such as; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide, preferably ethers (especially tetrahydrofuran).
Mixed acid anhydrides include, for example, halogenoformic acid C ₁ -C ₄ alkyl such as ethyl chloroformate or isobutyl chloroformate, C ₁ -C ₅ alkanoyl halides such as pivaloyl chloride or diethylcyanophosphate Or C ₁ -C ₄ alkyl such as diphenylcyanophosphoric acid or di C ₆ -C ₁₄ arylcyanophosphoric acid, preferably halogenoformatic acid C ₁ -C ₄ alkyl (particularly isobutyl chloroformate).
Bases to be used include, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; Or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec- Organic amines such as 7-ene (DBU), preferably organic amines (particularly triethylamine).
The reaction temperature in the reaction for producing the mixed acid anhydride varies depending on the raw material compound, the reagent and the like, and is usually -50 ° C to 100 ° C (preferably -10 ° C to 50 ° C).
The reaction time in the reaction for producing the mixed acid anhydride varies depending on the raw material compound, the reagent and the reaction temperature, and is usually 5 minutes to 20 hours (preferably 10 minutes to 10 hours).
The solvent used in the reaction of the mixed acid anhydride and ammonia is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. For example, diethylene ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane or diethylene glycol dimethyl ether or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide, preferably ethers (especially tetrahydrofuran) .
The reaction temperature in the reaction of the mixed acid anhydride and ammonia varies depending on the raw material compound, the reagent and the like, and is usually -30 ° C to 100 ° C (preferably 0 ° C to 80 ° C).
The reaction time in the reaction of the mixed acid anhydride and ammonia varies depending on the raw material compound, the reagent and the reaction temperature, and is usually 5 minutes to 24 hours (preferably 10 minutes to 5 hours).
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, distilling off the solvent or pouring the residue into the residue from which the solvent is distilled off, and adding a solvent (for example, benzene, ether, ethyl acetate, etc.) that are not miscible with water to add the target compound After extraction, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain a target compound. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
The condensation method is carried out by directly reacting with ammonia in the presence of a condensing agent in an inert solvent.
The condensing agent used may be, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-chloro-pyridinium iodide-triethylamine, preferably dicyclohexylcarbodiy It's mid.
This reaction can be carried out under the same conditions as the reaction for producing the active ester.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is extracted by distilling off the solvent or by pouring water into the residue from which the solvent is distilled off, thereby adding a solvent (eg, benzene, ether, ethyl acetate, etc.) which is not miscible with water. The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
Reaction (i):
The reaction for converting the carbamoyl group in the reaction (i) to a cyano group is carried out by a method well known in organic synthetic chemistry. For example, it is performed by reacting with a dehydrating agent in an inert solvent.
The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Esters such as methyl acetate or ethyl acetate; Ketones such as acetone; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethyl phosphate triamide or hexamethyl phosphite triamide; Or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably ethers, amides or sulfoxides, more preferably amides (particularly dimethylformamide).
The dehydrating agent used may be, for example, phosphorus oxychloride, trifluoroacetic anhydride, methanesulfonyl chloride, paratoluenesulfonyl chloride or phosphorus pentaoxide, preferably phosphorus oxychloride.
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -30 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 5 minutes to 10 hours, preferably 10 minutes to 3 hours.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, the solvent is distilled and poured into the reaction solution to extract a solvent (e.g., benzene, ether, ethyl acetate, etc.) that are not miscible with water, and the organic layer is washed with water, followed by anhydrous magnesium sulfate or the like. After drying, the target compound can be obtained by distilling off the solvent. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
Reaction (j):
The reaction for converting the aromatic cyclic alkoxy group in the reaction (j) into a hydroxyl group is carried out by a method well known in organic synthetic chemistry. For example, it is carried out by reacting with aluminum chloride in an inert solvent.
The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether or esters such as methyl acetate or ethyl acetate, preferably halogenated hydrocarbons (especially methylene Chloride).
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 100 ° C, preferably 10 ° C to 50 ° C.
The reaction time varies depending on the raw material compound, the reagent, and the reaction temperature, and is usually 1 hour to 72 hours, preferably 2 hours to 30 hours.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, the solvent is distilled, water is poured into the reaction solution and neutralized as desired, followed by extraction by adding a solvent (eg, benzene, ether, ethyl acetate, etc.) that is not mixed with water, and the organic layer is washed with water. After drying with anhydrous magnesium sulfate, the target compound can be obtained by distilling off the solvent. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
Reaction (k):
The reaction which acylates a hydroxyl group or an amino group in reaction (k) is performed by the method well known in organic synthetic chemistry. For example, acylating agents (preferably alkanoyl halides, formic acid and acetic acid are mixed acid anhydrides, alkanecarboxylic acid anhydrides, arylcarbonyl halides in an inert solvent, with or without a base (preferably present)). Or arylcarboxylic acid anhydride).
Alkanoyl halides used are, for example, straight chains of 2 to 6 carbon atoms, such as acetyl chloride, propionyl chloride, butyryl chloride, butyryl bromide, isobutyryl chloride, valeryl chloride, pivaloyl chloride or hexanoyl chloride Or branched chain alkanoyl halides, preferably C ₂ -C ₄ alkanoylchloride, more preferably acetylchloride.
The alkancarboxylic acid anhydrides used are, for example, straight or branched chain alkancarboxylic acids having 4 to 12 carbon atoms such as acetic anhydride, propionic anhydride, butanoic anhydride, valeric anhydride, pivalic anhydride, pentanic anhydride or hexanoic anhydride It may be an acid anhydride, preferably C ₄ -C ₈ alkanecarboxylic acid anhydride, more preferably acetic anhydride.
The arylcarbonyl halides used are, for example, benzoyl chloride, benzoyl bromide, fluorobenzoyl chloride, chlorobenzoyl chloride, dichlorobenzoyl chloride, toluoyl chloride, anisoyl chloride, indenoyl chloride, indenoyl bromide, naphthoyl chloride, C ₆ -C ₁₀ arylcarboxylic acid halides such as naphthoylbromide, phenanthrenoylchloride or anthracenoylchloride, preferably benzoylchloride.
The arylcarboxylic anhydrides used are, for example, C ₆ -such as benzoic anhydride, fluorobenzoic anhydride, chlorobenzoic anhydride, methylbenzoic anhydride, methoxybenzoic anhydride, indenyl carboxylic acid anhydride or naphthylcarboxylic anhydride. C ₁₀ arylcarboxylic acid anhydride, preferably benzoic anhydride.
Bases to be used include, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; Or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec- Organic amines such as 7-ene (DBU), preferably organic amines (especially triethylamine, diisopropylethylamine, pyridine or 4- (N, N-dimethylamino) pyridine).
The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Ketones such as acetone and methyl ethyl ketone; Or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide, preferably ethers (especially tetrahydrofuran).
The reaction temperature varies depending on the starting compound, the reagent and the like, and is usually -50 ° C to 100 ° C (preferably 0 ° C to 50 ° C).
The reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually 5 minutes to 20 hours (preferably 10 minutes to 10 hours).
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, distilling off the solvent or pouring the residue into the residue from which the solvent is distilled off, and adding a solvent (for example, benzene, ether, ethyl acetate, etc.) that are not miscible with water to add the target compound After extraction, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain a target compound. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
Reaction (l):
The reaction for aralkylating the hydroxyl group or the amino group in the reaction (l) is carried out by a method well known in organic synthetic chemistry. For example, it is carried out by reacting with an aralkyl halide in an inert solvent, in the presence or absence (preferably present) of a base.
The C ₆ -C ₄₈ aralkyl halides used are, for example, benzylchloride, benzylbromide, 4-chlorobenzylchloride, 4-chlorobenzylbromide, 4-bromobenzylchloride, 4-bromobenzylbromide, 2,4 Difluorobenzylchloride, 2,4-dichlorobenzylchloride, 2,4-dichlorobenzylbromide, 4-methoxybenzylchloride, 4-methoxybenzylbromide, tritylchloride, tritylbromide, dimethoxytritylchloride Or C ₆ -C ₄₈ which may have 1 to 3 substituents which are the same or differently selected from the group consisting of halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, such as α-naphthyldiphenylmethylchloride aralkyl may be an alkyl halide, preferably a halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy groups the same or benzyl which may be different from one to three substituents selected have claws at consisting of La And de or bromide, more preferably chloride or bromide.
Bases to be used include, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; Alkali metal hydrogen carbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; Alkali metal hydroxides such as lithium hydride, sodium hydride or potassium hydride; Alkali metal hydrides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1 , 5-diazabicyclo [4.3.0] nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] Organic amines such as deck-7-ene (DBU); Alkyllithiums such as methyllithium, ethyllithium or butyllithium; Or lithium alkylamides such as lithium diisopropylamide or lithium dicyclonucleoamide, preferably alkali metal carbonates, alkali metal hydrides or organic amines, more preferably alkali metal carbonates (especially sodium carbonate) Or potassium carbonate) or alkali metal hydrides (especially sodium hydride).
The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Ketones such as acetone and methyl ethyl ketone; Or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide, preferably amides (particularly dimethylformamide).
The reaction temperature varies depending on the starting compound, the reagent and the like, and is usually -50 ° C to 100 ° C (preferably 0 ° C to 50 ° C).
The reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually 5 minutes to 24 hours (preferably 10 minutes to 5 hours).
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, solvent is not mixed with water after distilling off the solvent or by pouring water into the residue from which the solvent is distilled off and neutralized as desired (for example, benzene, ether, ethyl acetate, etc.). The target compound can be obtained by adding to extract the target compound, washing the extracted organic layer with water, drying with anhydrous magnesium sulfate, and distilling off the solvent. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
Reaction (m):
The reaction for converting the nitro group in the reaction (m) to an amino group is performed by a method well known in organic synthetic chemistry. For example, it is carried out by reacting with zinc in the presence of acetic acid in an inert solvent.
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; Diamines such as N, N, N ', N'-tetramethylethylenediamine; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethyl phosphate triamide or hexamethyl phosphite triamide; Sulfoxides such as dimethyl sulfoxide or sulfolane; Or water or a mixed solvent of water and the solvent, preferably water.
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, and is usually 10 minutes to 10 hours, preferably 30 minutes to 3 hours.
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, the solvent is distilled off or the solvent is distilled off and neutralized by adding water to a solvent which is not miscible with water (for example, benzene, ether, ethyl acetate, etc.). The desired compound can be obtained by extracting the target compound, washing the extracted organic layer with water, drying with anhydrous magnesium sulfate, and distilling off the solvent. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
Reaction (n):
Reaction which removes the protecting group of the amino group contained in R <^3a> etc. in reaction (n) is performed on the same conditions as the said A3 process.
In addition, the compound having the formula (II) which is the starting raw material compound of the present invention may be a known compound or may be prepared according to a known method [for example, Chemical Abtract, Vol. 74, pp. 125521 (1970). (Chem Abstr., 74,125521 (1970).), By Sangen Gentssho, vol. 22, p. 215 (1970), Aggregation and Biological Chemistry, vol. 50, p. 1831 ( 1986) [Agric. Biol. Chem., EN. 50, 1831 (1986).], Canadian Journal of Chemistry, Vol. 48, p. 1371 (1970). J. Chem ,. 48, 1371 (1970)], JP-A-59-216881, JP-A-43-14704, etc.].
In addition, the compound having formula (IV) or formula (IVa) may be a known compound, or may be prepared according to a known method [for example, synthesis, p. 366 (1990) [Synthesis. 366 (1990).], Journal of Medical Chemistry, Vol. 34, pp. 1258 (1991) [J.Med. Chem ,. 34, 1258 (1991).].
In addition, the compound (II) which is the starting raw material compound of the present invention is a known compound, or a compound having the formula (VI), (XIII) or (XIII) which can be prepared according to a known method, the method described below. It can also manufacture separately by making it react.
Wherein R ¹ , R ² and Z represent the same meaning as described above, and R ² a represents a specific group of substituents in R ² (the substituent being a halogen atom, a C ₁ -C ₆ alkyl group, a halogen or a C ₁ -C) C ₁ -C ₆ alkyl group substituted with ₆ alkoxy, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ cycloalkenyl group, C ₂ -C ₆ An alkanoyl group and a C ₁ -C ₆ alkoxycarbonyl group), and R ⁴ represents a C ₁ -C ₆ alkyl group.
The alkyl group in R ⁴ is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group , Neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2- Straight or branched carbon atoms of 1 to 6 carbon atoms such as dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group or 2-ethylbutyl group It may be a chain alkyl group, preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group.
Method D (Scheme D) is a method for producing compound (II) which is a starting material compound in method A or B.
The first step D1 is a compound having the formula (VI),
(a) reacting with an active esterification agent in an inert solvent to produce an active ester, and then reacting with a compound having formula (VII) in an inert solvent;
(b) reacted with a halogenating agent in an inert solvent followed by reaction with compound (iii), or
(c) A step of producing a compound having the formula (VIII) by reacting with compound (VIII) in the presence of an acid in an inert solvent.
The D1a process and the D1b process are performed under the same conditions as the reaction (f2) and the reaction (f3) in the C1 process, respectively.
The acid used in the step D1c is not particularly limited as long as it is generally used in organic synthetic chemistry techniques, including inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, or phosphoric acid; Sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; Or a carboxylic acid such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably an inorganic acid (especially sulfuric acid).
The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Ketones such as acetone and methyl ethyl ketone; Alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphate triamide, preferably alcohols (especially methanol or ethanol) ) to be.
The reaction temperature varies depending on the starting compound, the reagent and the like, and is usually -50 ° C to 150 ° C (preferably 20 ° C to 100 ° C).
The reaction time varies depending on the starting compound, the reagent and the reaction temperature, and is usually 5 minutes to 24 hours (preferably 10 minutes to 5 hours).
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, by distilling off the solvent or by pouring water into the residue from which the solvent is distilled off, a solvent (e.g., benzene, ether, ethyl acetate, etc.) which is not miscible with water is added to extract the target compound, The extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the target compound. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
The second step D2 is a step of producing a compound having the formula (VII) by reacting a halogen molecule with the compound (VII) in an inert solvent.
The halogen molecule used may be, for example, a chlorine molecule or a bromine molecule, preferably a bromine molecule.
The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Ketones such as acetone and methyl ethyl ketone; Alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol or amides such as formamide, dimethylformamide, dimethylacetamide or hexamethyl phosphate triamide, preferably halogenated hydrocarbons (especially chloroform Or carbon tetrachloride).
The reaction temperature varies depending on the starting compound, the reagent and the like, and is usually -50 ° C to 100 ° C (preferably 0 ° C to 50 ° C).
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, which is usually 5 minutes to 12 hours (preferably 10 minutes to 5 hours).
After completion of the reaction, the target compound of the reaction is taken from the reaction mixture according to a conventional method. For example, after completion of the reaction, distilling off the solvent or pouring the residue into the residue from which the solvent is distilled off, and adding a solvent (for example, benzene, ether, ethyl acetate, etc.) that are not miscible with water to add the target compound After extraction, the extracted organic layer is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain a target compound. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
The D3 process involves the addition of hydroxylamine or hydroxylamine to the compound (iii) in the presence or absence of a base in an inert solvent (preferably in the presence of a base) (preferably an inorganic acid salt of hydroxylamine). It is a process of manufacturing compound (II) by making it react.
The inorganic acid salt of the hydroxylamine used may be, for example, hydrofluoric acid hydroxylamine, hydroxylamine hydrochloride, hydroxylamine hydrobromide, hydroxyliodic hydrochloride amine, nitrate hydroxylamine, perchloric acid hydroxylamine, or hydroxylamine sulfate Or hydroxylamine phosphate, preferably hydroxylamine hydrochloride.
E method (Scheme E) is a method of separately preparing compound (II) which is a starting material compound in A method or B method.
Step E1 is a step of producing a compound having formula (XI) by reacting compound (VII) with a compound having formula (XI) in the presence of a base in an inert solvent.
The solvent to be used is not particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably aromatic hydrocarbons, halogenated hydrocarbons or ethers, more preferably aromatic hydrocarbons (especially benzene) or ethers (especially tetrahydrofuran). Or dioxane).
Bases to be used include, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate; Alkali metal hydrogen carbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; Mercaptan alkali metals such as methyl mercaptan sodium or ethyl mercaptan sodium; Triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1 , 5-diazabicyclo [4.3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] undec-7 Organic amines such as ene (DBU); alkyllithiums such as methyllithium, ethyllithium or butyllithium; Lithium alkylamides such as lithium diisopropylamide or lithium dicyclohexylamide, preferably lithium alkylamides (particularly lithium diisopropylamide) or organic amines (particularly 1,8-diazabicyclo [5.4.0] Undeck-7-yen (DBU)).
The reaction temperature varies depending on the starting compound, the reagent, and the like, and is usually -100 ° C to 100 ° C, preferably -70 ° C to 50 ° C.
The reaction time varies depending on the starting compound, the reagent, and the reaction temperature, which is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
After completion of the reaction, the target compound of the process is taken from the reaction mixture according to conventional methods. For example, the solvent is distilled and water is poured into the reaction solution to make the reaction solution slightly acidic, followed by extraction by adding a solvent (eg, benzene, ether, ethyl acetate, etc.) that is incompatible with water, and extracting the organic layer with water. After washing, drying with anhydrous magnesium sulfate and the like, the target compound can be obtained by distilling off the solvent. If desired, the target compound can be further purified by conventional methods such as recrystallization, reprecipitation or chromatography.
Process E2 is carried out in the presence or absence of a base in an inert solvent (preferably in the presence of a base), to the compound (XII) with hydroxylamine or an inorganic acid salt of hydroxylamine (preferably an inorganic acid salt of hydroxylamine). The reaction is carried out under the same conditions as the step D3 to produce compound (II).
Method F (Scheme F), in the intermediates (ⅩⅡ) of method E, R ² is a halogen atom, C ₁ -C ₆ alkyl, halogen or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group substituted by, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₃ -C ₁₀ cycloalkyl group, C ₃ -C ₁₀ cycloalkenyl group, C ₂ -C ₆ alkanoyl group or C ₁ -C ₆ alkoxycarbonyl group It is a method of manufacturing (XIIIa) separately.
The F1 step is a step for producing the compound (XIIa) by reacting a compound having the formula (XIII) with a compound having the formula (XIV) in the presence of a base in an insoluble solvent, under the same conditions as in the E1 step. .
Since the isoxazole derivative (I) of the present invention has excellent type A monoamine oxidase inhibitory activity and also has low toxicity, manic-depressive disease, Parkinson's disease, Alzheimer's type dementia (such as cognitive disorder based on Alzheimer's disease) or cerebrovascular dementia (brain) It is useful as a therapeutic or prophylactic agent (especially therapeutic drug) for neurological diseases (especially manic-depressive diseases) such as cognitive disorders based on vascular dementia.
In the following, Examples, Reference Examples, Test Examples, and Formulation Examples are shown and the present invention will be described in more detail, but the scope of the present invention is not limited thereto.
Example 1
3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (Example Compound No .: 1)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole
Triphenylphosphine (0.87 g) was dissolved in tetrahydrofuran (10 mL), and diethyl azodicarboxylic acid (0.57 g) was added dropwise under ice-cooling stirring, and the mixture was stirred at the same temperature for 10 minutes. 3-hydroxy-5-phenylisoxazole (0.48 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.48 g) were added, stirred for 10 minutes under ice-cooling, and then at room temperature for 24 hours. Was stirred. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; cyclohexane / ethyl acetate = 4/1) and crystallized from isopropyl ether to obtain the target compound (0.63 g, 69%) was obtained as colorless crystals.
Melting point: 125-126 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3322, 1721, 1710, 1619;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.56 (2H, q, J = 5.1 Hz), 4.35 (2H, t, J = 5.1 Hz), 4.94 (1H, brs), 6.14 (1H , s), 7.43-7.51 (3H, m), 7.71-7.74 (2H, m).
(b) 3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride
To 4- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.50 g) was added 4 N hydrochloric acid / 1,4-dioxane solution (4.0 mL), Stir at room temperature for 15 minutes. The precipitated crystals were collected by filtration and washed with ethyl acetate to obtain the target compound (0.39 g, 99%) as colorless crystals.
Melting point: 215-218 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3132, 2693, 2810, 2756, 1620, 1597, 1579;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = 5.1 Hz), 6.85 (1H, s), 7.51-7.57 (3H, m) , 7.84-7.87 (2H, m), 8.25 (3H, broad singlet).
Example 2
3- (2-Aminoethoxy) -4-chloro-5-phenylisoxazole hydrochloride (Example Compound No. 5)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-4-chloro-5-phenylisoxazole
Reaction of 4-chloro-3-hydroxy-5-phenylisoxazole (0.58 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.48 g) in the same manner as in Example 1 (a) After working up to give the title compound (0.73 g, 72%) as colorless crystals.
Melting point: 115-116 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3346, 1720, 1709, 1616;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.61 (2H, q, J = 5.1 Hz), 4.42 (2H, t, J = 5.1 Hz), 4.97 (1H, brs), 7.46-7.53 (3H, m), 7.94-8.00 (2H, m).
(b) 3- (2-aminoethoxy) -4-chloro-5-phenylisoxazole hydrochloride
By post-treating 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-chloro-5-phenylisoxazole (0.54 g) in the same manner as in Example 1 (b) , Target compound (0.41 g, 93%) was obtained as colorless crystals.
Melting point: 204-207 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 2971, 2905, 2848, 2775, 1606, 1575, 1534;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.31 (2H, t, J = 5.1 Hz), 4.56 (2H, t, J = 5.1 Hz), 7.59-7.67 (3H, m), 7.92-7.97 (2H, m), 8.27 (3H, broad singlet).
Example 3
3- (2-Aminoethoxy) -5- (4-chlorophenyl) -isoxazole hydrochloride (Example Compound No .: 143)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (4-chlorophenyl) isoxazole
5- (4-chlorophenyl) -3-hydroxyaminoisoxazole (0.58 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.48 g) in the same manner as in Example 1 (a) By reacting and working up, the target compound (0.69 g, 68%) was obtained as colorless crystals.
Melting point: 128-129 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3378, 1683, 1622;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.56 (2H, q, J = 5.1 Hz), 4.35 (2H, t, J = 5.1 Hz), 4.93 (1H, brs), 6.14 (1H , s), 7.43 (2H, d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz).
(b) 3- (2-aminoethoxy) -5- (4-chlorophenyl) isoxazole hydrochloride
By post-treating 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.54 g) in the same manner as in Example 1 (b) , Target compound (0.43 g, 98%) was obtained as colorless crystals.
Melting point: 218-223 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3135, 2998, 2809, 1618, 1603, 1594, 1575, 1567;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = 5.1 Hz), 6.91 (1H, s), 7.63 (2H, d, J = 8.7 Hz), 7.89 (2H, d, J = 8.7 Hz), 8.25 (3H, brs).
Example 4
3- (2-Aminoethoxy) -4-isopropyl-5-phenylisoxazole hydrochloride (Example Compound No. 9)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5-phenylisoxazole
3-hydroxy-4-isopropyl-5-phenylisoxazole (0.50 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g) in the same manner as in Example 1 (a) By reacting and working up, the target compound (0.60 g, 69%) was obtained as colorless crystals.
Melting point: 98-99 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3386, 1686, 1642;
NMR spectrum (CDCl ₃ ) δ ppm: 1.29 (6H, d, J = 6.8 Hz), 1.46 (9H, s), 3.06 (1H, q, J = 6.8 Hz), 3.60 (2H, q, J = 5.1 Hz ), 4.38 (2H, t, J = 5.1 Hz), 4.85 (1H, brs), 7.42-7.50 (3H, m), 7.55-7.60 (2H, m).
(b) 3- (2-aminoethoxy) -4-isopropyl-5-phenylisoxazole hydrochloride
Post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5-phenylisoxazole (0.50 g) in the same manner as in Example 1 (b) This resulted in the target compound (0.39 g, 95%) as colorless crystals.
Melting point: 202-210 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2975, 2939, 1642, 1599, 1575;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (6H, d, J = 6.8 Hz), 3.04 (1H, q, J = 6.8 Hz), 3.28 (2H, t, J = 5.1 Hz), 4.46 (2H , t, J = 5.1 Hz), 7.50-7.64 (5H, m), 8.26 (3H, brs).
Example 5
3- (2-aminoethoxy) -5- (2-thienyl) isoxazole hydrochloride (Example Compound No .: 535)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (2-thienyl) isoxazole
3-hydroxy-5- (2-thienyl) isoxazole (0.42 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g) were reacted in the same manner as in Example 1 (a) After working up, the target compound (0.63 g, 82%) was obtained as colorless crystals.
Melting point: 129-130 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3323, 1708, 1694, 1618;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.56 (2H, q, J = 5.1 Hz), 4.34 (2H, t, J = 5.1 Hz), 4.93 (1H, brs), 6.05 (1H , s), 7.11 (1H, doublet of doublets, J = 5.1 Hz, J = 3.7 Hz), 7.43-7.48 (2H, m).
(b) 3- (2-aminoethoxy) -5- (2-thienyl) isoxazole hydrochloride
By post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-thiethyl) isoxazole (0.05 g) in the same manner as in Example 1 (b) , Target compound (0.37 g, 95%) was obtained as colorless crystals.
Melting point: 278-283 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3108, 3086, 2993, 2978, 2913, 1613, 1596;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.25 (2H, t, J = 5.1 Hz), 4.44 (2H, t, J = 5.1 Hz), 6.69 (1H, s), 7.25 (1H, dd, J = 5.5 Hz, J = 3.7 Hz), 7.71 (1H, d, J = 3.7 Hz), 7.84 (1H, d, J = 5.5 Hz), 8.25 (3H, brs).
Example 6
3- (2-aminoethoxy) -4-chloro-5- (2-thienyl) isoxazole hydrochloride (Example Compound No .: 539)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (2-thienyl) isoxazole
4-Chloro-3-hydroxy-5- (2-thienyl) isoxazole (0.50 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g) were prepared in Example 1 (a) and Reaction and post-treatment in the same manner afforded the target compound (0.57 g, 66%) as colorless crystals.
Melting point: 94-95 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3342, 1718, 1708, 1622;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.60 (2H, q, J = 5.1 Hz), 4.40 (2H, t, J = 5.1 Hz), 4.96 (1H, brs), 7.19 (1H , dd, J = 5.2 Hz, J = 3.6 Hz), 7.56 (1H, d, J = 5.2 Hz), 7.74 (1H, d, J = 3.6 Hz).
(b) 3- (2-aminoethoxy) -4-chloro-5- (2-thienyl) isoxazole hydrochloride
Reaction of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-chloro-5- (2-thiethyl) isoxazole (0.40 g) in the same manner as in Example 1 (b) After working up, the target compound (0.31 g, 95%) was obtained as colorless crystals.
Melting point: 278-283 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3109, 2960, 2897, 1626, 1596, 1579;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.30 (2H, t, J = 5.1 Hz), 4.54 (2H, t, J = 5.1 Hz), 7.34 (1H, dd, J = 5.1 Hz, J = 3.6 Hz ), 7.83 (1H, d, J = 3.6 Hz), 8.01 (1H,, J = 5.1 Hz), 8.26 (3H, brs).
Example 7
3- (2-aminoethoxy) -5- (3-pyridyl) isoxazole hydrochloride (Example Compound No .: 1056)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (3-pyridyl) isoxazole
3-hydroxy-5- (3-pyridyl) isoxazole (0.41 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g) were reacted in the same manner as in Example 1 (a) After working up, the target compound (0.50 g, 65%) was obtained as colorless crystals.
Melting point: 97-98 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3249, 3145, 1712, 1626;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.57 (2H, q, J = 5.1 Hz), 4.37 (2H, t, J = 5.1 Hz), 4.94 (1H, brs), 6.25 (1H , s), 7.42 (1H, dd, J = 8.0 Hz, J = 4.9 Hz), 8.04 (1H, d, J = 8.0 Hz), 8.64 (1H, d, J = 4.9 Hz), 8.97 (1H, s ).
(b) 3- (2-aminoethoxy) -5- (3-pyridyl) isoxazole dihydrochloride
By post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-pyridyl) isoxazole (0.48 g) in the same manner as in Example 1 (b) , Target compound (0.41 g, 92%) was obtained as colorless crystals.
Melting point: 222-227 캜;
IR spectrum (KBr) ν max cm ⁻¹ : 3096, 3068, 3043, 2967, 2886, 2813, 1641, 1597, 1539;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (2H, q, J = 5.1 Hz), 4.48 (2H, t, J = 5.1 Hz), 7.11 (1H, s), 7.77 (1H, dd, J = 8.0 Hz, J = 5.1 Hz), 8.38 (3H, brs), 8.46 (1H, d, J = 8.0 Hz), 8.79 (1H, d, J = 5.1 Hz), 9.21 (1H, s).
Example 8
3- (2-aminoethoxy) -4-chloro-5- (3-pyridyl) isoxazole hydrochloride (Example Compound No .: 1061)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-4-chloro-5- (3-pyridyl) isoxazole
4-Chloro-3-hydroxy-5- (3-pyridyl) isoxazole (0.49 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.40 g) were prepared in Example 1 (a) and By reaction in the same manner and post-treatment, the target compound (0.54 g, 63%) was obtained as colorless crystals.
Melting point: 76-77 ° C;
IR spectrum (KBr) ν max cm ⁻¹ : 3353, 3248, 1754, 1721, 1709, 1616;
NMR spectrum (CDCl ₃ ) δ ppm: 1.47 (9H, s), 3.62 (2H, q, J = 5.1 Hz), 4.43 (2H, t, J = 5.1 Hz), 4.97 (1H, brs), 7.45 (1H , dd, J = 8.0Hz, J = 5.1Hz), 8.24 (1H, ddd, J = 8.0Hz, J = 2.0Hz, J = 1.5Hz), 8.72 (1H, dd, J = 5.1Hz, 1.5Hz) , 9.24 (1H, doublet, J = 2.0 Hz).
(b) 3- (2-aminoethoxy) -4-chloro-5- (3-pyridyl) isoxazole dihydrochloride
Reaction of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-chloro-5- (3-pyridyl) isoxazole (0.40 g) in the same manner as in Example 1 (b) After working up, the target compound (0.35 g, 96%) was obtained as colorless crystals.
Melting point: 205-210 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3103, 3053, 2937, 2899, 2875, 2823, 2800, 1634, 1607, 1590, 1541;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.31 (2H, q, J = 5.1 Hz), 4.59 (2H, t, J = 5.1 Hz), 7.74 (1H, dd, J = 8.0 Hz, J = 5.1 Hz ), 8.40 (1H, ddd, J = 8.0 Hz, J = 2.0 Hz, J = 1.5 Hz), 8.40 (3H, brs), 8.82 (1H, dd, J = 5.1 Hz, J = 1.5 Hz), 9.15 ( 1H, d, J = 2.0 Hz).
Example 9
3- (2-aminoethoxy) -5- (2-methoxyphenyl) isoxazole hydrochloride (Example Compound No. 357)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (2-methoxyphenyl) isoxazole
Triphenylphosphine (0.45 g) was dissolved in tetrahydrofuran (5 mL), and diethyl azodicarboxylic acid (0.27 mL) was added dropwise under ice-cooling stirring, followed by stirring at the same temperature for 30 minutes, followed by 2- (N -tert-butoxycarbonylamino) ethanol (0.20 g) and 3-hydroxy-5- (2-methoxyphenyl) isoxazole (0.22 g) were added and stirred for 10 minutes under ice-cooling, followed by stirring at room temperature for 24 hours. It was. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain the target compound (0.33 g, 86%) as a colorless solid. It was.
Melting point: 131-133 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3309, 1712, 1620;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.57 (2H, q, J = 5.2 Hz), 3.95 (3H, s), 4.36 (2H, t, J = 5.2 Hz), 4.96 (1H , brs), 6.43 (1H, s), 7.00 (1H, d, J = 7.8 Hz), 7.06 (1H, t, J = 7.8 Hz), 7.41 (1H, ddd, J = 7.8 Hz, J = 7.8 Hz , J = 1.7 Hz), 7.91 (1H, dd, J = 7.8 Hz, J = 1.7 Hz).
(b) 3- (2-aminoethoxy) -5- (2-methoxyphenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methoxyphenyl) isoxazole (0.31 g) was added with 4 N hydrochloric acid / 1,4-dioxane solution (2.3 mL). ) Was stirred for 30 minutes at room temperature. The residue obtained by distilling off the solvent under reduced pressure was recrystallized using a mixed solvent of ethanol and isopropanol to give the target compound (0.21 g, 84%) as colorless crystals.
Melting point: 160-162 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3000, 2959, 2837, 1621, 1614;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.25 (2H, t, J = 5.1 Hz, 3.94 (3H, s), 4.45 (2H, t, J = 5.1 Hz), 6.56 (1H, s), 7.11 ( 1H, t, J = 7.8Hz), 7.23 (1H, d, J = 7.8Hz), 7.52 (1H, ddd, J = 7.8Hz, J = 7.8Hz, J = 1.7Hz), 7.81 (1H, dd, J = 7.8 Hz, J = 1.7 Hz), 8.25 (3H, br s).
Example 10
3- (2-aminoethoxy) -5- (3-methoxyphenyl) isoxazole hydrochloride (Example Compound No .: 363)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (3-methoxyphenyl) isoxazole
3-hydroxy-5- (3-methoxyphenyl) isoxazole (0.22 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g) in the same manner as in Example 9 (a) Reaction and post-treatment gave the target compound (0.31 g, 82%) as a colorless powder.
Melting point: 89-90 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3312, 1710;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.56 (2H, q, J = 5.2 Hz), 3.86 (3H, s), 4.35 (2H, t, J = 5.2 Hz), 4.93 (1H , brs), 6.13 (1H, s), 6.96-7.00 (1H, m), 7.26-7.42 (3H, m).
(b) 3- (2-aminoethoxy) -5- (3-methoxyphenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-methoxyphenyl) isoxazole (0.29 g) was reacted in the same manner as in Example 9 (b), and ethanol and By recrystallization using a mixed solvent of isopropanol, the desired compound (0.19 g, 83%) was obtained as colorless crystals.
Melting point: 180-182 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2995, 2976, 2914, 1591;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (2H, t, J = 5.1 Hz), 3.84 (3H, s), 4.45 (2H, t, J = 5.1 Hz), 6.88 (1H, s), 7.09 -7.11 (1H, m), 7.38-7.48 (3H, m), 8.28 (3H, brs).
Example 11
3- (2-aminoethoxy) -5- (4-methoxyphenyl) isoxazole hydrochloride (Example Compound No. 350)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (4-methoxyphenyl) isoxazole
3-hydroxy-5- (4-methoxyphenyl) isoxazole (0.22 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g) in the same manner as in Example 9 (a) The reaction was worked up to give the target compound (0.32 g, 84%) as a colorless powder.
Melting point: 117-118 캜;
IR spectrum (KBr) ν max cm ⁻¹ : 3344, 1719, 1623;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.56 (2H, q, J = 5.2 Hz), 3.86 (3H, s), 4.34 (2H, t, J = 5.2 Hz), 4.95 (1H , brs), 6.02 (1H, s), 6.96 (2H, d, J = 8.9 Hz), 7.66 (2H, d, J = 8.9 Hz).
(b) 3- (2-aminoethoxy) -5- (4-methoxyphenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methoxyphenyl) isoxazole (0.30 g) was reacted in the same manner as in Example 9 (b), and ethanol and By recrystallization using a mixed solvent of isopropanol, the desired compound (0.17 g, 71%) was obtained as colorless crystals.
Melting point: 190-193 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 2990, 2969, 2950, 2900, 1617;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.25 (2H, t, J = 5.1 Hz), 3.83 (3H, s), 4.43 (2H, t, J = 5.1 Hz), 6.69 (1H, s), 7.09 (2H, d, J = 8.9 Hz), 7.79 (2H, d, J = 8.9 Hz), 8.25 (3H, brs).
Example 12
3- (2-aminoethoxy) -5- (2-chlorophenyl) isoxazole hydrochloride (Example Compound No. 111)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (2-chlorophenyl) isoxazole
5- (2-chlorophenyl) -3-hydroxyisoxazole (0.23 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g) were reacted in the same manner as in Example 9 (a) After working up to give the target compound (0.35 g, 88%) as a colorless powder.
Melting point: 125-127 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3333, 1710, 1697, 1618;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.57 (2H, q, J = 5.2 Hz), 4.37 (2H, t, J = 5.2 Hz), 4.96 (1H, brs), 6.59 (1H , s), 7.33-7.43 (2H, m), 7.46-7.54 (1H, m), 7.87-7.94 (1H, m).
(b) 3- (2-aminoethoxy) -5- (2-chlorophenyl) isoxazole hydrochloride
Reaction of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-chlorophenyl) isoxazole (0.33 g) in the same manner as in Example 9 (b), followed by isopropanol By recrystallization using, the target compound (0.20 g, 74%) was obtained as colorless crystals.
Melting point: 141-144 캜 (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3003, 2965, 1610;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.278 (2H, t, J = 5.1 Hz), 4.48 (2H, t, J = 5.1 Hz), 6.80 (1H, s), 7.52-7.60 (2H, m) , 7.68 (1H, doublet of doublets, J = 7.5 Hz, J = 1.9 Hz), 7.87 (1H, doublet of doublets, J = 7.5 Hz, J = 1.9 Hz), 8.27 (3H, brs).
Example 13
3- (2-aminoethoxy) -5- (3-chlorophenyl) isoxazole hydrochloride (Example Compound No. 125)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (3-chlorophenyl) isoxazole
5- (3-chlorophenyl) -3-hydroxy-isoxazole (0.23 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.20 g) in the same manner as in Example 9 (a) The reaction was worked up to give the target compound (0.34 g, 85%) as a colorless powder.
Melting point: 117-119 캜;
IR spectrum (KBr) ν max cm ⁻¹ : 3385, 1685;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.57 (2H, q, J = 5.2 Hz), 4.36 (2H, t, J = 5.2 Hz), 4.93 (1H, brs), 6.16 (1H , s), 7.36-7.44 (2H, m), 7.57-7.67 (1H, m), 7.70 (1H, s).
(b) 3- (2-aminoethoxy) -5- (3-chlorophenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3-chlorophenyl) isoxazole (0.33 g) was reacted in the same manner as in Example 9 (b), followed by ethanol And recrystallization using a mixed solvent of isopropanol to give the target compound (0.21 g, 78%) as colorless crystals.
Melting point: 204-208 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 2996, 2980, 2920, 1619;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = 5.1 Hz), 6.98 (1H, s), 7.56-7.63 (2H, m) , 7.80-7.84 (1H, m), 7.96 (1H, s), 8.22 (3H, brs).
Example 14
3- (2-Aminoethoxy) -4-methyl-5-phenylisoxazole hydrochloride (Example Compound No. 6)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methyl-5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.30 g) is dissolved in tetrahydrofuran (10 ml) and at -70 ° C under nitrogen atmosphere. An n-butyllithium / n-hexane solution (1.56 M, 1.4 ml) was added dropwise and stirred for 10 minutes. Subsequently, methyl iodide (0.09 ml) was added dropwise and stirred for 10 minutes, and then the temperature was raised to 0 ° C. The reaction solution was poured into ice water, the pH of the solution was adjusted to 6 using an aqueous potassium phosphate solution, and then ethyl acetate. The organic layer was extracted with, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain the target compound (0.29 g, 94%). Obtained as a colorless powder.
Melting point: 118-120 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3334, 2974, 1719, 1708;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 2.12 (3H, s), 3.59 (2H, q, J = 5.1 Hz), 4.38 (2H, t, J = 5.1 Hz), 4.94 (1H , brs), 7.40-7.53 (3H, m), 7.69 (2H, d, J = 7.9 Hz).
(b) 3- (2-aminoethoxy) -4-methyl-5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methyl-5-phenylisoxazole (0.29 g) was reacted in the same manner as in Example 9 (b), and then methanol And recrystallization using a mixed solvent of ethanol to obtain the target compound (0.18 g, 78%) as colorless crystals.
Melting point: 245-250 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3003, 2892, 1516;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.13 (3H, s), 3.28 (2H, t, J = 5.1 Hz), 4.46 (2H, t, J = 5.1 Hz), 7.50-7.59 (3H, m) , 7.73 (2H, doublet, J = 7.2 Hz), 8.21 (3H, broad singlet).
Example 15
3- (2-Aminoethoxy) -4-ethyl-5-phenylisoxazole hydrochloride (Example Compound No. 7)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-ethyl-5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3 g) and ethyl iodide (0.12 mL) were reacted in the same manner as in Example 14 (a). After workup, the target compound (0.24 g, 73%) was obtained as a colorless oily substance.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3460, 2980, 1713;
NMR spectrum (CDCl ₃ ) δ ppm: 1.21 (3H, t, J = 7.5 Hz), 1.46 (9H, s), 2.56 (2H, q, J = 7.5 Hz), 3.59 (2H, q, J = 5.2 Hz ), 4.38 (2H, t, J = 5.2 Hz), 4.90 (1H, brs), 7.37-7.51 (3H, m), 7.64-7.68 (2H, m).
(b) 3- (2-aminoethoxy) -4-ethyl-5-phenylisoxazole hydrochloride
By reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-ethyl-5-phenylisoxazole (0.21 g) in the same manner as in Example 9 (b), , Target compound (0.12 g, 71%) was obtained as colorless crystals.
Melting point: 210-215 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2968, 2886, 1518;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.15 (3H, t, J = 7.5 Hz), 2.58 (2H, q, J = 7.5 Hz), 3.29 (2H, t, J = 5.1 Hz), 4.46 (2H , t, J = 5.1 Hz), 7.51-7.59 (3H, m), 7.67-7.70 (2H, m), 8.25 (3H, brs).
Example 16
3- (2-aminoethoxy) -5-phenyl-4-propylisoxazole hydrochloride (Example Compound No. 8)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl-4-propylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3 g) and propyl iodide (0.29 mL) were reacted in the same manner as in Example 14 (a) After workup, the target compound (0.22 g, 65%) was obtained as a colorless oily substance.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3460, 2966, 1713;
NMR spectrum (CDCl ₃ ) δ ppm: 0.97 (3H, t, J = 7.4 Hz), 1.46 (9H, s), 1.56-1.69 (2H, m), 2.51 (2H, t, J = 7.6 Hz), 3.58 (2H, q, J = 5.2 Hz), 4.37 (2H, t, J = 5.2 Hz), 4.90 (1H, brs), 7.43-7.53 (3H, m), 7.65-7.68 (2H, m).
(b) 3- (2-aminoethoxy) -5-phenyl-4-propylisoxazole hydrochloride
By post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl-4-propylisoxazole (0.18 g) in the same manner as in Example 9 (b) , Target compound (0.10 g, 71%) was obtained as colorless crystals.
Melting point: 119-121 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2960, 2933, 2872, 1518;
NMR spectrum (DMSO-d ₆ ) δ ppm: 0.91 (3H, t, J = 7.3 Hz), 1.51-1.61 (2H, m), 2.54 (2H, t, J = 7.7 Hz), 3.28 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = 5.1 Hz), 7.50-7.59 (3H, m), 7.68-7.70 (2H, m), 8.20 (3H, brs).
Example 17
3- (2-aminoethoxy) -4-butyl-5-phenylisoxazole hydrochloride (Example Compound No. 10)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-butyl-5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.3 g) and butyl iodide (0.17 mL) were reacted in the same manner as in Example 14 (a). After workup, the target compound (0.23 g, 66%) was obtained as a colorless oily substance.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3460, 2962, 1713;
NMR spectrum (CDCl ₃ ) δ ppm: 0.93 (3H, t, J = 7.3 Hz), 1.31-1.63 (4H, m), 1.46 (9H, s), 2.53 (2H, t, J = 7.6 Hz), 3.58 (2H, q, J = 5.3 Hz), 4.38 (2H, t, J = 5.3 Hz), 4.90 (1H, brs), 7.42-7.51 (3H, m), 7.65-7.68 (2H, m).
(b) 3- (2-aminoethoxy) -4-butyl-5-phenylisoxazole hydrochloride
By post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-butyl-5-phenylisoxazole (0.20 g) in the same manner as in Example 9 (b) , Target compound (0.12 g, 75%) was obtained as colorless crystals.
Melting point: 104-106 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3006, 2963, 2951, 2931, 2869, 1516;
NMR spectrum (DMSO-d ₆ ) δ ppm: 0.87 (3H, t, J = 7.3 Hz), 1.27-1.37 (2H, m), 1.47-1.55 (2H, m), 2.57 (2H, t, J = 7.7 Hz), 3.28 (2H, t, J = 5.1 Hz), 4.46 (2H, t, J = 5.1 Hz), 7.51-7.59 (3H, m), 7.68-7.70 (2H, m), 8.23 (3H, brs ).
Example 18
3- (2-aminoethoxy) -4-hexyl-5-phenylisoxazole hydrochloride (Example Compound No .: 1388)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-hexyl-5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.4 g) and hexyl iodide (0.23 mL) were reacted in the same manner as in Example 14 (a). After workup, the target compound (0.31 g, 61%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3387, 2936, 1715;
NMR spectrum (CDCl ₃ ) δ ppm: 0.88 (3H, t, J = 6.6 Hz), 1.23-1.42 (6H, m), 1.46 (9H, s), 1.53-1.70 (2H, m), 2.52 (2H, t, J = 7.7 Hz), 3.58 (2H, q, J = 5.1 Hz), 4.37 (2H, t, J = 5.1 Hz), 4.90 (1H, brs), 7.40-7.51 (3H, m), 7.65- 7.68 (2 H, m).
(b) 3- (2-aminoethoxy) -4-hexyl-5-phenylisoxazole hydrochloride
By post-treatment by reacting 3- (2-N-tert-butoxycarbonylamino) ethoxy) -4-hexyl-5-phenylisoxazole (0.2 g) in the same manner as in Example 9 (b), The desired compound (0.13 g, 81%) was obtained as colorless crystals.
Melting point: 99-101 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 2954, 2930, 1515;
NMR spectrum (DMSO-d ₆ ) δ ppm: 0.83 (3H, t, J = 6.9 Hz), 1.18-1.32 (6H, m), 1.48-1.55 (2H, m), 2.56 (2H, t, J = 7.7 Hz), 3.28 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = 5.1 Hz), 7.50-7.59 (3H, m), 7.67-7.69 (2H, m), 8.16 (3H, brs ).
Example 19
3- (2-aminoethoxy) -4-carboxy-5-phenylisoxazole hydrochloride (Example Compound No .: 1408)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (2.00 g) was dissolved in tetrahydrofuran (20 mL), at -70 ° C under nitrogen atmosphere. Butyl lithium (1.56 M hexane solution, 9.3 ml) was added dropwise and stirred for 10 minutes. Subsequently, the carbon dioxide gas was bubbled for 10 minutes and then heated up to 0 ° C. The reaction solution was poured into iced water, the pH of the solution was adjusted to 6 using aqueous potassium phosphate solution, extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was washed with ether to give the target compound (2.18 g, 95%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 2982, 1706;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.38 (9H, s), 3.38 (2H, q, J = 5.7 Hz), 4.29 (2H, t, J = 5.7 Hz), 7.01 (1H, brs), 7.51 -7.62 (3H, m), 7.84-7.91 (2H, m).
(b) 3- (2-aminoethoxy) -4-carboxy-5-phenylisoxazole hydrochloride
By post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole (0.12 g) in the same manner as in Example 9 (b) , Target compound (0.06 g, 60%) was obtained as colorless crystals.
Melting point: 180-183 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 3149, 2873, 2820, 1755, 1709;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.30 (2H, t, J = 5.3 Hz), 4.54 (2H, t, J = 5.3 Hz), 7.54-7.65 (3H, m), 7.85-7.87 (2H, m), 8.22 (3H, broad singlet).
Example 20
3- (2-aminoethoxy) -4-carbamoyl-5-phenylisoxazole hydrochloride (Example Compound No .: 1414)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole (0.6 g) was dissolved in tetrahydrofuran (6 mL), under ice-cooled stirring, Carbonyldiimidazole (0.31 g) was added, followed by stirring at room temperature for 30 minutes. Ammonia water (1 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into iced water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to give the target compound (0.60 g, quant.) As a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3439, 3371, 3149, 1694, 1680;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.39 (9H, s), 3.39 (2H, q, J = 5.0 Hz), 4.30 (2H, t, J = 5.0 Hz), 7.38 (1H, brs), 7.51 -7.57 (3H, m), 7.71 (1H, broad singlet), 7.91-7.94 (2H, m).
(b) 3- (2-aminoethoxy) -4-carbamoyl-5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-5-phenylisoxazole (0.22 g) was reacted in the same manner as in Example 9 (b), and then By treatment, the desired compound (0.13 g, 72%) was obtained as colorless crystals.
Melting point: 225-230 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3407, 3213, 2963, 2878, 1662;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.32 (2H, t, J = 4.9 Hz), 4.54 (2H, t, J = 4.9 Hz), 7.52-7.60 (4H, m), 7.77 (1H, brs) , 7.92-7.94 (2H, m), 8.29 (3H, brs).
Example 21
3- (2-aminoethoxy) -4-cyano-5-phenylisoxazole hydrochloride (Example Compound No .: 1406)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyano-5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carbamoyl-5-phenylisoxazole (0.38 g) is dissolved in dimethylformamide (4 mL) and nitrogen atmosphere Phosphorus oxychloride (0.11 ml) was added dropwise at 5 ° C, and then stirred at room temperature for 30 minutes. The reaction solution was poured into iced water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to obtain the target compound (0.28 g, 78%). Obtained as a colorless solid.
IR spectrum (KBr) ν max cm ⁻¹ : 3384, 2237, 1690, 1680;
NMR spectrum (CDCl ₃ ) δ ppm: 1.47 (9H, s), 3.61 (2H, q, J = 5.2 Hz), 4.43 (2H, t, J = 5.2 Hz), 4.97 (1H, brs), 7.52-7.64 (3H, m), 8.01-8.05 (2H, m).
(b) 3- (2-aminoethoxy) -4-cyano-5-phenylisoxazole hydrochloride
Post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyano-5-phenylisoxazole (0.25 g) in the same manner as in Example 9 (b) This resulted in the target compound (0.13 g, 65%) as colorless crystals.
Melting point: 200-205 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2967, 2236, 1611;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.32 (2H, t, J = 5.1 Hz), 4.60 (2H, t, J = 5.1 Hz), 7.68-7.76 (3H, m), 7.98-8.01 (2H, m), 8.29 (3H, broad singlet).
Example 22
3- (2-Aminoethoxy) -4-methoxycarbonyl-5-phenylisoxazole hydrochloride (Example Compound No .: 1412)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methoxycarbonyl-5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole (0.2 g) was added to a mixed solution of methanol and benzene (1: 5, 10 ml). It melt | dissolved, and trimethylsilyl diazomethane (0.6 mL, 2.0 M hexane solution) was dripped under ice-cooling, and it stirred at room temperature for 30 minutes. The reaction solution was poured into iced water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to obtain the target compound (0.17 g, 81%). Obtained as a colorless solid.
IR spectrum (KBr) ν max cm ⁻¹ : 3355, 1725, 1691;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.62 (2H, q, J = 5.1 Hz), 3.85 (3H, s), 4.43 (3H, t, J = 5.1 Hz), 5.03 (1H , brs), 7.46-7.54 (3H, m), 7.87-7.91 (2H, m).
(b) 3- (2-aminoethoxy) -4-methoxycarbonyl-5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methoxycarbonyl-5-phenylisoxazole (0.16 g) was reacted in the same manner as in Example 9 (b) After workup, the target compound (0.08 g, 62%) was obtained as colorless crystals.
Melting point: 195-198 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3148, 2870, 2848, 2821, 1708;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.30 (2H, t, J = 5.2 Hz), 3.77 (3H, s), 4.54 (2H, t, J = 5.2 Hz), 7.56-7.66 (3H, m) , 7.85-7.87 (2H, m), 8.24 (3H, brs).
Example 23
3- (2-aminoethoxy) -4-methylaminocarbonyl-5-phenylisoxazole hydrochloride (Example Compound No .: 1416)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-methylaminocarbonyl-5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-carboxy-5-phenylisoxazole (0.2 g) and methylamine (30% methanol solution, 0.12 mL) were used in Example 20 After the reaction was carried out in the same manner as in (a), the resultant compound (0.18 g, 87%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3405, 3369, 1677;
NMR spectrum (CDCl ₃ ) δ ppm: 1.45 (9H, s), 2.97 (3H, d, J = 5.0 Hz), 3.64 (2H, q, J = 5.1 Hz), 4.44 (2H, t, J = 5.1 Hz ), 4.90 (1H, brs), 7.30 (1H, brs), 7.46-7.50 (3H, m), 8.05-8.09 (2H, m).
(b) 3- (2-aminoethoxy) -4-methylaminocarbonyl-5-phenylisoxazole hydrochloride
3- (2-N-tert-butoxycarbonylamino) ethoxy) -4-methylaminocarbonyl-5-phenylisoxazole (0.17 g) was reacted in the same manner as in Example 14 (a), and then By treatment, the desired compound (0.08 g, 57%) was obtained as colorless crystals.
Melting point: 223-226 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 3102, 2935, 2879, 1646;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.78 (3H, d, J = 4.4 Hz), 3.32 (2H, t, J = 4.8 Hz), 4.53 (2H, t, J = 4.8 Hz), 7.51-7.60 (3H, m), 7.89-7.92 (2H, m), 8.18 (1H, d, J = 4.4 Hz), 8.31 (3H, brs).
Example 24
3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-methylisoxazole hydrochloride (Example Compound No. 148)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-methylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.25 g) and methyl iodide (0.06 mL) were the same as in Example 14 (a) Reaction and post-treatment by the method gave the target compound (0.23 g, 89%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3344, 2980, 1682;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 2.10 (3H, s), 3.58 (2H, q, J = 5.2 Hz), 4.37 (2H, t, J = 5.2 Hz), 4.90 (1H , brs), 7.45 (2H, d, J = 8.6 Hz), 7.63 (2H, d, J = 8.6 Hz).
(b) 3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-methylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-methylisoxazole (0.22 g) in the same manner as in Example 9 (b) The reaction was worked up to give the target compound (0.09 g, 50%) as colorless crystals.
Melting point: 248-253 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3020, 2991, 2884, 1513;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.12 (3H, s), 3.27 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = 5.1 Hz), 7.63 (2H, d, J = 8.6 Hz), 8.23 (3H, broad singlet).
Example 25
3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-ethylisoxazole hydrochloride (Example Compound No. 149)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-ethylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.4 g) and ethyl iodide (0.11 mL) were the same as in Example 14 (a) By reacting and post-treatment by the method, the target compound (0.26 g, 61%) was obtained as a colorless oily substance.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3460, 2980, 1713;
NMR spectrum (CDCl ₃ ) δ ppm: 1.20 (3H, t, J = 7.4 Hz), 1.46 (9H, s), 2.54 (2H, q, J = 7.4 Hz), 3.59 (2H, q, J = 5.2 Hz ), 4.37 (2H, t, J = 5.2 Hz), 4.90 (1H, brs), 7.45 (2H, d, J = 8.5 Hz), 7.59 (2H, d, J = 8.5 Hz).
(b) 3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-ethylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-ethylisoxazole (0.22 g) in the same manner as in Example 9 (b) The reaction was worked up to give the target compound (0.13 g, 72%) as colorless crystals.
Melting point: 217-220 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2972, 2892, 1515;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.14 (3H, t, J = 7.5 Hz), 2.58 (2H, q, J = 7.5 Hz), 3.28 (2H, t, J = 5.2 Hz), 4.46 (2H , t, J = 5.2 Hz), 7.64 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz), 8.20 (3H, brs).
Example 26
3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-propylisoxazole hydrochloride (Example Compound No .: 150)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-propylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) isoxazole (0.4 g) and propyl iodide (0.14 mL) were the same as in Example 14 (a) Reaction and post-treatment by the method gave the target compound (0.21 g, 47%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3392, 2963, 1685;
NMR spectrum (CDCl ₃ ) δ ppm: 0.96 (3H, t, J = 7.4 Hz), 1.46 (9H, s), 1.57-1.69 (2H, m), 2.49 (2H, t, J = 7.6 Hz), 3.58 (2H, q, J = 5.2 Hz), 4.37 (2H, t, J = 5.2 Hz), 4.87 (1H, brs), 7.45 (2H, d, J = 8.6 Hz), 7.60 (2H, d, J = 8.6 Hz).
(b) 3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-propylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-propylisoxazole (0.19 g) in the same manner as in Example 9 (b) The reaction was worked up to give the target compound (0.13 g, 81%) as colorless crystals.
Melting point: 146-149 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2958, 2871, 2829, 1516;
NMR spectrum (DMSO-d ₆ ) δ ppm: 0.90 (3H, t, J = 7.3 Hz), 1.50-1.59 (2H, m), 2.54 (2H, t, J = 7.3 Hz), 3.28 (2H, t, J = 5.2 Hz), 4.45 (2H, t, J = 5.2 Hz), 7.63 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 8.21 (3H, brs).
Example 27
3- (2-aminoethoxy) -5- (4-methylphenyl) isoxazole hydrochloride (Example Compound No. 260)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methylphenyl) -4-isoxazole
3-hydroxy-5- (4-methylphenyl) isoxazole (1.5 g) and 2-((N-tert-butoxycarbonylamino) ethanol (1.5 g) were reacted in the same manner as in Example 9 (a) After working up to give the target compound (2.2 g, 82%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3375, 3356, 3332, 1719, 1684;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 2.40 (3H, s), 3.56 (2H, q, J = 5.1 Hz), 4.35 (2H, t, J = 5.1 Hz), 4.94 (1H , brs), 6.09 (1H, s), 7.26 (2H, d, J = 8.1 Hz).
(b) 3- (2-aminoethoxy) -5- (4-methylphenyl) isoxazole hydrochloride
By post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-methylphenyl) isoxazole (0.3 g) in the same manner as in Example 9 (b), The desired compound (0.16 g, 67%) was obtained as colorless crystals.
Melting point: 215-220 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2993, 2979, 1622;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.37 (3H, s), 3.25 (2H, t, J = 5.0 Hz), 4.44 (2H, t, J = 5.0 Hz), 6.76 (1H, s), 7.35 (2H, d, J = 8.1 Hz), 7.74 (2H, d, J = 8.1 Hz), 8.26 (3H, brs).
Example 28
3- (2-aminoethoxy) -5- (4-trifluoromethylphenyl) isoxazole hydrochloride (Example Compound No. 332)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-trifluoromethylphenyl) isoxazole
3-hydroxy-5- (4-trifluoromethylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.15 g) in the same manner as in Example 9 (a) The reaction product was worked up to give a target compound (0.26 g, 81%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3376, 1679, 1608;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.58 (2H, q, J = 5.1 Hz), 4.37 (2H, t, J = 5.1 Hz), 4.92 (1H, brs), 6.25 (1H , s), 7.72 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.2 Hz).
(b) 3- (2-aminoethoxy) -5- (4-trifluoromethylphenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-trifluoromethylphenyl) isoxazole (0.24 g) was reacted in the same manner as in Example 9 (b), and then By treatment, the desired compound (0.14 g, 70%) was obtained as colorless crystals.
Melting point: 226-232 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2993, 2965, 2914, 1608;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.27 (2H, t, J = 5.1 Hz), 4.47 (2H, t, J = 5.1 Hz), 7.07 (1H, s), 7.93 (2H, d, J = 8.3 Hz), 8.09 (2H, d, J = 8.3 Hz), 8.26 (3H, brs).
Example 29
3- (2-aminoethoxy) -5- (4-fluorophenyl) isoxazole hydrochloride (Example Compound No. 66)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-fluorophenyl) isoxazole
5- (4-fluorophenyl) -3-hydroxyisoxazole (0.06 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.06 g) in the same manner as in Example 9 (a) The reaction was worked up to give the target compound (0.08 g, 74%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3375, 1682;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.56 (2H, q, J = 5.1 Hz), 4.35 (2H, t, J = 5.1 Hz), 4.93 (1H, brs), 6.09 (1H , s), 7.15 (2H, t, J = 8.6 Hz), 7.71 (2H, dd, J = 8.6 Hz, J = 5.3 Hz).
(b) 3- (2-aminoethoxy) -5- (4-fluorophenyl) isoxazole hydrochloride
Post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-fluorophenyl) isoxazole (0.05 g) in the same manner as in Example 9 (b) This resulted in the target compound (0.02 g, 56%) as colorless crystals.
Melting point: 232-238 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2993, 2978, 2911, 1621;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (2H, t, J = 5.0 Hz), 4.44 (2H, t, J = 5.0 Hz), 6.84 (1H, s), 7.40 (2H, t, J = 8.8 Hz), 7.93 (2H, doublet of doublets, J = 8.8 Hz, J = 5.3 Hz), 8.25 (3H, brs).
Example 30
3- (2-aminoethoxy) -5- (1-naphthyl) isoxazole hydrochloride (Example Compound No. 475)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (1-naphthyl) isoxazole
3-hydroxy-5- (1-naphthyl) isoxazole (0.20 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.17 g) were reacted in the same manner as in Example 9 (a) After working up to give the target compound (0.30 g, 89%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3318, 1712;
NMR spectrum (CDCl ₃ ) δ ppm: 1.47 (9H, s), 3.61 (2H, q, J = 5.3 Hz), 4.42 (2H, t, J = 5.3 Hz), 4.97 (1H, brs), 6.25 (1H , s), 7.52-7.61 (3H, m), 7.77-7.79 (1H, m), 7.90-7.99 (2H, m), 8.27-8.31 (1H, m).
(b) 3- (2-aminoethoxy) -5- (1-naphthyl) isoxazole hydrochloride
By post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (1-naphthyl) isoxazole (0.28 g) in the same manner as in Example 9 (b) , Target compound (0.18 g, 78%) was obtained as colorless crystals.
Melting point: 201-205 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3002, 2968, 2913, 1602;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.31 (2H, t, J = 5.1 Hz), 4.52 (2H, t, J = 5.1 Hz), 6.83 (1H, s), 7.63-7.70 (3H, m) , 7.87-7.89 (1 H, m), 8.07-8.25 (3 H, m), 8.30 (3 H, brs).
Example 31
3- (2-aminoethoxy) -4-bromo-5-phenylisoxazole hydrochloride (Example Compound No .: 1357)
(a) 4-bromo-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole
4-Bromo-3-hydroxy-5-phenylisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.15 g) in the same manner as in Example 9 (a) Reaction and post-treatment gave the target compound (0.26 g, 81%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3352, 2976, 1719, 1709;
NMR spectrum (CDCl ₃ ) δ ppm: 1.47 (9H, s), 3.61 (2H, q, J = 5.1 Hz), 4.41 (2H, t, J = 5.1 Hz), 4.97 (1H, brs), 7.47-7.55 (3H, m), 7.98-8.04 (2H, m).
(b) 3- (2-aminoethoxy) -4-bromo-5-phenylisoxazole hydrochloride
Post-treatment by reacting 4-bromo-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.24 g) in the same manner as in Example 9 (b) This resulted in the target compound (0.13 g, 65%) as colorless crystals.
Melting point: 192-198 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2991, 2921, 2894, 1614, 1594, 1574;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.32 (2H, t, J = 5.1 Hz), 4.54 (2H, t, J = 5.1 Hz), 7.60-7.66 (3H, m), 7.95-7.98 (2H, m), 8.19 (3H, broad singlet).
Example 32
3- (2-aminoethoxy) -4-iodine-5-phenylisoxazole hydrochloride (Example Compound No .: 1359)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-iodine-5-phenylisoxazole
3-hydroxy-4-iodine-5-phenylisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.12 g) were reacted in the same manner as in Example 9 (a) After working up to give the target compound (0.22 g, 73%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3328, 2977, 1696;
NMR spectrum (CDCl ₃ ) δ ppm: 1.47 (9H, s), 3.61 (2H, q, J = 5.2 Hz), 4.41 (2H, t, J = 5.2 Hz), 4.97 (1H, brs), 747-7.55 (3H, m), 7.99-8.06 (2H, m).
(b) 3- (2-aminoethoxy) -4-iodine-5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-iodine-5-phenylisoxazole (0.20 g) was reacted in the same manner as in Example 9 (b), and then worked up. , Target compound (0.12 g, 71%) was obtained as colorless crystals.
Melting point: 201-206 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2961, 2912, 1591;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.30 (2H, t, J = 5.3 Hz), 4.51 (2H, t, J = 5.3 Hz), 7.58-7.64 (3H, m), 7.96-8.01 (2H, m), 8.22 (3H, broad singlet).
Example 33
3- (2-aminoethoxy) -5- (4-isopropylphenyl) isoxazole hydrochloride (Example Compound No .: 1618)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-isopropylphenyl) isoxazole
3-hydroxy-5- (4-isopropylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.17 g) in the same manner as in Example 9 (a) The reaction was worked up to give the target compound (0.26 g, 77%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3326, 2973, 1713, 1697, 1623;
NMR spectrum (CDCl ₃ ) δ ppm: 1.27 (6H, d, J = 6.9 Hz), 1.46 (9H, s), 2.95 (1H, qq, J = 6.9 Hz, J = 6.9 Hz), 3.56 (2H, q , J = 5.1 Hz), 4.35 (2H, t, J = 5.1 Hz), 4.94 (1H, brs), 6.09 (1H, s), 7.31 (2H, d, J = 8.3 Hz), 7.65 (2H, d , J = 8.3 Hz).
(b) 3- (2-aminoethoxy) -5- (4-isopropylphenyl) isoxazole hydrochloride
Post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-isopropylphenyl) isoxazole (0.25 g) in the same manner as in Example 9 (b) By this, the target compound (0.11 g, 55%) was obtained as colorless crystals.
Melting point: 162-166 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 3000, 2959, 2924, 1623, 1604;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.23 (6H, d, J = 6.9 Hz), 2.96 (1H, qq, J = 6.9 Hz, J = 6.9 Hz), 3.26 (2H, t, J = 5.1 Hz ), 4.44 (2H, t, J = 5.1 Hz), 6.77 (1H, s), 7.41 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz), 8.20 (3H, brs ).
Example 34
3- (2-aminoethoxy) -5- (2-methylphenyl) isoxazole hydrochloride (Example Compound No. 224)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methylphenyl) isoxazole
3-hydroxy-5- (2-methylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.2 g) were reacted in the same manner as in Example 9 (a). After workup, the target compound (0.31 g, 86%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3315, 1710, 1619;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 2.49 (3H, s), 3.57 (2H, q, J = 5.2 Hz), 4.37 (2H, t, J = 5.2 Hz), 4.95 (1H , brs), 6.06 (1H, s), 7.19-7.39 (3H, m), 7.65-7.69 (1H, m).
(b) 3- (2-aminoethoxy) -5- (2-methylphenyl) isoxazole hydrochloride
By post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-methylphenyl) isoxazole (0.30 g) in the same manner as in Example 9 (b), The desired compound (0.18 g, 75%) was obtained as colorless crystals.
Melting point: 165-167 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 2996, 2976, 2911, 1613;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.46 (3H, s), 3.26 (2H, t, J = 5.2 Hz), 4.46 (2H, t, J = 5.2 Hz), 6.59 (1H, s), 7.34 -7.46 (3H, m), 7.67-7.69 (1H, m), 8.21 (3H, brs).
Example 35
3- (2-aminoethoxy) -5- (4-phenylphenyl) isoxazole hydrochloride (Example Compound No .: 368)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenylphenyl) isoxazole
Reacting 3-hydroxy-5- (4-phenylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.15 g) in the same manner as in Example 9 (a) After work-up, the desired compound (0.22 g, 69%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3345, 1694;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.58 (2H, q, J = 5.1 Hz), 4.37 (2H, t, J = 5.1 Hz), 4.95 (1H, brs), 6.18 (1H , s), 7.37-7.51 (3H, m), 7.61-7.70 (4H, m), 7.79-7.82 (2H, m).
(b) 3- (2-aminoethoxy) -5- (4-phenylphenyl) isoxazole hydrochloride
By post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenylphenyl) isoxazole (0.2 g) in the same manner as in Example 9 (b) , Target compound (0.1 g, 63%) was obtained as colorless crystals.
Melting point: 212-218 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2996, 2966, 2909, 1619, 1602;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.27 (2H, t, J = 5.1 Hz), 4.46 (2H, t, J = 5.1 Hz), 6.90 (1H, s), 7.41-7.55 (3H, m) , 7.74-7.76 (2H, m), 7.84-7.87 (2H, m), 7.94-7.96 (2H, m), 8.18 (3H, brs).
Example 36
3- (2-aminoethoxy) -5- (4-phenoxyphenyl) isoxazole hydrochloride (Example Compound No .: 1632)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenoxyphenyl) isoxazole
3-hydroxy-5- (4-phenoxyphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.14 g) in the same manner as in Example 9 (a) By reacting and working up, the target compound (0.23 g, 74%) was obtained as a colorless powder.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3331, 1720;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.56 (2H, q, J = 5.2 Hz), 4.34 (2H, t, J = 5.2 Hz), 4.95 (1H, brs), 6.06 (1H , s), 7.02-7.08 (4H, m), 7.15-7.20 (1H, m), 7.35-7.42 (2H, m), 7.65-7.70 (2H, m).
(b) 3- (2-aminoethoxy) -5- (4-phenoxyphenyl) isoxazole hydrochloride
Post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-phenoxyphenyl) isoxazole (0.18 g) in the same manner as in Example 9 (b) This resulted in the target compound (0.1 g, 67%) as colorless crystals.
Melting point: 207-213 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3000, 2959, 2909, 1625;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (2H, t, J = 5.1 Hz), 4.43 (2H, t, J = 5.1 Hz), 6.76 (1H, s), 7.10-7.14 (4H, m) , 7.21-7.25 (1H, m), 7.44-7.48 (2H, m), 7.85-7.88 (2H, m), 8.18 (3H, brs).
Example 37
3- (2-aminoethoxy) -5- (2-trifluoromethylphenyl) isoxazole hydrochloride (Example compound number: 296)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-trifluoromethylphenyl) isoxazole
3-hydroxy-5- (2-trifluoromethylphenyl) isoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.23 g) in the same manner as in Example 9 (a) The reaction product was worked up to give a target compound (0.36 g, 74%) as a colorless oily substance.
IR spectrum (KBr) ν max cm ⁻¹ : 3457, 2983, 1712;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.58 (2H, q, J = 5.2 Hz), 4.37 (2H, t, J = 5.2 Hz), 4.96 (1H, brs), 6.21 (1H , s), 7.56-7.69 (2H, m), 7.75-7.82 (2H, m).
(b) 3- (2-aminoethoxy) -5- (2-trifluoromethylphenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-trifluoromethylphenyl) isoxazole (0.35 g) was reacted in the same manner as in Example 9 (b), and then By treatment, the desired compound (0.22 g, 76%) was obtained as colorless crystals.
Melting point: 118-122 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2996, 2917, 1622;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.28 (2H, t, J = 5.1 Hz), 4.46 (2H, t, J = 5.1 Hz), 6.63 (1H, s), 7.79-7.89 (3H, m) , 7.96-7.98 (1 H, m), 8.22 (3 H, brs).
Example 38
3- (2-aminoethoxy) -5- (4-hydroxyphenyl) isoxazole hydrochloride (Example Compound No .: 1674)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole
3-hydroxy-5- (4-hydroxyphenyl) isoxazole (0.1 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.1 g) in the same manner as in Example 9 (a) The reaction was worked up to give the target compound (0.12 g, 67%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3331, 3247, 1698, 1666, 1645, 1619;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.38 (9H, s), 3.32 (2H, q, J = 5.6 Hz), 4.17 (2H, t, J = 5.6 Hz), 6.53 (1H, s), 6.87 (2H, d, J = 8.8 Hz), 7.05 (1H, brs), 7.63 (2H, d, J = 8.8 Hz), 8.98 (1H, brs).
(b) 3- (2-aminoethoxy) -5- (4-hydroxyphenyl) isoxazole hydrochloride
Post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole (0.12 g) in the same manner as in Example 9 (b) This resulted in the target compound (0.05 g, 56%) as colorless crystals.
Melting point: 240-245 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3145, 3056, 1620;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.24 (2H, t, J = 5.1 Hz), 4.41 (2H, t, J = 5.1 Hz), 6.58 (1H, s), 6.90 (2H, d, J = 8.7 Hz), 7.67 (2H, d, J = 8.7 Hz), 8.13 (3H, brs).
Example 39
3- (2-aminoethoxy) -5- (2,4-dichlorophenyl) isoxazole hydrochloride (Example compound number: 170)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) isoxazole
5- (2,4-dichlorophenyl) -3-hydroxyisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.17 g) in the same manner as in Example 9 (a) The reaction product was worked up to give a target compound (0.26 g, 81%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3386, 1681, 1606;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.57 (2H, q, J = 5.2 Hz), 4.37 (2H, t, J = 5.2 Hz), 4.94 (1H, brs), 6.58 (1H , s), 7.38 (1H, dd, J = 8.5 Hz, J = 2.1 Hz), 7.53 (1H, d, J = 2.1 Hz), 7.85 (1H, d, J = 8.5 Hz).
(b) 3- (2-aminoethoxy) -5- (2,4-dichlorophenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) isoxazole (0.24 g) was reacted in the same manner as in Example 9 (b), and then By treatment, the desired compound (0.12 g, 60%) was obtained as colorless crystals.
Melting point: 192-195 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3069, 3005, 2967, 1611;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.27 (2H, t, J = 5.1 Hz), 4.47 (2H, t, J = 5.1 Hz), 6.84 (1H, s), 7.64 (1H, dd, J = 8.7 Hz, J = 2.1 Hz), 7.89 (1H, d, J = 2.1 Hz), 7.90 (1H, d, J = 8.7 Hz), 8.20 (3H, brs).
Example 40
3- (2-aminoethoxy) -5- (3,4-dichlorophenyl) isoxazole hydrochloride (Example Compound No .: 1604)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3,4-dichlorophenyl) isoxazole
5- (3,4-dichlorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.23 g) in the same manner as in Example 9 (a) After the reaction was carried out to give a target compound (0.41 g, 85%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3369, 1687;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.56 (2H, q, J = 5.1 Hz), 4.35 (2H, t, J = 5.1 Hz), 4.91 (1H, brs), 6.16 (1H , s), 7.54 (2H, s), 7.80 (1H, s).
(b) 3- (2-aminoethoxy) -5- (3,4-dichlorophenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (3,4-dichlorophenyl) isoxazole (0.4 g) was reacted in the same manner as in Example 9 (b), and then By treatment, the desired compound (0.22 g, 67%) was obtained as colorless crystals.
Melting point: 202-210 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2993, 2977, 2915, 1617;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = 5.1 Hz), 7.02 (1H, s), 7.84 (1H, d, J = 8.9 Hz), 7.85 (1H, d, J = 8.9 Hz), 8.17 (4H, brs).
Example 41
3- (2-aminoethoxy) -5- (2,3-dichlorophenyl) isoxazole hydrochloride (Example Compound No .: 1526)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,3-dichlorophenyl) isoxazole
5- (2,3-dichlorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.23 g) in the same manner as in Example 9 (a) The reaction product was reacted with and then worked up to obtain the target compound (0.37 g, 77%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3381, 1688, 1607;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.58 (2H, q, J = 5.1 Hz), 4.37 (2H, t, J = 5.1 Hz), 4.95 (1H, brs), 6.60 (1H , s), 7.34 (1H, t, J = 7.9 Hz), 7.58 (1H, dd, J = 7.9 Hz, J = 1.4 Hz), 7.81 (1H, dd, J = 7.9 Hz, J = 1.4 Hz), 7.81 (1H, doublet of doublets, J = 7.9 Hz, J = 1.4 Hz).
(b) 3- (2-aminoethoxy) -5- (2,3-dichlorophenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,3-dichlorophenyl) isoxazole (0.36 g) was reacted in the same manner as in Example 9 (b), and then By treatment, the desired compound (0.20 g, 67%) was obtained as colorless crystals.
Melting point: 183-186 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3010, 2979, 2908, 1604;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.27 (2H, t, J = 5.1 Hz), 4.48 (2H, t, J = 5.1 Hz), 6.87 (1H, s), 7.57 (1H, t, J = 7.8 Hz), 7.82-7.87 (2H, m), 8.19 (3H, brs).
Example 42
3- (2-aminoethoxy) -5- (2,6-dichlorophenyl) isoxazole hydrochloride (Example Compound No .: 188)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,6-dichlorophenyl) isoxazole
5- (2,6-dichlorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.23 g) in the same manner as in Example 9 (a) The reaction product was worked up to give a target compound (0.31 g, 65%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3358, 1703, 1626;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.58 (2H, q, J = 5.1 Hz), 4.39 (2H, t, J = 5.1 Hz), 4.96 (1H, brs), 6.11 (1H , s), 7.32-7.44 (3H, m).
(b) 3- (2-aminoethoxy) -5- (2,6-dichlorophenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,6-dichlorophenyl) isoxazole (0.16 g) was reacted in the same manner as in Example 9 (b), and then By treatment, the desired compound (0.07 g, 54%) was obtained as colorless crystals.
Melting point: 148-151 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 3005, 2966, 2935, 1631;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.27 (2H, t, J = 5.0 Hz), 4.47 (2H, t, J = 5.0 Hz), 6.69 (1H, s), 7.61-7.71 (3H, m) , 8.15 (3H, broad singlet).
Example 43
3- (2-aminoethoxy) -5- (2,4-difluorophenyl) isoxazole hydrochloride (Example Compound No. 93)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-difluorophenyl) isoxazole
5- (2,4-difluorophenyl) -3-hydroxyisoxazole (0.3 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.27 g) were prepared in Example 9 (a) and By reaction in the same manner and post-treatment, the target compound (0.44 g, 85%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3382, 1694;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.57 (2H, q, J = 5.1 Hz), 4.36 (2H, t, J = 5.1 Hz), 4.93 (1H, brs), 6.30 (1H , s), 6.90-7.05 (2H, m), 7.85-7.94 (1H, m).
(b) 3- (2-aminoethoxy) -5- (2,4-difluorophenyl) isoxazole hydrochloride
Reaction of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-difluorophenyl) isoxazole (0.42 g) in the same manner as in Example 9 (b) After working up, the target compound (0.32 g, 94%) was obtained as colorless crystals.
Melting point: 226-232 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2997, 298O, 2922, 1626;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (2H, t, J = 5.1 Hz), 4.47 (2H, t, J = 5.1 Hz), 6.63 (1H, s), 7.29-7.34 (1H, m) , 7.53-7.59 (1 H, m), 7.94-8.00 (1 H, m), 8.21 (3 H, brs).
Example 44
3- (2-aminoethoxy) -4- (1-chloroethyl) -5-phenylisoxazole hydrochloride (Example Compound No .: 1390)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyethyl) -5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.8 g) was dissolved in tetrahydrofuran (16 mL) and under nitrogen atmosphere at -70 ° C. Butyl lithium (1.6 M hexane solution, 3.7 ml) was added dropwise and stirred for 10 minutes. After dropping acetoaldehyde (0.22 mL), the mixture was stirred for 10 minutes and heated to 0 ° C. The reaction solution was poured into iced water, and the pH of the solution was adjusted to 6 using an aqueous solution of potassium phosphate. After extracting with ethyl acetate, washing the organic layer with saturated brine, and distilling off the solvent under reduced pressure, the residue obtained was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1). , Target compound (0.90 g, 98%) was obtained as a colorless oily substance.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3602, 3459, 2982, 1712;
NMR spectrum (CDCl ₃ ) δ ppm: 1.45 (9H, s), 1.60 (3H, d, J = 6.7 Hz), 2.64 (1H, brs), 3.58 (2H, q, J = 5.0 Hz), 4.39 (2H , t, J = 5.0 Hz), 4.90-5.10 (2H, m), 7.45-7.50 (3H, m), 7.64-7.6 (2H, m).
(b) 3- (2-aminoethoxy) -4- (1-chloroethyl) -5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyethyl) -5-phenylisoxazole (0.2 g) in the same manner as in Example 1 (b) The reaction product was reacted with and then worked up to obtain target compound (0.13 g, 75%) as colorless crystals.
Melting point: 200-204 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2975, 1640;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.86 (3H, d, J = 7.0 Hz), 3.27 (2H, t, J = 5.2 Hz), 4.52 (2H, t, J = 5.2 Hz), 5.46 (1H , q, J = 7.0 Hz), 7.60-7.68 (3H, m), 7.71-7.77 (2H, m), 8.20 (3H, brs).
Example 45
4-acetyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (Example Compound No .: 1410)
(a) 4-acetyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyethyl) -5-phenylisoxazole (0.3 g) was dissolved in methylene chloride (3 mL) Pyridium dichromate (0.49 g) was added at room temperature, and it stirred at the same temperature for 24 hours. After completion of the reaction, the insolubles were filtered off, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain the target compound ( 0.26 g, 87%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3359, 1685;
NMR spectrum (CDCl ₃ ) δ ppm: 1.47 (9H, s), 2.51 (3H, s), 3.65 (2H, q, J = 5.2 Hz), 4.48 (2H, t, J = 5.2 Hz), 4.87 (1H , brs), 7.40-7.63 (3H, m), 7.93-7.96 (2H, m).
(b) 4-acetyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride
By reacting 4-acetyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.2 g) in the same manner as in Example 9 (b), , Target compound (0.12 g, 75%) was obtained as colorless crystals.
Melting point: 150-152 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3006, 2909, 1682;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.52 (3H, s), 3.35 (2H, t, J = 5.0 Hz), 4.59 (2H, t, J = 5.0 Hz), 7.54-7.64 (3H, m) , 7.85-7.88 (2H, m), 8.30 (3H, brs).
Example 46
3- (2-aminoethoxy) -4-isopropenyl-5-phenylisoxazole hydrochloride (Example Compound No .: 1394)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisopropyl) -5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.8 g) was dissolved in tetrahydrofuran (16 mL) and under nitrogen atmosphere at -70 ° C. Butyl lithium (1.6 M hexane solution, 3.7 ml) was added dropwise, followed by stirring for 10 minutes at the same temperature. Subsequently, acetone (0.3 ml) was added dropwise, the mixture was stirred for 10 minutes, and then heated to 0 ° C. The reaction solution was poured into iced water, the pH of the solution was adjusted to 6 using aqueous potassium phosphate solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. Was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give the target compound (0.42 g, 44%) as a colorless oily substance.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3460, 2982, 2936, 1713;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.50 (6H, s), 2.52 (1H, brs), 3.60 (2H, q, J = 5.3 Hz), 4.41 (2H, t, J = 5.3 Hz), 4.87 (1 H, brs), 7.41-7.49 (3H, m), 7.52-7.56 (2H, m).
(b) 3- (2-aminoethoxy) -4-isopropenyl-5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisopropyl) -5-phenylisoxazole (0.13 g) was added to 4N hydrochloric acid / 1,4- It was dissolved in dioxane solution (10 mL) and stirred at 100 degreeC for 1 hour. After completion of the reaction, the reaction solution was allowed to cool, and then the solvent was distilled off under reduced pressure, and the residue obtained was washed with ethyl acetate to obtain the target compound (0.10 g, 83%) as colorless crystals.
Melting point: 130-133 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2974, 1591, 1572;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.95 (3H, s), 3.28 (2H, t, J = 5.2 Hz), 4.48 (2H, t, J = 5.2 Hz), 5.23 (1H, s), 5.33 (1H, s), 7.53-7.58 (3H, m), 7.62-7.71 (2H, m), 8.20 (3H, brs).
Example 47
3- (2-aminoethoxy) -5- (4-nitrophenyl) isoxazole hydrochloride (Example Compound No .: 1660)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-nitrophenyl) isoxazole
3-hydroxy-5- (4-nitrophenyl) isoxazole (0.64 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.55 g) were reacted in the same manner as in Example 9 (a) After working up to give the target compound (0.86 g, 80%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3385, 1681;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.57 (2H, q, J = 5.2H), 4.38 (2H, t, J = 5.2 Hz), 4.90 (1H, brs), 6.33 (1H , s), 7.90 (2H, d, J = 8.6 Hz), 8.33 (2H, d, J = 8.6 Hz).
(b) 3- (2-aminoethoxy) -5- (4-nitrophenyl) isoxazole hydrochloride
By reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy-5- (4-nitrophenyl) isoxazole (0.28 g) in the same manner as in Example 9 (b), and post-treatment, The desired compound (0.12 g, 52%) was obtained as colorless crystals.
Melting point: 216-220 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2994, 2977, 2913, 1620, 1608;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.28 (2H, t, J = 5.1 Hz), 4.47 (2H, t, J = 5.1 Hz), 7.16 (1H, s), 8.15 (2H, d, J = 8.9 Hz), 8.22 (3H, broad singlet), 8.39 (2H, d, J = 8.9 Hz).
Example 48
3- (2-aminoethoxy) -5- (4-aminophenyl) isoxazole dihydrochloride (Example Compound No .: 1702)
(a) 5- (4-aminophenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-nitrophenyl) isoxazole (0.55 g) was dissolved in a mixed solvent of acetic acid and water (9: 1, 5.5 mL). After adding zinc powder (0.55 g) at room temperature, the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the zinc powder was filtered off, the filtrate was extracted with ethyl acetate, and then the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain the target compound (0.45 g, 90%). Obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3391, 3378, 3300, 1712, 1615;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.55 (2H, q, J = 5.1 Hz), 4.00 (2H, brs), 4.33 (2H, t, J = 5.1 Hz), 4.96 (1H , brs), 5.94 (1H, s), 6.70 (2H, d, J = 8.7 Hz), 7.52 (2H, d, J = 8.7 Hz).
(b) 3- (2-aminoethoxy) -5- (4-aminophenyl) isoxazole dihydrochloride
By post-treatment by reacting 5- (4-aminophenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.25 g) in the same manner as in Example 9 (b) , Target compound (0.15 g, 65%) was obtained as colorless crystals.
Melting point: 242-248 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3039, 2939, 2584, 1625, 1597;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.25 (2H, t, J = 5.0 Hz), 4.21 (2H, brs), 4.42 (2H, t, J = 5.0 Hz), 6.56 (1H, s), 6.94 (2H, d, J = 8.3 Hz), 7.65 (2H, d, J = 8.3 Hz), 8.25 (3H, brs).
Example 49
3- (2-aminoethoxy) -5- (4-benzoylaminophenyl) isoxazole hydrochloride (Example Compound No .: 1716)
(a) 5- (4-benzoylaminophenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole
5- (4-aminophenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.1 g) was dissolved in tetrahydrofuran (1 mL), under nitrogen atmosphere, Triethylamine (0.05 mL), and then benzoyl chloride (0.04 mL) were dripped at 5 degreeC, and it stirred at room temperature for 30 minutes. The reaction solution was poured into iced water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to obtain the target compound (0.08 g, 62%). Obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3375, 1712;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.57 (2H, q, J = 5.1 Hz), 4.35 (2H, t, J = 5.1 Hz), 4.96 (1H, brs), 6.12 (1H , s), 7.52-7.61 (3H, m), 7.72-7.80 (4H, m), 7.87-7.95 (3H, m).
(b) 3- (2-aminoethoxy) -5- (4-benzoylaminophenyl) isoxazole hydrochloride
Post-treatment by reacting 5- (4-benzoylaminophenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.07 g) in the same manner as in Example 9 (b) This resulted in the title compound (0.04 g, 68%) as colorless crystals.
Melting point: 242-248 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3322, 2959, 2910, 1645, 1621;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.26 (2H, t, J = 5.1 Hz), 4.44 (2H, t, J = 5.1 Hz), 6.75 (1H, s), 7.53-7.65 (3H, m) , 7.83-8.00 (6H, m), 8.20 (3H, brs), 10.55 (1H, s).
Example 50
3- (2-aminoethoxy) -5- (2,4-dichloro-3-methylphenyl) isoxazole hydrochloride (Example Compound No .: 1576)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3-methylphenyl) isoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) isoxazole (0.3 g) and methyl iodide (0.08 mL) were used in Example 14 (a) After the reaction in the same manner as in the post-treatment, the target compound (0.14 g, 45%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3342, 1710;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 2.56 (3H, s), 3.58 (2H, q, J = 5.1 Hz), 7.38 (2H, t, J = 5.1 Hz), 4.95 (1H , brs), 6.54 (1H, s), 7.39 (1H, d, J = 8.5 Hz), 7.76 (1H, d, J = 8.5 Hz).
(b) 3- (2-aminoethoxy) -5- (2,4-dichloro-3-methylphenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3-methylphenyl) isoxazole (0.13 g) in the same manner as in Example 9 (b) The reaction was worked up to give the target compound (0.06 g, 55%) as colorless crystals.
Melting point: 197-200 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3130, 2969, 2897, 1607;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.52 (3H, s), 3.27 (2H, t, J = 5.1 Hz), 4.47 (2H, t, J = 5.1 Hz), 6.82 (1H, s), 7.65 (1H, d, J = 8.5 Hz), 7.71 (1H, d, J = 8.5 Hz), 8.17 (3H, brs).
Example 51
3- (2-aminoethoxy) -5- (2,4-dichloro-3-ethylphenyl) isoxazole hydrochloride (Example Compound No .: 1590)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3-ethylphenyl) isoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) isoxazole (0.3 g) and ethyl iodide (0.1 mL) were used in Example 14 (a) After the reaction in the same manner as in the post-treatment, the target compound (0.25 g, 78%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3342, 1702;
NMR spectrum (CDCl ₃ ) δ ppm: 1.21 (3H, t, J = 7.5 Hz), 1.46 (9H, s), 3.05 (2H, q, J = 7.5 Hz), 3.57 (2H, q, J = 5.1 Hz ), 4.36 (2H, t, J = 5.1 Hz), 4.94 (1H, brs), 6.54 (1H, s), 7.40 (1H, d, J = 8.5 Hz), 7.65 (1H, d, J = 8.5 Hz ).
(b) 3- (2-aminoethoxy) -5- (2,4-dichloro-3-ethylphenyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichloro-3-ethylphenyl) isoxazole (0.23 g) in the same manner as in Example 9 (b) The reaction product was worked up to give a target compound (0.14 g, 74%) as colorless crystals.
Melting point: 173-176 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 2970, 2935, 2876, 1608;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.16 (3H, t, J = 7.4 Hz), 3.00 (2H, q, J = 7.4 Hz), 3.27 (2H, t, J = 5.1 Hz), 4.47 (2H , t, J = 5.1 Hz), 6.82 (1H, s), 7.65 (1H, d, J = 8.4 Hz), 7.70 (1H, d, J = 8.4 Hz), 8.21 (3H, brs).
Example 52
5- (4-acetoxyphenyl) -3- (2-aminoethoxy) isoxazole hydrochloride (Example Compound No .: 1688)
(a) 5- (4-acetoxyphenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole (0.15 g) was dissolved in tetrahydrofuran (1.5 mL) and under nitrogen atmosphere. Triethylamine (0.07 mL) and then acetyl chloride (0.04 mL) were dripped at 5 degreeC, and it stirred at room temperature for 30 minutes. The reaction solution was poured into iced water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain the target compound (0.12 g, 71%). Obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3345, 1696;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 2.33 (3H, s), 3.56 (2H, q, J = 5.2 Hz), 4.35 (2H, t, J = 5.2 Hz), 4.94 (1H , brs), 6.12 (1H, s), 7.20 (2H, d, J = 8.8 Hz), 7.74 (2H, d, J = 8.8 Hz).
(b) 5- (4-acetoxyphenyl) -3- (2-aminoethoxy) isoxazole hydrochloride
Post-treatment by reacting 5- (4-acetoxyphenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.1 g) in the same manner as in Example 9 (b) This resulted in the title compound (0.05 g, 63%) as colorless crystals.
Melting point: 202-212 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 2996, 2977, 2912, 1755, 1621;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.30 (3H, s), 3.26 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = 5.1 Hz), 6.84 (1H, s), 7.32 (2H, d, J = 8.6 Hz), 7.91 (2H, d, J = 8.6 Hz), 8.22 (3H, brs).
Example 53
3- (2-aminoethoxy) -5- (4-benzyloxyphenyl) isoxazole hydrochloride (Example Compound No .: 1646)
(a) 5- (4-benzyloxyphenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-hydroxyphenyl) isoxazole (0.2 g) is dissolved in dimethylformamide (2 mL) and under nitrogen atmosphere. 55% sodium hydride (oily, 0.03 g) was added at 5 ° C, and stirred for 10 minutes at the same temperature. Subsequently, benzyl bromide (0.08 ml) was added dropwise and stirred at room temperature for 30 minutes. The reaction solution was poured into iced water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to obtain the target compound (0.14 g, 54%). Obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3338, 1698;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.56 (2H, q, J = 5.0 Hz), 4.34 (2H, t, J = 5.0 Hz), 4.94 (1H, brs), 5.12 (2H , s), 6.02 (1H, s), 7.04 (2H, d, J = 8.7 Hz), 7.28-7.47 (5H, m), 7.66 (2H, d, J = 8.7 Hz).
(b) 3- (2-aminoethoxy) -5- (4-benzyloxyphenyl) isoxazole hydrochloride
Post-treatment by reacting 5- (4-benzyloxyphenyl) -3- (2- (N-tert-butoxycarbonylamino) ethoxy) isoxazole (0.13 g) in the same manner as in Example 9 (b) This resulted in the title compound (0.07 g, 64%) as colorless crystals.
Melting point: 205-210 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2997, 2966, 2912, 1621, 1604;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.25 (2H, t, J = 5.1 Hz), 4.43 (2H, t, J = 5.1 Hz), 5.19 (2H, s), 6.69 (1H, s), 7.17 (2H, d, J = 9.0 Hz), 7.33-7.48 (5H, m), 7.79 (2H, d, J = 9.0 Hz), 8.21 (3H, brs).
Example 54
3- (2-aminoethoxy) -5- (2-furyl) -4-isopropylisoxazole hydrochloride (Example Compound No. 510)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-furyl) -4-isopropylisoxazole
5- (2-furyl) -3-hydroxy-4-isopropylisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.18 g) were prepared in Example 9 (a). After the reaction in the same manner as in the post-treatment, the target compound (0.29 g, 83%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3317, 2985, 1690;
NMR spectrum (CDCl ₃ ) δ ppm: 1.28 (6H, d, J = 7.2 Hz), 1.46 (9H, s), 3.33 (1H, qq, J = 7.2 Hz, J = 7.2 Hz), 3.58 (2H, q , J = 5.1Hz), 4.35 (2H, t, J = 5.1Hz), 4.84 (1H, brs), 6.52 (1H, dd, J = 3.4Hz, J = 1.8Hz), 6.80 (1H, d, J = 3.4 Hz), 7.55 (1H, d, J = 1.8 Hz).
(b) 3- (2-aminoethoxy) -5- (2-furyl) -4-isopropylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-furyl) -4-isopropylisoxazole (0.27 g) in the same manner as in Example 1 (b) The reaction was worked up to give the target compound (0.17 g, 77%) as colorless crystals.
Melting point: 137-139 캜;
IR spectrum (KBr) ν max cm ⁻¹ : 2972, 2898, 1560, 1513;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (6H, d, J = 7.0 Hz), 3.24 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.28 (2H, t, J = 5.2 Hz ), 4.44 (2H, t, J = 5.2 Hz), 6.73 (1H, dd, J = 3.4 Hz, J = 1.8 Hz), 7.01 (1H, d, J = 3.4 Hz), 7.97 (1H, d, J = 1.8 Hz), 8.21 (3H, br s).
Example 55
3- (2-Aminoethoxy) -4- (tert-butyl) -5-phenylisoxazole hydrochloride (Example Compound No. 13)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (tert-butyl) -5-phenylisoxazole
4- (tert-butyl) -3-hydroxy-5-phenylisoxazole (0.15 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.12 g) were prepared in Example 9 (a) and By reaction in the same manner and post-treatment, the target compound (0.16 g, 64%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3374, 2974, 1683;
NMR spectrum (CDCl ₃ ) δ ppm: 1.18 (9H, s), 1.46 (9H, s), 3.60 (2H, q, J = 5.2 Hz), 4.38 (2H, t, J = 5.2 Hz), 4.85 (1H , brs), 7.36-7.55 (5H, m).
(b) 3- (2-aminoethoxy) -4- (tert-butyl) -5-phenylisoxazole hydrochloride
Reaction of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (tert-butyl) -5-phenylisoxazole (0.14 g) in the same manner as in Example 1 (b) After working up, the target compound (0.09 g, 82%) was obtained as colorless crystals.
Melting point: 230-234 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2961, 2910, 2890, 1516;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.16 (9H, s), 3.30 (2H, t, J = 5.3 Hz), 4.46 (2H, t, J = 5.3 Hz), 7.44-7.57 (5H, m) , 8.20 (3H, broad singlet).
Example 56
3- (2-Aminoethoxy) -4-cyclopropyl-5-phenylisoxazole hydrochloride (Example Compound No .: 1400)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopropyl-5-phenylisoxazole
4-cyclopropyl-3-hydroxy-5-phenylisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.18 g) in the same manner as in Example 9 (a) The reaction was worked up to give the target compound (0.25 g, 74%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3369, 1692, 1536, 1520;
NMR spectrum (CDCl ₃ ) δ ppm: 0.66-0.75 (2H, m), 0.88-0.95 (2H, m), 1.46 (9H, s), 1.67-1.73 (1H, m), 3.58 (2H, q, J = 5.1 Hz), 4.35 (2H, t, J = 5.1 Hz), 4.90 (1H, brs), 7.40-7.51 (3H, m), 7.84-7.87 (2H, m).
(b) 3- (2-aminoethoxy) -4-cyclopropyl-5-phenylisoxazole hydrochloride
Post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopropyl-5-phenylisoxazole (0.15 g) in the same manner as in Example 1 (b) This resulted in the target compound (0.06 g, 49%) as colorless crystals.
Melting point: 180-182 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 2919, 2851, 1713, 1519;
NMR spectrum (DMSO-d ₆ ) δ ppm: 0.68-0.76 (2H, m), 0.83-0.92 (2H, m), 1.71-1.78 (1H, m), 3.27 (2H, t, J = 5.2 Hz), 4.44 (2H, t, J = 5.2 Hz), 7.51-7.60 (3H, m), 7.83-7.86 (2H, m), 8.20 (3H, brs).
Example 57
3- (2-aminoethoxy)-5- (2,4-dichlorophenyl) -4-isopropylisoxazole hydrochloride (Example Compound No. 176)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) -4-isopropylisoxazole
Example 9 of 5- (2,4-dichlorophenyl) -3-hydroxy-4-isopropylisoxazole (0.06 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.04 g) After the reaction was carried out in the same manner as in (a), the target compound (0.078 g, 86%) was obtained as a colorless oily substance.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3460, 2975, 2936, 1713;
NMR spectrum (CDCl ₃ ) δ ppm: 1.18 (6H, d, J = 7.0 Hz), 1.46 (9H, s), 2.69 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.59 (2H, q , J = 5.2 Hz), 4.38 (2H, t, J = 5.2 Hz), 4.85 (1H, brs), 7.30 (1H, d, J = 8.3 Hz), 7.35 (1H, dd, J = 8.3 Hz, J = 1.9 Hz), 7.52 (1H, d, J = 1.9 Hz).
(b) 3- (2-aminoethoxy-5- (2,4-dichlorophenyl) -4-isopropylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-dichlorophenyl) -4-isopropylisoxazole (0.07 g) was prepared in Example 1 (b) and By reaction in the same manner and post-treatment, the target compound (0.04 g, 68%) was obtained as colorless crystals.
Melting point: 171-173 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 2968, 2934, 2875, 1514;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.13 (6H, d, J = 7.0 Hz), 2.69 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.29 (2H, t, J = 5.3 Hz ), 4.46 (2H, t, J = 5.3 Hz), 7.56 (1H, d, J = 8.5 Hz), 7.62 (1H, dd, J = 8.5 Hz, J = 2.0 Hz), 7.89 (1H, d, J = 2.0 Hz), 8.18 (3H, br s).
Example 58
3- (2-aminoethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole hydrochloride (Example Compound No. 117)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole
5- (2-chlorophenyl) -3-hydroxy-4-isopropylisoxazole (0.13 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.1 g) were prepared in Example 9 (a Reaction and post-treatment were carried out in the same manner as) to obtain the target compound (0.15 g, 72%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3382, 2974, 1691;
NMR spectrum (CDCl ₃ ) δ ppm: 1.18 (6H, d, J = 6.9 Hz), 1.46 (9H, s), 2.71 (1H, qq, J = 6.9 Hz, J = 6.9 Hz), 3.60 (2H, q , J = 5.2 Hz), 4.39 (2H, t, J = 5.2 Hz), 4.87 (1H, brs), 7.34-7.51 (4H, m).
(b) 3- (2-aminoethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole (0.13 g) in the same manner as in Example 1 (b) The reaction product was worked up to give a target compound (0.08 g, 73%) as colorless crystals.
Melting point: 143-145 캜;
IR spectrum (KBr) ν max cm ⁻¹ : 2970, 2937, 2896, 2879, 1513;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.13 (6H, d, J = 7.0 Hz), 3.69 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.29 (2H, t, J = 5.2 Hz ), 4.47 (2H, t, J = 5.2 Hz), 7.50-7.68 (4H, m), 8.24 (3H, brs).
Example 59
3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole hydrochloride (Example Compound No. 151)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole
5- (4-chlorophenyl) -3-hydroxy-4-isopropylisoxazole (0.15 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.11 g) were prepared in Example 9 (a Reaction and post-treatment were carried out in the same manner as) to obtain the target compound (0.19 g, 79%) as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3382, 2966, 1685;
NMR spectrum (CDCl ₃ ) δ ppm: 1.29 (6H, d, J = 7.0 Hz), 1.46 (9H, s), 3.03 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.59 (2H, q , J = 5.1 Hz), 4.36 (2H, t, J = 5.1 Hz), 7.44 (2H, d, J = 8.7 Hz), 7.52 (2H, d, J = 8.7 Hz).
(b) 3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole (0.18 g) in the same manner as in Example 1 (b) The reaction product was worked up to give a target compound (0.12 g, 80%) as colorless crystals.
Melting point: 224-227 캜;
IR spectrum (KBr) ν max cm ⁻¹ : 2971, 2919, 2851, 1639;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.26 (6H, d, J = 7.0 Hz), 3.02 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.28 (2H, t, J = 5.3 Hz ), 4.45 (2H, t, J = 5.3 Hz), 7.62 (2H, d, J = 9.0 Hz), 7.63 (2H, d, J = 9.0 Hz), 8.18 (3H, brs).
Example 60
4-allyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (Example Compound No .: 1392)
(a) 4-allyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole
4-allyl-3-hydroxy-5-phenylisoxazole (1.00 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.96 g) were reacted in the same manner as in Example 1 (a) After working up, the target compound (1.57 g, 91%) was obtained as colorless crystals.
Melting point: 78-79 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3327, 1708, 1644, 1526, 1518;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.27-3.29 (2H, m), 3.57 (2H, q, J = 5.1 Hz), 4.38 (2H, t, J = 5.1 Hz), 4.90 (1H, brs), 5.05-5.15 (2H, m), 5.91-6.01 (1H, m), 7.41-7.49 (3H, m), 7.63-7.68 (2H, m).
(b) 4-allyl-3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride
4-allyl-3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (200 mg) was reacted in the same manner as in Example 1 (b) to post-treat , Target compound (160 mg, 98%) was obtained as colorless crystals.
Melting point: 95-96 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 2967, 2912, 2885, 2817, 2694, 1643, 1601, 1577, 1514, 1495;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.25-3.30 (2H, m), 3.35 (2H, t, J = 5.1 Hz), 4.46 (2H, t, J = 5.1 Hz), 5.03-5.09 (2H, m), 5.91-6.00 (1H, m), 7.52-7.58 (3H, m), 7.67-7.70 (2H, m), 8.20 (3H, brs).
Example 61
3- (2-aminoethoxy) -5-phenyl-4-propargyl soxazole hydrochloride (Example Compound No .: 1398)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl-4-propargyl soxazole
3-hydroxy-5-phenyl-4-propargyl soxazole (1.00 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.96 g) were prepared in the same manner as in Example 1 (a). By reacting and post-treatment, the target compound (1.44 g, 84%) was obtained as a colorless oily substance.
IR spectrum (KBr) ν max cm ⁻¹ : 3352, 3302, 1711, 1643, 1600, 1577, 1520, 1499;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 2.09 (1H, t, J = 2.8 Hz), 3.43 (2H, d, J = 2.8 Hz), 3.60 (2H, q, J = 5.1 Hz ), 4.41 (2H, t, J = 5.1 Hz), 5.02 (1H, brs), 7.45-7.55 (3H, m), 7.74-7.76 (2H, m).
(b) 3- (2-aminoethoxy) -5-phenyl-4-propargyl soxazole hydrochloride
Post-treatment was carried out by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenyl-4-propargyl soxazole (200 mg) in the same manner as in Example 1 (b) This resulted in the target compound (152 mg, 94%) as colorless crystals.
Melting point: 210-212 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 3258, 2959, 2899, 2830, 1632, 1601, 1577, 1523;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.97 (1H, t, J = 2.8 Hz), 3.30 (1H, t, J = 5.1 Hz), 3.59 (2H, d, J = 2.8 Hz), 4.47 (2H , t, J = 5.1 Hz), 7.56-7.62 (3H, m), 7.79-7.82 (2H, m), 8.13 (3H, brs).
Example 62
3- (2-aminoethoxy) -4-isobutyl-5-phenylisoxazole hydrochloride (Example Compound No. 11)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isobutyl-5-phenylisoxazole
3-hydroxy-4-isobutyl-5-phenylisoxazole (217 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193 mg) were prepared in the same manner as in Example 1 (a). The reaction was worked up to give the target compound (303 mg, 84%) as colorless crystals.
Melting point: 80-81 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3377, 1683, 1637, 1516, 1498;
NMR spectrum (CDCl ₃ ) δ ppm: 0.93 (6H, d, J = 6.8 Hz), 1.46 (9H, s), 1.89-1.96 (1H, m), 2.42 (2H, d, J = 7.3 Hz), 3.58 (2H, q, J = 5.1 Hz), 4.37 (2H, t, J = 5.1 Hz), 4.88 (1H, brs), 7.40-7.49 (3H, m), 7.66-7.70 (2H, m).
(b) 3- (2-aminoethoxy) -4-isobutyl-5-phenylisoxazole hydrochloride
Post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isobutyl-5-phenylisoxazole (200 mg) in the same manner as in Example 1 (b) This resulted in the target compound (160 mg, 98%) as colorless crystals.
Melting point: 202-210 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3005, 2957, 2869, 1629, 1601, 1576, 1514, 1495;
NMR spectrum (DMSO-d ₆ ) δ ppm: 0.86 (6H, d, J = 6.8 Hz), 2.47 (2H, d, J = 7.3 Hz), 3.27 (2H, t, J = 5.1 Hz), 4.45 (2H , t, J = 5.1 Hz), 7.49-7.58 (3H, m), 7.70-7.74 (2H, m), 8.19 (3H, brs).
Example 63
3- (2-Aminoethoxy) -4-cyclopentyl-5-phenylisoxazole hydrochloride (Example Compound No .: 1402)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopentyl-5-phenylisoxazole
3-hydroxy-4-cyclopentyl-5-phenylisoxazole (229 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193 mg) were prepared in the same manner as in Example 1 (a). By reacting and post-treatment, the target compound (308 mg, 83%) was obtained as colorless crystals.
Melting point: 112-113 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3391, 1691, 1655, 1643, 1531, 1515;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.56-1.67 (2H, m), 1.71-1.92 (6H, m), 3.03-3.12 (1H, m), 3.58 (2H, q, J = 5.1 Hz), 4.38 (2H, t, J = 5.1 Hz), 4.82 (1H, brs), 7.41-7.49 (3H, m), 7.55-7.61 (2H, m).
(b) 3- (2-aminoethoxy) -4-cyclopentyl-5-phenylisoxazole hydrochloride
Post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-cyclopentyl-5-phenylisoxazole (200 mg) in the same manner as in Example 1 (b) This resulted in the target compound (161 mg, 97%) as colorless crystals.
Melting point: 197-199 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 2954, 2869, 1637, 1599, 1576, 1511, 1490;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.57-1.63 (2H, m), 1.72-1.91 (6H, m), 2.98-3.07 (1H, m), 3.27 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = J = 5.1 Hz), 7.51-7.61 (5H, m), 8.07 (3H, brs).
Example 64
3- (2-aminoethoxy) -4- (2-cyclopentenyl) -5-phenylisoxazole hydrochloride (Example Compound No .: 1404)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (2-cyclopentenyl) -5-phenylisoxazole
3-hydroxy-4- (2-cyclopentenyl) -5-phenylisoxazole (227 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193 mg) were prepared in Example 1 (a). Reaction and post-treatment were carried out in the same manner as) to obtain the target compound (295 mg, 80%) as colorless crystals.
Melting point: 81-82 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3394, 1690, 1636, 1515, 1495;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.88-1.98 (1H, m), 2.24-2.34 (1H, m), 2.39-2.49 (1H, m), 2.52-2.61 (1H, m ), 3.47-3.59 (2H, m), 4.01-4.06 (1H, m), 4.30-4.36 (2H, m), 4.86 (1H, brs), 5.63-5.67 (1H, m), 5.89-5.92 (1H , m), 7.42-7.49 (3H, m), 7.60-7.63 (2H, m).
(b) 3- (2-aminoethoxy) -4- (2-cyclopentenyl) -5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (2-cyclopentenyl) -5-phenylisoxazole (200 mg) in the same manner as in Example 1 (b) The reaction product was reacted with and then worked up to obtain target compound (156 mg, 94%) as colorless crystals.
Melting point: 157-160 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3051, 2954, 2901, 2852, 1635, 1599, 1575, 1516, 1492;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.79-1.99 (1H, m), 2.21-2.41 (2H, m), 2.44-2.53 (1H, m), 3.25 (2H, brs), 3.95-4.02 (1H , m), 4.38-4.48 (2H, m), 5.56-5.71 (1H, m), 5.85-5.89 (1H, m), 7.51-7.57 (3H, m), 7.59-7.63 (2H, m), 8.12 (3H, brs).
Example 65
3- (2-aminoethoxy) -4-pentyl-5-phenylisoxazole hydrochloride (Example Compound No .: 1386)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-pentyl-5-phenylisoxazole
3-hydroxy-4-pentyl-5-phenylisoxazole (231 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193 mg) were reacted in the same manner as in Example 1 (a) After working up, the target compound (305 mg, 82%) was obtained as a colorless oily substance.
IR spectrum (KBr) ν max cm ⁻¹ : 3461, 1713, 1640, 1510, 1496;
NMR spectrum (CDCl ₃ ) δ ppm: 0.89 (3H, t, J = 7.0 Hz), 1.26-1.38 (2H, m), 1.46 (9H, s), 1.49-1.61 (2H, m), 2.52 (2H, t, J = 7.7 Hz), 3.59 (2H, q, J = 5.1 Hz), 4.37 (2H, t, J = 5.1 Hz), 4.89 (1H, brs), 7.40-7.49 (3H, m), 7.64- 7.69 (2 H, m).
(b) 3- (2-aminoethoxy) -4-pentyl-5-phenylisoxazole hydrochloride
By post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-pentyl-5-phenylisoxazole (100 mg) in the same manner as in Example 1 (b) , Target compound (80 mg, 95%) was obtained as colorless crystals.
Melting point: 107-109 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3008, 2955, 2930, 2869, 1641, 1601, 1576, 1566, 1516, 1496;
NMR spectrum (DMSO-d ₆ ) δ ppm: 0.83 (3H, t, J = 7.0 Hz), 1.25-1.30 (4H, m), 1.48-1.56 (2H, m), 2.55 (2H, t, J = 7.7 Hz), 3.28 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = 5.1 Hz), 7.51-7.59 (3H, m), 7.66-7.69 (2H, m), 8.10 (3H, brs ).
Example 66
3- (2-aminoethoxy) -4- (2-butenyl) -5-phenylisoxazole hydrochloride (Example Compound No .: 1396)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (2-butenyl) -5-phenylisoxazole
3-hydroxy-4- (2-butenyl) -5-phenylisoxazole (215 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193 mg) were prepared in Example 1 (a). After the reaction in the same manner as in the post-treatment, the target compound (292 mg, 82%) was obtained as colorless crystals.
Melting point: 62-63 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3378, 1682, 1634, 1514, 1497;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 1.68-1.74 (3H, m), 3.19-3.21 (2H, m), 3.57 (2H, q, J = 5.1 Hz), 4.37 (2H, t, J = 5.1 Hz), 4.89 (1H, brs), 5.46-5.60 (2H, m), 7.40-7.52 (3H, m), 7.64-7.68 (2H, m).
(b) 3- (2-aminoethoxy) -4- (2-butenyl) -5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (2-butenyl) -5-phenylisoxazole (200 mg) in the same manner as in Example 1 (b) By reacting and post-treatment, the target compound (162 mg, 98%) was obtained as colorless crystals.
Melting point: 123-125 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3028, 2961, 2934, 2916, 2855, 1641, 1601, 1577, 1570, 1515, 1494;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.60-1.70 (3H, m), 3.26-3.28 (2H, m), 3.33 (2H, t, J = 5.1 Hz), 4.45 (2H, t, J = 5.1 Hz), 5.43-5.59 (2H, m), 7.50-7.58 (3H, m), 7.65-7.70 (2H, m), 8.10 (3H, brs).
Example 67
3- (2-aminoethoxy) -4-isopropyl-5- (2-thienyl) isoxazole hydrochloride (Example compound number: 543)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (2-thienyl) isoxazole
3-hydroxy-4-isopropyl-5- (2-thienyl) isoxazole (209 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (193 mg) were prepared in Example 1 (a). After the reaction in the same manner as in the post-treatment, the target compound (301 mg, 86%) was obtained as colorless crystals.
Melting point: 94-95 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3325, 1711, 1693, 1635, 1542, 1528, 1508;
NMR spectrum (CDCl ₃ ) δ ppm: 1.29 (6H, d, J = 7.1 Hz), 1.46 (9H, s), 3.19 (1H, m), 3.58 (2H, q, J = 5.1 Hz), 4.36 (2H , t, J = 5.1 Hz), 4.83 (1H, brs), 7.14 (1H, dd, J = 5.3 Hz, J = 3.7 Hz), 7.42 (1H, dd, J = 3.4 Hz, J = 1.4 Hz), 7.46 (1H, doublet, J = 5.3 Hz).
(b) 3- (2-aminoethoxy) -4-isopropyl-5- (2-thienyl) isoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (2-thienyl) isoxazole (200 mg) in the same manner as in Example 1 (b) The reaction was worked up to give the target compound (150 mg, 93%) as colorless crystals.
Melting point: 192-194 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3105, 3087, 2973, 1644, 1579, 1527, 1498;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.27 (6H, d, J = 7.2 Hz), 3.16 (1H, m), 3.28 (2H, t, J = 5.1 Hz), 4.44 (2H, t, J = 5.1 Hz), 7.26 (1H, dd, J = 5.2 Hz, J = 1.4 Hz), 7.54 (1H, dd, J = 4.7 Hz, J = 1.0 Hz), 7.87 (1H, d, J = 5.2 Hz), 8.13 (3H, broad singlet).
Example 68
3- (2-Aminoethoxy) -4-fluoro-5-phenylisoxazole hydrochloride (Example Compound No. 4)
(a) 3-methoxymethoxy-5-phenylisoxazole
3-hydroxy-5-phenylisoxazole (8.05 g) was dissolved in dimethylformamide (80 mL), sodium methoxide (28% methanol solution, 3.24 g) was added, followed by stirring at room temperature for 1 hour. . The reaction solution was cooled to 5 ° C, chloromethylmethyl ether (4.83 g) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into ice water (200 mL), ether extraction (200 mL × 2) was performed, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain the target compound (6.30 g, 61%). Obtained as a colorless oily substance.
IR spectrum (KBr) ν max cm ⁻¹ : 1621, 1596, 1577, 1512;
NMR spectrum (CDCl ₃ ) δ ppm: 3.58 (3H, s), 5.37 (2H, s), 7.40-7.48 (3H, m), 7.71-7.95 (2H, m).
(b) 4-fluoro-3-methoxymethoxy-5-phenylisoxazole
3-methoxymethoxy-5-phenylisoxazole (2.05 g) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to -78 ° C, and then butyllithium (1.68 M hexane solution, 7.1 mL) was added. It was dripped and stirred for 15 minutes at the same temperature. Subsequently, after adding N-fluoro dibenzene sulfonimide (3.15g) and stirring for 15 minutes at the same temperature, the cooling bath was removed and it heated up to room temperature. The reaction solution was added to ice water (200 mL), followed by ether extraction (200 mL x 2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain the target compound (1.78 g, 80%). Obtained as a colorless oily substance.
IR spectrum (KBr) ν max cm ⁻¹ : 1672, 1545;
NMR spectrum (CDCl ₃ ) δ ppm: 3.62 (3H, s), 5.45 (2H, s), 7.43-7.52 (3H, m), 7.70-7.80 (2H, m).
(c) 4-fluoro-3-hydroxy-5-phenylisoxazole
4-fluoro-3-methoxymethoxy-5-phenylisoxazole (0.44 g) was dissolved in 4N hydrochloric acid / dioxane solution (5.0 mL) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure and the crystals obtained were washed with dichloromethane (10 mL) to obtain the target compound (0.30 g, 83%) as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3059, 3014, 2995, 2919, 2851, 2822, 2747, 2645, 2565, 1674, 1582, 1527;
NMR spectrum (DMSO-d ₆ ) δ ppm: 7.51-7.61 (3H, m), 7.73-7.74 (2H, m), 12.6 (1H, brs).
(d) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-fluoro-5-phenylisoxazole
4-fluoro-3-hydroxy-5-phenylisoxazole (100 mg) and 2- (N-tert-butoxycarbonylamino) ethanol (108 mg) were prepared in the same manner as in Example 1 (a). Reaction and post-treatment gave the target compound (132 mg, 73%) as colorless crystals.
Melting point: 103-104 캜;
IR spectrum (KBr) ν max cm ⁻¹ : 3325, 1718, 1667, 1549, 1532;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 3.60 (2H, q, J = 5.1 Hz), 4.41 (2H, t, J = 5.1 Hz), 4.97 (1H, brs), 7.41-7.52 (3H, m), 7.76-7.79 (2H, m).
(e) 3- (2-aminoethoxy) -4-fluoro-5-phenylisoxazole hydrochloride
Post-treatment by reacting 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-fluoro-5-phenylisoxazole (110 mg) in the same manner as in Example 1 (b) This resulted in the target compound (82 mg, 93%) as colorless crystals.
Melting point: 207-211 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2999, 2965, 2909, 2845, 1665, 1602, 1581, 1555, 1532;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.32 (2H, t, J = 5.1 Hz), 4.55 (2H, t, J = 5.1 Hz), 7.55-7.64 (3H, m), 7.75-7.78 (2H, m), 8.17 (3H, broad singlet).
Example 69
3- (2-dimethylaminoethoxy) -5-phenylisoxazole hydrochloride (Example Compound No. 27)
(a) 3- (2-bromoethoxy) -5-phenylisoxazole
Triphenylphosphine (15.7 g) was dissolved in toluene (200 mL), cooled to 5 ° C, and diethyl azodicarboxylate (10.4 g) was added and stirred at the same temperature for 10 minutes. Subsequently, 3-hydroxy-5-phenylisoxazole (8.0 g) and 2-bromoethanol (7.5 g) were sequentially added, followed by stirring at the same temperature for 10 minutes and again at room temperature for 2 hours. The insolubles were filtered off, and then the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain the target compound (12.1 g, 90%). Was obtained as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3148, 1623, 1597, 1576, 1510;
NMR spectrum (CDCl ₃ ) δ ppm: 3.71 (2H, t, J = 5.9 Hz), 4.62 (2H, t, J = 5.9 Hz), 6.19 (1H, s), 7.42-7.49 (3H, m), 7.70 -7.77 (2H, m).
(b) 3- (2-dimethylaminoethoxy) -5-phenylisoxazole
Dimethylamine hydrochloride (815 mg) was dissolved in methanol (50 mL), and then 3- (2-bromoethoxy) -5-phenylisoxazole (268 mg) and triethylamine (2.8 mL) were added to 8 It was heated to reflux for time. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue obtained was dissolved in ether (20 mL), washed with brine (20 mL), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the target compound (146 mg, 63%) as colorless crystals. .
Melting point: 28-29 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 2980, 2951, 1625, 1597, 1577, 1514;
NMR spectrum (CDCl ₃ ) δ ppm: 2.34 (6H, s), 2.75 (2H, t, J = 5.4 Hz), 4.40 (2H, t, J = 5.4 Hz), 6.18 (1H, s), 7.40-7.48 (3H, m), 7.69-7.73 (2H, m).
(c) 3- (2-dimethylaminoethoxy) -5-phenylisoxazole hydrochloride
3- (2-dimethylaminoethoxy) -5-phenylisoxazole (130 mg) was dissolved in dioxane (1.0 mL), tetrahydrochloric acid / dioxane solution (0.2 mL) was added, and then at room temperature. It was left for 15 minutes. The solvent obtained by distilling off under reduced pressure was washed with ethyl acetate (5 ml) to give the target compound (148 mg, 98%) as colorless crystals.
Melting point: 163-164 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3133, 1624, 1597, 1577, 1513;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.84 (6H, s), 3.55 (2H, t, J = 5.0 Hz), 4.61 (2H, t, J = 5.0 Hz), 7.50-7.58 (3H, m) , 7.81-7.87 (2H, m), 10.31 (1H, brs).
Example 70
5-phenyl-3- (2- (1-piperidyl) ethoxy) isoxazole hydrochloride (Example Compound No. 28)
(a) 5-phenyl-3- (2- (1-piperidyl) ethoxy) isoxazole
3- (2-bromoethoxy) -5-phenylisoxazole (268 mg) was dissolved in methanol (1.0 mL), and piperidine (426 mg) was added, followed by heating to reflux for 3 hours. The reaction solution was added to ice water (20 mL), followed by ether extraction (20 mL x 2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the target compound (251 mg, 92%) as colorless crystals. .
Melting point: 75-76 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3149, 1625, 1598, 1577, 1513;
NMR spectrum (CDCl ₃ ) δ ppm: 1.42-1.48 (2H, m), 1.54-1.67 (4H, m), 2.50 (4H, brs), 2.79 (2H, t, J = 5.8 Hz), 4.42 (2H, t, J = 5.8 Hz), 6.16 (1H, s), 7.41-7.48 (3H, m), 7.69-7.75 (2H, m).
(b) 5-phenyl-3- (2- (1-piperidyl) ethoxy) isoxazole hydrochloride
5-phenyl-3- (2-piperidylethoxy) isoxazole (200 mg) was reacted and worked up in the same manner as in Example 1 (b), whereby the target compound (181 mg, 80%) was colorless. Obtained as a crystal.
Melting point: 190-192 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2950, 2938, 1620, 1595, 1576, 1511;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.32-1.44 (2H, m), 1.68-1.86 (4H, m), 2.95-3.04 (2H, m), 3.45-3.58 (4H, m), 4.64 (2H , t, J = 4.7 Hz), 6.87 (1H, s), 7.50-7.58 (3H, m), 7.81-7.85 (2H, m), 9.94-10.05 (1H, brs).
Example 71
5-phenyl-3- (2- (1-pyrrolidinyl) ethoxy) isoxazole hydrochloride (Example Compound No .: 1350)
(a) 5-phenyl-3- (2- (1-pyrrolidinyl) ethoxy) isoxazole
Pyrrolidine (710 mg) was added to 3- (2-bromoethoxy) -5-phenylisoxazole (268 mg), and it stirred at 100 degreeC for 1 hour. Ice water (20 mL) was added to the reaction solution, ether extraction (20 mL × 2) was performed, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the target compound (211 mg, 82%) as colorless crystals. .
Melting point: 61-62 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 1623, 1596, 1575, 1509;
NMR spectrum (CDCl ₃ ) δ ppm: 1.77-1.87 (4H, m), 2.57-2.65 (4H, m), 2.92 (2H, t, J = 5.5 Hz), 4.43 (2H, t, J = 5.5 Hz) , 6.18 (1H, s), 7.40-7.48 (3H, m), 7.69-7.75 (2H, m).
(b) 5-phenyl-3- (2- (1-pyrrolidinyl) ethoxy) isoxazole hydrochloride
5-phenyl-3- (2- (1-pyrrolidinyl) ethoxy) isoxazole (200 mg) was reacted and worked up in the same manner as in Example 1 (b) to give a target compound (211 mg, 93% ) Was obtained as colorless crystals.
Melting point: 182-184 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 2982, 2950, 2884, 2848, 2671, 2653, 2607, 2560, 2480, 1619, 1595, 1511;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.83-2.08 (4H, m), 3.01-3.21 (2H, m), 3.50-3.68 (4H, m), 4.60 (2H, t, J = 5.1 Hz), 6.87 (1H, s), 7.50-7.58 (3H, m), 7.81-7.87 (2H, m), 10.63 (1H, brs).
Example 72
3- (2- (4-morpholinyl) ethoxy) -5-phenylisoxazole hydrochloride (Example Compound No. 29)
(a) 3- (2- (4-morpholinyl) ethoxy) -5-phenylisoxazole
Morpholine (871 mg) was added to 3- (2-bromoethoxy) -5-phenylisoxazole (268 mg), and it stirred at 100 degreeC for 1 hour. Ice water (20 mL) was added to the reaction solution, ether extraction (20 mL × 2) was performed, and the organic layer was dried using anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the target compound (250 mg, 91%) as colorless crystals. It was.
Melting point: 66-67 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3152, 1623, 1596, 1575, 1512;
NMR spectrum (CDCl ₃ ) δ ppm: 2.57 (2H, t, J = 5.4 Hz), 2.82 (2H, t, J = 5.4 Hz), 3.75 (2H, t, J = 5.5 Hz), 4.44 (2H, t , J = 5.5 Hz), 6.17 (1H, s), 7.41-7.50 (3H, m), 7.69-7.76 (2H, m).
(b) 3- (2- (4-morpholinyl) ethoxy) -5-phenylisoxazole hydrochloride
3- (2- (4-morpholinyl) ethoxy) -5-phenylisoxazole (200 mg) was reacted and worked up in the same manner as in Example 1 (b) to give a target compound (202 mg, 89 %) Was obtained as colorless crystals.
Melting point: 180-182 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 2981, 2925, 2897, 2878, 2683, 2646, 2584, 2512, 2469, 2429, 1620, 1595, 1576, 1512;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.10-3.25 (2H, m), 3.40-3.55 (2H, m), 3.55-3.65 (2H, m), 3.70-3.85 (2H, m), 3.90-4.05 (2H, m), 4.67 (2H, brs), 6.86 (1H, s), 7.50-7.58 (3H, m), 7.81-7.87 (2H, m), 10.96 (1H, brs).
Example 73
5-phenyl-3- (2- (1-piperazinyl) ethoxy) isoxazole dihydrochloride (Example Compound No .: 1351)
(a) 3- (2- (4-N-tert-butoxycarbonyl-1-piperazinyl) ethoxy) -5-phenylisoxazole
3- (2-bromoethoxy) -5-phenylisoxazole (268 mg) was dissolved in methanol (1.0 mL), and piperazine (861 mg) was added, followed by heating to reflux for 3 hours. The reaction solution was added to a diluted saline solution (40 mL), followed by dichloromethane extraction (40 mL x 2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue obtained was dissolved in dichloromethane (5 mL), di-tert-butyldicarbonate (1.09 g) was added, and stirred at room temperature for 30 minutes. After the completion of the reaction, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain the target compound (310 mg, 83%). Obtained as colorless crystals.
Melting point: 110-111 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3146, 1696, 1626, 1598, 1577, 1514;
NMR spectrum (CDCl ₃ ) δ ppm: 1.46 (9H, s), 2.51 (2H, t, J = 5.0 Hz), 2.83 (2H, t, J = 5.5 Hz), 3.47 (2H, t, J = 5.0 Hz ), 4.43 (2H, t, J = 5.5 Hz), 6.16 (1H, s), 7.41-7.49 (3H, m), 7.69-7.75 (2H, m).
(b) 5-phenyl-3- (2- (1-piperazinyl) ethoxy) isoxazole dihydrochloride
Post-treatment by reacting 3- (2- (4-tert-butoxycarbonyl-1-piperazinyl) ethoxy) -5-phenylisoxazole (250 mg) in the same manner as in Example 1 (b) This resulted in the target compound (222 mg, 95%) as colorless crystals.
Melting point: 216-222 deg.
IR spectrum (KBr) ν max cm ⁻¹ : 3443, 3189, 3123, 3001, 2972, 2950, 2915, 2771, 2715, 2623, 2527, 2422, 1704, 1648, 1621, 1596, 1578, 1565, 1514;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.00-3.85 (10H, brs), 4.64 (2H, brs), 6.86 (1H, s), 7.50-7.57 (3H, m), 7.82-7.85 (2H, m ), 9.10-9.80 (1 H, brs).
Example 74
3- (2-N-methylaminoethoxy) -5-phenylisoxazole hydrochloride (Example Compound No. 25)
(a) 3- (2- (N-tert-butoxycarbonyl-N-methylamino) ethoxy) -5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (304 mg) was dissolved in dimethylformamide (3 mL) and sodium hydride [> 55% (oily) ), 52 mg] was added and stirred at room temperature for 1 hour. After cooling the reaction solution to 5 ° C, methyl iodide (220 mg) was added, and the mixture was stirred at the same temperature for 15 minutes and again at room temperature for 1 hour. After completion of the reaction, the reaction solution was added to ice water (20 mL) to perform ether extraction (20 mL x 2), and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to thereby give the target compound (296 mg, 93%) as colorless crystals. Obtained as.
Melting point: 72-73 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3125, 1680, 1626, 1596, 1578, 1514;
NMR spectrum (CDCl ₃ ) δ ppm: 1.49 (9H, s), 2.97 (3H, s), 3.64 (2H, brs), 4.41 (2H, brs), 6.14 (1H, s), 7.41-7.52 (3H, m), 7.69-7.75 (2H, m).
(b) 3- (2-methylaminoethoxy) -5-phenylisoxazole hydrochloride
By post-treating 3- (2- (N-tert-butoxycarbonyl-N-methylamino) ethoxy) -5-phenylisoxazole (250 mg) in the same manner as in Example 1 (b) , Target compound (197 mg, 99%) was obtained as colorless crystals.
Melting point: 219-221 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3134, 3022, 2981, 2954, 2883, 2869, 2843, 2803, 2785, 2734, 1621, 1597, 1578, 1516;
NMR spectrum (DMSO-d ₆ ) δ ppm: 2.62 (3H, s), 3.37 (2H, t, J = 5.1 Hz), 4.50 (1H, t, J = 5.1 Hz), 6.85 (1H, s), 7.50 -7.58 (3H, m), 7.82-7.88 (2H, m), 8.79 (2H, brs).
Example 75
3- (2-acetylaminoethoxy) -5-phenylisoxazole (Example Compound No .: 1347)
3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 mL), cooled to 5 ° C., and then acetyl chloride (94 mg) and triethyl Amine (243 mg) was added and stirred for 30 minutes at the same temperature. After the reaction was completed, the reaction solution was added to ice water (40 mL), ethyl acetate extraction (40 mL x 2) was performed, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the crystals obtained by distilling off the solvent under reduced pressure were recrystallized using ethyl acetate to obtain the target compound (225 mg, 91%) as colorless crystals.
Melting Point: 144-145 ℃
IR spectrum (KBr) ν max cm ⁻¹ : 3316, 1641, 1624, 1597, 1578, 1547, 1509;
NMR spectrum (CDCl ₃ ) δ ppm: 2.03 (3H, s), 3.70 (2H, q, J = 5.1 Hz), 4.39 (2H, q, J = 5.1 Hz), 6.16 (1H, brs), 6.26 (1H , s), 7.41-7.49 (3H, m), 7.70-7.75 (2H, m).
Example 76
3- (2-benzoylaminoethoxy) -5-phenylisoxazole (Example Compound No .: 1349)
3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 mL), cooled to 5 ° C., and then benzoyl chloride (168 mg) and triethyl Amine (243 mg) was added and stirred for 30 minutes at the same temperature. After the reaction was completed, the reaction solution was added to ice water (40 mL), ethyl acetate extraction (40 mL x 2) was performed, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the crystals obtained by distilling off the solvent under reduced pressure were recrystallized with ethyl acetate to obtain the target compound (276 mg, 90%) as colorless crystals.
Melting point: 129-130 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3359, 1641, 1626, 1597, 1578, 1534, 1518;
NMR spectrum (CDCl ₃ ) δ ppm: 3.92 (2H, q, J = 5.1 Hz), 4.52 (2H, q, J = 5.1 Hz), 6.17 (1H, s), 6.74 (1H, brs), 7.42-7.53 (6H, m), 7.71-7.74 (2H, m), 7.79-7.88 (2H, m).
Example 77
3- (2-methoxycarbonylaminoethoxy) -5-phenylisoxazole (Example Compound No .: 1348)
3- (2-aminoethoxy) -5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 mL), cooled to 5 ° C., and then methyl chloroformate (113 mg) and tri Ethylamine (243 mg) was added and stirred for 30 minutes at the same temperature. After completion of the reaction, the reaction solution was added to ice water (40 mL), ethyl acetate extraction (40 mL x 2) was performed, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the crystals obtained by distilling off the solvent under reduced pressure were recrystallized using a mixed solvent of ethyl acetate and ether to obtain the target compound (233 mg, 89%) as colorless crystals.
Melting point: 95-96 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3293, 1729, 1624, 1596, 1577, 1552, 1516;
NMR spectrum (CDCl ₃ ) δ ppm: 3.63 (2H, q, J = 5.1 Hz), 3.70 (3H, s), 4.37 (2H, q, J = 5.1 Hz), 5.11 (1H, brs), 6.14 (1H , s), 7.40-7.49 (3H, m), 7.69-7.75 (2H, m).
Example 78
3- (2-aminoethylthio) -5-phenylisoxazole hydrochloride (Example Compound No. 15)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-phenylisoxazole
2- (N-tert-butoxycarbonylamino) ethanethiol (300 mg) was dissolved in dimethylformamide (3.0 mL), cooled to 5 ° C. and then sodium hydride [> 55% (oily), 73 mg ] Was added and stirred for 30 minutes at the same temperature. Subsequently, 3-chloro-5-phenylisoxazole (300 mg) was added, and the mixture was stirred at the same temperature for 30 minutes and again at room temperature for 3 days. After the reaction was completed, the reaction solution was added to ice water (40 mL), ethyl acetate extraction (40 mL x 2) was performed, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain the target compound (130 mg, 24%). Obtained as colorless crystals.
Melting point: 87-88 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 3376, 1682, 1613, 1572, 1521, 1494;
NMR spectrum (CDCl ₃ ) δ ppm: 1.44 (9H, s), 3.27 (2H, t, J = 6.3 Hz), 3.53 (2H, q, J = 6.3 Hz), 5.01 (1H, brs), 6.44 (1H , s), 7.42-7.50 (3H, m), 7.71-7.76 (2H, m).
(b) 3- (2-aminoethylthio) -5-phenylisoxazole hydrochloride
By reacting 3- (2- (N-tert-butoxycarbonylamino) ethylthio) -5-phenylisoxazole (64 mg) in the same manner as in Example 1 (b), the target compound ( 40 mg, 78%) was obtained as colorless crystals.
Melting point: 196-198 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3141, 2988, 2951, 2923, 1609, 1590, 1569, 1492;
NMR spectrum (DMSO-d ₆ ) δ ppm: 3.18 (2H, t, J = 7.2 Hz), 3.36 (2H, t, J = 7.2 Hz), 7.23 (1H, s), 7.53-7.59 (3H, m) , 7.83-7.97 (2H, m), 7.97 (3H, brs).
Example 79
3- (2-aminoethoxy) -4-isopropyl-5- (3-pyridyl) isoxazole dihydrochloride (example compound number: 1065)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (3-pyridyl) isoxazole
3-hydroxy-4-isopropyl-5- (3-pyridyl) isoxazole (0.12 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.09 g) were prepared in Example 9 (a). After the reaction in the same manner as in the post-treatment, the target compound (0.14 g, 74%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3323, 3247, 2979, 1753, 1690;
NMR spectrum (CDCl ₃ ) δ ppm: 1.31 (6H, d, J = 6.8 Hz), 1.46 (9H, s), 3.06 (1H, qq, J = 6.8 Hz, J = 6.8 Hz), 3.60 (2H, q , J = 5.2 Hz), 4.39 (2H, t, J = 5.2 Hz), 4.84 (1H, brs), 7.43 (1H, dd, J = 8.0 Hz, J = 4.7 Hz), 7.90 (1H, ddd, J = 8.0 Hz, J = 2.0 Hz, J = 1.4 Hz), 8.69 (1H, dd, J = 4.7 Hz, J = 1.4 Hz), 8.83 (1H, d, J = 2.0 Hz).
(b) 3- (2-aminoethoxy) -4-isopropyl-5- (3-pyridyl) isoxazole dihydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (3-pyridyl) isoxazole (0.13 g) in the same manner as in Example 9 (b) The reaction was worked up to give the target compound (0.07 g, 64%) as colorless crystals.
Melting point: 193-197 ° C. (decomposition);
IR spectrum (KBr) ν max cm ⁻¹ : 3049, 2963, 2874, 1549;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.27 (6H, d, J = 7.0 Hz), 3.03 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.29 (2H, t, J = 5.4 Hz ), 4.48 (2H, t, J = 5.4 Hz), 7.68 (1H, dd, J = 8.0 Hz, J = 5.0 Hz), 8.12 (1H, ddd, J = 8.0 Hz, J = 2.0 Hz, J = 1.4 Hz), 8.28 (3H, brs), 8.78 (1H, doublet of doublets, J = 5.0 Hz, J = 1.4 Hz), 8.85 (1H, d, J = 2.0 Hz).
Example 80
3- (2-aminoethoxy) -4- (1-chloropropyl) -5-phenylisoxazole hydrochloride (Example Compound No .: 1802)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxypropyl) -5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.2 g), butyllithium (1.6 M hexane solution, 0.9 mL) and propionaldehyde (0.06 mL) By reacting and working in the same manner as in Example 44 (a), the target compound (0.14 g, 58%) was obtained as a colorless oily substance.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3602, 3459, 2980, 2937, 1712;
NMR spectrum (CDCl ₃ ) δ ppm: 0.95 (3H, t, J = 7.4 Hz), 1.45 (9H, s), 1.83-2.08 (2H, m), 2.51 (1H, brs), 3.57 (2H, q, J = 5.2 Hz), 4.39 (2H, t, J = 5.2 Hz), 4.68 (1H, t, J = 7.2 Hz), 4.94 (1H, brs), 7.43-7.52 (3H, m), 7.64-7.75 ( 2H, m).
(b) 3- (2-aminoethoxy) -4- (1-chloropropyl) -5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxypropyl) -5-phenylisoxazole (0.13 g) in the same manner as in Example 1 (b) The reaction product was reacted with and then worked up to obtain target compound (0.10 g, 91%) as colorless crystals.
Melting point: 122-124 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 2974, 2936, 2878, 1631, 1600, 1577;
NMR spectrum (DMSO-d ₆ ) δ ppm: 0.94 (3H, t, J = 7.3 Hz), 2.11-2.28 (2H, m), 3.31 (2H, t, J = 5.1 Hz), 4.50 (2H, t, J = 5.1 Hz), 5.14 (1H, t, J = 6.5 Hz), 7.61-7.65 (3H, m), 7.72-7.75 (2H, m).
Example 81
3- (2-aminoethoxy) -4- (1-chloroisobutyl) -5-phenylisoxazole hydrochloride (Example Compound No .: 1804)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisobutyl) -5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.2 g), butyllithium (1.6 M hexane solution, 0.9 mL) and isobutylaldehyde (0.07 mL) Was reacted and worked up in the same manner as in Example 44 (a) to give the target compound (0.21 g, 84%) as a colorless oily substance.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3606, 3459, 2981, 2937, 1712, 1637;
NMR spectrum (CDCl ₃ ) δ ppm: 0.79 (3H, d, J = 6.6 Hz), 1.11 (3H, d, J = 6.6 Hz), 1.45 (9H, s), 2.16-2.29 (1H, m), 2.56 (1H, brs), 3.58 (2H, q, J = 5.1 Hz), 4.30-4.48 (3H, m), 4.94 (1H, brs), 7.46-7.51 (3H, m), 7.70-7.74 (2H, m ).
(b) 3- (2-aminoethoxy) -4- (1-chloroisobutyl) -5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisobutyl) -5-phenylisoxazole (0.20 g) was the same as in Example 1 (b) By reacting and post-treatment by the method, the target compound (0.11 g, 65%) was obtained as colorless crystals.
Melting point: 165-167 ° C .;
IR spectrum (KBr) ν max cm ⁻¹ : 2967, 2902, 2870, 1636, 1600;
NMR spectrum (DMSO-d ₆ ) δ ppm: 0.78 (3H, d, J = 6.6 Hz), 1.15 (3H, d, J = 6.6 Hz), 2.53-2.63 (1H, m), 3.30 (2H, t, J = 5.2 Hz), 4.50 (2H, t, J = 5.2 Hz), 4.85 (1H, d, J = 10.7 Hz), 7.60-7.65 (3H, m), 7.71-7.75 (2H, m), 8.25 ( 3H, brs).
Example 82
3- (2-aminoethoxy) -4- (1-chloroisopentyl) -5-phenylisoxazole hydrochloride (Example Compound No .: 1806)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisopentyl) -5-phenylisoxazole
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5-phenylisoxazole (0.2 g), butyllithium (1.6 M hexane solution, 0.9 mL) and isobaraldehyde (0.09 mL) Was reacted and worked up in the same manner as in Example 44 (a) to give the target compound (0.2 g, 77%) as a colorless oily substance.
IR spectrum (CHCl ₃ ) ν max cm ⁻¹ : 3601, 3459, 2981, 2961, 2936, 1712, 1639;
NMR spectrum (CDCl ₃ ) δ ppm: 0.87 (3H, d, J = 6.3 Hz), 0.92 (3H, d, J = 6.3 Hz), 1.45 (9H, s), 1.63-1.78 (2H, m), 1.83 -1.98 (1H, m), 3.58 (2H, q, J = 5.2 Hz), 4.40 (2H, t, J = 5.2 Hz), 4.75-5.00 (2H, m), 7.44-7.50 (3H, m), 7.66-7.71 (2H, m).
(b) 3- (2-aminoethoxy) -4- (1-chloroisopentyl) -5-phenylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4- (1-hydroxyisopentyl) -5-phenylisoxazole (0.19 g) was the same as in Example 1 (b) Reaction and post-treatment by the method gave the target compound (0.11 g, 69%) as colorless crystals.
Melting point: 134-136 캜;
IR spectrum (KBr) ν max cm ⁻¹ : 2961, 2905, 2873, 1630;
NMR spectrum (DMSO-d ₆ ) δ ppm: 0.79 (3H, d, J = 6.6 Hz), 0.82 (3H, d, J = 6.6 Hz), 1.57 (1H, qq, J = 6.6 Hz, J = 6.6 Hz ), 2.00-2.12 (2H, m), 3.31 (2H, t, J = 5.4 Hz), 4.51 (2H, t, J = 5.4 Hz), 5.21 (1H, t, J = 8.0 Hz), 7.62-7.65 (3H, m), 7.69-7.72 (2H, m), 8.22 (3H, brs).
Example 83
3- (2-aminoethoxy) -5- (2,4-difluorophenyl) -4-isopropylisoxazole hydrochloride (Example Compound No. 99)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-difluorophenyl) -4-isopropylisoxazole
5- (2,4-difluorophenyl) -3-hydroxy-4-isopropylisoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.16 g) were carried out. By reacting and post-treatment in the same manner as in Example 1 (a), the target compound (0.25 g, 78%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3400, 2980, 2936, 1683;
NMR spectrum (CDCl ₃ ) δ ppm: 1.22 (6H, d, J = 6.9 Hz), 1.46 (9H, s), 2.78 (1H, qq, J = 6.9 Hz, J = 6.9 Hz), 3.59 (2H, q , J = 5.2 Hz), 4.38 (2H, t, J = 5.2 Hz), 4.86 (1H, brs), 6.90-7.03 (2H, m), 7.42-7.50 (1H, m).
(b) 3- (2-aminoethoxy) -5- (2,4-difluorophenyl) -4-isopropylisoxazole hydrochloride
3- (2- (N-tert-butoxycarbonylamino) ethoxy) -5- (2,4-difluorophenyl) -4-isopropylisoxazole (0.24 g) was prepared in Example 1 (b) Reaction and post-treatment were carried out in the same manner as) to obtain the target compound (0.17 g, 85%) as colorless crystals.
Melting point: 177-179 캜;
IR spectrum (KBr) ν max cm ⁻¹ : 2973, 2936, 1642, 1614, 1590;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.18 (6H, d, J = 6.9 Hz), 2.76 (1H, qq, J = 6.9 Hz, J = 6.9 Hz), 3.29 (2H, t, J = 5.3 Hz ), 4.46 (2H, t, J = 5.3 Hz), 7.28-7.33 (1H, m), 7.50-7.56 (1H, m), 7.60-7.66 (1H, m), 8.12 (3H, brs).
Example 84
3- (2-aminoethoxy) -4-isopropyl-5- (4-methylphenyl) isoxazole hydrochloride (Example compound number: 266)
(a) 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (4-methylphenyl) isoxazole
3-hydroxy-4-isopropyl-5- (4-methylphenyl) isoxazole (0.2 g) and 2- (N-tert-butoxycarbonylamino) ethanol (0.16 g) were prepared in Example 1 (a) and By reaction in the same manner and post-treatment, the target compound (0.27 g, 82%) was obtained as a colorless powder.
IR spectrum (KBr) ν max cm ⁻¹ : 3383, 2965, 1686;
NMR spectrum (CDCl ₃ ) δ ppm: 1.28 (6H, d, J = 7.0 Hz), 1.46 (9H, s), 2.41 (3H, s), 3.06 (1H, qq, J = 7.0 Hz, J = 7.0 Hz ), 3.59 (2H, q, J = 5.2 Hz), 4.37 (2H, t, J = 5.2 Hz), 4.84 (1H, brs), 7.27 (2H, d, J = 8.1 Hz), 7.46 (2H, d , J = 8.1 Hz).
(b) 3- (2-aminoethoxy) -4-isopropyl-5- (4-methylphenyl) isoxazole hydrochloride
Reaction of 3- (2- (N-tert-butoxycarbonylamino) ethoxy) -4-isopropyl-5- (4-methylphenyl) isoxazole (0.25 g) in the same manner as in Example 1 (b) After working up, the target compound (0.13 g, 65%) was obtained as colorless crystals.
Melting point: 208-210 캜;
IR spectrum (KBr) ν max cm ⁻¹ : 2971, 2877, 1641, 1522;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.25 (6H, d, J = 7.0 Hz), 2.38 (3H, s), 3.02 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 3.28 (2H , t, J = 5.2 Hz), 4.44 (2H, t, J = 5.2 Hz), 7.37 (2H, d, J = 8.1 Hz), 7.47 (2H, d, J = 8.1 Hz), 8.20 (3H, brs ).
Reference Example 1
4-chloro-5- (4-chlorophenyl) -3-hydroxyisoxazole
(a) 4-chloro cinnamic acid ethyl ester
4-chloro cinnamic acid (300 g) was suspended in benzene (1200 mL), and ethanol (340 g) and concentrated sulfuric acid (14 mL) were added, followed by heating to reflux for 15 hours. The reaction solution was washed in the order of diluted saline (500 mL), saturated aqueous sodium hydrogen carbonate solution (500 mL) and diluted saline (500 mL), and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was distilled off under reduced pressure to obtain the target compound (334 g, 97%) as a colorless liquid.
Boiling point: 147-148 ° C. (4 mmHg);
NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, t, J = 7.0 Hz), 4.30 (2H, q, J = 7.0 Hz), 6.47 (1H, d, J = 16.0 Hz), 7.63 (4H, ca .s).
(b) α, β-dibromo-4-chloro cinnamic acid ethyl ester
4-chloro cinnamic acid ethyl ester (330 g) was dissolved in carbon tetrachloride (1200 mL), and bromine (251 g) was added dropwise under room temperature stirring. After stirring at room temperature for 4 hours, it was left overnight. By distilling off the solvent under reduced pressure, the target compound (572 g, 99%) was obtained as colorless crystals.
Melting Point: 67-68 ℃
NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, t, J = 7.0 Hz), 4.37 (2H, q, J = 7.0 Hz), 4.80 (1H, d, J = 12.0 Hz), 5.32 (1H, d , J = 12.0 Hz), 7.37 (4H, ca.s).
(c) 5- (4-chlorophenyl) -3-hydroxyisoxazole
Sodium hydroxide (151 g) was dissolved in methanol (600 mL), and stirred at 0 ° C., an aqueous solution of hydroxylamine (45 g) (50 mL) was added dropwise, followed by α, β-dibromo- Dioxane (200 mL) solution of 4-chloro cinnamic acid ethyl ester (200 g) was added dropwise. The mixture was stirred at room temperature for 4 hours, further heated to reflux for 5 hours, cooled to 5 ° C, the pH of the solution was adjusted to 2 using concentrated hydrochloric acid, and then added to water (5 L). The precipitated crystals were collected by filtration, washed with water (2 L), and then washed with ethanol (1 L) to obtain 90 g (85%) of the target compound as a pale yellow powder.
Melting point: 215-220 ° C. (decomposition);
NMR spectrum (DMF-d ₇ ) δ ppm: 6.66 (1H, s), 7.52-8.20 (4H, m), 11.5-12.0 (1H, brs).
(d) 4-chloro-5- (4-chlorophenyl) -3-hydroxyisoxazole
5- (4-Chlorophenyl) -3-hydroxyisoxazole (50.0 g) was dissolved in dry tetrahydrofuran (300 mL), stirred at 5 ° C, and sulfuryl chloride (34.5 g) was dried benzene (50 And dissolved in mL) was added dropwise. The mixture was stirred at the same temperature for 30 minutes, stirred at room temperature for 1 hour, heated to reflux for 3 hours, and then the solvent was distilled off under reduced pressure, and the solid obtained was recrystallized from ethanol to give the target compound (44.2 g, 76.8%) as colorless. Obtained as a needle-shaped crystal of.
Melting point: 235-238 ° C. (decomposition);
NMR spectrum (DMF-d ₇ ) δ ppm: 7.60-8.20 (4H, m), 12.6-13.6 (1H, brs).
Reference Example 2
3-hydroxy-5- (2-thienyl) isoxazole
2-thiophenacrylic acid was reacted and worked up in the same manner as in Reference Example 1 (a) and Reference Example 1 (b), followed by Reference Example 1 (c) to obtain a target compound.
Melting point: 163-165 deg.
NMR spectrum (DMSO-d ₆ ) δ ppm: 6.38 (1H, s), 7.20-7.25 (1H, m), 7.60-7.80 (2H, m), 11.2-11.6 (1H, brs).
Reference Example 3
4-chloro-3-hydroxy-5- (2-thienyl) isoxazole
3-hydroxy-5- (2-thienyl) isoxazole was reacted and worked up in the same manner as in Reference Example 1 (d) to obtain a target compound.
Melting point: 191-194 ° C .;
NMR spectrum (DMF-d ₇ ) δ ppm: 7.21-7.45 (1H, m), 7.70-8.20 (2H, m), 10.0-13.0 (1H, brs).
Reference Example 4
3-hydroxy-5- (3-pyridyl) isoxazole
3-pyridine acrylic acid was reacted in the same manner as in Reference Example 1 (a), Reference Example 1 (b) and then Reference Example 1 (c), followed by post-treatment to obtain the target compound.
Melting point: 212-214 ° C. (decomposition);
NMR spectrum (DMF-d ₇ ) δ ppm: 6.76 (1H, s), 7.40-7.80 (1H, m), 8.10-8.50 (1H, m), 8.66-9.00 (1H, m), 9.05-9.33 (1H , m).
Reference Example 5
4-chloro-3-hydroxy-5- (2-pyridyl) isoxazole
3-hydroxy-5- (2-pyridyl) isoxazole was reacted and worked up in the same manner as in Reference Example 1 (d) to obtain the target compound.
Reference Example 6
3-hydroxy-4-isopropyl-5-phenylisoxazole
Ethyl benzoyl acetate was reacted in the same manner as described in Aggregate and Biological Chemistry, Vol. 50, p. 1831 (Agric. Biol. Chem., EN., 50,1831 (1986).). Post-treatment gave the target compound.
Melting point: 203-205 캜;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.24 (6H, d, J = 7.1 Hz), 3.01 (1H, q, J = 7.1 Hz), 7.47-7.61 (5H, m), 11.2-11.6 (1H, brs).
Reference Example 7
2- (N-tert-butoxycarbonylamino) ethanol
2-aminoethanol (6.1 g) was dissolved in a mixed solution of tetrahydrofuran and water (1: 1,100 mL), and di-tert-butyldicarbonate (21.8 g) was added dropwise under ice-cooling stirring for 1 hour at the same temperature. Then, the mixture was stirred at room temperature for 5 hours. Ethyl acetate (200 mL) was added to the reaction mixture, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and then the solvent was evaporated under reduced pressure to give the target compound (15.3 g, 95%) as colorless. Obtained as an oily substance.
Rf value: 0.35 (developing solvent: cyclohexane / ethyl acetate = 1/1);
NMR spectrum (CDCl ₃ ) δ ppm: 1.45 (9H, s), 2.35-2.50 (1H, brs), 3.29 (2H, q, J = 5.3 Hz), 3.71 (2H, q, J = 5.3 Hz), 4.85 -5.05 (1 H, br s).
Reference Example 8
4- (tert-butyl) -3-hydroxy-5-phenylisoxazole
(a) 2-benzoyl-3,3-dimethylbutyric acid ethyl ester
Diisopropylamine (5.6 mL) was dissolved in tetrahydrofuran (56 mL), and stirred under a nitrogen atmosphere at 5 ° C., butyllithium (1.6 M hexane solution, 25 mL) was added dropwise and stirred for 15 minutes. After the reaction solution was cooled to -70 ° C, 3,3-dimethylbutyric acid ethyl ester (6.7 ml) was added dropwise and stirred for 10 minutes, and then benzoyl chloride (2.3 ml) was added dropwise and stirred at the same temperature for 10 minutes. After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 20/1) to obtain the target compound (4.5 g, 91%). Obtained as a colorless oil.
(b) 4- (tert-butyl) -3-hydroxy-5-phenylisoxazole
2-benzoyl-3,3-dimethylbutyric acid ethyl ester (2.0 g) was dissolved in methanol (20 mL), and sodium methoxide (28% methanol solution, 1.6 mL) was added dropwise at 5 ° C under a nitrogen atmosphere. Stir for 10 minutes. After cooling the reaction solution to -30 ° C, methanol suspension (10 ml) of hydroxylamine hydrochloride (1.1 g) and sodium methoxide (28% methanol solution, 6.2 ml) was added dropwise and stirred at the same temperature for 30 minutes. 6N hydrochloric acid (14 mL) was added and stirred at 80 ° C for 1 hour. After completion of the reaction, the residue obtained by distilling off the solvent under reduced pressure was poured into iced water, extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was crystallized with isopropyl ether to give the target compound (0.35 g, 20%) as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3027, 2993, 2960, 2936, 2869, 2790, 2697, 2623, 2574, 1644, 1600;
NMR spectrum (CDCl ₃ ) δ ppm: 1.22 (9H, s), 7.39-7.50 (5H, m).
Reference Example 9
5- (4-chlorophenyl) -3-hydroxy-4-isopropylisoxazole
(a) 2- (4-chlorobenzoyl) isovaleric acid ethyl ester
4-chlorobenzoyl chloride (2.5 mL) and isovaleric acid ethyl ester (1.5 mL) were reacted and worked up in the same manner as in Reference Example 8 (a) to give the target compound (2.2 g, 82%) as a colorless oily substance. Obtained as
(b) 5- (4-chlorophenyl) -3-hydroxy-4-isopropylisoxazole
2- (4-chlorobenzoyl) isovaleric acid ethyl ester (2.1 g), hydroxylamine hydrochloride (1.1 g) and sodium methoxide (28% methanol solution, 7.5 ml) were prepared in the same manner as in Reference Example 8 (b). The reaction was worked up to give the target compound (1.3 g, 71%) as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3065, 3018, 2970, 2935, 2875, 2820, 2768, 2695, 2609, 1646;
NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (6H, d, J = 7.0 Hz), 3.06 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.54 (2H, doublet, J = 8.6 Hz).
Reference Example 10
5- (2,4-difluorophenyl) -3-hydroxyisoxazole
(a) 2,4-difluoro cinnamic acid ethyl ester
2,4-difluoro cinnamic acid (10.1 g) was dissolved in ethanol (100 mL), concentrated sulfuric acid (1 mL) was added, and the mixture was heated to reflux for 3 hours. The residue obtained by distilling off the solvent under reduced pressure was poured into iced water, extracted with ethyl acetate, the extract was washed sequentially with 5% aqueous sodium hydrogen carbonate solution and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. I was. After filtration, the solvent was distilled off under reduced pressure to obtain the target compound (11.2 g, 97%) as a colorless oily substance.
(b) α, β-dibromo-2,4-difluorocinnamic acid ethyl ester
2,4-difluoro cinnamic acid ethyl ester (11.2 g) was dissolved in carbon tetrachloride (110 mL), bromine (2.7 mL) was added dropwise under nitrogen stirring, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain the target compound (19.6 g, quantitative) as a colorless powder.
(c) 5- (2,4-difluorophenyl) -3-hydroxyisoxazole
Sodium hydroxide (10.9 g) was dissolved in methanol (110 mL), stirred at 5 ° C, and dropwise added a solution of hydroxylamine hydrochloride (4.2 g) in water (10 mL), followed by α, β-dibromo- A tetrahydrofuran (20 mL) solution of 2,4-difluoro cinnamic acid ethyl ester (19.6 g) is added dropwise, stirred at room temperature for 2 hours, and then heated to reflux for 5 hours. The residue obtained by distilling off the solvent under reduced pressure was poured into iced water, the pH of the solution was adjusted to 2 with concentrated hydrochloric acid, extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was sulfuric anhydride. Dry with magnesium. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified using silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 1/1) to obtain the target compound (8.2 g, 79%). Was obtained as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3170, 3090, 3028, 2848, 2806, 2689, 2655, 2603, 1630;
NMR spectrum (DMSO-d ₆ ) δ ppm: 6.38 (1H, s), 7.25-7.32 (1H, m), 7.47-7.56 (1H, m), 7.89-7.99 (1H, m), 11.62 (1H, brs ).
Reference Example 11
3-hydroxy-5- (2-trifluoromethylphenyl) isoxazole
(a) 2-trifluoromethyl cinnamic acid ethyl ester
2-trifluoromethyl cinnamic acid (10.1 g), concentrated sulfuric acid (1 ml) and ethanol (100 ml) were reacted and worked up in the same manner as in Reference Example 10 (a) to give a target compound (10.8 g, 95%). Was obtained as a colorless oily substance.
(b) α, β-dibromo-2-trifluoromethyl cinnamic acid ethyl ester
2-trifluoromethyl cinnamic acid ethyl ester (10.8 g) and bromine (2.3 mL) were reacted and worked up in the same manner as in Reference Example 10 (b) to give the target compound (17.9 g, quantitative) as a colorless powder. It was.
(c) 3-hydroxy-5- (2-trifluoromethylphenyl) isoxazole
α, β-dibromo-2-trifluoromethyl cinnamic acid ethyl ester (17.9 g), hydroxylamine hydrochloride (3.8 g) and sodium hydroxide (9.1 g) were reacted in the same manner as in Reference Example 10 (c) After workup, the target compound (7.6 g, 76%) was obtained as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3176, 3096, 3022, 2950, 2836, 2796, 2669, 1620, 1600;
NMR spectrum (DMSO-d ₆ ) δ ppm: 6.34 (1H, s), 7.73-7.87 (3H, m), 7.92-7.95 (1H, m), 11.58 (1H, brs).
Reference Example 12
3-hydroxy-5- (4-trifluoromethylphenyl) isoxazole
(a) 4-trifluoromethyl cinnamic acid ethyl ester
4-Trifluoromethyl cinnamic acid (10.2 g), concentrated sulfuric acid (1 mL) and ethanol (100 mL) were reacted and worked up in the same manner as in Reference Example 10 (a) to give a target compound (10.9 g, 95%). Was obtained as a colorless oily substance.
(b) α, β-dibromo-4-trifluoromethyl cinnamic acid ethyl ester
4-trifluoromethyl cinnamic acid ethyl ester (10.8 g) and bromine (2.4 mL) were reacted and worked up in the same manner as in Reference Example 10 (b) to give the target compound (17.9 g, quantitative) as a colorless powder. It was.
(c) 3-hydroxy-5- (4-trifluoromethylphenyl) isoxazole
α, β-dibromo-4-trifluoromethyl cinnamic acid ethyl ester (17.9 g), hydroxylamine (3.8 g) and sodium hydroxide (9.1 g) were reacted in the same manner as in Reference Example 10 (c) After workup, the target compound (8.3 g, 83%) was obtained as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3154, 3018, 2987, 2838, 2788, 2673, 2637, 2607, 2547, 1631, 1614;
NMR spectrum (DMSO-d ₆ ) δ ppm: 6.77 (1H, s), 7.88 (2H, d, J = 8.4 Hz), 8.03 (2H, d, J = 8.4 Hz), 11.60 (1H, brs).
Reference Example 13
3-hydroxy-5- (4-isopropylphenyl) isoxazole
(a) 4-isopropyl cinnamic acid ethyl ester
4-isopropyl cinnamic acid (5.0 g), concentrated sulfuric acid (0.5 mL) and ethanol (50 mL) were reacted and worked up in the same manner as in Reference Example 10 (a) to give the target compound (5.5 g, 97%) as colorless Obtained as an oily substance.
(b) α, β-dibromo-4-isopropyl cinnamic acid ethyl ester
4-isopropyl cinnamic acid ethyl ester (5.5 g) and bromine (1.3 mL) were reacted and worked up in the same manner as in Reference Example 10 (b) to give the target compound (9.5 g, quantitative) as a colorless powder.
(c) 3-hydroxy-5- (4-isopropylphenyl) isoxazole
α, β-dibromo-4-isopropyl cinnamic acid ethyl ester (9.5 g), hydroxylamine (2.2 g) and sodium hydroxide (5.2 g) were reacted in the same manner as in Reference Example 10 (c), and then worked up. This resulted in the target compound (3.6 g, 71%) as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3013, 2964, 2934, 2893, 2872, 2793, 2665, 2631, 2542, 1624;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.22 (6H, d, J = 6.9 Hz), 2.94 (1H, qq, J = 6.9H, J = 6.9 Hz), 6.48 (1H, s), 7.39 (2H , d, J = 8.3 Hz), 7.72 (2H, d, J = 8.3 Hz).
Reference Example 14
3-hydroxy-5- (4-phenoxyphenyl) isoxazole
(a) 4-phenoxy clock
4-phenoxybenzaldehyde (10.0 g) and potassium acetate (9.8 g) were suspended in acetic anhydride (9.5 mL) and heated to reflux at 180 ° C for 5 hours. After completion of the reaction, the pH of the solution was adjusted to 2 using hydrochloric acid, extracted with ethyl acetate, the extract was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain the target compound (6.5 g, 54%). Obtained as colorless crystals.
(b) 4-phenoxy cyanic acid ethyl ester
4-Phenoxydipic acid (4.0 g), concentrated sulfuric acid (0.4 mL) and ethanol (40 mL) were reacted and worked up in the same manner as in Reference Example 10 (a) to give the target compound (4.4 g, 98%) as colorless. Obtained as an oily substance.
(c) α, β-dibromo-4-phenoxycyanic acid ethyl ester
4-Phenoxyphenic acid ethyl ester (4.4 g) and bromine (0.84 mL) were reacted and worked up in the same manner as in Reference Example 10 (b) to give the target compound (7.0 g, quantitative) as a colorless powder.
(d) 3-hydroxy-5- (4-phenoxyphenyl) isoxazole
α, β-dibromo-4-phenoxycyanic acid ethyl ester (7.0 g), hydroxylamine hydrochloride (1.4 g) and sodium hydroxide (3.3 g) were reacted in the same manner as in Reference Example 10 (c) and then worked up. This resulted in the target compound (3.4 g, 83%) as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3147, 3013, 2951, 2852, 2785, 2614, 2557, 1627;
NMR spectrum (DMSO-d ₆ ) δ ppm: 6.47 (1H, s), 7.07-7.25 (5H, m), 7.42-7.48 (2H, m), 7.79-7.83 (2H, m), 11.36 (1H, brs ).
Reference Example 15
3-hydroxy-5- (1-naphthyl) isoxazole
(a) 1-naphthyl acrylic acid
1-naphthoaldehyde (30.5 g), potassium acetate (38.3 g) and acetic anhydride (36.9 mL) were reacted and worked up in the same manner as in Reference Example 14 (a) to give the target compound (22.4 g, 58%). Obtained as a colorless powder.
(b) 1-naphthyl acrylate ethyl ester
The target compound (10.2 g, 94%) was colorless by reacting 1-naphthylacrylic acid (9.5 g), concentrated sulfuric acid (1 mL) and ethanol (100 mL) in the same manner as in Reference Example 10 (a). Obtained as an oily substance.
(c) α, β-dibromo-1-naphthyl acrylic acid ethyl ester
1-naphthylacrylic acid ethyl ester (10.1 g) and bromine (2.5 mL) were reacted and worked up in the same manner as in Reference Example 10 (b) to give the target compound (17.2 g, quantitative) as a colorless powder.
(d) 3-hydroxy-5- (1-naphthyl) isoxazole
α, β-dibromo-1-naphthylacrylic acid ethyl ester (6.0 g), hydroxylamine hydrochloride (1.3 g) and sodium hydroxide (7.2 g) were reacted in the same manner as in Reference Example 10 (c) and then worked up. This resulted in the target compound (2.6 g, 78%) as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3136, 3045, 3017, 2790, 2710, 2640, 2569, 1628;
NMR spectrum (DMSO-d ₆ ) δ ppm: 6.53 (1H, s), 7.61-7.70 (3H, m), 7.84-7.87 (1H, m), 8.03-8.13 (2H, m), 8.22-8.28 (1H , m).
Reference Example 16
3-hydroxy-5- (4-hydroxyphenyl) isoxazole
3-hydroxy-5- (4-methoxyphenyl) isoxazole (5.0 g) was suspended in dichloromethane (50 mL), and aluminum chloride (7.0 g) was added and heated to reflux for 66 hours. After completion of the reaction, the reaction solution was poured into iced water, 6N hydrochloric acid was added, extracted with ethyl acetate, the extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the residue obtained by distilling off the solvent under reduced pressure was purified using silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 2/1) to obtain the target compound (3.8 g, 83%). Was obtained as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3140, 3074, 1624, 1588;
NMR spectrum (DMSO-d ₆ ) δ ppm: 6.24 (1H, s), 6.86 (2H, d, J = 8.2 Hz), 7.62 (2H, s, J = 8.2 Hz), 10.03 (1H, s), 11.24 (1H, brs).
Reference Example 17
5- (2,4-difluorophenyl) -3-hydroxy-4-isopropylisoxazole
(a) 2- (2,4-difluorobenzoyl) isovaleric acid ethyl ester
2,4-difluorobenzoyl chloride (4.9 ml) and isovaleric acid ethyl ester (3.0 ml) were reacted and worked up in the same manner as in Reference Example 8 (a) to give the target compound (3.65 g, 68%). Obtained as a colorless liquid.
(b) 5- (2,4-difluorophenyl) -3-hydroxy-4-isopropylisoxazole
2- (2,4-difluorobenzoyl) isovaleric acid ethyl ester (1.7 g), hydroxylamine hydrochloride (0.9 g) and sodium methoxide (28% methanol solution, 7.5 mL) were referred to. The reaction was carried out in the same manner as in the post treatment to give the target compound (0.59 g, 39%) as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3082, 3033, 2980, 2968, 2935, 2913, 2877, 2836, 2795, 2699, 2636, 2604, 1660, 1610;
NMR spectrum (DMSO-d ₆ ) δ ppm: 1.28 (6H, d, J = 7.0 Hz), 2.81 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 6.91-7.05 (2H, m), 7.43 -7.52 (1 H, m).
Reference Example 18
4-cyclopropyl-3-hydroxy-5-phenylisoxazole
(a) 2-benzoyl-2-cyclopropylacetic acid methyl ester
After treatment by reacting benzoyl chloride (1.0 ml) with 2-cyclopropylacetic acid methyl ester (2.0 g) in the same manner as in Reference Example 8 (a), the target compound (1.05 g, 28%) was obtained as a colorless liquid. It was.
(b) 4-cyclopropyl-3-hydroxy-5-phenylisoxazole
2-benzoyl-2-cyclopropylacetic acid methyl ester (0.9 g), hydroxylamine hydrochloride (0.6 g) and sodium methoxide (28% methanol solution, 4.0 mL) were reacted in the same manner as in Reference Example 8 (b) After workup, the target compound (0.32 g, 39%) was obtained as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3085, 3066, 3012, 2972, 2909, 2851, 2778, 2716, 2652, 2601, 1646;
NMR spectrum (CDCl ₃ ) δ ppm: 0.79-0.85 (2H, m), 0.91-0.98 (2H, m), 1.67-1.77 (1H, m), 7.43-7.53 (3H, m), 7.86-7.90 (2H , m).
Reference Example 19
3-hydroxy-4-isopropyl-5- (3-pyridyl) isoxazole
(a) 2-nicotinoyl isovaleric acid ethyl ester
Niacin chloride hydrochloride (0.9 g) and isovaleric acid ethyl ester (2.3 mL), diisopropylamine (2.1 mL) and butyllithium (1.6 M hexane solution, 9.4 mL) in the same manner as in Reference Example 8 (a) The reaction was worked up to give the target compound (0.78 g, 44%) as a colorless liquid.
(b) 3-hydroxy-4-isopropyl-5- (3-pyridyl) isoxazole
2-Nicotinoylisovaleric acid ethyl ester (0.76 g), hydroxylamine hydrochloride (0.46 g) and sodium methoxide (28% methanol solution, 3.1 mL) were reacted in the same manner as in Reference Example 8 (b). By treatment, the desired compound (0.15 g, 23%) was obtained as colorless crystals.
IR spectrum (KBr) ν max cm ⁻¹ : 3069, 3035, 2970, 2934, 2876, 2809, 2770, 2709, 2665, 2605, 2576, 2529, 1511;
NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (6H, d, J = 7.0 Hz), 3.10 (1H, qq, J = 7.0 Hz, J = 7.0 Hz), 7.45 (1H, dd, J = 7.9 Hz, J = 4.4 Hz), 7.94 (1H, d, J = 7.9 Hz), 8.72 (1H, d, J = 4.4 Hz), 8.88 (1H, s).
Reference Example 20
4-chloro-3-hydroxy-5- (3-pyridyl) isoxazole
3-hydroxy-5- (3-pyridyl) isoxazole was reacted and worked up in the same manner as in Reference Example 1 (d) to obtain the target compound.
Melting point: 220-224 ° C. (decomposition);
NMR spectrum (DMF-d ₇ ) δ ppm: 7.60-8.20 (4H, m), 12.6-13.6 (1H, brs).
Test Example 1
Type A monoamine oxidase inhibitory activity
Biochemical Permaology, Vol. 12, p. 1439 (1963) [Biochem. Pharmacol., 12, 1439 (1963)] and Journal of Neurochemistry, Vol. 35, p. 109 (1980) [J. Neurochem., 35, 109 (1980)]. To 30 µl of mouse encephalocyte mitochondrial specimens (30 µg protein), 210 µl of phosphate buffer (pH 7.4) and 30 µl of the test compound (dissolved in 10% DMSO-water) were added and preliminary at 38 ° C for 20 minutes. Incubated. Then ¹⁴ C-5-hydroxytrytamine (5-HT, final concentration: 100 μM) is added and reacted at 38 ° C. for 20 minutes. After adding 2N hydrochloric acid (200 µl) to stop the reaction, the metabolite obtained by the enzyme reaction labeled ¹⁴ C was extracted with a solvent (ethyl acetate: toluene = 1: 1), and the ¹⁴ C radioactivity was liquid. measured by a scintillation counter, it was determined for ¹⁴ C radioactivity in the control concentration of compound that reduced 50% (IC _50).
As a result of using this test, for example, the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 54, 57, 58, 59, 60, 62 and 67 have particularly good IC ₅₀ below 28 nM. Action was shown.
Formulation Example 1
Hard Capsule
50 mg of the compound of Example 4, 128.7 mg of lactose, 70 mg of cellulose, and 1.3 mg of magnesium stearate were mixed to filter a 60 mesh sieve, and then the powder was placed in 250 mg of No. 3 gelatin capsule. Shall be.
Formulation Example 2
refine
50 mg of the powdered compound of Example 4, 124 mg of lactose, 25 mg of cellulose, and 1 mg of magnesium stearate are mixed and tableted with a tableting machine to give a tablet of 200 mg. This refinement | purification can be performed as needed.
Since the isoxazole derivative (I) of the present invention has an excellent type A monoamine oxidase inhibitory activity and also has low toxicity, manic-depressive disease, Perkyson's disease, Alzheimer's type dementia (such as dementia based on Alzheimer's disease) or cerebrovascular dementia (cerebrovascularity) It is useful as a therapeutic or prophylactic agent (especially therapeutic drug) for neurological diseases (especially manic-depressive diseases) such as dementia based on dementia.
In the case of using the compound (I) of the present invention or pharmacologically acceptable salts thereof as the therapeutic or prophylactic agent for the neurological diseases, such as tablets, capsules and granules, mixed with itself or with appropriate pharmacologically acceptable excipients and diluents, etc. It may be administered orally by powder or syrup, or parenterally by injection or suppository.
These agents include excipients (e.g., sugar derivatives such as lactose, white sugar, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl). Cellulose derivatives such as cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, internal crosslinked carboxymethyl cellulose sodium; gum arabic; dextran; pullane; hard silicic anhydride, synthetic aluminum silicate, magnesium aluminate Silicate derivatives; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate, sulfate derivatives such as calcium sulfate, etc.), binders (e.g., excipients; gelatin; polyvinylpyrrolidone; magrogor, etc.), disintegrants ( Such excipients, croscarmellose sodium, carboxymethyls Hexasodium, chemically modified starch such as crosslinked polyvinylpyrrolidone, cellulose derivatives, etc., glidants (e.g., talc; stearic acid; calcium stearate, magnesium stearate; colloidal silica; bum, gay) Lactose such as low; boric acid; glycol; fumaric acid; carboxylic acid such as adipic acid; sodium carboxylate salt such as sodium benzoate; sulfate salt such as sodium sulfate; leucine; sodium lauryl sulfate; magnesium lauryl sulfate Uryl sulfate; silicic acid such as silicic anhydride, silicic acid hydrate; starch derivative in the above excipients; stabilizers (e.g., paraoxybenzoic acid esters such as methylparaben, propylparaben; Alcohols such as; benzalkonium chloride; phenols such as phenol and cresol; thimelosal; acetic anhydride; sorbic acid, etc.) Using an additive such as gyochwije (for example, commonly used sweeteners, acidulants, flavors and the like), diluent, injection solvent (e.g., water, ethanol, glycerin, etc.) for the preparation of which is well-known methods. The amount varies depending on the condition and age, but in the case of oral administration, the lower limit is 1 mg (preferably 10 mg) per day, and the upper limit is 2000 mg (preferably 400 mg). It is preferable to administer the lower limit 0.1 mg (preferably 1 mg) per day and the upper limit 500 mg (preferably 300 mg) to an adult 1 to 6 times as a symptom per day.

权利要求:
Claims (32)
[1" claim-type="Currently amended] Isoxazole derivatives having the general formula (I) or their pharmacologically acceptable salts:
[Formula I]
Wherein R ¹ may have the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent groups, or may have 1 to 3 such substituents, and may be a nitrogen atom or an oxygen atom And a 5 to 6 membered aromatic heterocyclic group having 1 to 2 heteroatoms identically or differently selected from the group consisting of sulfur atoms (wherein the substituent group is halogen; C ₁ -C ₆ alkyl; halogen or C _1- C ₁ -C ₆ alkyl substituted with C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl, C ₇ -C ₁₈ which may have the same or different substituents from 1 to 3 selected from the following groups: Aralkyl, C ₆ -C ₁₄ aryloxy or C ₇ -C ₁₈ aralkyloxy (the substituent group being halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); cyano; nitro; hydroxyl; C ₁ -C ₇ alkanoyl; C ₁ -C ₇ alkanoyloxy; C ₂ -C ₇ alkoxycarbonyl Carbonyl; amino; carbamoyl; mono (C ₁ -C ₆ alkyl) carbamoyl; di (C ₁ -C ₆ alkyl) carbamoyl, and the same or differently have 1 to 3 substituents selected from the following group Mono C ₇ -C ₁₅ arylcarbonylamino, wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy],
R ² is a hydrogen atom; Halogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkyl groups substituted with halogen or C ₁ -C ₆ alkoxy; C ₂ -C ₆ alkenyl group; C ₂ -C ₆ alkynyl group; C ₃ -C ₁₀ cycloalkyl group; C ₃ -C ₁₀ cycloalkenyl group; C ₁ -C ₆ alkoxy group; Cyano group; Carboxyl group; C ₁ -C ₇ alkanoyl group; C ₂ -C ₇ alkoxycarbonyl group; Carbamoyl group; Mono (C ₁ -C ₆ alkyl) carbamoyl group or di (C ₁ -C ₆ alkyl) carbamoyl group,
R ³ is an amino group, a mono C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group, a mono C ₁ -C ₇ alkanoylamino group, a mono C ₂ -C ₇ alkoxycarbonylamino group, the same or differently Mono C ₇ -C ₁₅ arylcarbonylamino groups which may have 1 to 3 substituents selected from the following group (wherein the substituent groups are halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy), or 1 A 5- to 6-membered saturated heterocyclic group containing a nitrogen atom, which may further contain one nitrogen atom or an oxygen atom, provided that the group is bonded on a nitrogen atom,
X represents an oxygen atom or a sulfur atom
n represents an integer of 2 to 6).
[2" claim-type="Currently amended] According to claim ¹ , R ¹ is the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent group, or may have 1 to 3 said substituents and a nitrogen atom, Isoxazole derivatives or pharmacologically acceptable salts thereof, which are 5- to 6-membered aromatic heterocyclic groups having 1 to 2 heteroatoms identically or differently selected from the group consisting of oxygen atoms and sulfur atoms, wherein the substituent group is halogen; C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent groups are halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy); Benzyl, fluorobenzyl, chlorobenzyl, difluorobenzyl, dichlorobenzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl; Phenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 2,4-dichlorophenoxy, 4-methylphenoxy, 4-methoxyphenoxy; Benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy, 2,4-difluorobenzyloxy, 2,4-dichlorobenzyloxy, 4-methylbenzyloxy, 2,4-dimethylbenzyloxy, 4- Methoxybenzyloxy; Cyano; Nitro; Hydroxyl group; Acetoxy; C ₂ -C ₇ alkoxycarbonyl; Amino; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; Di (C ₁ -C ₆ alkyl) carbamoyl; Benzoylamino, 4-fluorobenzoylamino, 4-chlorobenzoylamino, 2,4-dichlorobenzoylamino, 4-toluoylamino and 4-anisoylamino].
[3" claim-type="Currently amended] According to claim ¹ , R ¹ is the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent group, or may have 1 to 3 said substituents and a nitrogen atom, Isoxazole derivatives or pharmacologically acceptable salts thereof, which are 5- to 6-membered aromatic heterocyclic groups having 1 to 2 heteroatoms identically or differently selected from the group consisting of oxygen atoms and sulfur atoms, wherein the substituent group is halogen; C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Cyano; C ₂ -C ₇ alkoxycarbonyl; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; And di (C ₁ -C ₆ alkyl) carbamoyl].
[4" claim-type="Currently amended] According to claim ¹ , R ¹ is the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent group, or may have 1 to 2 said substituents and a nitrogen atom, Isoxazole derivatives or pharmacologically acceptable salts thereof, which are 5- to 6-membered aromatic heterocyclic groups having 1 to 2 heteroatoms identically or differently selected from the group consisting of oxygen atoms and sulfur atoms [The substituent group is halogen, C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ Alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methyl Carbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-di Ethylcarbamoyl].
[5" claim-type="Currently amended] 2. The bivalent moiety according to claim 1, wherein R ¹ is the same or differently, a phenyl group which may have 1 to 3 substituents selected from the following substituent groups, or a furyl group, thienyl group or pyridyl group which may have 1 to 2 substituents. Solazole derivatives or pharmacologically acceptable salts thereof [The corresponding substituent groups are halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarba Mole and N, N-dimethylcarbamoyl].
[6" claim-type="Currently amended] The isoxazole derivative according to claim 1, wherein R ¹ is the same or different phenyl group which may have 1 to 2 substituents selected from the following substituent groups, or a furyl group, thienyl group or pyridyl group which may have 1 substituent. Or a pharmacologically acceptable salt thereof, wherein the substituent group is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy.
[7" claim-type="Currently amended] 2. A double bond according to claim 1, wherein R ¹ is a phenyl group, fluorophenyl group, chlorophenyl group, difluorophenyl group, dichlorophenyl group, methylphenyl group, 2-furyl group, 3-furyl group, 2-thienyl group or 3-thienyl group Sazole derivatives or pharmacologically acceptable salts thereof.
[8" claim-type="Currently amended] The isoxazole derivative according to claim 1, wherein R ¹ is a phenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2-furyl group or 2-thienyl group Or pharmacologically acceptable salts thereof.
[9" claim-type="Currently amended] R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, 2-fluoroethyl group, 1-chloroethyl group, 2-chloro Ethyl group, 2,2,2-trifluoroethyl group, methoxymethyl group, methoxyethyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, 2 -Cyclopentenyl group, 3-cyclopentenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, methoxy group, ethoxy group, cyano group, carboxyl group, formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, Isoxazole derivatives which are carbamoyl groups, methylcarbamoyl groups, ethylcarbamoyl groups or N, N-dimethylcarbamoyl groups or pharmacologically acceptable salts thereof.
[10" claim-type="Currently amended] The isoxazole derivative according to claim ₁ or a pharmacologically acceptable salt thereof, wherein R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group.
[11" claim-type="Currently amended] The isoxazole derivative according to claim ₁ or a pharmacologically acceptable salt thereof, wherein R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, an allyl group, isopropenyl group, 2-butenyl group, or propargyl group.
[12" claim-type="Currently amended] The isoxazole derivative according to claim 1 or a pharmacologically acceptable salt thereof, wherein R ² is a hydrogen atom, a chlorine atom, an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a t-butyl group.
[13" claim-type="Currently amended] The isoxazole derivative according to claim 1 or a pharmacologically acceptable salt thereof, wherein R ² is a hydrogen atom or an isopropyl group.
[14" claim-type="Currently amended] A compound according to claim 1, wherein R ³ contains an amino group, a mono C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group or one nitrogen atom, and further contains one nitrogen atom or an oxygen atom Isoxazole derivatives or pharmacologically acceptable salts thereof which are 5- to 6-membered saturated heterocyclic groups which can be bonded on a nitrogen atom.
[15" claim-type="Currently amended] The isoxazole derivative according to claim 1 or a pharmacologically acceptable salt thereof, wherein R ³ is an amino group, a methylamino group, an ethylamino group, an N, N-dimethylamino group, a piperidyl group, or a morpholinyl group.
[16" claim-type="Currently amended] The isoxazole derivative according to claim 1 or a pharmacologically acceptable salt thereof, wherein R ³ is an amino group.
[17" claim-type="Currently amended] The isoxazole derivative according to claim 1 or a pharmacologically acceptable salt thereof, wherein X is an oxygen atom.
[18" claim-type="Currently amended] The isoxazole derivative according to claim 1 or a pharmacologically acceptable salt thereof.
[19" claim-type="Currently amended] According to claim ¹ , R ¹ is the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent group, or may have 1 to 3 said substituents and a nitrogen atom, It is a 5-6 membered aromatic heterocyclic group which has 1-2 heteroatoms selected from the same or differently from the group which consists of an oxygen atom and a sulfur atom [The substituent group is halogen; C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Cyano; C ₂ -C ₇ alkoxycarbonyl; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; And di (C ₁ -C ₆ alkyl) carbamoyl],
R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group,
R ³ contains an amino group, a mono C ₁ -C ₆ alkylamino group, a di (C ₁ -C ₆ alkyl) amino group or one nitrogen atom, and may further contain one nitrogen atom or oxygen atom to five to one member Isoxazole derivatives or pharmacologically acceptable salts thereof which are six-membered saturated heterocyclic groups, provided that the groups are bonded on a nitrogen atom.
[20" claim-type="Currently amended] According to claim ¹ , R ¹ is the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent group, or may have 1 to 3 said substituents and a nitrogen atom, It is a 5-6 membered aromatic heterocyclic group which has 1-2 heteroatoms selected from the same or differently from the group which consists of an oxygen atom and a sulfur atom [The substituent group is halogen; C ₁ -C ₆ alkyl; A C ₁ -C ₆ alkyl substituted with halogen or C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkoxy; C ₆ -C ₁₄ aryl which may have 1 to 3 substituents, identically or differently selected from the following group (wherein the substituent group is halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy); Cyano; C ₂ -C ₇ alkoxycarbonyl; Carbamoyl; Mono (C ₁ -C ₆ alkyl) carbamoyl; And di (C ₁ -C ₆ alkyl) carbamoyl],
R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group,
R ³ is an amino group,
X is an oxygen atom,
Isoxazole derivatives wherein n is 2 or a pharmacologically acceptable salt thereof.
[21" claim-type="Currently amended] According to claim ¹ , R ¹ is the same or different C ₆ -C ₁₄ aryl group which may have 1 to 3 substituents selected from the following substituent group, or may have 1 to 2 said substituents and a nitrogen atom, It is a 5-6 membered aromatic heterocyclic group which has 1-2 heteroatoms selected from the same or differently from the group which consists of an oxygen atom and a sulfur atom. [The substituent group is halogen; C ₁ -C ₄ alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, C ₁ -C ₄ alkoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano, methoxycarbonyl, ethoxycarbonyl, carbamoyl, Methylcarbamoyl, ethylcarbamoyl, N, N-dimethylcarbamoyl and N, N-diethylcarbamoyl],
R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, an allyl group, isopropenyl group, 2-butenyl group or propargyl group,
R ³ is an amino group,
X is an oxygen atom,
Isoxazole derivatives wherein n is 2 or a pharmacologically acceptable salt thereof.
[22" claim-type="Currently amended] The compound according to claim 1, wherein R ¹ is the same or different, is a phenyl group which may have 1 to 3 substituents selected from the following substituent groups, or a furyl group, thienyl group or pyridyl group which may have 1 to 2 substituents described above. [The pertinent substituent group is halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl and N, N-dimethylcar It's bar-moil] R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₄ alkyl group, an allyl group, isopropenyl group, 2-butenyl group or propargyl group,
R ³ is an amino group,
X is an oxygen atom,
Isoxazole derivatives wherein n is 2 or a pharmacologically acceptable salt thereof.
[23" claim-type="Currently amended] The compound according to claim 1, wherein R ¹ is the same or different, is a phenyl group which may have 1 to 2 substituents selected from the following substituent groups, or a furyl group, thienyl group or pyridyl group which may have one of the above substituents. Substituent groups are fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy],
R ² is a hydrogen atom, a chlorine atom, an ethyl group, a propyl group, isopropyl group, isobutyl group or t-butyl group,
R ³ is an amino group,
X is an oxygen atom,
Isoxazole derivatives wherein n is 2 or a pharmacologically acceptable salt thereof.
[24" claim-type="Currently amended] The compound according to claim 1, wherein R ¹ is a fluorophenyl group, a chlorophenyl group, a difluorophenyl group, a dichlorophenyl group, a methylphenyl group, 2-furyl group, 3-furyl group, 2-thiethyl group, or 3-thienyl group,
R ² is a hydrogen atom, a chlorine atom, an ethyl group, a propyl group, isopropyl group, isobutyl group or t-butyl group,
R ³ is an amino group,
X is an oxygen atom,
Isoxazole derivatives wherein n is 2 or a pharmacologically acceptable salt thereof.
[25" claim-type="Currently amended] The compound according to claim 1, wherein R ¹ is a phenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2-furyl group or 2-thienyl group,
R ² is a hydrogen atom or an isopropyl group,
R ³ is an amino group,
X is an oxygen atom,
Isoxazole derivatives wherein n is 2 or a pharmacologically acceptable salt thereof.
[26" claim-type="Currently amended] The compound of claim 1, wherein 3- (2-aminoethoxy) -5-phenylisoxazole,
3- (2-aminoethoxy) -4-chloro-5-phenylisoxazole,
3- (2-aminoethoxy) -4-ethyl-5-phenylisoxazole,
3- (2-aminoethoxy) -5-phenyl-4-propylisoxazole,
3- (2-aminoethoxy) -4-isopropyl-5-phenylisoxazole,
3- (2-aminoethoxy) -4-isobutyl-5-phenylisoxazole,
3- (2-aminoethoxy) -5- (2-chlorophenyl) -4-isopropylisoxazole,
3- (2-aminoethoxy) -5- (4-chlorophenyl) isoxazole,
3- (2-aminoethoxy) -5- (4-chlorophenyl) -4-isopropylisoxazole,
3- (2-aminoethoxy) -5- (2,4-dichlorophenyl) -4-isopropylisoxazole,
3- (2-aminoethoxy) -5- (2-furyl) -4-isopropylisoxazole,
3- (2-aminoethoxy) -5- (2-thienyl) isoxazole,
3- (2-aminoethoxy) -4-chloro-5- (2-thienyl) isoxazole,
3- (2-aminoethoxy) -4-isopropyl-5- (2-thienyl) isoxazole or
4-allyl-3- (2-aminoethoxy) -5-phenylisoxazole or its pharmacologically acceptable salt.
[27" claim-type="Currently amended] A composition for treating or preventing neurological diseases, comprising the isoxazole derivative according to any one of claims 1 to 26 or a pharmacologically acceptable salt thereof as an active ingredient.
[28" claim-type="Currently amended] A composition for the treatment or prevention of manic-depressive diseases comprising the isoxazole derivative according to any one of claims 1 to 26 or a pharmacologically acceptable salt thereof as an active ingredient.
[29" claim-type="Currently amended] Use of the isoxazole derivative according to any one of claims 1 to 26 or a pharmacologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of neurological diseases.
[30" claim-type="Currently amended] Use of the isoxazole derivatives or pharmacologically acceptable salts thereof for the manufacture of a medicament for the treatment or prevention of manic-depressive diseases of the isoxazole derivatives or pharmacologically acceptable salts thereof according to claim 1 to 26.
[31" claim-type="Currently amended] A method for treating or preventing neurological diseases in which a pharmacologically effective amount of the isoxazole derivative according to any one of claims 1 to 26 or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal.
[32" claim-type="Currently amended] A method for treating or preventing a manic-depressive disease in which a pharmacologically effective amount of the isoxazole derivative according to any one of claims 1 to 26 or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal.

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同族专利:

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公开号 | 公开日

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NO983920L|1998-10-27|

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WO1997031906A1|1997-09-04|

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EP0885891A4|2001-02-21|

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HU9900400A2|1999-05-28|

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HU9900400A3|2001-06-28|

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NO983920D0|1998-08-26|

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CZ272598A3|1999-01-13|

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US6005116A|1999-12-21|

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AU1812297A|1997-09-16|

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CA2247439A1|1997-09-04|

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RU2165415C2|2001-04-20|

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CN1216986A|1999-05-19|

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EP0885891A1|1998-12-23|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1996-02-27|Priority to JP3981996

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1996-02-27|Priority to JP96-39819

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1997-02-27|Application filed by 가와무라 요시부미, 상꾜 가부시키가이샤

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1999-12-27|Publication of KR19990087339A

优先权:

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申请号 | 申请日 | 专利标题

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JP3981996|1996-02-27|

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JP96-39819|1996-02-27|