WO2010023946A1 - Novel uracil compound having nitrogenated heterocyclic ring or salt thereof - Google Patents

Novel uracil compound having nitrogenated heterocyclic ring or salt thereof Download PDF

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WO2010023946A1
WO2010023946A1 PCT/JP2009/004229 JP2009004229W WO2010023946A1 WO 2010023946 A1 WO2010023946 A1 WO 2010023946A1 JP 2009004229 W JP2009004229 W JP 2009004229W WO 2010023946 A1 WO2010023946 A1 WO 2010023946A1
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group
carbon atoms
added
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atom
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PCT/JP2009/004229
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French (fr)
Japanese (ja)
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正哲 福岡
達史 横川
成司 宮原
均 宮腰
稚子 矢野
淳子 田口
弥生 高尾
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大鵬薬品工業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a novel uracil compound or a salt thereof having excellent human deoxyuridine triphosphatase inhibitory activity and useful as a therapeutic agent for diseases related to deoxyuridine triphosphatase, such as an antitumor agent.
  • Deoxyuridine triphosphatase (hereinafter also referred to as dUTPase (EC3.6.1.23)) is a preventive DNA repair enzyme. It is an enzyme that specifically recognizes only deoxyuridine triphosphate (hereinafter referred to as dUTP) among natural nucleic acid triphosphates and decomposes it into deoxyuridine monophosphate (hereinafter referred to as dUMP) and pyrophosphate (Non-patent Document 1) , (1) reduce the amount of dUTP pool in the cell to avoid accidental incorporation of uracil into DNA instead of thymine, (2) important de novo for supplying thymine in DNA It is thought to be responsible for two reactions: supplying the substrate dUMP of thymidylate synthase responsible for the pathway (Non-patent Document 2).
  • DUTPase is known to be essential for cell survival in both prokaryotes and eukaryotes. Therefore, this enzyme is an antitumor drug (Non-Patent Documents 3 and 4), an antimalarial drug (Patent Documents 1 and 5), an antituberculosis drug (Non-Patent Document 6), and an anti-pylori drug (Patent Document 2).
  • Anti-parasitic drugs such as trypanosoma and leishmania (non-patent document 7), and herpesviruses such as human herpes simplex virus, cytomegalovirus, Epstein-Barr virus (non-patent document 8) and vaccinia virus (non-patent document 9). It has been suggested that it can be a target for antiviral drugs such as
  • dUTPase is attracting attention as a target for therapeutic agents for various diseases, and dUTPase inhibitors are also widely studied.
  • dUTPase inhibitors for example, triphosphate mimic type low molecular weight compounds (for example, Patent Document 3, Non-Patent Document 10 and the like), 5′-O-substituted phenyl-deoxyuridine compounds (Non-Patent Document 11) are known. Yes. However, none of these compounds have sufficient inhibitory activity against human dUTPase and are not compounds used as pharmaceuticals. Therefore, development of a dUTPase inhibitor having a superior human dUTPase inhibitory activity and useful as a therapeutic agent for a disease related to dUTPase, such as an antitumor agent, is strongly desired.
  • An object of the present invention is to provide a uracil compound having a nitrogen-containing heterocyclic ring or a salt thereof, which has excellent human dUTPase inhibitory activity and is useful as an antitumor agent or the like.
  • a uracil compound having a nitrogen-containing heterocycle in the uracil ring N-1 side chain or a salt thereof has excellent human dUTPase inhibitory activity.
  • the present invention was completed by discovering that it is useful as a medicine such as an antitumor drug.
  • X represents a divalent hydrocarbon group which may have a hetero atom between carbon atoms or at the terminal
  • Y represents a hydrogen atom or a fluorine atom
  • A represents a nitrogen-containing unsaturated heterocyclic group which may have a substituent
  • R 1 and R 2 are the same or different and are a hydrogen atom, a cyano group, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon atom having 2 to An alkenyl group having 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms which may have a substituent, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group, an aryl group, an unsaturated heterocyclic group, or a substituent.
  • the aralkyl group which may be sufficient is shown.
  • the uracil compound represented by these, or its salt is provided.
  • the present invention also provides a pharmaceutical composition containing a uracil compound represented by the formula (I) or a salt thereof. Moreover, this invention provides the human dUTPase inhibitor containing the uracil compound or its salt represented by a formula (I). The present invention also provides use of the uracil compound represented by the formula (I) or a salt thereof for producing a human dUTPase inhibitor. The present invention also provides a method for inhibiting human dUTPase, comprising administering a compound represented by formula (I) or a salt thereof.
  • novel uracil compound or a salt thereof of the present invention has excellent human dUTPase inhibitory activity, and is useful as a drug for diseases related to dUTPase, such as antitumor drugs.
  • the novel uracil compound of the present invention is represented by the above general formula (I) and has a feature that the uracil ring N-1 substituent has a nitrogen-containing heterocyclic structure.
  • Patent Document 1 as a terminal of the uracil ring N-1 position substituent, a substituent such as a trityl group or a triphenylsilyl group (-E (R 6 ) (R 7 ) (R 8 A uracil compound having a) group) is disclosed, which shows dUTPase inhibitory activity and is useful as an antimalarial drug.
  • a compound having a nitrogen-containing unsaturated heterocyclic structure of the compound of the present invention is not disclosed. Further, as shown in Test Examples described later, compounds having a trityl group at the terminal of the uracil ring N-1 position substituent showed almost no human dUTPase inhibitory activity.
  • examples of the “substituent” include a halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, halogenoalkyl group, alkoxyalkyl group, cycloalkyl group, cycloalkyl-alkyl group, aralkyl group, alkenyl group.
  • examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.
  • the alkyl group and the halogenoalkyl group preferably represent a linear or branched alkyl group having 1 to 6 carbon atoms or a group obtained by substituting the halogen atom for the alkyl group, Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a monofluoromethyl group, a trifluoromethyl group, and a 2,2-difluoroethyl group.
  • the alkoxyalkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted with linear or branched alkoxy having 1 to 6 carbon atoms, such as a methoxymethyl group or ethoxymethyl group. Group, methoxyethyl group and the like.
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • the cycloalkyl-alkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted with cycloalkyl having 3 to 7 carbon atoms, and includes a cyclopropylmethyl group, a cyclopropylethyl group, a cyclopropyl group, A butylmethyl group, a cyclopentylmethyl group, etc. are mentioned.
  • the aralkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms substituted with an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as a benzyl group, A phenylethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group, etc. are mentioned.
  • the alkenyl group includes a carbon-carbon double bond, preferably a hydrocarbon group having 2 to 6 carbon atoms, and includes a vinyl group, an allyl group, a methylvinyl group, a propenyl group, a butenyl group, A pentenyl group, a hexenyl group, etc. are mentioned.
  • the alkynyl group is a hydrocarbon group containing a carbon-carbon triple bond, preferably 2 to 6 carbon atoms, and examples thereof include an ethynyl group and a propargyl group.
  • the alkoxy group and the halogenoalkoxy group preferably represent a linear or branched alkoxy group having 1 to 6 carbon atoms, or a group in which the above halogen atom is substituted for these alkoxy groups.
  • Methoxy group, ethoxy group, n-propoxy group isopropoxy group, 1-methylpropoxy group, n-butoxy group, sec-butoxy group, isobutoxy group, 2-methyl-butoxy group, neopentyloxy group, pentane-2 -Yloxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 1,1-difluoroethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2, 2-tetrafluoroethoxy group, perfluoroethoxy group, 3-fluoro-2- (fluoromethyl) -propyl Epoxy group, 1,3-difluoro-2-yloxy group, 2,2,3,3,3-pentafluoro-1-propoxy group and the like.
  • the cycloalkoxy group is preferably a cycloalkoxy group having 3 to 7 carbon atoms, and examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
  • the cycloalkyl-alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms substituted by cycloalkyl having 3 to 7 carbon atoms, such as cyclopropylmethoxy group, 1-methylcyclopropylmethoxy group.
  • the aralkyloxy group is preferably an oxy group having the aralkyl group, and examples thereof include a benzyloxy group, a phenylethoxy group, a phenylpropoxy group, a naphthylmethoxy group, and a naphthylethoxy group.
  • the mono- or dialkylamino group represents an amino group mono- or di-substituted by the alkyl group, and includes a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, and a methylethylamino group. Etc.
  • the cycloalkyl-alkylamino group represents an alkylamino group substituted with the above cycloalkyl group, and examples thereof include a cyclopropylmethylamino group, a cyclobutylmethylamino group, and a cyclopentylmethylamino group.
  • examples of the cycloalkylidene structure include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.
  • the acyl group includes a straight or branched carbon number of 1 to 6 such as formyl group, acetyl group, propionyl group, n-butyryl group, isobutyryl group, valeryl group, isovaleryl group, and pivaloyl group.
  • the acyloxy group includes straight or branched carbon such as acetoxy group, propionyloxy group, n-butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group, etc. Examples thereof include an acyloxy group of 1 to 6 and a benzoyloxy group.
  • the saturated or unsaturated heterocyclic group is preferably a monocyclic or bicyclic saturated group having preferably one or two oxygen atoms, nitrogen atoms and sulfur atoms.
  • an unsaturated heterocyclic group for example, pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, morpholino group, thiomorpholino group, homopiperidinyl group, tetrahydrofuryl group, tetrahydropyryl group, imidazolyl group, thienyl group, furyl Group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolinyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group, pyridaziny
  • the aryl group is preferably an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group.
  • the saturated heterocyclic oxy group is a monocyclic saturated heterocyclic group having one or two oxygen atoms, nitrogen atoms or sulfur atoms, for example, pyrrolidinyl group, piperidinyl group, An oxy group having a piperazinyl group, a hexamethyleneimino group, a morpholino group, a thiomorpholino group, a homopiperidinyl group or the like, such as a tetrahydrofuryloxy group or a tetrahydropyryloxy group.
  • the “divalent hydrocarbon group optionally having a heteroatom between carbon atoms or terminals” represented by X has a heteroatom between carbon atoms or terminals.
  • Aryl-alkyl groups are preferred.
  • examples of the “heteroatom” include an oxygen atom, a nitrogen atom, and a sulfur atom.
  • the “heteroatom” that may be present between carbon atoms or at the terminal of an alkylene group having 1 to 6 carbon atoms Is preferably an oxygen atom, and a heteroatom which may be present between or at the terminals of a divalent alkyl-aryl-alkyl group having 6 to 20 carbon atoms is preferably an oxygen atom or a sulfur atom.
  • C 1-6 alkylene group is preferably a linear or branched C 1-6 alkylene group, for example, methylene, ethylene, trimethylene, tetra Examples include methylene group, pentamethylene group, hexamethylene group, propylene group, butylene group, dimethyltrimethylene group, dimethyltetramethylene group, and ethyltrimethylene group.
  • a linear alkylene group having 2 to 3 carbon atoms and a branched alkylene group having 4 to 6 carbon atoms are preferable, and an ethylene group, a trimethylene group, and a dimethyltrimethylene group are more preferable.
  • examples of the “divalent aryl group having 6 to 14 carbon atoms” include a phenylene group and a naphthylene group, and a phenylene group is preferable. Of these, a 1,3-phenylene group is particularly preferred.
  • the divalent alkyl-aryl-alkyl group having 6 to 20 carbon atoms is preferably a C 1-6 alkyl-C 6-10 aryl-C 1-6 alkyl group.
  • examples of the C 6-10 aryl group include a phenylene group and a naphthylene group, but a phenylene group is preferable, and a 1,2-phenylene group is particularly preferable.
  • alkyl-aryl-alkyl group examples include the following general formula (II)
  • Z represents an oxygen atom or a sulfur atom
  • R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • the Z terminal in Formula (II) is the same as in Formula (I)).
  • It binds to a methylene group
  • the carbon terminal in formula (II) binds to A in formula (I).
  • the group represented by these is preferable.
  • examples of the alkyl group having 1 to 6 carbon atoms represented by R 3 include the same alkyl groups as the above-mentioned “substituent”, but an alkyl group having 1 to 3 carbon atoms is preferable.
  • a methyl group is more preferable.
  • X is an ethylene group, a trimethylene group, and the following formulas (IV) to (VII) in terms of human dUTPase inhibitory action.
  • the oxygen end in formula (IV) is bonded to the methylene group in formula (I), the methylene end in formula (IV) is bonded to A in formula (I), and the methylene group in formula (VII)
  • the terminal is bonded to the methylene group in formula (I), and the dimethylmethylene terminal in formula (VII) is bonded to A in formula (I).
  • any group selected from the group represented by formula (II) and the group represented by formula (II) is preferable.
  • an ethylene group, a trimethylene group or a group represented by the formula (IV) is particularly preferable.
  • Y is a fluorine atom
  • a trimethylene group or a group represented by the formula (IV) is particularly preferable.
  • the “nitrogen-containing unsaturated heterocyclic group” of the “nitrogen-containing unsaturated heterocyclic group which may have a substituent” represented by A includes at least one in the ring structure.
  • An unsaturated heterocyclic group containing a nitrogen atom for example, imidazolyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolinyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group, Examples include a pyridazinyl group, an indolyl group, an isoindolyl group, an indazolyl group, a benzimidazolyl group, a benzoxazole group, a benzothiazolyl group, a purinyl group, a quinolyl group, an is
  • a 3- to 6-membered nitrogen-containing unsaturated heterocyclic group is preferred, a 5-membered nitrogen-containing unsaturated heterocyclic group is more preferred, and a pyrrolyl group, pyrazolinyl group, triazolyl group, or tetrazolyl group is more preferred.
  • any one of the nitrogen-containing unsaturated heterocyclic groups selected from the following is preferable, and any nitrogen-containing unsaturated heterocyclic group selected from the formulas (X) to (XII) or the formula (XV) is particularly preferable.
  • Y is a fluorine atom
  • a nitrogen-containing unsaturated heterocyclic group represented by the formula (XII) is particularly preferable.
  • the “alkyl group having 1 to 6 carbon atoms” is linear or branched.
  • An alkyl group having 1 to 6 carbon atoms is preferable, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, etc.
  • An alkyl group having 1 to 3 carbon atoms is preferable, a methyl group or an ethyl group is more preferable, and a methyl group is more preferable.
  • the “substituent” that the alkyl group having 1 to 6 carbon atoms may have is preferably a halogen atom, a hydroxyl group, or an alkoxy group having 1 to 6 carbon atoms. More preferred are groups, methoxy groups and ethoxy groups.
  • the “optionally substituted alkyl group having 1 to 6 carbon atoms” represented by R 1 and R 2 includes a methyl group, a monofluoromethyl group, a difluoroethyl group, a methoxymethyl group, an ethoxy group.
  • a methyl group, a methoxyethyl group and an ethoxyethyl group are preferred.
  • the “alkenyl group having 2 to 6 carbon atoms” may be, for example, the above “substituent”. Although the same alkenyl group is mentioned, a vinyl group is preferable and unsubstituted is preferable.
  • the “alkynyl group having 2 to 6 carbon atoms” represented by R 1 and R 2 includes, for example, the above “substituent” and although the same alkynyl group is mentioned, an ethynyl group is preferable and unsubstituted is preferable.
  • Examples of the “monoalkylaminocarbonyl group” represented by R 1 and R 2 include a carbonyl group having a monoalkylamino group similar to the above “substituent”.
  • dialkylaminocarbonyl group represented by R 1 and R 2 include a carbonyl group having a dialkylamino group similar to the above “substituent”, and a dimethylaminocarbonyl group is preferred.
  • Examples of the “aryl group” represented by R 1 and R 2 include aryl groups having 6 to 14 carbon atoms such as a phenyl group and a naphthyl group.
  • Examples of the “unsaturated heterocyclic group” represented by R 1 and R 2 include unsaturated heterocyclic groups similar to the above “substituent”, but a thiazolyl group is preferred.
  • the “aralkyl group optionally having substituent (s)” represented by R 1 and R 2 is, for example, an aralkyl group having 7 to 24 carbon atoms, such as a C 6-10 aryl-C 1-6 alkyl group. More preferred is a phenyl-C 1-6 alkyl group. Specifically, a benzyl group which may have a substituent and a phenylethyl group which may have a substituent are preferable.
  • R 6 and R 7 are the same or different and each represents a hydrogen atom or a phenyl group
  • R 8 and R 9 are the same or different and each represents a hydrogen atom or (This represents an optionally substituted alkoxy group having 1 to 6 carbon atoms.)
  • the benzyl group represented by these is preferable.
  • the “substituent” as the “substituent” as described above for the “alkoxy group having 1 to 6 carbon atoms” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 Although the same alkoxy group is mentioned, a methoxy group is preferable.
  • the “substituent” in the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 is preferably a cycloalkyl group, more preferably a cyclopropyl group. .
  • R 6 and R 7 are the same or different.
  • R 8 and R 9 are the same or different and represent a hydrogen atom, a halogen atom
  • a good phenyl group or a thienyl group optionally having a substituent. Is preferred.
  • Examples of the “alkyl group having 1 to 6 carbon atoms” represented by R 4 and R 5 include the same alkyl groups as the above “substituent”, but a methyl group is preferred.
  • Examples of the “alkyl group having 1 to 6 carbon atoms” represented by R 6 and R 7 include the same alkyl groups as described above, preferably a methyl group, an ethyl group and an isopropyl group, more preferably an ethyl group. preferable.
  • the substituent of the “optionally substituted phenyl group” represented by R 6 and R 7 is preferably a halogen atom, an alkoxy group having 1 to 6 carbon atoms, a fluorine atom, a chlorine atom, a methoxy group Is more preferable.
  • halogen atom represented by R 8 and R 9 include the same halogen atoms as the above “substituent”, but a chlorine atom and a fluorine atom are more preferable.
  • alkoxy group having 1 to 6 carbon atoms” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 include, for example, the above “substituent” and Although the same alkoxy group is mentioned, a linear or branched alkoxy group having 1 to 6 carbon atoms is preferable, and a methoxy group, an ethoxy group, an isobutoxy group, and a sec-butoxy group are more preferable.
  • Examples of the “substituent” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 include the same substituents as the above “substituent”.
  • a halogen atom and a cycloalkyl group having 3 to 7 carbon atoms are preferable, and a fluorine atom, a cyclopropyl group, a 1-methylcyclopropyl group, a cyclobutyl group, and a cycloalkylidenyl group are more preferable.
  • the cycloalkylidenyl group preferably has a cycloalkylidene structure having 3 to 6 carbon atoms. Specific examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene, which inhibit human dUTPase inhibition. From the viewpoint of action, cyclopropylidene is preferred.
  • Examples of the “C3-C7 cycloalkoxy group optionally having an oxygen atom between carbon atoms” represented by R 8 and R 9 include, for example, the above-mentioned “substituent” cycloalkoxy group and saturated complex Although the same group as a ring oxy group is mentioned, A cyclobutyloxy group, a cyclopentyloxy group, a tetrahydrofuryloxy group, and a tetrahydropyryloxy group are preferable.
  • Examples of the substituent of the “optionally substituted phenyl group” represented by R 8 and R 9 include the same halogen atoms as the above “substituent”, but a fluorine atom and a chlorine atom are more preferable. . Examples of the substituent of the “optionally substituted thienyl group” represented by R 8 and R 9 include the same substituents as the above “substituent”.
  • R 4 and R 5 are preferably a hydrogen atom and a methyl group, and particularly preferably a hydrogen atom, from the viewpoint of human dUTPase inhibitory action.
  • R 6 is preferably a hydrogen atom or a hydroxyl group from the viewpoint of human dUTPase inhibitory action
  • R 7 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a fluorine as a substituent from the viewpoint of human dUTPase inhibitory action.
  • a phenyl group optionally having an atom, a chlorine atom, or an alkoxy group having 1 to 6 carbon atoms is particularly preferred.
  • R 8 and R 9 have a hydrogen atom, a fluorine atom, a chlorine atom, a halogen atom as a substituent, a cycloalkyl group having 3 to 7 carbon atoms or a cycloalkylidenyl group from the viewpoint of human dUTPase inhibitory action.
  • Preferred phenyl group or thienyl group is preferable.
  • R 1 is a hydrogen atom, a cyano group, a methyl group, a monofluoromethyl group, a difluoroethyl group, a vinyl group, an ethynyl group, or a methoxy group.
  • a dimethyl ether group, a dimethylaminocarbonyl group or a phenyl group, wherein R 2 is a hydrogen atom, a phenyl group, a benzyl group (n 0) represented by the general formula (III), or a general formula (III).
  • a phenylethyl group (n 1), or a thiazolyl group.
  • the uracil N-1 compound of the present invention can be produced according to the following reaction process formula. [Process A]
  • the hydroxyl group of the compound represented by the general formula (1) that can be easily obtained or obtained by a known method is methanesulfonylated by a generally known method, and then reacted with an azido reagent.
  • a compound represented by the general formula (2) can be produced.
  • the reaction solvent used for azidation is not particularly limited as long as it does not affect the reaction, but N, N-dimethylformamide (hereinafter DMF), tetrahydrofuran (hereinafter THF), dioxane, acetonitrile, toluene, dichloromethane, etc. And is preferably DMF.
  • Examples of the azidation reagent to be used include sodium azide and lithium azide, and sodium azide is preferred.
  • the number of equivalents is 0.8 to 10 equivalents, preferably 1.0 to 6.0 equivalents.
  • the reaction temperature is 10 to 120 ° C, preferably 50 to 100 ° C.
  • the reaction time is 1.0 to 24 hours, preferably 3.0 to 12 hours.
  • the compound represented by the general formula (3) can be produced by reacting the compound represented by the general formula (2) with triphenylphosphine in the presence of water and then treating with hydrochloric acid.
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include DMF, THF, dioxane, acetonitrile and the like, preferably THF.
  • the number of equivalents of triphenylphosphine used is 1.0 to 5.0 equivalents, preferably 1.1 to 2.0 equivalents.
  • the reaction temperature is 0 to 120 ° C, preferably 10 to 60 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1.0 to 3.0 hours.
  • Examples of the base to be used include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and preferably triethylamine.
  • the number of equivalents is 1.0 to 10 equivalents, preferably 1.1 to 3.0 equivalents.
  • the reaction temperature is -78 to 50 ° C, preferably -40 to 30 ° C.
  • the reaction time is 1.0 to 24 hours, preferably 2.0 to 3.0 hours.
  • the compound represented by the general formula (5) can be produced by reacting the compound represented by the general formula (4) with a generally known acid.
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include ethyl acetate, dioxane, water, methanol, ethanol and the like, and dioxane is preferable.
  • the acid to be used include inorganic acids such as hydrogen chloride, hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid, and hydrogen chloride is preferable.
  • the number of equivalents is 0.5-1000 equivalents, preferably 1.0-100 equivalents.
  • the reaction temperature is 0 to 100 ° C., preferably 10 to 30 ° C.
  • the reaction time is 0.1 to 5.0 hours, preferably 0.5 to 1.0 hours.
  • 2,4-bis (trimethylsilyloxy) pyrimidine can be produced by the method described in Nucleosides & Nucleotides, 4, 565-585 (1985), and 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine is easy Is available.
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but acetone, THF, diethyl ether, dioxane, 1,2-dichloromethane, dichloroethane and the like are exemplified, and 1,2-dichloroethane is preferable. It is.
  • the number of equivalents of 2,4-bis (trimethylsilyloxy) pyrimidine or 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents.
  • the Lewis acid used include boron trichloride (hereinafter referred to as BCl 3 ), boron tribromide, trimethylsilyl iodide, and the like, and BCl 3 is preferred.
  • the number of equivalents is 0.1 to 2.0 equivalents, preferably 0.2 to 0.4 equivalents.
  • the number of equivalents of iodine is 0.001 to 0.5 equivalents, preferably 0.1 to 0.2 equivalents.
  • the reaction temperature is 50 to 120 ° C, preferably 60 to 100 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1.0 to 10 hours.
  • the compound represented by the general formula (6) obtained by a generally known method is activated with a base and reacted with a readily available chloroformate to represent the compound represented by the general formula (7).
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include DMF, THF, dioxane, diethyl ether, etc., preferably THF.
  • Examples of the base to be used include metal hydride, n-butyllithium, sec-butyllithium, tert-butyllithium and the like, preferably n-butyllithium.
  • the number of equivalents is 0.8 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents.
  • the number of equivalents of chloroformate is 0.8 to 2.0 equivalents, preferably 1.0 to 1.2 equivalents.
  • the reaction temperature is ⁇ 100 to 100 ° C., preferably ⁇ 78 to 0 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1.0 to 5.0 hours.
  • Examples of the reagent used in the Mitsunobu reaction include diisopropyl azodicarboxylate, diethyl azodicarboxylate, and the like, and preferably diisopropyl azodicarboxylate.
  • the number of equivalents is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents.
  • the number of equivalents of triphenylphosphine is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents.
  • the number of equivalents of the compound represented by the general formula (1) is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents.
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, acetone, toluene and the like, preferably THF.
  • the reaction temperature is 0 to 100 ° C., preferably 10 to 30 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.2 to 3.0 hours.
  • Step B-1 the compound represented by the general formula (10) obtained by a known method is converted into the same method as in Step A-1, the method described in Tetrahedron Lett., 48, 7109-7172 (2007), or diphenylphosphoryl.
  • an azide compound represented by the general formula (11) can be produced.
  • R 8 is a halogen atom and R 9 is an optionally substituted alkoxy group having 1 to 6 carbon atoms, for example, easily available 4-fluoro-3-hydroxybenzoic acid is used as a starting material.
  • a compound represented by the general formula (10) can be obtained by using a Grignard reaction or the like.
  • Step B-2 the compound represented by the general formula (11) and the alkyne compound (5) or (8) produced in Step A are reacted in the presence of a ruthenium catalyst and cyclized, and then a protected carboxyl group.
  • the compound of the present invention represented by the general formula (12) can be produced by converting (R 1 ) as necessary.
  • the reaction solvent used in the cyclization reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include toluene, dichloromethane, acetonitrile, THF, dioxane and the like, and dioxane is preferable.
  • ruthenium catalyst As the ruthenium catalyst to be used, various organic ruthenium catalysts such as chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II), pentamethylcyclopentadienylbis (triphenylphosphine) ruthenium (II) chloride, etc. Illustrative examples include chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II). The number of equivalents is 0.001 to 0.5 equivalents, preferably 0.01 to 0.3 equivalents.
  • the reaction temperature is 0 to 100 ° C., preferably 20 to 90 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1.0 to 5.0 hours.
  • R 1 , R 4 to R 9 , X, Rc, and n are as defined above, and Rh represents a protecting group for a hydroxyl group.
  • Step C-2 the compound represented by the general formula (13) and the compound represented by the general formula (11) are subjected to a cyclization reaction in the same manner as in Step B-2 to thereby represent the compound represented by the general formula (14). Can be produced.
  • the compound represented by the general formula (15) can be produced by converting the protected carboxyl group of the compound represented by the general formula (14).
  • the protected carboxyl group is reduced by a generally known method to obtain a hydroxylmethyl group
  • an alkylation reaction or a halogen substitution reaction can be performed.
  • a vinyl form can be produced by reacting with methyltriphenylphosphonium bromide under basic conditions, and Eur. J. Org.
  • An ethynyl compound can also be produced by reacting dimethyl 1-diazo-2-oxopropylphosphonate obtained by the method described in Chem., 5, 821-832 (2003) in the presence of a base.
  • an amide body can also be manufactured by deprotecting a carboxyl group and condensing with various amines by a conventionally well-known method.
  • R 4 to R 9 , X, Rh, and n are as defined above.
  • reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, acetonitrile, DMF, ethanol, methanol, n-butanol, and the like. Is n-butanol.
  • Examples of the base to be used include potassium carbonate, cesium carbonate, sodium hydrogen carbonate and the like, and potassium carbonate is preferable.
  • the number of equivalents is 0.1 to 3.0 equivalents, preferably 0.12 to 2.0 equivalents.
  • the number of equivalents of acetohydrazide is 0.1 to 20 equivalents, preferably 0.2 to 10 equivalents.
  • the reaction temperature is -78 to 200 ° C, preferably 120 to 160 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1.0 to 5.0 hours.
  • reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, acetonitrile, DMF, and the like, preferably DMF.
  • Examples of the base to be used include metal hydride, n-butyl lithium, bis (trimethylsilyl) amide sodium salt (hereinafter referred to as NaHMDS), and sodium hydride is preferred.
  • the number of equivalents is 0.8 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents.
  • the number of equivalents of the mesyl compound of the general formula (10) is 0.5 to 2.0 equivalents, preferably 0.7 to 1.2 equivalents.
  • the reaction temperature is -78 to 100 ° C, preferably 0 to 60 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1.0 to 10 hours.
  • R 4 to R 9 , X, Rh, and n are as defined above.
  • Examples of the base used include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and imidazole, and triethylamine is preferable.
  • the number of equivalents is 0.8 to 5.0 equivalents, preferably 1.0 to 1.2 equivalents.
  • the reaction solvent used in this step is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, ethanol, methanol, DMF and the like, preferably ethanol. is there.
  • Examples of the acid to be used include acetic acid, sulfuric acid, methanesulfonic acid, hydrochloric acid and the like, and acetic acid is preferable.
  • the number of equivalents is 1.0 to 10 equivalents, preferably 2.0 to 5.0 equivalents.
  • the reaction temperature is -90 to 200 ° C, preferably 10 to 100 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 9.0 hours.
  • R 1 , R 4 to R 9 , X, Rh, and n are as defined above.
  • R 4 to R 9 , X, Rh, and n are as defined above, Rn represents an amino-protecting group, and m represents an integer of 1-6. ]
  • the number of equivalents is 0.5 to 10 equivalents, preferably 0.8 to 5.0 equivalents.
  • the reaction solvent used in the reaction with triphosgene is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, DMF, and the like, preferably toluene.
  • the reaction temperature is -90 to 200 ° C, preferably -78 to 10 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.2 to 5.0 hours.
  • Examples of the base used in the reaction with the compound represented by the general formula (25) include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, imidazole, and the like. Is triethylamine.
  • the number of equivalents is 0.2 to 10 equivalents, preferably 0.5 to 5.0 equivalents.
  • the reaction solvent used in the reaction with the compound represented by the general formula (25) is not particularly limited as long as it does not affect the reaction, but THF, dioxane, diethyl ether, toluene, dichloromethane, DMF, acetonitrile Etc., and preferably a mixed solvent of toluene and acetonitrile.
  • the reaction temperature is -90 to 200 ° C, preferably 0 to 70 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.2 to 10 hours.
  • the compound represented by the general formula (27) can be produced by reacting the compound represented by the general formula (26) under basic conditions.
  • the base to be used include sodium hydroxide and potassium hydroxide, and sodium hydroxide is preferable.
  • the number of equivalents is 0.2 to 100 equivalents, preferably 1.0 to 50 equivalents.
  • the reaction solvent to be used include water, methanol, ethanol, n-propanol, n-butanol, THF, dioxane and the like, and a mixed solvent of water and dioxane is preferable.
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 120 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.2 to 10 hours.
  • the amino group of the uracil ring of the compound represented by the general formula (31) is protected by a generally known method, and then reacted with an azide reagent in the presence of triphenylphosphine and dialkyl azodicarboxylate.
  • the compound of the present invention represented by the general formula (32) can be produced by removing the amino-protecting group by a generally known method.
  • the reaction solvent used for the reaction with the azidation reagent is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, DMF, toluene, dichloromethane and the like, preferably THF. is there.
  • Examples of the azodicarboxylic acid ester used include diethyl azodicarboxylate and diisopropyl azodicarboxylate, with diisopropyl azodicarboxylate being preferred.
  • the number of equivalents is 0.9 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents.
  • Examples of the azide reagent used include azido acid, sodium azide, potassium azide, trimethylsilyl azide and the like, and trimethylsilyl azide is preferred.
  • the number of equivalents is 0.8 to 5.0 equivalents, preferably 1.0 to 4.0 equivalents.
  • the number of equivalents of triphenylphosphine is 0.8 to 5.0 equivalents, preferably 1.0 to 4.0 equivalents.
  • the reaction temperature is 0 to 100 ° C., preferably 10 to 60 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 5.0 to 24 hours.
  • the compound represented by the general formula (38) can be produced by reacting the compound represented by the general formula (37) in the same manner as in Step A-5.
  • the compound represented by the general formula (39) can be easily obtained or acetylene which can be obtained by a known method, for example, the method described in J. Org. Chem., 53, 2489-2496 (1988).
  • the compound of the present invention represented by the general formula (40) can be produced.
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include toluene, THF, dioxane, DMF, and the like, preferably toluene or DMF.
  • the number of equivalents of the acetylene compound is 0.8 to 100 equivalents, preferably 1.0 to 50 equivalents.
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 160 ° C.
  • the reaction time is 0.1 to 120 hours, preferably 0.5 to 100 hours.
  • the compound of the present invention and the synthetic intermediate thus produced can be usually isolated and purified by known separation and purification means such as recrystallization, crystallization, distillation, column chromatography and the like.
  • the compounds of the present invention and synthetic intermediates can usually form pharmacologically acceptable salts by known methods, and can be converted into each other.
  • the uracil compound or salt thereof of the present invention has excellent human dUTPase inhibitory activity, and thus is useful as a pharmaceutical represented by an antitumor drug and the like.
  • uracil compound of the present invention or a salt thereof When the uracil compound of the present invention or a salt thereof is contained in a pharmaceutical composition, it can be combined with a pharmaceutical carrier as necessary, and various administration forms can be employed depending on the purpose of prevention or treatment. For example, oral agents, injections, suppositories, ointments, patches and the like can be mentioned, and oral agents are preferred. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
  • the pharmaceutical carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants, colorants in solid preparations; solvents, dissolution aids, suspensions in liquid preparations. It is blended as a turbidity agent, tonicity agent, buffering agent, soothing agent and the like. Moreover, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers and the like can be used as necessary.
  • a binder, a disintegrating agent, a lubricant, a coloring agent, a corrigent / flavoring agent, etc. to the compound of the present invention, a tablet is prepared by a conventional method. Coated tablets, granules, powders, capsules and the like can be produced.
  • excipient examples include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid.
  • binder examples include water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, ⁇ -starch solution, gelatin solution, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, Shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned.
  • disintegrant examples include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • Examples of the lubricant include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol.
  • Examples of the colorant include titanium oxide and iron oxide.
  • Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
  • an oral solution, syrup, elixir and the like can be produced by adding a flavoring agent, a buffer, a stabilizer, a flavoring agent and the like to the compound of the present invention by conventional methods.
  • the flavoring / flavoring agent may be those listed above
  • examples of the buffer include sodium citrate
  • examples of the stabilizer include tragacanth, gum arabic, and gelatin.
  • an enteric coating or a coating can be applied to the oral preparation by a known method for the purpose of sustaining the effect. Examples of such a coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80 (registered trademark), and the like.
  • a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous injections are prepared by conventional methods.
  • the pH adjuster and buffer in this case include sodium citrate, sodium acetate, and sodium phosphate.
  • the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • local anesthetics include procaine hydrochloride and lidocaine hydrochloride.
  • isotonic agents include sodium chloride, glucose, D-mannitol, glycerin and the like.
  • a formulation carrier known in the art such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., and an interface such as Tween 80 (registered trademark), if necessary, are added to the compound of the present invention. After adding an activator etc., it can manufacture by a conventional method.
  • bases, stabilizers, wetting agents, preservatives and the like that are usually used for the compound of the present invention are blended as necessary, and mixed and formulated by a conventional method.
  • the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like.
  • the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.
  • the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method.
  • a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane film or foam sheet made of cotton, suf, chemical fiber is suitable.
  • the amount of the compound of the present invention to be formulated in each of the above dosage unit forms is not constant depending on the symptoms of the patient to which the compound is to be applied or the dosage form thereof, but is generally about an oral dosage form per dosage unit form. 0.05 to 1000 mg, about 0.01 to 500 mg for injections, and about 1 to 1000 mg for suppositories.
  • the daily dose of the drug having the above-mentioned dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally.
  • the dose is about 5000 mg, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into about 2 to 3 times a day.
  • Diseases that can be treated by administering the pharmaceutical composition containing the compound of the present invention include malignant tumors, malaria, tuberculosis, etc.
  • malignant tumors in the case of malignant tumors, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectum Cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular cancer, bone / soft tissue sarcoma, leukemia, malignant lymphoma, Examples include multiple myeloma, skin cancer, brain tumor and the like.
  • antitumor agent that can be used in combination is not particularly limited, but antitumor agents having an inhibitory action on thymidylate synthetase, such as antimetabolite such as 5-Fu and antifolate, are preferable.
  • the compound of the present invention can be used as an anti-pylori drug, an antiparasitic drug, or an antiviral drug.
  • the obtained compound was suspended in a hydrogen chloride-dioxane solution (4.0 M, 40 mL) and heated to reflux at 100 ° C. for 30 minutes. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was azeotroped with toluene (10 mL ⁇ 5) to give the title compound (1.9 g) as a pale yellow solid.
  • the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
  • the obtained compound was dissolved in DCE (5.0 mL), and 2,4-bis (trimethylsilyloxy) pyrimidine (531 mg) obtained by the method described in the literature (Nucleosides & Nucleotides, 4, 565-585 (1985)) and Iodine (40 mg) was added, and the mixture was heated to reflux at 93 ° C. for 3 hours.
  • the reaction mixture was allowed to cool, and water (10 mL) and saturated aqueous sodium thiosulfate solution (1.0 mL) were added to separate the layers.
  • the obtained compound was dissolved in THF (30 mL), TBAF in THF (1.0 M, 46 mL) was added, and the mixture was stirred at room temperature for 1 hr.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane).
  • the resulting compound was dissolved in dichloromethane (20 mL).
  • Triethylamine (2.18 mL) and methanesulfonyl chloride (975 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes.
  • a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the phases were separated.
  • the obtained compound was dissolved in THF (30 mL), water (3.0 mL) and triphenylphosphine (2.26 g) were added, and the mixture was stirred at 50 ° C. for 2 hr.
  • the reaction mixture was concentrated under reduced pressure, chloroform (50 mL) was added to the residue, and the mixture was extracted with 1N hydrochloric acid (50 mL ⁇ 2).
  • the aqueous layer was concentrated under reduced pressure and azeotroped with toluene (10 mL ⁇ 3).
  • the obtained compound was suspended in a hydrogen chloride-dioxane solution (4.0 M, 4.0 mL) and stirred at room temperature for 2 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to obtain the title compound (410 mg) as a pale yellow solid.
  • silyl compound (1.05 g of 3.95 g) was dissolved in THF (10 mL), and a hexane solution of n-butyllithium (2.77 M, 1.13 mL) was added dropwise at -78 ° C. Stir for hours.
  • Methyl chloroformate (242 ⁇ L) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution (5.0 mL) was added to the reaction solution to separate the layers.
  • the title compound (2.1 g) was obtained as a colorless oil by synthesis from easily available 4-pentyn-1-ol (1.5 g) according to the method of Reference Example 8.
  • Methyl 5- (methoxymethoxy) pent-2-inoate (15 g) obtained in Reference Example 10 was dissolved in dichloromethane (70 mL), and a dichloromethane solution (1.0 M, 16.9 mL) of BCl 3 was added under ice cooling at room temperature. Stir for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCE (100 mL), and 2,4-bis (trimethylsilyloxy) pyrimidine ( 21.6 g) and iodine (1.2 g) were added, and the mixture was heated to reflux at 93 ° C. for 3 hours.
  • the reaction mixture was allowed to cool, water (60 mL) and saturated aqueous sodium thiosulfate solution (10 mL) were added for liquid separation, and the aqueous layer was extracted with 10% methanol / chloroform (100 mL). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol / chloroform) to obtain the title compound (6.1 g) as a foam.
  • the obtained compound was dissolved in a methanol solution of methylamine (40%, 7.0 mL) and stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (75% ethyl acetate / hexane) to give the title compound (1.3 g) as a white solid.
  • the obtained compound (500 mg of 3.25 g) was dissolved in dichloromethane (10 mL), triethylamine (540 ⁇ L) and methanesulfonyl chloride (242 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added for liquid separation. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (10 mL), sodium azide (423 mg) was added, and the mixture was stirred at 50 ° C. for 3 hr.
  • Reference Examples 15 to 27 were synthesized from the respective raw materials shown in the following table according to the method of Reference Example 14.
  • ethyl 2- (3- (cyclopropylmethoxy) phenyl) acetate (1.0 g out of 1.2 g) was dissolved in ethanol (2.0 mL) and water (1.6 mL), and an aqueous sodium hydroxide solution (4.0 M, 3.2 mL) was added and the mixture was stirred at 50 ° C. for 3 hours.
  • Hydrochloric acid (2.0 M, 10 mL) was added to the reaction solution to make it acidic, and the reaction solution was concentrated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL).
  • the residue was purified by silica gel column chromatography (17% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (6.0 mL), and a THF solution (1.0 M, 1.7 mL) of bis (trimethylsilyl) amide sodium salt (hereinafter NaHMDS) was added dropwise at ⁇ 78 ° C., followed by stirring at ⁇ 78 ° C. for 1.5 hours. did.
  • a solution of methyl iodide (490 ⁇ L) in THF (1.0 mL) was added dropwise to the reaction solution, and the mixture was stirred at ⁇ 78 ° C. for 2 hours.
  • a saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution at room temperature, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (14% ethyl acetate / hexane). The obtained compound was dissolved in THF (2.0 mL), a THF solution (2.0 M, 1.2 mL) of lithium borohydride was added, and the mixture was stirred at room temperature for 12 hours. To the reaction solution was added saturated brine (10 mL) under ice-cooling, and the mixture was extracted with ethyl acetate (10 mL ⁇ 2).
  • the title compound (190 mg) was obtained as a pale yellow oily substance by synthesis according to the method of Reference Example 28 from readily available 2- (3-hydroxyphenyl) acetic acid (1.0 g).
  • the title compound (151 mg) was obtained as a pale yellow oily substance by synthesis according to the method of Reference Example 28 from readily available 2- (3-hydroxyphenyl) acetic acid (2.0 g).
  • a saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution at room temperature, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound (260 mg of 300 mg) was dissolved in dichloromethane (3.0 mL), triethylamine (262 ⁇ L) and methanesulfonyl chloride (117 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers.
  • N, O-dimethylhydroxylamine hydrochloride (3.3 g) and triethylamine (4.9 mL) were added, and the mixture was stirred at room temperature for 3 hours.
  • the obtained compound was dissolved in THF (70 mL), and a THF solution of ethylmagnesium bromide (1.0 M, 22 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution to separate the layers.
  • the organic layer was washed with water (50 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • Methyltriphenylphosphonium bromide (10.8 g) was suspended in THF (80 mL), a THF solution of NaHMDS (1.0 M, 30 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to ⁇ 78 ° C., the ketone body (4.98 g) obtained in the previous reaction was added, and the mixture was stirred at room temperature for 3 hours. Acetic acid (2.0 mL) was added and the mixture was concentrated under reduced pressure. The residue was suspended in 10% ethyl acetate / hexane (80 mL).
  • the reaction solution was concentrated under reduced pressure, the residue was suspended in 10% ethyl acetate / hexane (100 mL), insolubles were filtered off, washed with 10% ethyl acetate / hexane (100 mL), and the combined filtrate was reduced in vacuo. Concentrated. The residue was purified by silica gel column chromatography (4% ethyl acetate / hexane). The obtained compound was dissolved in ethanol (10 mL) and water (10 mL), aqueous sodium hydroxide solution (4.0 M, 22 mL) was added, and the mixture was stirred at 50 ° C. for 3 hr.
  • the reaction mixture was concentrated under reduced pressure, acidified with dilute hydrochloric acid (1.0 M, 100 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Dissolve the residue in DMF (80 mL), add EDCHCl (8.0 g) and HOBt (5.0 g), add N, O-dimethylhydroxylamine hydrochloride (3.3 g) and triethylamine (4.9 mL), and Stir for 3 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (70 mL), and a THF solution of ethylmagnesium bromide (1.0 M, 25 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and the phases were separated.
  • the organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • Methyltriphenylphosphonium bromide (10.8 g) was suspended in THF (80 mL), a THF solution of NaHMDS (1.0 M, 30 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to ⁇ 78 ° C., and the ketone body (4.98 g) obtained in the previous reaction was added, followed by stirring at room temperature for 3 hours. Acetic acid (2.0 mL) was added, and the mixture was concentrated under reduced pressure.
  • the obtained compound was dissolved in THF (70 mL), and a THF solution of ethylmagnesium bromide (1.0 M, 25 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • Methyltriphenylphosphonium bromide (10.8 g) was suspended in THF (80 mL), a THF solution of NaHMDS (1.0 M, 30 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to ⁇ 78 ° C., and the ketone body (4.98 g) obtained in the previous reaction was added, followed by stirring at room temperature for 3 hours. Acetic acid (2.0 mL) was added and the mixture was concentrated under reduced pressure. The residue was suspended in 10% ethyl acetate / hexane (80 mL).
  • silyl compound (1.55 g out of 5.2 g) was dissolved in THF (25 mL), and a THF solution of 4-fluorophenylmagnesium bromide (1.0 M, 28 mL) was added dropwise at 0 ° C. Stir for hours.
  • a saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution to separate the layers.
  • the organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (20 mL), a TBAF solution in THF (1.0 M, 20 mL) was added, and the mixture was stirred at room temperature for 2 hr.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane).
  • the resulting diol (1.0 g out of 1.3 g) was dissolved in dichloromethane (20 mL), triethylamine (831 ⁇ L) and methanesulfonyl chloride (371 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes.
  • a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the phases were separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (40 mL), sodium azide (1.0 g) was added, and the mixture was stirred at 70 ° C. for 12 hr. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (300 mg) as a pale yellow oil.
  • the azide forms shown in the following table are based on easily available 2-hydroxyethyl acetate, and using a readily available Grignard reagent or a Grignard reagent that can be prepared from a readily available bromo form by a generally known method. Synthesized according to the method of Reference Example 61.
  • the title compound (710 mg) was obtained as a pale yellow oily substance by synthesis according to the method of Reference Example 65 from readily available 2- (hydroxymethyl) phenol (700 mg).
  • Aqueous ammonium chloride solution (10 mL) was added to the reaction solution and the phases were separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (14% ethyl acetate / hexane). The obtained compound was dissolved in methanol (3.0 mL), 10% palladium-carbon (700 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1 hr. The insoluble material was removed by filtration, washed with methanol (20 mL), and the combined filtrate was concentrated under reduced pressure.
  • a THF solution (2.4 M, 11.6 mL) of lithium aluminum hydride (hereinafter referred to as LAH) was dissolved in THF (20 mL), and the residue obtained from the previous reaction (2.2 g out of 5.7 g, 2.2 g) of THF (under ice cooling) 5.0 mL) solution was added dropwise and stirred at room temperature for 3 hours.
  • Water (5.0 mL) was slowly added to the reaction solution at 0 ° C., and the resulting solid was filtered off, washed with ethyl acetate (50 mL) and THF (50 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was azeotroped with toluene (10 mL ⁇ 3), dissolved in chloroform (100 mL), manganese dioxide (7.0 g) was added, and the mixture was heated to reflux at 80 ° C. for 2 hours.
  • the insoluble material was filtered off using celite, washed with chloroform (200 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was azeotroped with toluene (5.0 mL ⁇ 2).
  • the obtained compound was dissolved in acetone (12 mL), 12N hydrochloric acid (6.0 mL) was added, and the mixture was stirred for 10 min.
  • the reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution (20 mL) and concentrated under reduced pressure.
  • Chloroform (20 mL) and water (10 mL) were added to the residue and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was dissolved in ethanol (20 mL), sodium borohydride (383 mg) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hr.
  • a saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution, and the mixture was partitioned. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (4.0 mL), sodium azide (277 mg) was added, and the mixture was stirred at 50 ° C. for 3 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (310 mg) as a pale yellow oil.
  • 2,2-diphenylethanol 500 mg was dissolved in THF (20 mL), triphenylphosphine (656 mg) and azodicarboxylate diisopropyltoluene solution (1.9 M, 1.32 mL) were added, and the mixture was stirred at room temperature for 5 minutes.
  • Diphenylphosphoryl azide (538 ⁇ L) was added dropwise to the reaction solution, and the mixture was stirred at 50 ° C. for 12 hours.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane) to give the title compound (300 mg) as a pale yellow oil.
  • the obtained compound was dissolved in THF (10 mL), and a THF solution of methylmagnesium bromide (1.0 M, 10 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to separate the layers.
  • the organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • Methyltriphenylphosphonium bromide (2.86 g) was suspended in THF (30 mL), a NaHMDS THF solution (1.0 M, 8.0 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to ⁇ 78 ° C., the ketone body (550 mg) obtained in the previous reaction was added, and the mixture was stirred at room temperature for 3 hours. Acetic acid (1.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was suspended in a 10% ethyl acetate / hexane solution (50 mL).
  • a sodium hydroxide aqueous solution (3.0 M, 1.75 mL) was added to the reaction solution at 0 ° C., and the mixture was stirred for 5 minutes, 30% aqueous hydrogen peroxide (1.75 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • a saturated aqueous sodium hydrogen sulfite solution (2.0 mL) was added to the reaction mixture at 0 ° C., and the mixture was acidified with hydrochloric acid (1.0 M, 5.0 mL), and extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • a saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added to the reaction solution to separate the layers.
  • the organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was dissolved in DMF (2.0 mL), sodium azide (138 mg) was added, and the mixture was stirred at 90 ° C. for 48 hr.
  • Water (5.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5.0 mL).
  • the organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (52 mg) as a pale yellow oil.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane).
  • the obtained compound (1.0 g out of 1.1 g) was dissolved in THF (7.0 mL), a THF solution of lithium borohydride (2.0 M, 1.48 mL) was added, and the mixture was heated to reflux at 80 ° C. for 5 hours.
  • the reaction mixture was allowed to cool, saturated brine (10 mL) was added, and the mixture was separated.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (840 mg) as a colorless oil.
  • the obtained compound was dissolved in THF (1.3 mL), a THF solution of TBAF (1.0 M, 1.31 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / chloroform) to give the title compound (180 mg) as a colorless oil.
  • the residue was purified by silica gel column chromatography (25% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (1.5 mL), a TBAF solution in THF (1.0 M, 1.5 mL) was added, and the mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform) to give the title compound (190 mg) as a colorless oil.
  • the obtained compound was dissolved in ethyl acetate (3.0 mL), 10% palladium-carbon (1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere for 1 hr.
  • the solid was filtered off using celite, washed with ethyl acetate (20 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was azeotroped with toluene (3 mL ⁇ 3), dissolved in THF (1.23 mL), TBAF in THF (1.0 M, 1.23 mL) was added, and the mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (190 mg) as a colorless oil.
  • a part (150 mg) of the obtained compound (650 mg) was suspended in methanol (600 ⁇ L) and water (100 ⁇ L), an aqueous sodium hydroxide solution (4.0 M, 203 ⁇ L) was added, and the mixture was stirred at 50 ° C. for 2 hours.
  • the reaction mixture was allowed to cool, acidified with hydrochloric acid (1.0 M, 1.0 mL), and separated by adding ethyl acetate (5.0 mL) and water (3.0 mL).
  • the aqueous layer was extracted with ethyl acetate (3.0 mL).
  • the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained compound (100 mg) was dissolved in THF (500 ⁇ L), a THF solution of TBAF (1.0 M, 500 ⁇ L) was added, and the mixture was stirred for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (70 mg) as a colorless oil.
  • Methyl 5- (methoxymethoxy) pent-2-inoate (1.53 g) obtained in Reference Example 10 and (S) -1-azido-2- (3- (cyclopropylmethoxy)- 4-Fluorophenyl) butan-2-ol (2.07 g) was dissolved in toluene (40 mL), and chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II) (281 mg) was added at 80 ° C. Stir for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (25 mL), a solution of lithium borohydride in THF (2.0 M, 8.8 mL) was added, and the mixture was stirred at 80 ° C. for 10 hr. To the reaction solution was added saturated brine (30 mL) at 0 ° C., and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2.5% methanol / chloroform).
  • the obtained diol (1.73 g, 400 mg) was dissolved in dichloromethane (4.0 mL), triethylamine (198 ⁇ L) and methanesulfonyl chloride (80 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes.
  • a saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers.
  • the organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was dissolved in THF (2.0 mL), TBAF in THF (1.0 M, 5.0 mL) was added, and the mixture was stirred at 50 ° C.
  • the reaction solution was allowed to cool, and ethyl acetate (20 mL), hexane (20 mL) and water (20 mL) were added to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and dried under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate / hexane). The obtained regioisomer mixture (279 mg) was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / ethyl acetate) to give the title compound (188 mg) as a colorless oil.
  • the obtained monoalcohol was dissolved in THF (20 mL), carbon tetrabromide (3.29 g) and triphenylphosphine (2.6 g) were added, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was concentrated under reduced pressure, and hexane (10 mL) and ethyl acetate (1.0 mL) were added to the residue.
  • the resulting solid was removed by filtration, washed with 10% ethyl acetate / hexane (30 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
  • the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
  • the obtained trimethylsilyl compound was dissolved in ethanol (4.0 mL), sodium hydroxide (420 mg) was added, and the mixture was stirred at room temperature for 3 hours.
  • the reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL).
  • the organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (3% ethyl acetate / hexane) to give the title compound (660 mg) as a pale yellow oil.
  • the obtained compound (890 mg) was dissolved in DMF (10 mL), sodium acetate (900 mg) and sodium iodide (549 mg) were added, and the mixture was stirred at 90 ° C. for 12 hours. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution and the phases were separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane).
  • the obtained compound (198 mg) was dissolved in a methanol solution of methylamine (40%, 2.0 mL) and stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • the obtained compound (140 mg) was dissolved in dimethyl sulfoxide (2.0 mL) and toluene (1.0 mL), EDC / HCl (270 mg), pyridine (38 ⁇ L), trifluoroacetic acid (20 ⁇ L) were added, and the mixture was stirred at room temperature for 1 hour. did.
  • the reaction mixture was concentrated under reduced pressure, water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane) to give the title compound (80 mg) as a pale yellow oil.
  • the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
  • the obtained compound was dissolved in methanol (20 mL), 10% palladium-carbon (2.0 g) was added, and the mixture was stirred at room temperature for 2 hr in a hydrogen atmosphere.
  • the insoluble material was removed by filtration, washed with methanol (50 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was dissolved in ethanol (1.6 mL) and water (1.6 mL), aqueous sodium hydroxide solution (4.0 M, 3.2 mL) was added, and the mixture was stirred at 50 ° C. for 2 hr.
  • the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (1.5 mL) and water (300 ⁇ L), acetic acid (300 ⁇ L) was added, and the mixture was stirred at room temperature for 3.5 hours.
  • the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution (5.0 mL) and extracted with ethyl acetate (10 mL).
  • the organic layer was washed with saturated brine (5.0 mL) and dried over anhydrous magnesium sulfate.
  • the residue was purified by silica gel column chromatography (2.5% ethyl acetate / hexane) to give the title compound (96 mg) as a colorless oil.
  • the obtained pale yellow oily substance (345 mg) was dissolved in DMF (6.0 mL), imidazole (371 mg) and tert-butyldimethylsilyl chloride (411 mg) were added, and the mixture was stirred at room temperature for 1 hour.
  • Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL).
  • the organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (15% ethyl acetate / hexane).
  • the obtained orange oily substance (153 mg) was dissolved in THF (1.0 mL), a THF solution of TBAF (1.0 M, 0.465 mL) was added, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C. for 30 minutes.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (110 mg) as a pale yellow oil.
  • the reaction mixture was concentrated under reduced pressure, water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10% ethyl acetate / hexane). The obtained compound was dissolved in a hydrogen chloride-dioxane solution (4.0 M, 3.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and azeotroped with toluene (2.0 mL ⁇ 3).
  • the obtained compound was dissolved in THF (1.0 mL), a TBAF solution in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to give the title compound (71 mg) as a colorless oil.
  • 2,2-bis4-chlorophenyl) ethanamine (320 mg) obtained by the method described in the literature (J. Am. Chem. Soc., 105, 3183-3188 (1983)) was dissolved in toluene (6.5 mL), Triethylamine (335 ⁇ L) was added and cooled to 0 ° C. Triphosgene (132 mg) was added to the reaction mixture, followed by stirring at 0 ° C. for 1.5 hours. The resulting precipitate was filtered off, washed with toluene (10 mL ⁇ 5), and the combined filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (6.0 mL).
  • the residue was purified by amino silica gel column chromatography (70% ethyl acetate / hexane). A part (513 mg) of the obtained compound (1.29 g) was dissolved in acetonitrile (6.5 mL), triethylamine (251 ⁇ L) and a toluene solution of the residue were added, and the mixture was stirred at 50 ° C. for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (60% ethyl acetate / hexane).
  • the obtained compound (179 mg) was dissolved in dioxane (2.5 mL), an aqueous sodium hydroxide solution (4.0 M, 2.5 mL) was added, and the mixture was heated to reflux at 100 ° C. for 5 hr.
  • the reaction mixture was allowed to cool, neutralized with hydrochloric acid (6.0 M, 1.7 mL), and extracted with ethyl acetate (15 mL ⁇ 2).
  • the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (60% ethyl acetate / hexane).
  • the obtained compound 120 mg was dissolved in dichloromethane (2.0 mL), and triethylamine (53 ⁇ L), N, N-dimethylamino-4-pyridine (4.6 mg) and di-tert-butyl dicarbonate (62 mg) were added. Stir at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate / hexane).
  • the obtained compound (131 mg) was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 270 ⁇ L) was added, and the mixture was stirred at 50 ° C. for 1.5 hr.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (77 mg) as a foam.
  • the obtained colorless foam (3.90 g) was dissolved in DMF (60 mL), sodium azide (1.07 g) was added, and the mixture was stirred at 70 ° C. for 2 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL ⁇ 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (3.28 g) as a colorless oil.
  • the obtained pale yellow gum (2.27 g) was dissolved in DMF (20 mL), potassium carbonate (2.0 g) and thioacetic acid (680 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes.
  • Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL ⁇ 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was dissolved in methanol (12 mL) and THF (3.0 mL), sodium methoxide (443 mg) was added, and the mixture was stirred at room temperature for 30 min.
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (12 mL), N, N-diisopropylethylamine (2.14 mL) and chloromethyl methyl ether (780 ⁇ L) were added, and the mixture was stirred at room temperature for 5 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL).
  • the reaction mixture was allowed to cool, saturated aqueous sodium sulfite solution (10 mL) and water (50 mL) were added, and the mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (70% ethyl acetate / hexane). The obtained pale yellow gum (381 mg) was dissolved in THF (4.0 mL), TBAF in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / chloroform).
  • the obtained colorless gum-like substance (200 mg) was dissolved in pyridine (4.0 mL), methanesulfonyl chloride (63 ⁇ L) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene (5.0 mL ⁇ 1) and purified by silica gel column chromatography (3% methanol / chloroform).
  • the obtained pale yellow gum (221 mg) was dissolved in DMF (4.0 mL), sodium azide (117 mg) was added, and the mixture was stirred at 55 ° C. for 16 hr.
  • the obtained colorless oily substance (5.62 g, 1.74 g) was dissolved in THF (5.0 mL), TBAF in THF (1.0 M, 5.0 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane).
  • the obtained colorless oily substance (393 mg of 771 mg) was dissolved in toluene (4.0 mL) and DMSO (4.0 mL), and pyridine (243 ⁇ L), trifluoroacetic acid (111 ⁇ L) and EDC ⁇ HCl (1.15 g) were added. Stir at room temperature for 1 hour.
  • the obtained colorless gum-like substance (220 mg) was dissolved in methanol (3.0 mL), sodium methoxide (61 mg) was added, and the mixture was stirred at 45 ° C. for 12 hours. After neutralization with hydrochloric acid (6.0 M, about 9 drops), the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (5.0 mL) and purified by silica gel column chromatography (4% methanol / chloroform). The resulting colorless gum (148 mg) was dissolved in pyridine (3.0 mL), methanesulfonyl chloride (44 ⁇ L) was added, and the mixture was stirred at room temperature for 3.5 hours.
  • Examples 2 to 118 were synthesized according to the method of Example 1 from alkynes and azides shown in the following table, respectively.
  • Example 8 3- (3- (1- (2- (cyclopentyloxy) phenethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
  • Example 31 (4- (1-((S) -2-hydroxy-2- (3-((R) -tetrahydrofuran-3-yloxy) phenyl) butyl) -1H-1,2,3-triazole-5- Yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
  • Example 40 1- (3- (1- (2,2-bis (4-fluorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H , 3H) -Dione
  • Example 46 (2-((1- (3- (cyclopropylmethoxy) -4-fluorophenethyl) -1H-1,2,3-triazol-5-yl) methoxy) ethyl) pyrimidine-2,4 (1H, 3H) -Dione
  • Example 50 (3- (1-phenethyl-1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
  • Example 54 (4- (1- (2-methoxyphenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
  • Example 60 (2- (1- (2,2-bis (4-fluorophenyl) -2-hydroxyethyl l) -1H-1,2,3-triazol-5-yl) ethyl) pyrimidine-2,4 ( 1H, 3H) -Dione
  • Example 64 (3- (1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -Dione
  • Example 65 (4- (1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -Dione
  • Example 66 1- (3- (1- (2,2-bis (4-chloro-3-methoxyphenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2 , 4 (1H, 3H) -Dione
  • Example 80 (3- (1- (2- (biphenyl-2-yl) ethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
  • Example 82 1- (3- (1- (2-hydroxy-2,2-bis (3-methoxyphenethyl) ethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H , 3H) -Dione
  • Example 100 1-((2- (1- (3- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -Dione
  • Example 102 (4- (1- (3- (cyclopentyloxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione
  • Example 104 (4- (1- (3- (2,2-difluoroethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) -5-fluoropyrimidine-2,4 (1H, 3H) -Dione
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform).
  • the obtained compound was dissolved in a methanol solution of methylamine (40%, 5.0 mL) and stirred at room temperature for 30 minutes.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform) to give the title compound (110 mg, yield 49%) as a foam.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform).
  • the obtained methyl ester compound (500 mg out of 1.2 g) was dissolved in THF (4.0 mL), a THF solution of lithium borohydride (2.0 M, 1.38 mL) was added, and the mixture was stirred at 50 ° C. for 3 hours.
  • Saturated brine (10 mL) was added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% methanol / chloroform) to give the title compound (120 mg, yield 25%) as a foam.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform).
  • the obtained methyl ester (5.8 g) was dissolved in methanol (7.0 mL) and water (5.0 mL), an aqueous sodium hydroxide solution (4.0 M, 8.1 mL) was added, and the mixture was stirred at 50 ° C. for 4 hr.
  • strongly acidic cation exchange resin (DIAIONPK212, H + form) was added to acidify the reaction solution, the resin was filtered off, washed with methanol (50 mL) and water (50 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was azeotroped with toluene (20 mL ⁇ 4).
  • Example 128 1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -5- (3- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) propyl) -N Of 2-methyll-1H-1,2,3-triazole-4-carboxamide
  • Examples 130 and 131 1- (4- (1- (3- (cyclopropylmethoxy) phenethyl) -4-methyl-1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H)- Dione and 1- (4- (1- (3- (cyclopropylmethoxy) phenethyl) -4-methyl-1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H ) -Dione synthesis
  • Example 130 54 mg, 39% yield
  • Example 131 40 mg, 29% yield
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1.5% methanol / chloroform).
  • the obtained compound was dissolved in a methanol solution of methylamine (40%, 3.0 mL) and stirred at room temperature for 30 minutes.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to give the title compound (150 mg, yield 51%) as a colorless gum.
  • Example 138 1- (3- (4- (2,2-bis (4-chlorophenyl) ethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) propyl) pyrimidine- Synthesis of 2,4 (1H, 3H) -dione
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (70% ethyl acetate / hexane).
  • the obtained compound was dissolved in a methanol solution of methylamine (40%, 1.5 mL) and stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene (2.0 mL ⁇ 2).
  • the residue was dissolved in a hydrogen chloride-dioxane solution (4.0 M, 1.5 mL) and stirred at room temperature for 1 hour.
  • reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene (2.0 mL ⁇ 3) and purified by silica gel column chromatography (8% methanol / chloroform) to give the title compound (48 mg, 66% yield). Obtained as a foam.
  • Examples 140-142 The following compounds are readily available from the compounds of Reference Examples 104 to 106 or from acetylene compounds obtained by the method described in the literature (Example 140: J. Org. Chem., 53, 2489-2496 (1988)). Synthesized according to the method of Example 139.
  • Example 140 1-((2- (2- (5- (thiazol-2-yl)-(1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H , 3H) -Dione
  • Examples 143 and 144 1-((2- (2- (5-phenyl-1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione and 1 Synthesis of-((2- (2- (4-phenyl-1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione
  • the compound is described in International Publication No. 2005-065689 as a compound having the strongest human deoxyuridine triphosphatase (hereinafter referred to as dUTPase) inhibitory activity, and described in International Publication No. WO2005-065689 in order to compare the activity with the compound of the present invention.
  • the method was synthesized.
  • the inhibitory activity against human dUTPase Test Example 1 Human dUTPase inhibitory activity present compound, the following methods [5- 3 H] deoxyuridine triphosphate (hereinafter, [5- 3 H] dUTP) [5- 3 H] from It was determined by measuring the production of deoxyuridine monophosphate (hereinafter referred to as [5- 3 H] dUMP).
  • the reaction was stopped by heating in a water bath at 100 ° C. for 1 minute, followed by centrifugation at 15000 rpm for 2 minutes. After centrifugation, a part of the obtained supernatant (150 ⁇ L) was analyzed with a high performance liquid chromatograph (Shimadzu Corporation, Prominence) using an AtlantisdC18 column (Waters, 4.6 ⁇ 250 mm).
  • Mobile phase A (10 mM potassium dihydrogen phosphate (pH 6.7), 10 mM tetrabutylammonium, 0.25% methanol) and mobile phase B (50 mM potassium dihydrogen phosphate (pH 6.7), 5.6 mM at a flow rate of 0.8 mL / min Elution was performed with a 30-minute concentration gradient from a 4: 6 mixture of tetrabutylammonium, 30% methanol) to mobile phase B.
  • the scintillator (Perkin Elmer, Ultima-FloAP) was mixed with the eluent at a ratio of 1: 2, and [5- 3 H] dUMP (RT10.2min) generated by RadiomaticFlowScintillationAnalyzer (PerkinElmer, 525TR) Radioactivity was measured.
  • the inhibitory activity of the test compound was determined by the following equation, and the concentration of the test solution that inhibits the amount of [5- 3 H] dUMP produced by human dUTPase by 50% is shown in Table 47 as IC 50 ( ⁇ M).
  • the following table shows human dUTPase inhibitory activity data.

Abstract

Disclosed is a uracil compound having a nitrogenated heterocyclic ring, represented by formula (I), having an excellent inhibitory activity on human dUTPase and useful as an anti-tumor agent or the like, or a salt of the uracil compound. [In the formula, X represents a divalent hydrocarbon which may have a hetero atom between carbon atoms or at the terminal; Y represents H or F; A represents a (substituted) nitrogenated unsaturated heterocyclic ring; and R1 and R2 independently represent H, CN, a (substituted) C1-4 alkyl, a (substituted) C2-4 alkenyl or alkynyl, a mono- or di-alkylaminocarbonyl, an aryl, an unsaturated heterocyclic ring, or a (substituted) aralkyl.]

Description

含窒素複素環を有する新規ウラシル化合物又はその塩Novel uracil compound having nitrogen-containing heterocycle or salt thereof
　本発明は、優れたヒトデオキシウリジントリホスファターゼ阻害活性を有し、デオキシウリジントリホスファターゼに関連する疾患の治療剤、例えば抗腫瘍薬等として有用な新規ウラシル化合物又はその塩に関するものである。 The present invention relates to a novel uracil compound or a salt thereof having excellent human deoxyuridine triphosphatase inhibitory activity and useful as a therapeutic agent for diseases related to deoxyuridine triphosphatase, such as an antitumor agent.
　デオキシウリジントリホスファターゼ（以下、dUTPase（EC3.6.1.23）ともいう。）は、予防的なDNA修復酵素である。天然型核酸トリリン酸体の中でデオキシウリジントリホスフェート（以下、dUTP）のみを特異的に認識し、デオキシウリジンモノホスフェート（以下、dUMP）とピロリン酸に分解する酵素であり（非特許文献１）、（１）細胞内のdUTPプールの量を下げることで、チミンの代わりにウラシルがDNA中へと誤って組み込まれるのを避ける、（２）DNA中にチミンを供給するための重要なde novo経路を担うチミジル酸合成酵素の基質dUMPを供給する（非特許文献２）、という２つの反応を担っていると考えられている。 Deoxyuridine triphosphatase (hereinafter also referred to as dUTPase (EC3.6.1.23)) is a preventive DNA repair enzyme. It is an enzyme that specifically recognizes only deoxyuridine triphosphate (hereinafter referred to as dUTP) among natural nucleic acid triphosphates and decomposes it into deoxyuridine monophosphate (hereinafter referred to as dUMP) and pyrophosphate (Non-patent Document 1) , (1) reduce the amount of dUTP pool in the cell to avoid accidental incorporation of uracil into DNA instead of thymine, (2) important de novo for supplying thymine in DNA It is thought to be responsible for two reactions: supplying the substrate dUMP of thymidylate synthase responsible for the pathway (Non-patent Document 2).
　dUTPaseは原核生物、真核生物両方で細胞の生存に必須であることが知られている。従って、本酵素は抗腫瘍薬（非特許文献３、４）、抗マラリア薬（特許文献１及び非特許文献５）、抗結核薬（非特許文献６）、抗ピロリ菌薬（特許文献２）、トリパノソーマやリーシュマニアなどの抗寄生虫薬（非特許文献７）、及びヒト単純ヘルペスウイルス、サイトメガロウイルス、Epstein-Barrウイルスのようなヘルペスウイルス（非特許文献８）やワクシニアウイルス（非特許文献９）などの抗ウイルス薬の標的と成り得ることが示唆されている。 DUTPase is known to be essential for cell survival in both prokaryotes and eukaryotes. Therefore, this enzyme is an antitumor drug (Non-Patent Documents 3 and 4), an antimalarial drug (Patent Documents 1 and 5), an antituberculosis drug (Non-Patent Document 6), and an anti-pylori drug (Patent Document 2). , Anti-parasitic drugs such as trypanosoma and leishmania (non-patent document 7), and herpesviruses such as human herpes simplex virus, cytomegalovirus, Epstein-Barr virus (non-patent document 8) and vaccinia virus (non-patent document 9). It has been suggested that it can be a target for antiviral drugs such as
　以上のように、dUTPaseは各種疾患に対する治療剤の標的として注目されており、dUTPase阻害剤についても広く研究されている。
　dUTPase阻害剤としては、例えば、トリリン酸ミミック型低分子化合物（例えば、特許文献３、非特許文献１０など）、５’-O-置換フェニル-デオキシウリジン化合物（非特許文献１１）が知られている。しかしながら、これらはいずれもヒトdUTPaseに対する阻害活性が十分ではなく、医薬品として用いられる化合物ではない。
　従って、より優れたヒトdUTPase阻害活性を有し、dUTPaseに関連する疾患の治療剤、例えば抗腫瘍薬等として有用なdUTPase阻害剤の開発が強く望まれている。 As described above, dUTPase is attracting attention as a target for therapeutic agents for various diseases, and dUTPase inhibitors are also widely studied.
As dUTPase inhibitors, for example, triphosphate mimic type low molecular weight compounds (for example, Patent Document 3, Non-Patent Document 10 and the like), 5′-O-substituted phenyl-deoxyuridine compounds (Non-Patent Document 11) are known. Yes. However, none of these compounds have sufficient inhibitory activity against human dUTPase and are not compounds used as pharmaceuticals.
Therefore, development of a dUTPase inhibitor having a superior human dUTPase inhibitory activity and useful as a therapeutic agent for a disease related to dUTPase, such as an antitumor agent, is strongly desired.
国際公開第2005/065689号パンフレットInternational Publication No. 2005/065689 Pamphlet 国際公開第2003/089461号パンフレットInternational Publication No. 2003/089461 Pamphlet 国際公開第1995/15332号パンフレットInternational Publication No. 1995/15332 Pamphlet
　本発明の課題は、優れたヒトdUTPase阻害活性を有し、抗腫瘍薬等として有用な、含窒素複素環を有するウラシル化合物又はその塩を提供することにある。 An object of the present invention is to provide a uracil compound having a nitrogen-containing heterocyclic ring or a salt thereof, which has excellent human dUTPase inhibitory activity and is useful as an antitumor agent or the like.
　本発明者らは、前記課題を解決すべく鋭意検討を重ねた結果、ウラシル環Ｎ－１位側鎖に含窒素複素環を有するウラシル化合物又はその塩が、優れたヒトdUTPase阻害活性を有し、抗腫瘍薬等の医薬品として有用であることを見出し、本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have found that a uracil compound having a nitrogen-containing heterocycle in the uracil ring N-1 side chain or a salt thereof has excellent human dUTPase inhibitory activity. The present invention was completed by discovering that it is useful as a medicine such as an antitumor drug.
　すなわち本発明は、一般式（Ｉ） That is, the present invention relates to the general formula (I)
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
〔一般式（Ｉ）中、Ｘは、炭素原子間又は末端にヘテロ原子を有していてもよい２価の炭化水素基を示し、Ｙは水素原子又はフッ素原子を示し、
Ａは置換基を有していてもよい含窒素不飽和複素環基を示し、
Ｒ１及びＲ２は、同一又は相異なって、水素原子、シアノ基、置換基を有していてもよい炭素数１～６のアルキル基、置換基を有していてもよい炭素数２～６のアルケニル基、置換基を有していてもよい炭素数２～６のアルキニル基、モノアルキルアミノカルボニル基、ジアルキルアミノカルボニル基、アリール基、不飽和複素環基、又は置換基を有していてもよいアラルキル基を示す。〕
で表されるウラシル化合物又はその塩を提供するものである。 [In General Formula (I), X represents a divalent hydrocarbon group which may have a hetero atom between carbon atoms or at the terminal, Y represents a hydrogen atom or a fluorine atom,
A represents a nitrogen-containing unsaturated heterocyclic group which may have a substituent,
R 1 and R 2 are the same or different and are a hydrogen atom, a cyano group, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon atom having 2 to An alkenyl group having 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms which may have a substituent, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group, an aryl group, an unsaturated heterocyclic group, or a substituent. The aralkyl group which may be sufficient is shown. ]
The uracil compound represented by these, or its salt is provided.
　また、本発明は、式（Ｉ）で表されるウラシル化合物又はその塩を含有する医薬組成物を提供するものである。
　また、本発明は、式（Ｉ）で表されるウラシル化合物又はその塩を含有するヒトdUTPase阻害剤を提供するものである。
　また、本発明は、式（Ｉ）で表されるウラシル化合物又はその塩の、ヒトdUTPase阻害剤製造のための使用を提供するものである。
　また、本発明は、式（Ｉ）で表される化合物又はその塩を投与することを特徴とするヒトdUTPase阻害方法を提供するものである。 The present invention also provides a pharmaceutical composition containing a uracil compound represented by the formula (I) or a salt thereof.
Moreover, this invention provides the human dUTPase inhibitor containing the uracil compound or its salt represented by a formula (I).
The present invention also provides use of the uracil compound represented by the formula (I) or a salt thereof for producing a human dUTPase inhibitor.
The present invention also provides a method for inhibiting human dUTPase, comprising administering a compound represented by formula (I) or a salt thereof.
　本発明の新規ウラシル化合物又はその塩は、優れたヒトdUTPase阻害活性を有し、dUTPaseに関連する疾患、例えば抗腫瘍薬等の医薬として有用である。 The novel uracil compound or a salt thereof of the present invention has excellent human dUTPase inhibitory activity, and is useful as a drug for diseases related to dUTPase, such as antitumor drugs.
　本発明の新規ウラシル化合物は、前記一般式（Ｉ）で表され、ウラシル環Ｎ－１位置換基に含窒素複素環構造を有するという特徴を有する。
　国際公開2005065689号公報（特許文献１）には、ウラシル環Ｎ－１位置換基の末端として、トリチル基、トリフェニルシリル基等の置換基（－E(R6)(R7)(R8)基）を有するウラシル化合物が開示され、dUTPase阻害活性を示し、抗マラリア薬として有用であることが記載されている。しかしながら、本発明化合物の有する含窒素不飽和複素環構造を有する化合物は開示されていない。また後述の試験例で示すように、ウラシル環Ｎ－１位置換基の末端としてトリチル基を有する化合物は、ヒトdUTPase阻害活性を殆ど示さなかった。 The novel uracil compound of the present invention is represented by the above general formula (I) and has a feature that the uracil ring N-1 substituent has a nitrogen-containing heterocyclic structure.
In International Publication No. 2005065689 (Patent Document 1), as a terminal of the uracil ring N-1 position substituent, a substituent such as a trityl group or a triphenylsilyl group (-E (R 6 ) (R 7 ) (R 8 A uracil compound having a) group) is disclosed, which shows dUTPase inhibitory activity and is useful as an antimalarial drug. However, a compound having a nitrogen-containing unsaturated heterocyclic structure of the compound of the present invention is not disclosed. Further, as shown in Test Examples described later, compounds having a trityl group at the terminal of the uracil ring N-1 position substituent showed almost no human dUTPase inhibitory activity.
　本願明細書において「置換基」としては、例えば、ハロゲン原子、ヒドロキシル基、シアノ基、ニトロ基、アルキル基、ハロゲノアルキル基、アルコキシアルキル基、シクロアルキル基、シクロアルキル-アルキル基、アラルキル基、アルケニル基、アルキニル基、アルコキシ基、ハロゲノアルコキシ基、シクロアルコキシ基、シクロアルキル-アルコキシ基、アラルキルオキシ基、アルキルチオ基、シクロアルキル-アルキルチオ基、アミノ基、モノ又はジアルキルアミノ基、シクロアルキル-アルキルアミノ基、シクロアルキリデン構造、アシル基、アシルオキシ基、オキソ基、飽和若しくは不飽和複素環基、アリール基、飽和複素環オキシ基等が挙げられ、前記置換基が存在する場合、その個数は典型的には１～４個である。 In the present specification, examples of the “substituent” include a halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, halogenoalkyl group, alkoxyalkyl group, cycloalkyl group, cycloalkyl-alkyl group, aralkyl group, alkenyl group. Group, alkynyl group, alkoxy group, halogenoalkoxy group, cycloalkoxy group, cycloalkyl-alkoxy group, aralkyloxy group, alkylthio group, cycloalkyl-alkylthio group, amino group, mono- or dialkylamino group, cycloalkyl-alkylamino group , A cycloalkylidene structure, an acyl group, an acyloxy group, an oxo group, a saturated or unsaturated heterocyclic group, an aryl group, a saturated heterocyclic oxy group, and the like. 1 to 4 pieces.
　前記の置換基において、ハロゲン原子としては、塩素原子、臭素原子、フッ素原子、ヨウ素原子が挙げられる。
　前記の置換基において、アルキル基、ハロゲノアルキル基としては、好ましくは炭素数１～６の直鎖状若しくは分枝状のアルキル基又はこれらのアルキル基に前記のハロゲン原子が置換した基を示し、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、モノフルオロメチル基、トリフルオロメチル基、２，２－ジフルオロエチル基等が挙げられる。 In the above substituent, examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.
In the above substituent, the alkyl group and the halogenoalkyl group preferably represent a linear or branched alkyl group having 1 to 6 carbon atoms or a group obtained by substituting the halogen atom for the alkyl group, Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a monofluoromethyl group, a trifluoromethyl group, and a 2,2-difluoroethyl group.
　前記の置換基において、アルコキシアルキル基としては、好ましくは炭素数１～６の直鎖状若しくは分枝状のアルコキシで置換された炭素数１～６のアルキル基であり、メトキシメチル基、エトキシメチル基、メトキシエチル基等が挙げられる。
　前記の置換基において、シクロアルキル基としては、好ましくは炭素数３～７のシクロアルキル基であり、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられる。 In the above-mentioned substituent, the alkoxyalkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted with linear or branched alkoxy having 1 to 6 carbon atoms, such as a methoxymethyl group or ethoxymethyl group. Group, methoxyethyl group and the like.
In the above substituent, the cycloalkyl group is preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
　前記の置換基において、シクロアルキル－アルキル基としては、好ましくは炭素数３～７のシクロアルキルで置換された炭素数１～６のアルキル基であり、シクロプロピルメチル基、シクロプロピルエチル基、シクロブチルメチル基、シクロペンチルメチル基等が挙げられる。 In the above-mentioned substituent, the cycloalkyl-alkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted with cycloalkyl having 3 to 7 carbon atoms, and includes a cyclopropylmethyl group, a cyclopropylethyl group, a cyclopropyl group, A butylmethyl group, a cyclopentylmethyl group, etc. are mentioned.
　前記の置換基において、アラルキル基としては、好ましくは炭素数６～１４の芳香族炭化水素基で置換された炭素数１～６の直鎖状若しくは分枝状のアルキル基を示し、ベンジル基、フェニルエチル基、フェニルプロピル基、ナフチルメチル基、ナフチルエチル基等が挙げられる。
　前記の置換基において、アルケニル基としては、炭素－炭素二重結合を含む、好ましくは炭素数２～６の炭化水素基を示し、ビニル基、アリル基、メチルビニル基、プロペニル基、ブテニル基、ペンテニル基、ヘキセニル基等が挙げられる。
　前記の置換基において、アルキニル基としては、炭素－炭素三重結合を含む、好ましくは炭素数２～６の炭化水素基を示し、エチニル基、プロパルギル基等が挙げられる。 In the above substituents, the aralkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms substituted with an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as a benzyl group, A phenylethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group, etc. are mentioned.
In the above substituents, the alkenyl group includes a carbon-carbon double bond, preferably a hydrocarbon group having 2 to 6 carbon atoms, and includes a vinyl group, an allyl group, a methylvinyl group, a propenyl group, a butenyl group, A pentenyl group, a hexenyl group, etc. are mentioned.
In the above substituent, the alkynyl group is a hydrocarbon group containing a carbon-carbon triple bond, preferably 2 to 6 carbon atoms, and examples thereof include an ethynyl group and a propargyl group.
　前記の置換基において、アルコキシ基、ハロゲノアルコキシ基としては、好ましくは炭素数１～６の直鎖状若しくは分枝状のアルコキシ基、又はこれらのアルコキシ基に前記のハロゲン原子が置換した基を示し、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、１－メチルプロポキシ基、ｎ－ブトキシ基、sec－ブトキシ基、イソブトキシ基、２－メチル－ブトキシ基、ネオペンチルオキシ基、ペンタン－２－イルオキシ基、フルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメトキシ基、１，１－ジフルオロエトキシ基、２，２－ジフルオロエトキシ基、２，２，２－トリフルオロエトキシ基、１，１，２，２－テトラフルオロエトキシ基、パーフルオロエトキシ基、３－フルオロ－２－（フルオロメチル）－プロポキシ基、１，３－ジフルオロプロパン－２－イルオキシ基、２，２，３，３，３－ペンタフルオロ－１－プロポキシ基等が挙げられる。 In the above substituent, the alkoxy group and the halogenoalkoxy group preferably represent a linear or branched alkoxy group having 1 to 6 carbon atoms, or a group in which the above halogen atom is substituted for these alkoxy groups. , Methoxy group, ethoxy group, n-propoxy group, isopropoxy group, 1-methylpropoxy group, n-butoxy group, sec-butoxy group, isobutoxy group, 2-methyl-butoxy group, neopentyloxy group, pentane-2 -Yloxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 1,1-difluoroethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2, 2-tetrafluoroethoxy group, perfluoroethoxy group, 3-fluoro-2- (fluoromethyl) -propyl Epoxy group, 1,3-difluoro-2-yloxy group, 2,2,3,3,3-pentafluoro-1-propoxy group and the like.
　前記の置換基において、シクロアルコキシ基としては、好ましくは炭素数３～７のシクロアルコキシ基であり、シクロプロポキシ基、シクロブトキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基等が挙げられる。
　前記の置換基において、シクロアルキル－アルコキシ基としては、好ましくは炭素数３～７のシクロアルキルで置換された炭素数１～６のアルコキシ基であり、シクロプロピルメトキシ基、１－メチルシクロプロピルメトキシ基、ジシクロプロピルメトキシ基、１－シクロプロピルエトキシ基、2-シクロプロピルエトキシ基、シクロブチルメトキシ基、シクロペンチルメトキシ基等が挙げられる。 In the above substituent, the cycloalkoxy group is preferably a cycloalkoxy group having 3 to 7 carbon atoms, and examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
In the above-mentioned substituent, the cycloalkyl-alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms substituted by cycloalkyl having 3 to 7 carbon atoms, such as cyclopropylmethoxy group, 1-methylcyclopropylmethoxy group. Group, dicyclopropylmethoxy group, 1-cyclopropylethoxy group, 2-cyclopropylethoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group and the like.
　前記の置換基において、アラルキルオキシ基としては、好ましくは、前記のアラルキル基を有するオキシ基を示し、ベンジルオキシ基、フェニルエトキシ基、フェニルプロポキシ基、ナフチルメトキシ基、ナフチルエトキシ基等が挙げられる。
　前記の置換基において、モノ又はジアルキルアミノ基としては、前記のアルキル基によりモノ置換又はジ置換されたアミノ基を示し、メチルアミノ基、ジメチルアミノ基、エチルアミノ基、ジエチルアミノ基、メチルエチルアミノ基等が挙げられる。
　前記の置換基において、シクロアルキル－アルキルアミノ基としては、前記のシクロアルキル基で置換されたアルキルアミノ基を示し、シクロプロピルメチルアミノ基、シクロブチルメチルアミノ基、シクロペンチルメチルアミノ基等が挙げられる。
　前記の置換基において、シクロアルキリデン構造としては、シクロプロピリデン、シクロブチリデン、シクロペンチリデン、シクロヘキシリデンが挙げられる。
　前記の置換基において、アシル基としては、ホルミル基、アセチル基、プロピオニル基、ｎ－ブチリル基、イソブチリル基、バレリル基、イソバレリル基、ピバロイル基などの直鎖又は分枝を有する炭素数１～６のアシル基、ベンゾイル基等が挙げられる。
　前記の置換基において、アシルオキシ基としては、アセトキシ基、プロピオニルオキシ基、ｎ－ブチリルオキシ基、イソブチリルオキシ基、バレリルオキシ基、イソバレリルオキシ基、ピバロイルオキシ基などの直鎖又は分枝を有する炭素数１～６のアシルオキシ基、ベンゾイルオキシ基等が挙げられる。 In the above substituent, the aralkyloxy group is preferably an oxy group having the aralkyl group, and examples thereof include a benzyloxy group, a phenylethoxy group, a phenylpropoxy group, a naphthylmethoxy group, and a naphthylethoxy group.
In the above substituent, the mono- or dialkylamino group represents an amino group mono- or di-substituted by the alkyl group, and includes a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, and a methylethylamino group. Etc.
In the above substituent, the cycloalkyl-alkylamino group represents an alkylamino group substituted with the above cycloalkyl group, and examples thereof include a cyclopropylmethylamino group, a cyclobutylmethylamino group, and a cyclopentylmethylamino group. .
In the above substituent, examples of the cycloalkylidene structure include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.
In the above substituents, the acyl group includes a straight or branched carbon number of 1 to 6 such as formyl group, acetyl group, propionyl group, n-butyryl group, isobutyryl group, valeryl group, isovaleryl group, and pivaloyl group. An acyl group, a benzoyl group, and the like.
In the above substituents, the acyloxy group includes straight or branched carbon such as acetoxy group, propionyloxy group, n-butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group, etc. Examples thereof include an acyloxy group of 1 to 6 and a benzoyloxy group.
　前記の置換基において、飽和若しくは不飽和複素環基としては、好ましくは酸素原子、窒素原子、硫黄原子のいずれかの原子を、好ましくは１個又は２個有する単環性又は二環性の飽和又は不飽和複素環基を示し、例えばピロリジニル基、ピペリジニル基、ピペラジニル基、ヘキサメチレンイミノ基、モルホリノ基、チオモルホリノ基、ホモピペリジニル基、テトラヒドロフリル基、テトラヒドロピリル基、イミダゾリル基、チエニル基、フリル基、ピロリル基、オキサゾリル基、イソキサゾリル基、チアゾリル基、イソチアゾリル基、ピラゾリニル基、トリアゾリル基、テトラゾリル基、ピリジル基、ピラジル基、ピリミジニル基、ピリダジニル基、インドリル基、イソインドリル基、インダゾリル基、メチレンジオキシフェニル基、エチレンジオキシフェニル基、ベンゾフラニル基、ジヒドロベンゾフラニル基、ベンゾイミダゾリル基、ベンゾオキサゾリル基、ベンゾチアゾリル基、プリニル基、キノリル基、イソキノリル基、キナゾリニル基、キノキサリル基等が挙げられる。 In the above-mentioned substituent, the saturated or unsaturated heterocyclic group is preferably a monocyclic or bicyclic saturated group having preferably one or two oxygen atoms, nitrogen atoms and sulfur atoms. Or an unsaturated heterocyclic group, for example, pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, morpholino group, thiomorpholino group, homopiperidinyl group, tetrahydrofuryl group, tetrahydropyryl group, imidazolyl group, thienyl group, furyl Group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolinyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group, pyridazinyl group, indolyl group, isoindolyl group, indazolyl group, methylenedioxy Phenyl group, Dioxy phenyl group, benzofuranyl group, dihydrobenzofuranyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, purinyl group, a quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalinyl group, and the like.
　前記の置換基において、アリール基としては、好ましくは炭素数６～１４のアリール基を示し、フェニル基、ナフチル基等が挙げられる。
　前記の置換基において、飽和複素環オキシ基としては、酸素原子、窒素原子、硫黄原子のいずれかの原子を１個又は２個有する単環性の飽和複素環基、例えばピロリジニル基、ピペリジニル基、ピペラジニル基、ヘキサメチレンイミノ基、モルホリノ基、チオモルホリノ基、ホモピペリジニル基等を有するオキシ基を示し、テトラヒドロフリルオキシ基、テトラヒドロピリルオキシ基等が挙げられる。 In the above substituent, the aryl group is preferably an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group.
In the above substituent, the saturated heterocyclic oxy group is a monocyclic saturated heterocyclic group having one or two oxygen atoms, nitrogen atoms or sulfur atoms, for example, pyrrolidinyl group, piperidinyl group, An oxy group having a piperazinyl group, a hexamethyleneimino group, a morpholino group, a thiomorpholino group, a homopiperidinyl group or the like, such as a tetrahydrofuryloxy group or a tetrahydropyryloxy group.
　一般式（Ｉ）中、Ｘで表される「炭素原子間又は末端にヘテロ原子を有していてもよい２価の炭化水素基」としては、炭素原子間又は末端にヘテロ原子を有していてもよい炭素数１～６のアルキレン基、炭素数６～１４の２価のアリール基、炭素原子間又は末端にヘテロ原子を有していてもよい炭素数６～２０の２価のアルキル－アリール－アルキル基が好ましい。 In the general formula (I), the “divalent hydrocarbon group optionally having a heteroatom between carbon atoms or terminals” represented by X has a heteroatom between carbon atoms or terminals. An alkylene group having 1 to 6 carbon atoms, a divalent aryl group having 6 to 14 carbon atoms, a divalent alkyl group having 6 to 20 carbon atoms which may have a hetero atom between or at the ends of the carbon atoms. Aryl-alkyl groups are preferred.
　また、Ｘにおいて、上記「ヘテロ原子」としては、酸素原子、窒素原子、硫黄原子が挙げられ、炭素数１～６のアルキレン基の炭素原子間又は末端に有していてもよい「ヘテロ原子」としては、酸素原子が好ましく、炭素数６～２０の２価のアルキル－アリール－アルキル基の炭素原子間又は末端に有していてもよいヘテロ原子としては、酸素原子又は硫黄原子が好ましい。 In X, examples of the “heteroatom” include an oxygen atom, a nitrogen atom, and a sulfur atom. The “heteroatom” that may be present between carbon atoms or at the terminal of an alkylene group having 1 to 6 carbon atoms Is preferably an oxygen atom, and a heteroatom which may be present between or at the terminals of a divalent alkyl-aryl-alkyl group having 6 to 20 carbon atoms is preferably an oxygen atom or a sulfur atom.
　また、Ｘにおいて、上記「炭素数１～６のアルキレン基」としては、直鎖状又は分枝状の炭素数１～６のアルキレン基が好ましく、例えば、メチレン基、エチレン基、トリメチレン基、テトラメチレン基、ペンタメチレン基、ヘキサメチレン基、プロピレン基、ブチレン基、ジメチルトリメチレン基、ジメチルテトラメチレン基、エチルトリメチレン基等が挙げられる。このうち、炭素数２～３の直鎖状アルキレン基、炭素数４～６の分岐状アルキレン基が好ましく、エチレン基、トリメチレン基、ジメチルトリメチレン基がより好ましい。 In X, the above “C 1-6 alkylene group” is preferably a linear or branched C 1-6 alkylene group, for example, methylene, ethylene, trimethylene, tetra Examples include methylene group, pentamethylene group, hexamethylene group, propylene group, butylene group, dimethyltrimethylene group, dimethyltetramethylene group, and ethyltrimethylene group. Among these, a linear alkylene group having 2 to 3 carbon atoms and a branched alkylene group having 4 to 6 carbon atoms are preferable, and an ethylene group, a trimethylene group, and a dimethyltrimethylene group are more preferable.
　また、Ｘにおいて、「炭素数６～１４の２価のアリール基」としては、例えば、フェニレン基、ナフチレン基等が挙げられるが、フェニレン基が好ましい。このうち、１，３－フェニレン基が特に好ましい。 In X, examples of the “divalent aryl group having 6 to 14 carbon atoms” include a phenylene group and a naphthylene group, and a phenylene group is preferable. Of these, a 1,3-phenylene group is particularly preferred.
　また、炭素数６～２０の２価のアルキル－アリール－アルキル基としては、Ｃ１－６アルキル－Ｃ６－１０アリール－Ｃ１－６アルキル基が好ましい。ここで、Ｃ６－１０アリール基としては、フェニレン基、ナフチレン基が挙げられるが、フェニレン基が好ましく、特に１，２－フェニレン基が好ましい。 Further, the divalent alkyl-aryl-alkyl group having 6 to 20 carbon atoms is preferably a C 1-6 alkyl-C 6-10 aryl-C 1-6 alkyl group. Here, examples of the C 6-10 aryl group include a phenylene group and a naphthylene group, but a phenylene group is preferable, and a 1,2-phenylene group is particularly preferable.
　当該アルキル－アリール－アルキル基の好ましい例としては、下記一般式(II) Preferred examples of the alkyl-aryl-alkyl group include the following general formula (II)
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
（式（II）中、Ｚは酸素原子又は硫黄原子を示し、Ｒ３は、水素原子又は炭素数1～６のアルキル基を示し、式（II）中のＺ末端は式（Ｉ）中のメチレン基と結合し、式（II）中の炭素末端は、式（Ｉ）中のＡと結合する。）
で表される基が好ましい。 (In Formula (II), Z represents an oxygen atom or a sulfur atom, R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the Z terminal in Formula (II) is the same as in Formula (I)). (It binds to a methylene group, and the carbon terminal in formula (II) binds to A in formula (I).)
The group represented by these is preferable.
　また、式（II）中、Ｒ３で示される炭素数１～６のアルキル基としては、例えば、上記「置換基」と同様のアルキル基が挙げられるが、炭素数１～３のアルキル基が好ましく、メチル基がより好ましい。 In the formula (II), examples of the alkyl group having 1 to 6 carbon atoms represented by R 3 include the same alkyl groups as the above-mentioned “substituent”, but an alkyl group having 1 to 3 carbon atoms is preferable. Preferably, a methyl group is more preferable.
　すなわち、Ｘとしては、ヒトdUTPase阻害作用の点で、エチレン基、トリメチレン基、下記式（IV）～（VII） That is, X is an ethylene group, a trimethylene group, and the following formulas (IV) to (VII) in terms of human dUTPase inhibitory action.
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
（式（IV）中の酸素末端は式（Ｉ）中のメチレン基と結合し、式（IV）中のメチレン末端は、式（Ｉ）中のＡと結合し、式（VII）中のメチレン末端は式（Ｉ）中のメチレン基と結合し、式（VII）中のジメチルメチレン末端は、式（Ｉ）中のＡと結合する。） (The oxygen end in formula (IV) is bonded to the methylene group in formula (I), the methylene end in formula (IV) is bonded to A in formula (I), and the methylene group in formula (VII) The terminal is bonded to the methylene group in formula (I), and the dimethylmethylene terminal in formula (VII) is bonded to A in formula (I).
で表される基及び一般式（II）で表される基から選ばれるいずれかの基が好ましい。このうち、エチレン基、トリメチレン基又は式（IV）で表される基が特に好ましい。
　Ｙがフッ素原子の場合には、トリメチレン基又は式（IV）で表される基が特に好ましい。 And any group selected from the group represented by formula (II) and the group represented by formula (II) is preferable. Among these, an ethylene group, a trimethylene group or a group represented by the formula (IV) is particularly preferable.
When Y is a fluorine atom, a trimethylene group or a group represented by the formula (IV) is particularly preferable.
　一般式（Ｉ）中、Ａで表される「置換基を有していてもよい含窒素不飽和複素環基」の「含窒素不飽和複素環基」としては、環構造中に少なくとも１つの窒素原子を含む不飽和複素環基をいい、例えば、イミダゾリル基、ピロリル基、オキサゾリル基、イソキサゾリル基、チアゾリル基、イソチアゾリル基、ピラゾリニル基、トリアゾリル基、テトラゾリル基、ピリジル基、ピラジル基、ピリミジニル基、ピリダジニル基、インドリル基、イソインドリル基、インダゾリル基、ベンゾイミダゾリル基、ベンゾオキサゾール基、ベンゾチアゾリル基、プリニル基、キノリル基、イソキノリル基、キナゾリニル基、キノキサリル基等が挙げられる。このうち、３～６員環の含窒素不飽和複素環基が好ましく、５員環の含窒素不飽和複素環基がより好ましく、ピロリル基、ピラゾリニル基、トリアゾリル基又はテトラゾリル基がさらに好ましい。 In the general formula (I), the “nitrogen-containing unsaturated heterocyclic group” of the “nitrogen-containing unsaturated heterocyclic group which may have a substituent” represented by A includes at least one in the ring structure. An unsaturated heterocyclic group containing a nitrogen atom, for example, imidazolyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolinyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group, Examples include a pyridazinyl group, an indolyl group, an isoindolyl group, an indazolyl group, a benzimidazolyl group, a benzoxazole group, a benzothiazolyl group, a purinyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, and a quinoxalyl group. Of these, a 3- to 6-membered nitrogen-containing unsaturated heterocyclic group is preferred, a 5-membered nitrogen-containing unsaturated heterocyclic group is more preferred, and a pyrrolyl group, pyrazolinyl group, triazolyl group, or tetrazolyl group is more preferred.
　また、Ａにおいて、上記ピロリル基、ピラゾリニル基、トリアゾリル基又はテトラゾリル基のうち、ヒトdUTPase阻害作用の点で、下記式(VIII)～(XV) In A, among the above pyrrolyl group, pyrazolinyl group, triazolyl group or tetrazolyl group, the following formulas (VIII) to (XV) are used in view of human dUTPase inhibitory action.
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
から選ばれるいずれかの含窒素不飽和複素環基が好ましく、式（Ｘ)～(XII)又は式(XV) から選ばれるいずれかの含窒素不飽和複素環基が特に好ましい。
　Ｙがフッ素原子の場合には、式(XII)で表される含窒素不飽和複素環基が特に好ましい。 Any one of the nitrogen-containing unsaturated heterocyclic groups selected from the following is preferable, and any nitrogen-containing unsaturated heterocyclic group selected from the formulas (X) to (XII) or the formula (XV) is particularly preferable.
When Y is a fluorine atom, a nitrogen-containing unsaturated heterocyclic group represented by the formula (XII) is particularly preferable.
　Ｒ1及びＲ2で表される「置換基を有していてもよい炭素数１～６のアルキル基」において「炭素数１～６のアルキル基」としては、直鎖状又は分枝状の炭素数１～６のアルキル基が好ましく、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、ｎ－ヘキシル基等が挙げられ、炭素数１～３のアルキル基が好ましく、メチル基、エチル基がより好ましく、メチル基がさらに好ましい。 In the “optionally substituted alkyl group having 1 to 6 carbon atoms” represented by R 1 and R 2 , the “alkyl group having 1 to 6 carbon atoms” is linear or branched. An alkyl group having 1 to 6 carbon atoms is preferable, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, etc. An alkyl group having 1 to 3 carbon atoms is preferable, a methyl group or an ethyl group is more preferable, and a methyl group is more preferable.
　Ｒ1及びＲ2において、炭素数１～６のアルキル基が有していてもよい「置換基」としては、ハロゲン原子、ヒドロキシル基及び炭素数１～６のアルコキシ基が好ましく、フッ素原子、ヒドロキシル基、メトキシ基及びエトキシ基がより好ましい。 In R 1 and R 2 , the “substituent” that the alkyl group having 1 to 6 carbon atoms may have is preferably a halogen atom, a hydroxyl group, or an alkoxy group having 1 to 6 carbon atoms. More preferred are groups, methoxy groups and ethoxy groups.
　すなわち、Ｒ1及びＲ2で表される「置換基を有していてもよい炭素数１～６のアルキル基」としては、メチル基、モノフルオロメチル基、ジフルオロエチル基、メトキシメチル基、エトキシメチル基、メトキシエチル基、エトキシエチル基が好ましい。 That is, the “optionally substituted alkyl group having 1 to 6 carbon atoms” represented by R 1 and R 2 includes a methyl group, a monofluoromethyl group, a difluoroethyl group, a methoxymethyl group, an ethoxy group. A methyl group, a methoxyethyl group and an ethoxyethyl group are preferred.
　Ｒ1及びＲ2で表される「置換基を有していてもよい炭素数２～６のアルケニル基」において「炭素数２～６のアルケニル基」としては、例えば、上記「置換基」と同様のアルケニル基が挙げられるが、ビニル基が好ましく、無置換が好ましい。
　Ｒ1及びＲ2で表される「置換基を有していてもよい炭素数２～６のアルキニル基」において「炭素数２～６のアルキニル基」としては、例えば、上記「置換基」と同様のアルキニル基が挙げられるが、エチニル基が好ましく、無置換が好ましい。 In the “optionally substituted alkenyl group having 2 to 6 carbon atoms” represented by R 1 and R 2 , the “alkenyl group having 2 to 6 carbon atoms” may be, for example, the above “substituent”. Although the same alkenyl group is mentioned, a vinyl group is preferable and unsubstituted is preferable.
In the “optionally substituted alkynyl group having 2 to 6 carbon atoms” represented by R 1 and R 2 , the “alkynyl group having 2 to 6 carbon atoms” includes, for example, the above “substituent” and Although the same alkynyl group is mentioned, an ethynyl group is preferable and unsubstituted is preferable.
　Ｒ１及びＲ２で表される「モノアルキルアミノカルボニル基」としては、例えば、上記「置換基」と同様のモノアルキルアミノ基を有するカルボニル基が挙げられる。 Examples of the “monoalkylaminocarbonyl group” represented by R 1 and R 2 include a carbonyl group having a monoalkylamino group similar to the above “substituent”.
　Ｒ１及びＲ２で表される「ジアルキルアミノカルボニル基」としては、例えば、上記「置換基」と同様のジアルキルアミノ基を有するカルボニル基が挙げられるが、ジメチルアミノカルボニル基が好ましい。 Examples of the “dialkylaminocarbonyl group” represented by R 1 and R 2 include a carbonyl group having a dialkylamino group similar to the above “substituent”, and a dimethylaminocarbonyl group is preferred.
　Ｒ１及びＲ２で表される「アリール基」としては、炭素数６～１４のアリール基、例えばフェニル基、ナフチル基等が挙げられる。
　Ｒ１及びＲ２で表される「不飽和複素環基」としては、例えば、上記「置換基」と同様の不飽和複素環基が挙げられるが、チアゾリル基が好ましい。 Examples of the “aryl group” represented by R 1 and R 2 include aryl groups having 6 to 14 carbon atoms such as a phenyl group and a naphthyl group.
Examples of the “unsaturated heterocyclic group” represented by R 1 and R 2 include unsaturated heterocyclic groups similar to the above “substituent”, but a thiazolyl group is preferred.
　Ｒ１及びＲ２で表される「置換基を有していてもよいアラルキル基」としては、例えば、炭素数７～２４のアラルキル基、例えば、Ｃ６－１０アリール－Ｃ１－６アルキル基が挙げれられ、より好ましくは、フェニル－Ｃ１－６アルキル基が挙げられる。具体的には、置換基を有していてもよいベンジル基、置換基を有していてもよいフェニルエチル基が好ましい。 The “aralkyl group optionally having substituent (s)” represented by R 1 and R 2 is, for example, an aralkyl group having 7 to 24 carbon atoms, such as a C 6-10 aryl-C 1-6 alkyl group. More preferred is a phenyl-C 1-6 alkyl group. Specifically, a benzyl group which may have a substituent and a phenylethyl group which may have a substituent are preferable.
　また、Ｒ１及びＲ２において、「置換基を有していてもよいベンジル基」としては、下記一般式（III） In R 1 and R 2 , the “benzyl group optionally having substituent (s)” is represented by the following general formula (III)
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
（式（III）中、ｎ＝０を示し、Ｒ6及びＲ7は、同一又は相異なって、水素原子又はフェニル基を示し、Ｒ8及びＲ9は、同一又は相異なって、水素原子又は置換基を有していてもよい炭素数１～６のアルコキシ基を示す。）
で表されるベンジル基が好ましい。 (In the formula (III), n = 0, R 6 and R 7 are the same or different and each represents a hydrogen atom or a phenyl group, and R 8 and R 9 are the same or different and each represents a hydrogen atom or (This represents an optionally substituted alkoxy group having 1 to 6 carbon atoms.)
The benzyl group represented by these is preferable.
　また、Ｒ8及びＲ9で表される「置換基を有していてもよい炭素数１～６のアルコキシ基」の「炭素数１～６のアルコキシ基」としては、上記「置換基」と同様のアルコキシ基が挙げられるが、メトキシ基が好ましい。
　また、Ｒ8及びＲ9で表される「置換基を有していてもよい炭素数１～６のアルコキシ基」の「置換基」としては、シクロアルキル基が好ましく、シクロプロピル基がより好ましい。 In addition, the “substituent” as the “substituent” as described above for the “alkoxy group having 1 to 6 carbon atoms” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 Although the same alkoxy group is mentioned, a methoxy group is preferable.
The “substituent” in the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 is preferably a cycloalkyl group, more preferably a cyclopropyl group. .
　また、Ｒ１及びＲ２において、上記「置換基を有していてもよいフェニルエチル基」としては、下記一般式（III） In R 1 and R 2 , the above-mentioned “phenylethyl group optionally having substituent (s)” is represented by the following general formula (III)
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
（式（III）中、ｎ＝１を示し、Ｒ4及びＲ5は、同一又は相異なって、水素原子又は炭素数１～６のアルキル基を示し、Ｒ6及びＲ7は、同一又は相異なって、水素原子、ヒドロキシル基、炭素数１～６のアルキル基又は置換基を有していてもよいフェニル基を示し、Ｒ8及びＲ9は、同一又は相異なって、水素原子、ハロゲン原子、置換基を有していてもよい炭素数１～６のアルコキシ基、炭素原子間に酸素原子を有していてもよい炭素数３～７のシクロアルコキシ基、置換基を有していてもよいフェニル基、又は置換基を有していてもよいチエニル基を示す。）で表されるフェニルエチル基が好ましい。 (In the formula (III), n = 1, R 4 and R 5 are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R 6 and R 7 are the same or different. Differently represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group, and R 8 and R 9 are the same or different and represent a hydrogen atom, a halogen atom, An alkoxy group having 1 to 6 carbon atoms which may have a substituent, a cycloalkoxy group having 3 to 7 carbon atoms which may have an oxygen atom between carbon atoms, and a substituent. A good phenyl group or a thienyl group optionally having a substituent.) Is preferred.
　また、Ｒ4及びＲ5で表される「炭素数１～６のアルキル基」としては、例えば、上記「置換基」と同様のアルキル基が挙げられるが、メチル基が好ましい。
　Ｒ6及びＲ7で表される「炭素数１～６のアルキル基」としては、例えば、上記と同様のアルキル基が挙げられるが、メチル基、エチル基、イソプロピル基が好ましく、エチル基がより好ましい。
　Ｒ6及びＲ7で表される「置換基を有していてもよいフェニル基」の置換基としては、ハロゲン原子、炭素数１～６のアルコキシ基が好ましく、フッ素原子、塩素原子、メトキシ基がより好ましい。 Examples of the “alkyl group having 1 to 6 carbon atoms” represented by R 4 and R 5 include the same alkyl groups as the above “substituent”, but a methyl group is preferred.
Examples of the “alkyl group having 1 to 6 carbon atoms” represented by R 6 and R 7 include the same alkyl groups as described above, preferably a methyl group, an ethyl group and an isopropyl group, more preferably an ethyl group. preferable.
The substituent of the “optionally substituted phenyl group” represented by R 6 and R 7 is preferably a halogen atom, an alkoxy group having 1 to 6 carbon atoms, a fluorine atom, a chlorine atom, a methoxy group Is more preferable.
　Ｒ8及びＲ9で表される「ハロゲン原子」としては、例えば、上記「置換基」と同様のハロゲン原子が挙げられるが、塩素原子及びフッ素原子がより好ましい。 Examples of the “halogen atom” represented by R 8 and R 9 include the same halogen atoms as the above “substituent”, but a chlorine atom and a fluorine atom are more preferable.
　Ｒ8及びＲ9で表される「置換基を有していてもよい炭素数１～６のアルコキシ基」の「炭素数１～６のアルコキシ基」としては、例えば、上記「置換基」と同様のアルコキシ基が挙げられるが、炭素数１～６の直鎖状又は分枝状のアルコキシ基が好ましく、メトキシ基、エトキシ基、イソブトキシ基、sec－ブトキシ基がより好ましい。
　Ｒ8及びＲ9で表される「置換基を有していてもよい炭素数１～６のアルコキシ基」の「置換基」としては、例えば、上記「置換基」と同様の置換基が挙げられるが、ハロゲン原子、炭素数３～７のシクロアルキル基が好ましく、フッ素原子、シクロプロピル基、１－メチルシクロプロピル基、シクロブチル基、シクロアルキリデニル基がより好ましい。
　また、上記シクロアルキリデニル基としては、炭素数３～６のシクロアルキリデン構造が好ましく、具体的には、シクロプロピリデン、シクロブチリデン、シクロペンチリデン、シクロヘキシリデンが挙げられ、ヒトdUTPase阻害作用の点で、シクロプロピリデンが好ましい。 Examples of the “alkoxy group having 1 to 6 carbon atoms” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 include, for example, the above “substituent” and Although the same alkoxy group is mentioned, a linear or branched alkoxy group having 1 to 6 carbon atoms is preferable, and a methoxy group, an ethoxy group, an isobutoxy group, and a sec-butoxy group are more preferable.
Examples of the “substituent” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 include the same substituents as the above “substituent”. However, a halogen atom and a cycloalkyl group having 3 to 7 carbon atoms are preferable, and a fluorine atom, a cyclopropyl group, a 1-methylcyclopropyl group, a cyclobutyl group, and a cycloalkylidenyl group are more preferable.
The cycloalkylidenyl group preferably has a cycloalkylidene structure having 3 to 6 carbon atoms. Specific examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene, which inhibit human dUTPase inhibition. From the viewpoint of action, cyclopropylidene is preferred.
　Ｒ8及びＲ9で表される「炭素原子間に酸素原子を有していてもよい炭素数３～７のシクロアルコキシ基」としては、例えば、上記「置換基」のシクロアルコキシ基及び飽和複素環オキシ基と同様の基が挙げられるが、シクロブチルオキシ基、シクロペンチルオキシ基、テトラヒドロフリルオキシ基及びテトラヒドロピリルオキシ基が好ましい。
　Ｒ8及びＲ9で表される「置換基を有していてもよいフェニル基」の置換基としては、上記「置換基」同様のハロゲン原子が挙げられるが、フッ素原子及び塩素原子がより好ましい。
　Ｒ8及びＲ9で表される「置換基を有していてもよいチエニル基」の置換基としては、上記「置換基」同様の置換基が挙げられる。 Examples of the “C3-C7 cycloalkoxy group optionally having an oxygen atom between carbon atoms” represented by R 8 and R 9 include, for example, the above-mentioned “substituent” cycloalkoxy group and saturated complex Although the same group as a ring oxy group is mentioned, A cyclobutyloxy group, a cyclopentyloxy group, a tetrahydrofuryloxy group, and a tetrahydropyryloxy group are preferable.
Examples of the substituent of the “optionally substituted phenyl group” represented by R 8 and R 9 include the same halogen atoms as the above “substituent”, but a fluorine atom and a chlorine atom are more preferable. .
Examples of the substituent of the “optionally substituted thienyl group” represented by R 8 and R 9 include the same substituents as the above “substituent”.
　また、Ｒ４及びＲ5としては、ヒトdUTPase阻害作用の点で、水素原子及びメチル基が好ましく、水素原子が特に好ましい。
　Ｒ6としては、ヒトdUTPase阻害作用の点で、水素原子又はヒドロキシル基が好ましく、Ｒ7としては、ヒトdUTPase阻害作用の点で、水素原子、炭素数１～６のアルキル基又は置換基としてフッ素原子、塩素原子、炭素数１～６のアルコキシ基を有していてもよいフェニル基が特に好ましい。
　Ｒ8及びＲ9としては、ヒトdUTPase阻害作用の点で、水素原子、フッ素原子、塩素原子、置換基としてハロゲン原子、炭素数３～７のシクロアルキル基若しくはシクロアルキリデニル基を有していてもよい炭素数１～６の直鎖状又は分枝状のアルコキシ基、シクロブチルオキシ基、シクロペンチルオキシ基、テトラヒドロフリルオキシ基、テトラヒドロピリルオキシ基、置換基としてハロゲン原子を有していてもよいフェニル基、又はチエニル基が好ましい。 Further, R 4 and R 5 are preferably a hydrogen atom and a methyl group, and particularly preferably a hydrogen atom, from the viewpoint of human dUTPase inhibitory action.
R 6 is preferably a hydrogen atom or a hydroxyl group from the viewpoint of human dUTPase inhibitory action, and R 7 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a fluorine as a substituent from the viewpoint of human dUTPase inhibitory action. A phenyl group optionally having an atom, a chlorine atom, or an alkoxy group having 1 to 6 carbon atoms is particularly preferred.
R 8 and R 9 have a hydrogen atom, a fluorine atom, a chlorine atom, a halogen atom as a substituent, a cycloalkyl group having 3 to 7 carbon atoms or a cycloalkylidenyl group from the viewpoint of human dUTPase inhibitory action. A linear or branched alkoxy group having 1 to 6 carbon atoms, a cyclobutyloxy group, a cyclopentyloxy group, a tetrahydrofuryloxy group, a tetrahydropyryloxy group, or a halogen atom as a substituent. Preferred phenyl group or thienyl group is preferable.
　また、式（Ｉ）において、Ｒ１及びＲ２の好適な組合せとしては、Ｒ１が、水素原子、シアノ基、メチル基、モノフルオロメチル基、ジフルオロエチル基、ビニル基、エチニル基、メトキシ基、ジメチルエーテル基、ジメチルアミノカルボニル基又はフェニル基を示し、Ｒ２が、水素原子、フェニル基、上記一般式（III）で表されるベンジル基（ｎ＝０）、上記一般式（III）で表されるフェニルエチル基（ｎ＝１）、又はチアゾリル基が挙げられる。このうち、ヒトdUTPase阻害作用の点で、Ｒ1が、水素原子を示し、Ｒ2が、上記一般式（III）で表されるフェニルエチル基（ｎ＝１）を示すのが特に好ましい。 In the formula (I), as a preferable combination of R 1 and R 2 , R 1 is a hydrogen atom, a cyano group, a methyl group, a monofluoromethyl group, a difluoroethyl group, a vinyl group, an ethynyl group, or a methoxy group. , A dimethyl ether group, a dimethylaminocarbonyl group or a phenyl group, wherein R 2 is a hydrogen atom, a phenyl group, a benzyl group (n = 0) represented by the general formula (III), or a general formula (III). A phenylethyl group (n = 1), or a thiazolyl group. Among these, it is particularly preferable that R 1 represents a hydrogen atom and R 2 represents a phenylethyl group (n = 1) represented by the above general formula (III) in terms of human dUTPase inhibitory action.
　本発明のウラシルＮ－１位化合物は、下記反応工程式に従い製造することが出来る。
〔工程Ａ〕 The uracil N-1 compound of the present invention can be produced according to the following reaction process formula.
[Process A]
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
〔式中、X、A、Yは上記と同義であり、Rcはカルボキシル基の保護基を示し、Rnはアミノ基の保護基を示し、MOMはメトキシメチル基を示す。なお工程A-5、A-7においては、X＝-O-CH2-X’-を示す。〕 [Wherein, X, A and Y are as defined above, Rc represents a protecting group for a carboxyl group, Rn represents a protecting group for an amino group, and MOM represents a methoxymethyl group. In Steps A-5 and A-7, X = —O—CH 2 —X′— is shown. ]
〔工程A-1〕
　本工程では、容易に入手可能又は公知の方法により入手可能な一般式(1)で表される化合物のヒドロキシル基を、通常公知の方法によりメタンスルホニル化した後、アジド化試薬と反応させることにより、一般式(2)で表される化合物を製造できる。
　アジド化に用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、N,N-ジメチルホルムアミド（以下DMF）、テトラヒドロフラン（以下THF）、ジオキサン、アセトニトリル、トルエン、ジクロロメタン等が例示され、好ましくはDMFである。用いるアジド化試薬としては、アジ化ナトリウム、アジ化リチウム等が例示され、好ましくはアジ化ナトリウムである。その当量数は0.8～10当量であり、好ましくは1.0～6.0当量である。反応温度は10～120℃であり、好ましくは50～100℃である。反応時間は1.0～24時間であり、好ましくは3.0～12時間である。 [Process A-1]
In this step, the hydroxyl group of the compound represented by the general formula (1) that can be easily obtained or obtained by a known method is methanesulfonylated by a generally known method, and then reacted with an azido reagent. A compound represented by the general formula (2) can be produced.
The reaction solvent used for azidation is not particularly limited as long as it does not affect the reaction, but N, N-dimethylformamide (hereinafter DMF), tetrahydrofuran (hereinafter THF), dioxane, acetonitrile, toluene, dichloromethane, etc. And is preferably DMF. Examples of the azidation reagent to be used include sodium azide and lithium azide, and sodium azide is preferred. The number of equivalents is 0.8 to 10 equivalents, preferably 1.0 to 6.0 equivalents. The reaction temperature is 10 to 120 ° C, preferably 50 to 100 ° C. The reaction time is 1.0 to 24 hours, preferably 3.0 to 12 hours.
〔工程A-2〕
　本工程では、一般式(2)で表される化合物を、水存在下、トリフェニルホスフィンと反応させた後、塩酸で処理することにより、一般式(3)で表される化合物を製造できる。
　用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、DMF、THF、ジオキサン、アセトニトリル等が例示され、好ましくはTHFである。用いるトリフェニルホスフィンの当量数は1.0～5.0当量であり、好ましくは1.1～2.0当量である。反応温度は0～120℃であり、好ましくは10～60℃である。反応時間は0.5～24時間であり、好ましくは1.0～3.0時間である。 [Process A-2]
In this step, the compound represented by the general formula (3) can be produced by reacting the compound represented by the general formula (2) with triphenylphosphine in the presence of water and then treating with hydrochloric acid.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include DMF, THF, dioxane, acetonitrile and the like, preferably THF. The number of equivalents of triphenylphosphine used is 1.0 to 5.0 equivalents, preferably 1.1 to 2.0 equivalents. The reaction temperature is 0 to 120 ° C, preferably 10 to 60 ° C. The reaction time is 0.5 to 24 hours, preferably 1.0 to 3.0 hours.
〔工程A-3〕
　本工程では、一般式(3)で表される化合物を、J. Heterocyclic Chem., 36, 293-295(1999)記載の方法により得られる3-メトキシ-2-プロペノイルイソシアネートと塩基存在下反応させることにより、一般式(4)で表される化合物を製造できる。
　用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、DMF、THF、ジオキサン、アセトニトリル、トルエン、ジクロロメタン等が例示され、好ましくはDMFである。3-メトキシ-2-プロペノイルイソシアネートの当量数は0.8～2.0当量であり、好ましくは0.9～1.3当量である。用いる塩基としては、トリエチルアミン、トリプロピルアミン、ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ルチジン、コリジン等の有機アミン類が例示され、好ましくはトリエチルアミンである。その当量数は1.0～10当量であり、好ましくは1.1～3.0当量である。反応温度は-78～50℃であり、好ましくは-40～30℃である。反応時間は1.0～24時間であり、好ましくは2.0～3.0時間である。 [Process A-3]
In this step, the compound represented by the general formula (3) is reacted with 3-methoxy-2-propenoyl isocyanate obtained by the method described in J. Heterocyclic Chem., 36, 293-295 (1999) in the presence of a base. By doing so, the compound represented by the general formula (4) can be produced.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include DMF, THF, dioxane, acetonitrile, toluene, dichloromethane, etc., preferably DMF. The number of equivalents of 3-methoxy-2-propenoyl isocyanate is 0.8 to 2.0 equivalents, preferably 0.9 to 1.3 equivalents. Examples of the base to be used include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and preferably triethylamine. The number of equivalents is 1.0 to 10 equivalents, preferably 1.1 to 3.0 equivalents. The reaction temperature is -78 to 50 ° C, preferably -40 to 30 ° C. The reaction time is 1.0 to 24 hours, preferably 2.0 to 3.0 hours.
〔工程A-4〕
　本工程では、一般式(4)で表される化合物を、通常公知の酸と反応させることにより、一般式(5)で表される化合物を製造することができる。
　用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、酢酸エチル、ジオキサン、水、メタノール、エタノール等が例示され、好ましくはジオキサンである。用いる酸としては塩化水素、塩酸、硫酸等の無機酸又はメタンスルホン酸等の有機酸が例示され、好ましくは塩化水素である。その当量数は0.5-1000当量であり、好ましくは1.0-100当量である。反応温度は0～100℃であり、好ましくは10～30℃である。反応時間は0.1～5.0時間であり、好ましくは0.5～1.0時間である。 [Process A-4]
In this step, the compound represented by the general formula (5) can be produced by reacting the compound represented by the general formula (4) with a generally known acid.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include ethyl acetate, dioxane, water, methanol, ethanol and the like, and dioxane is preferable. Examples of the acid to be used include inorganic acids such as hydrogen chloride, hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid, and hydrogen chloride is preferable. The number of equivalents is 0.5-1000 equivalents, preferably 1.0-100 equivalents. The reaction temperature is 0 to 100 ° C., preferably 10 to 30 ° C. The reaction time is 0.1 to 5.0 hours, preferably 0.5 to 1.0 hours.
〔工程A-5〕
　本工程では、通常公知の方法により得られる一般式(6)で表される化合物を、ルイス酸で活性化した後、ヨウ素存在下、2, 4-ビス(トリメチルシリルオキシ)ピリミジン又は5-フルオロ－2, 4-ビス(トリメチルシリルオキシ)ピリミジンと反応させることにより、一般式(5)で表される化合物を製造できる（本工程においては、X=-O-(CH2)-X’-を示す）。2, 4-ビス(トリメチルシリルオキシ)ピリミジンは、Nucleosides & Nucleotides, 4, 565-585(1985)記載の方法により製造することができ、5-フルオロ－2, 4-ビス(トリメチルシリルオキシ)ピリミジンは容易に入手可能である。
　用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、アセトン、THF、ジエチルエーテル、ジオキサン、1,2-ジクロロメタン、ジクロロエタン等が例示され、好ましくは1,2-ジクロロエタンである。2,4-ビス(トリメチルシリルオキシ)ピリミジン又は5-フルオロ－2, 4-ビス(トリメチルシリルオキシ)ピリミジンの当量数は1.0～3.0当量であり、好ましくは1.5～2.0当量である。用いるルイス酸としては三塩化ホウ素 (以下BCl3)、三臭化ホウ素、ヨウ化トリメチルシリル等が例示されるが、好ましくはBCl3である。その当量数は0.1～2.0当量であり、好ましくは0.2～0.4当量である。ヨウ素の当量数は0.001～0.5当量であり、好ましくは0.1～0.2当量である。反応温度は50～120℃であり、好ましくは60～100℃である。反応時間は0.5～24時間であり、好ましくは1.0～10時間である。 [Process A-5]
In this step, a compound represented by the general formula (6) obtained by a generally known method is activated with a Lewis acid, and then 2,4-bis (trimethylsilyloxy) pyrimidine or 5-fluoro- in the presence of iodine. By reacting with 2,4-bis (trimethylsilyloxy) pyrimidine, a compound represented by the general formula (5) can be produced (in this step, X = -O- (CH 2 ) -X'- is shown. ). 2,4-bis (trimethylsilyloxy) pyrimidine can be produced by the method described in Nucleosides & Nucleotides, 4, 565-585 (1985), and 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine is easy Is available.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but acetone, THF, diethyl ether, dioxane, 1,2-dichloromethane, dichloroethane and the like are exemplified, and 1,2-dichloroethane is preferable. It is. The number of equivalents of 2,4-bis (trimethylsilyloxy) pyrimidine or 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents. Examples of the Lewis acid used include boron trichloride (hereinafter referred to as BCl 3 ), boron tribromide, trimethylsilyl iodide, and the like, and BCl 3 is preferred. The number of equivalents is 0.1 to 2.0 equivalents, preferably 0.2 to 0.4 equivalents. The number of equivalents of iodine is 0.001 to 0.5 equivalents, preferably 0.1 to 0.2 equivalents. The reaction temperature is 50 to 120 ° C, preferably 60 to 100 ° C. The reaction time is 0.5 to 24 hours, preferably 1.0 to 10 hours.
〔工程A-6〕
　本工程では、通常公知の方法により得られる一般式(6)で表される化合物を、塩基で活性化し、容易に入手可能なクロロギ酸エステルと反応させることにより、一般式(7)で表される化合物を製造できる。
　用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、DMF、THF、ジオキサン、ジエチルエーテル等が例示され、好ましくはTHFである。用いる塩基は金属水素化物、n-ブチルリチウム、sec-ブチルリチウム、tert-ブチルリチウム等が例示され、好ましくはn-ブチルリチウムである。その当量数は0.8～2.0当量であり、好ましくは1.0～1.5当量である。クロロギ酸エステルの当量数は0.8～2.0当量であり、好ましくは1.0～1.2当量である。反応温度は-100～100℃であり、好ましくは-78～0℃である。反応時間は0.5～24時間であり、好ましくは1.0～5.0時間である。 [Process A-6]
In this step, the compound represented by the general formula (6) obtained by a generally known method is activated with a base and reacted with a readily available chloroformate to represent the compound represented by the general formula (7). Can be produced.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include DMF, THF, dioxane, diethyl ether, etc., preferably THF. Examples of the base to be used include metal hydride, n-butyllithium, sec-butyllithium, tert-butyllithium and the like, preferably n-butyllithium. The number of equivalents is 0.8 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents. The number of equivalents of chloroformate is 0.8 to 2.0 equivalents, preferably 1.0 to 1.2 equivalents. The reaction temperature is −100 to 100 ° C., preferably −78 to 0 ° C. The reaction time is 0.5 to 24 hours, preferably 1.0 to 5.0 hours.
〔工程A-7〕
　本工程では、一般式(7)で表される化合物を、工程A-5と同様の方法により反応させることにより、一般式(8)で表される化合物を製造できる（本工程においては、X=-O-(CH2)-X’を示す）。 [Process A-7]
In this step, the compound represented by the general formula (8) can be produced by reacting the compound represented by the general formula (7) by the same method as in Step A-5 (in this step, X = -O- (CH 2 ) -X ′).
〔工程A-8〕
　本工程では、容易に入手可能又は公知の方法により入手可能な一般式(1)で表される化合物と一般式(9)で表される化合物、例えばJ. Med. Chem., 50, 6032-6038(2007)記載の方法に準じて得られるN3-ベンゾイルウラシルを、トリフェニルホスフィン存在下、光延反応させた後、アミノ基の保護基を通常公知の方法で除去することにより、一般式(5)で表される化合物を製造できる。
　光延反応に用いる試薬としてはアゾジカルボン酸ジイソプロピル、アゾジカルボン酸ジエチル等が例示され、好ましくはアゾジカルボン酸ジイソプロピルである。その当量数は1.0～3.0当量であり、好ましくは1.5～2.0当量である。トリフェニルホスフィンの当量数は1.0～3.0当量であり、好ましくは1.5～2.0当量である。一般式(1)で表される化合物の当量数は1.0～3.0当量であり、好ましくは1.5～2.0当量である。用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、THF、ジオキサン、ジエチルエーテル、アセトン、トルエン等が例示され、好ましくはTHFである。反応温度は0～100℃であり 、好ましくは10～30℃である。反応時間は0.1～24時間であり、好ましくは0.2～3.0時間である。 [Process A-8]
In this step, a compound represented by the general formula (1) and a compound represented by the general formula (9) which can be easily obtained or obtained by a known method, for example, J. Med. Chem., 50, 6032- N 3 -benzoyluracil obtained according to the method described in 6038 (2007) is subjected to Mitsunobu reaction in the presence of triphenylphosphine, and then the amino-protecting group is removed by a generally known method to give a general formula ( The compound represented by 5) can be produced.
Examples of the reagent used in the Mitsunobu reaction include diisopropyl azodicarboxylate, diethyl azodicarboxylate, and the like, and preferably diisopropyl azodicarboxylate. The number of equivalents is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents. The number of equivalents of triphenylphosphine is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents. The number of equivalents of the compound represented by the general formula (1) is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, acetone, toluene and the like, preferably THF. The reaction temperature is 0 to 100 ° C., preferably 10 to 30 ° C. The reaction time is 0.1 to 24 hours, preferably 0.2 to 3.0 hours.
〔工程B〕 [Process B]
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
〔式中、R1、R4～R9、n、X及びYは上記と同義である。〕 [Wherein R 1 , R 4 to R 9 , n, X and Y are as defined above. ]
〔工程B-1〕
　本工程では、公知の方法により得られる一般式(10)で表される化合物を、工程A-1と同様の方法、Tetrahedron Lett., 48, 7109-7172(2007)記載の方法、或いはジフェニルホスホリルアジド／DBUで反応させることにより、一般式(11)で表されるアジド化合物を製造出来る。R8がハロゲン原子、R9が置換基を有していてもよい炭素数１～６のアルコキシ基である場合には、例えば容易に入手可能な4-フルオロ-3-ヒドロキシ安息香酸を出発原料として、Grignard反応等用いることにより、一般式(10)で表される化合物を入手できる。 [Process B-1]
In this step, the compound represented by the general formula (10) obtained by a known method is converted into the same method as in Step A-1, the method described in Tetrahedron Lett., 48, 7109-7172 (2007), or diphenylphosphoryl. By reacting with azide / DBU, an azide compound represented by the general formula (11) can be produced. When R 8 is a halogen atom and R 9 is an optionally substituted alkoxy group having 1 to 6 carbon atoms, for example, easily available 4-fluoro-3-hydroxybenzoic acid is used as a starting material. As described above, a compound represented by the general formula (10) can be obtained by using a Grignard reaction or the like.
〔工程B-2〕
　本工程では、一般式(11)で表される化合物と工程Aで製造されたアルキン化合物(5)又は(8)を、ルテニウム触媒存在下に反応させて環化した後、保護されたカルボキシル基（R1）を必要に応じて変換することにより、一般式(12)で表される本発明化合物を製造できる。
　環化反応に用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、トルエン、ジクロロメタン、アセトニトリル、THF、ジオキサン等が例示され、好ましくはジオキサンである。用いるルテニウム触媒としては、クロロ(ペンタメチルシクロペンタジエニル)(シクロオクタジエン)ルテニウム(II)、ペンタメチルシクロペンタジエニルビス(トリフェニルホスフィン)ルテニウム(II)クロリド等、種々の有機ルテニウム触媒が例示されるが、好ましくはクロロ(ペンタメチルシクロペンタジエニル)(シクロオクタジエン)ルテニウム(II)である。その当量数は0.001～0.5当量であり、好ましくは0.01～0.3当量である。反応温度は0～100℃であり、好ましくは20～90℃である。反応時間は0.5～24時間であり、好ましくは1.0～5.0時間である。 [Process B-2]
In this step, the compound represented by the general formula (11) and the alkyne compound (5) or (8) produced in Step A are reacted in the presence of a ruthenium catalyst and cyclized, and then a protected carboxyl group. The compound of the present invention represented by the general formula (12) can be produced by converting (R 1 ) as necessary.
The reaction solvent used in the cyclization reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include toluene, dichloromethane, acetonitrile, THF, dioxane and the like, and dioxane is preferable. As the ruthenium catalyst to be used, various organic ruthenium catalysts such as chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II), pentamethylcyclopentadienylbis (triphenylphosphine) ruthenium (II) chloride, etc. Illustrative examples include chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II). The number of equivalents is 0.001 to 0.5 equivalents, preferably 0.01 to 0.3 equivalents. The reaction temperature is 0 to 100 ° C., preferably 20 to 90 ° C. The reaction time is 0.5 to 24 hours, preferably 1.0 to 5.0 hours.
〔工程C〕 [Process C]
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
〔式中、R1、R4～R9、X、Rc、及びnは上記と同義であり、Rhはヒドロキシル基の保護基を示す。〕 [Wherein R 1 , R 4 to R 9 , X, Rc, and n are as defined above, and Rh represents a protecting group for a hydroxyl group. ]
〔工程C-1〕
　本工程では、容易に入手可能又は公知の方法により入手可能な一般式(1)で表される化合物、例えば5-ヘキシン-1-オールのヒドロキシル基を、通常公知の方法により保護した後、工程A-6と同様に反応させることにより、一般式(13)で表される化合物を製造できる。 [Process C-1]
In this step, the compound represented by the general formula (1) that can be easily obtained or obtained by a known method, for example, the hydroxyl group of 5-hexyn-1-ol is usually protected by a known method, and then the step. By reacting in the same manner as A-6, the compound represented by the general formula (13) can be produced.
〔工程C-2〕
　本工程では、一般式(13)で表される化合物と一般式(11)で表される化合物を、工程B-2と同様の方法で環化反応させることにより、一般式(14)で表される化合物を製造できる。 [Process C-2]
In this step, the compound represented by the general formula (13) and the compound represented by the general formula (11) are subjected to a cyclization reaction in the same manner as in Step B-2 to thereby represent the compound represented by the general formula (14). Can be produced.
〔工程C-3〕
　本工程では、一般式(14)で表される化合物の保護されたカルボキシル基を変換することにより、一般式(15)で表される化合物を製造することができる。
　例えば、保護されたカルボキシル基を通常公知の方法で還元してヒドロキシルメチル基を得た後、アルキル化反応やハロゲン置換反応することができる。また、ヒドロキシメチル基を酸化してアルデヒド体を得た後、塩基性条件下、メチルトリフェニルホスホニウムブロミドと反応させることによりビニル体を製造することができ、またアルデヒド体にEur. J. Org. Chem., 5, 821-832(2003)に記載の方法で得られるジメチル 1-ジアゾ-2-オキソプロピルホスホネートを塩基存在下反応させることにより、エチニル体を製造することもできる。また、カルボキシル基を脱保護し、種々のアミンと通常公知の方法で縮合させることでアミド体を製造することもできる。 [Process C-3]
In this step, the compound represented by the general formula (15) can be produced by converting the protected carboxyl group of the compound represented by the general formula (14).
For example, after the protected carboxyl group is reduced by a generally known method to obtain a hydroxylmethyl group, an alkylation reaction or a halogen substitution reaction can be performed. In addition, after oxidizing the hydroxymethyl group to obtain an aldehyde form, a vinyl form can be produced by reacting with methyltriphenylphosphonium bromide under basic conditions, and Eur. J. Org. An ethynyl compound can also be produced by reacting dimethyl 1-diazo-2-oxopropylphosphonate obtained by the method described in Chem., 5, 821-832 (2003) in the presence of a base. Moreover, an amide body can also be manufactured by deprotecting a carboxyl group and condensing with various amines by a conventionally well-known method.
〔工程D〕 [Process D]
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
〔式中、R4～R9、X、Rh、及びnは上記と同義である。〕 [Wherein, R 4 to R 9 , X, Rh, and n are as defined above. ]
〔工程D-1〕
　本工程では、例えばSynLett, (20), 3160-3162(2005)に記載の方法により得られる一般式(16)で表される化合物を、塩基存在下、アセトヒドラジドと反応させることにより、一般式(17)で表される化合物を製造できる。
　用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、THF、ジオキサン、ジエチルエーテル、トルエン、ジクロロメタン、アセトニトリル、DMF、エタノール、メタノール、n-ブタノール等が例示され、好ましくはn-ブタノールである。用いる塩基としては炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム等が例示され、好ましくは炭酸カリウムである。その当量数は0.1～3.0当量であり、好ましくは0.12～2.0当量である。アセトヒドラジドの当量数は0.1～20当量であり、好ましくは0.2～10当量である。反応温度は-78～200℃であり 、好ましくは120～160℃である。反応時間は0.5～48時間であり、好ましくは1.0～5.0時間である。 [Process D-1]
In this step, for example, the compound represented by the general formula (16) obtained by the method described in SynLett, (20), 3160-3162 (2005) is reacted with acetohydrazide in the presence of a base to give a general formula The compound represented by (17) can be produced.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, acetonitrile, DMF, ethanol, methanol, n-butanol, and the like. Is n-butanol. Examples of the base to be used include potassium carbonate, cesium carbonate, sodium hydrogen carbonate and the like, and potassium carbonate is preferable. The number of equivalents is 0.1 to 3.0 equivalents, preferably 0.12 to 2.0 equivalents. The number of equivalents of acetohydrazide is 0.1 to 20 equivalents, preferably 0.2 to 10 equivalents. The reaction temperature is -78 to 200 ° C, preferably 120 to 160 ° C. The reaction time is 0.5 to 48 hours, preferably 1.0 to 5.0 hours.
〔工程D-2〕
　本工程では、一般式(17)で表される化合物を塩基で活性化した後、一般式(10)で表される化合物のヒドロキシル基をメタンスルホニル化した化合物と反応させることにより、一般式(18)で表される化合物を製造できる。
　用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、THF、ジオキサン、ジエチルエーテル、トルエン、ジクロロメタン、アセトニトリル、DMF等が例示され、好ましくはDMFである。用いる塩基としては金属水素化物、n-ブチルリチウム、ビス(トリメチルシリル)アミドナトリウム塩（以下NaHMDS）等が例示され、好ましくは水素化ナトリウムである。その当量数は0.8～3.0当量であり、好ましくは1.0～1.2当量である。一般式(10)のメシル体化合物の当量数は0.5～2.0当量であり、好ましくは0.7～1.2当量である。反応温度は-78～100℃であり、好ましくは0～60℃である。反応時間は0.5～48時間であり、好ましくは1.0～10時間である。 [Process D-2]
In this step, after activating the compound represented by the general formula (17) with a base, the compound represented by the general formula (10) is reacted with a compound obtained by methanesulfonylation of the hydroxyl group of the general formula (10). 18) can be produced.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, acetonitrile, DMF, and the like, preferably DMF. Examples of the base to be used include metal hydride, n-butyl lithium, bis (trimethylsilyl) amide sodium salt (hereinafter referred to as NaHMDS), and sodium hydride is preferred. The number of equivalents is 0.8 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents. The number of equivalents of the mesyl compound of the general formula (10) is 0.5 to 2.0 equivalents, preferably 0.7 to 1.2 equivalents. The reaction temperature is -78 to 100 ° C, preferably 0 to 60 ° C. The reaction time is 0.5 to 48 hours, preferably 1.0 to 10 hours.
〔工程E〕 [Process E]
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
〔式中、R4～R9、X、Rh、及びnは上記と同義である。〕 [Wherein, R 4 to R 9 , X, Rh, and n are as defined above. ]
〔工程E-1〕
　本工程では、一般式(19)で表される化合物に、一般式(10)で表される化合物から製造可能な一般式(20)で表される化合物を酸存在下に反応させることにより、一般式(21)で表される化合物を製造できる。
　一般式(19)で表される化合物は、例えばTetrahedron, 61(5), 1127-1140(2005)記載の方法で得られるエチニル化合物を、アセチル化剤と反応させることにより製造できる。
　また、この工程では一般式(20)で表される化合物を塩基によって活性化する必要がある。用いる塩基としてはトリエチルアミン、トリプロピルアミン、ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ルチジン、コリジン、イミダゾール等の有機アミン類が例示され、好ましくはトリエチルアミンである。その当量数は0.8～5.0当量であり、好ましくは1.0～1.2当量である。
　本工程で用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、THF、ジオキサン、ジエチルエーテル、トルエン、ジクロロメタン、エタノール、メタノール、DMF等が例示され、好ましくはエタノールである。用いる酸としては酢酸、硫酸、メタンスルホン酸、塩酸等が例示されるが、好ましくは酢酸である。その当量数は1.0～10当量であり、好ましくは2.0～5.0当量である。反応温度は-90～200℃であり、好ましくは10～100℃である。反応時間は0.1～48時間であり、好ましくは0.5～9.0時間である。 [Process E-1]
In this step, the compound represented by the general formula (19) is reacted with the compound represented by the general formula (20) that can be produced from the compound represented by the general formula (10) in the presence of an acid. A compound represented by the general formula (21) can be produced.
The compound represented by the general formula (19) can be produced, for example, by reacting an ethynyl compound obtained by the method described in Tetrahedron, 61 (5), 1127-1140 (2005) with an acetylating agent.
In this step, it is necessary to activate the compound represented by the general formula (20) with a base. Examples of the base used include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and imidazole, and triethylamine is preferable. The number of equivalents is 0.8 to 5.0 equivalents, preferably 1.0 to 1.2 equivalents.
The reaction solvent used in this step is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, ethanol, methanol, DMF and the like, preferably ethanol. is there. Examples of the acid to be used include acetic acid, sulfuric acid, methanesulfonic acid, hydrochloric acid and the like, and acetic acid is preferable. The number of equivalents is 1.0 to 10 equivalents, preferably 2.0 to 5.0 equivalents. The reaction temperature is -90 to 200 ° C, preferably 10 to 100 ° C. The reaction time is 0.1 to 48 hours, preferably 0.5 to 9.0 hours.
〔工程F〕 [Process F]
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
〔式中、R1、R4～R9、X、Rh、及びnは上記と同義である。〕 [Wherein R 1 , R 4 to R 9 , X, Rh, and n are as defined above. ]
〔工程F-1〕
　本工程では、例えばTetrahedron, 60, 1197-1204(2004）記載の方法に準じて得られるヒドロキシル化合物を通常公知の方法により保護して得られる一般式（22）で表される化合物を塩基で活性化した後、一般式(10)で表される化合物のヒドロキシル基をメタンスルホニル化して得られる化合物と、工程D-2と同様の方法で反応させることにより、一般式(23)で表される化合物を製造できる。 [Process F-1]
In this step, for example, a compound represented by the general formula (22) obtained by protecting a hydroxyl compound obtained according to the method described in Tetrahedron, 60, 1197-1204 (2004) by a generally known method is activated with a base. Then, the compound obtained by methanesulfonylating the hydroxyl group of the compound represented by the general formula (10) is reacted with the compound in the same manner as in Step D-2, thereby being represented by the general formula (23). Compounds can be produced.
〔工程G〕 [Process G]
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
〔式中、R4～R9、X、Rh、及びnは上記と同義であり、Rnはアミノ基の保護基を示し、mは1～6の整数を示す。〕 [Wherein R 4 to R 9 , X, Rh, and n are as defined above, Rn represents an amino-protecting group, and m represents an integer of 1-6. ]
〔工程G-1〕
　本工程では、一般式(10)で表される化合物から製造可能な一般式(24)で表される化合物にトリホスゲンを塩基存在下反応させた後、容易に入手可能なヒドラジド化合物を通常公知の方法により保護して得られる一般式（25）で表される化合物を塩基存在下反応させることにより、一般式(26)で表される化合物を製造できる。
　トリホスゲンとの反応で用いる塩基としては、トリエチルアミン、トリプロピルアミン、ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ルチジン、コリジン、イミダゾール等の有機アミン類が例示され、好ましくはトリエチルアミンである。その当量数は0.5～10当量であり、好ましくは0.8～5.0当量である。
　トリホスゲンとの反応で用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、THF、ジオキサン、ジエチルエーテル、トルエン、ジクロロメタン、DMF等が例示され、好ましくはトルエンである。反応温度は-90～200℃であり、好ましくは-78～10℃である。反応時間は0.1～48時間であり、好ましくは0.2～5.0時間である。
　一般式（25）で表される化合物との反応で用いる塩基としては、トリエチルアミン、トリプロピルアミン、ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジン、ルチジン、コリジン、イミダゾール等の有機アミン類が例示され、好ましくはトリエチルアミンである。その当量数は0.2～10当量であり、好ましくは0.5～5.0当量である。
　一般式（25）で表される化合物との反応で用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、THF、ジオキサン、ジエチルエーテル、トルエン、ジクロロメタン、DMF、アセトニトリル等が例示され、好ましくはトルエンとアセトニトリルの混合溶媒である。反応温度は-90～200℃であり、好ましくは0～70℃である。反応時間は0.1～48時間であり、好ましくは0.2～10時間である。 [Process G-1]
In this step, after reacting triphosgene with a compound represented by the general formula (24) that can be produced from the compound represented by the general formula (10) in the presence of a base, a readily available hydrazide compound is generally known. The compound represented by the general formula (26) can be produced by reacting the compound represented by the general formula (25) obtained by protection by the method in the presence of a base.
Examples of the base used in the reaction with triphosgene include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and imidazole, with triethylamine being preferred. The number of equivalents is 0.5 to 10 equivalents, preferably 0.8 to 5.0 equivalents.
The reaction solvent used in the reaction with triphosgene is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, DMF, and the like, preferably toluene. The reaction temperature is -90 to 200 ° C, preferably -78 to 10 ° C. The reaction time is 0.1 to 48 hours, preferably 0.2 to 5.0 hours.
Examples of the base used in the reaction with the compound represented by the general formula (25) include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, imidazole, and the like. Is triethylamine. The number of equivalents is 0.2 to 10 equivalents, preferably 0.5 to 5.0 equivalents.
The reaction solvent used in the reaction with the compound represented by the general formula (25) is not particularly limited as long as it does not affect the reaction, but THF, dioxane, diethyl ether, toluene, dichloromethane, DMF, acetonitrile Etc., and preferably a mixed solvent of toluene and acetonitrile. The reaction temperature is -90 to 200 ° C, preferably 0 to 70 ° C. The reaction time is 0.1 to 48 hours, preferably 0.2 to 10 hours.
〔工程G-2〕
　本工程では、一般式(26)で表される化合物を塩基性条件下反応させることにより、一般式（27）で表される化合物を製造できる。
　用いる塩基としては水酸化ナトリウム、水酸化カリウム等が例示され、好ましくは水酸化ナトリウムである。その当量数は0.2～100当量であり、好ましくは1.0～50当量である。
　用いる反応溶媒としては、水、メタノール、エタノール、n-プロパノール、n-ブタノール、THF、ジオキサン等が例示され、好ましくは水とジオキサンの混合溶媒である。反応温度は0～200℃であり、好ましくは20～120℃である。反応時間は0.1～48時間であり、好ましくは0.2～10時間である。 [Process G-2]
In this step, the compound represented by the general formula (27) can be produced by reacting the compound represented by the general formula (26) under basic conditions.
Examples of the base to be used include sodium hydroxide and potassium hydroxide, and sodium hydroxide is preferable. The number of equivalents is 0.2 to 100 equivalents, preferably 1.0 to 50 equivalents.
Examples of the reaction solvent to be used include water, methanol, ethanol, n-propanol, n-butanol, THF, dioxane and the like, and a mixed solvent of water and dioxane is preferable. The reaction temperature is 0 to 200 ° C, preferably 20 to 120 ° C. The reaction time is 0.1 to 48 hours, preferably 0.2 to 10 hours.
〔工程G-3〕
　本工程では、一般式(27)で表される化合物のヒドロキシル基及びオキソトリアゾリル基を通常公知の方法により保護した後、ヒドロキシル基の保護基を選択的に除去することにより、一般式（28）で表される化合物を製造できる。 [Process G-3]
In this step, the hydroxyl group and the oxotriazolyl group of the compound represented by the general formula (27) are protected by a generally known method, and then the protective group of the hydroxyl group is selectively removed, whereby the general formula ( 28) can be produced.
〔工程H〕 [Process H]
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
〔式中、Ｙ、及びRnは上記と同義である。〕 [Wherein, Y and Rn are as defined above. ]
〔工程H-1〕
　本工程では、一般式(9)で表される化合物、例えばJ. Med. Chem., 50, 6032-6038(2007))記載の方法に準じて得られるN3-ベンゾイルウラシルと一般式(15), (18), (21), (23)で表される化合物のRhを除去して得られる化合物又は一般式(28)で表される化合物を、工程A-8と同様の方法で反応させることにより、一般式(I)で表される本発明化合物を製造できる。 [Process H-1]
In this step, the compound represented by the general formula (9), for example, N 3 -benzoyluracil obtained according to the method described in J. Med. Chem., 50, 6032-6038 (2007)) and the general formula (15 ), (18), (21), a compound obtained by removing Rh from the compound represented by (23) or a compound represented by the general formula (28) in the same manner as in Step A-8. The compound of the present invention represented by the general formula (I) can be produced.
〔工程I〕 [Process I]
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
〔式中、R8、R9、X、Yは上記と同義である。〕 [Wherein R 8 , R 9 , X, and Y are as defined above. ]
〔工程I-1〕
　本工程では、公知の方法、例えばJ. Med. Chem., 49, 4183-4195(2006)、或いはJ. Heterocyclic Chem., 18, 947-951(1981)記載の方法により得られる一般式(29)で表される化合物に、容易に入手可能又は公知の方法により入手可能な一般式(30)で表される化合物を、通常公知の方法によりアミド化して一般式(31)で表される化合物を製造できる。 [Process I-1]
In this step, a general formula (29) obtained by a known method, for example, the method described in J. Med. Chem., 49, 4183-4195 (2006) or J. Heterocyclic Chem., 18, 947-951 (1981). The compound represented by the general formula (31) obtained by amidating the compound represented by the general formula (30) which is easily available or obtained by a known method into the compound represented by Can be manufactured.
〔工程I-2〕
　本工程では、一般式(31)で表される化合物のウラシル環のアミノ基を通常公知の方法で保護した後、トリフェニルホスフィン及びアゾジカルボン酸ジアルキル存在下、アジド化試薬と反応させ、最後にアミノ基の保護基を通常公知の方法で除去することにより、一般式(32)で表される本発明化合物を製造できる。
　アジド化試薬との反応に用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、THF、ジオキサン、ジエチルエーテル、DMF、トルエン、ジクロロメタン等が例示され、好ましくはTHFである。用いるアゾジカルボン酸エステルとしてはアゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピルが例示されるが好ましくはアゾジカルボン酸ジイソプロピルである。その当量数は0.9～5.0当量であり、好ましくは1.0～3.0当量である。用いるアジド化試薬としてはアジド酸、アジ化ナトリウム、アジ化カリウム、トリメチルシリルアジド等が例示され、好ましくはトリメチルシリルアジドである。その当量数は0.8～5.0当量であり、好ましくは1.0～4.0当量である。トリフェニルホスフィンの当量数は0.8～5.0当量であり、好ましくは1.0～4.0当量である。反応温度は0～100℃であり、好ましくは10～60℃である。反応時間は0.5～48時間であり、好ましくは5.0～24時間である。 [Process I-2]
In this step, the amino group of the uracil ring of the compound represented by the general formula (31) is protected by a generally known method, and then reacted with an azide reagent in the presence of triphenylphosphine and dialkyl azodicarboxylate. The compound of the present invention represented by the general formula (32) can be produced by removing the amino-protecting group by a generally known method.
The reaction solvent used for the reaction with the azidation reagent is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, DMF, toluene, dichloromethane and the like, preferably THF. is there. Examples of the azodicarboxylic acid ester used include diethyl azodicarboxylate and diisopropyl azodicarboxylate, with diisopropyl azodicarboxylate being preferred. The number of equivalents is 0.9 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents. Examples of the azide reagent used include azido acid, sodium azide, potassium azide, trimethylsilyl azide and the like, and trimethylsilyl azide is preferred. The number of equivalents is 0.8 to 5.0 equivalents, preferably 1.0 to 4.0 equivalents. The number of equivalents of triphenylphosphine is 0.8 to 5.0 equivalents, preferably 1.0 to 4.0 equivalents. The reaction temperature is 0 to 100 ° C., preferably 10 to 60 ° C. The reaction time is 0.5 to 48 hours, preferably 5.0 to 24 hours.
〔工程J〕 [Process J]
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
〔式中、R4～R9、X、Y、及びnは上記と同義である。〕 [Wherein R 4 to R 9 , X, Y, and n are as defined above. ]
〔工程J-1〕
　本工程では、公知の方法、例えばTetahedron, 36, 865-870 (1980)、或いはJ. Heterocyclic Chem., 18, 947-951(1981)に記載の方法により入手可能な一般式(33)で表される化合物に、一般式(10)で表される化合物より製造可能な一般式(34)で表される化合物を、工程B-2と同様の方法で反応させることにより、一般式(35)で表される本発明化合物を製造できる。 [Process J-1]
This step is represented by the general formula (33) which can be obtained by a known method such as Tetahedron, 36, 865-870 (1980) or the method described in J. Heterocyclic Chem., 18, 947-951 (1981). By reacting the compound represented by the general formula (34) that can be produced from the compound represented by the general formula (10) with the compound represented by the general formula (10) in the same manner as in Step B-2, the general formula (35) This invention compound represented by these can be manufactured.
〔工程K〕 [Process K]
〔式中、MOM、R1～R3、Y、Z、及びRhは上記と同義である。〕 [Wherein, MOM, R 1 to R 3 , Y, Z, and Rh are as defined above. ]
〔工程K-1〕
　本工程では、公知の方法により入手可能な一般式(36)で表される化合物、例えばJ. Org. Chem., 52, 1027-1035(1987)記載の方法により得られる2-(2-(ヒドロキシメチル)フェニル)エタノールのフェネチル位ヒドロキシル基を、通常公知の保護基で保護した後、通常公知の方法でメトキシメチル（MOM）化することにより、一般式(37)で表される化合物を製造できる。 [Process K-1]
In this step, a compound represented by the general formula (36) which can be obtained by a known method, for example, 2- (2- (2- ( A compound represented by the general formula (37) is produced by protecting the hydroxyl group of hydroxymethyl) phenyl) ethanol with a generally known protecting group and then converting to methoxymethyl (MOM) by a generally known method. it can.
〔工程K-2〕
　本工程では、一般式(37)で表される化合物を、工程A-5と同様の方法で反応させることにより、一般式(38)で表される化合物を製造できる。 [Process K-2]
In this step, the compound represented by the general formula (38) can be produced by reacting the compound represented by the general formula (37) in the same manner as in Step A-5.
〔工程K-3〕
　本工程では、一般式(38)で表される化合物のフェネチル位ヒドロキシル基の保護基を通常公知の方法により除去した後、工程A-1と同様の方法で反応させることにより、一般式(39)で表される化合物を製造できる。 [Process K-3]
In this step, the protecting group for the hydroxyl group of the phenethyl position of the compound represented by the general formula (38) is removed by a generally known method, and then reacted in the same manner as in the step A-1, whereby the general formula (39 ) Can be produced.
〔工程K-4〕
　本工程では、一般式(39)で表される化合物に、容易に入手可能又は公知の方法、例えばJ.Org.Chem., 53, 2489-2496(1988)に記載の方法により入手可能なアセチレン化合物を反応させることにより、一般式（40）で表される本発明化合物を製造できる。
　用いる反応溶媒としては、反応に影響を及ぼさないものであれば特に制限はないが、トルエン、THF、ジオキサン、DMF等が例示され、好ましくはトルエン又はDMFである。アセチレン化合物の当量数は、0.8～100当量であり、好ましくは1.0～50当量である。反応温度は0～200℃であり、好ましくは20～160℃である。反応時間は、0.1～120時間であり、好ましくは0.5～100時間である。 [Process K-4]
In this step, the compound represented by the general formula (39) can be easily obtained or acetylene which can be obtained by a known method, for example, the method described in J. Org. Chem., 53, 2489-2496 (1988). By reacting the compound, the compound of the present invention represented by the general formula (40) can be produced.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include toluene, THF, dioxane, DMF, and the like, preferably toluene or DMF. The number of equivalents of the acetylene compound is 0.8 to 100 equivalents, preferably 1.0 to 50 equivalents. The reaction temperature is 0 to 200 ° C, preferably 20 to 160 ° C. The reaction time is 0.1 to 120 hours, preferably 0.5 to 100 hours.
　以上、このように製造された本発明化合物及び合成中間体は、通常、公知の分離精製手段例えば、再結晶、晶出、蒸留、カラムクロマトグラフィー等により単離し、精製することができる。本発明化合物及び合成中間体は、通常、公知の方法でその薬理学的に許容される塩の形成が可能であり、また、相互に変換可能である。 As described above, the compound of the present invention and the synthetic intermediate thus produced can be usually isolated and purified by known separation and purification means such as recrystallization, crystallization, distillation, column chromatography and the like. The compounds of the present invention and synthetic intermediates can usually form pharmacologically acceptable salts by known methods, and can be converted into each other.
　後述の実施例に示すとおり、本発明のウラシル化合物又はその塩は、優れたヒトdUTPase阻害活性を有するため、抗腫瘍薬等に代表される医薬品として有用である。 As shown in the examples described later, the uracil compound or salt thereof of the present invention has excellent human dUTPase inhibitory activity, and thus is useful as a pharmaceutical represented by an antitumor drug and the like.
　本発明のウラシル化合物又はその塩を医薬組成物に含有せしめる場合、必要に応じて薬学的担体と配合し、予防又は治療目的に応じて各種の投与形態を採用可能であり、該形態としては、例えば、経口剤、注射剤、坐剤、軟膏剤、貼付剤等が挙げられるが、経口剤が好ましい。これらの投与形態は、各々当業者に公知慣用の製剤方法により製造できる。 When the uracil compound of the present invention or a salt thereof is contained in a pharmaceutical composition, it can be combined with a pharmaceutical carrier as necessary, and various administration forms can be employed depending on the purpose of prevention or treatment. For example, oral agents, injections, suppositories, ointments, patches and the like can be mentioned, and oral agents are preferred. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
　薬学的担体は、製剤素材として慣用の各種有機或いは無機担体物質が用いられ、固形製剤における賦形剤、結合剤、崩壊剤、滑沢剤、着色剤；液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等として配合される。また、必要に応じて防腐剤、抗酸化剤、着色剤、甘味剤、安定化剤等の製剤添加物を用いることもできる。
　経口用固形製剤を調製する場合は、本発明化合物に賦形剤、必要に応じて、結合剤、崩壊剤、滑沢剤、着色剤、矯味・矯臭剤等を加えた後、常法により錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤等を製造することができる。 As the pharmaceutical carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants, colorants in solid preparations; solvents, dissolution aids, suspensions in liquid preparations. It is blended as a turbidity agent, tonicity agent, buffering agent, soothing agent and the like. Moreover, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers and the like can be used as necessary.
When preparing an oral solid preparation, after adding an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a corrigent / flavoring agent, etc. to the compound of the present invention, a tablet is prepared by a conventional method. Coated tablets, granules, powders, capsules and the like can be produced.
　賦形剤としては、乳糖、白糖、Ｄ－マンニトール、ブドウ糖、デンプン、炭酸カルシウム、カオリン、微結晶セルロース、無水ケイ酸等が挙げられる。
　結合剤としては、水、エタノール、１－プロパノール、２－プロパノール、単シロップ、ブドウ糖液、α－デンプン液、ゼラチン液、Ｄ－マンニトール、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルスターチ、メチルセルロース、エチルセルロース、シェラック、リン酸カルシウム、ポリビニルピロリドン等が挙げられる。 Examples of the excipient include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid.
Examples of the binder include water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, α-starch solution, gelatin solution, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, Shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned.
　崩壊剤としては、乾燥デンプン、アルギン酸ナトリウム、カンテン末、炭酸水素ナトリウム、炭酸カルシウム、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、乳糖等が挙げられる。 Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
　滑沢剤としては、精製タルク、ステアリン酸塩ナトリウム、ステアリン酸マグネシウム、ホウ砂、ポリエチレングリコール等が挙げられる。
　着色剤としては、酸化チタン、酸化鉄等が挙げられる。
　矯味・矯臭剤としては白糖、橙皮、クエン酸、酒石酸等が挙げられる。 Examples of the lubricant include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol.
Examples of the colorant include titanium oxide and iron oxide.
Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
　経口用液体製剤を調製する場合は、本発明化合物に矯味剤、緩衝剤、安定化剤、矯臭剤等を加えて常法により内服液剤、シロップ剤、エリキシル剤等を製造することができる。この場合矯味・矯臭剤としては、前記に挙げられたものでよく、緩衝剤としては、クエン酸ナトリウム等が、安定剤としては、トラガント、アラビアゴム、ゼラチン等が挙げられる。必要により、腸溶性コーティング又は、効果の持続を目的として、経口製剤に公知の方法により、コーティングを施すこともできる。このようなコーティング剤にはヒドロキシプロピルメチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ポリオキシエチレングリコール、Ｔｗｅｅｎ８０(登録商標)等が挙げられる。 When preparing an oral liquid preparation, an oral solution, syrup, elixir and the like can be produced by adding a flavoring agent, a buffer, a stabilizer, a flavoring agent and the like to the compound of the present invention by conventional methods. In this case, the flavoring / flavoring agent may be those listed above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin. If necessary, an enteric coating or a coating can be applied to the oral preparation by a known method for the purpose of sustaining the effect. Examples of such a coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80 (registered trademark), and the like.
　注射剤を調製する場合は、本発明化合物にｐＨ調節剤、緩衝剤、安定化剤、等張化剤、局所麻酔剤等を添加し、常法により皮下、筋肉内及び静脈内用注射剤を製造することができる。この場合のｐＨ調節剤及び緩衝剤としては、クエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウム等が挙げられる。安定化剤としては、ピロ亜硫酸ナトリウム、ＥＤＴＡ、チオグリコール酸、チオ乳酸等が挙げられる。局所麻酔剤としては、塩酸プロカイン、塩酸リドカイン等が挙げられる。等張化剤としては、塩化ナトリウム、ブドウ糖、Ｄ－マンニトール、グリセリン等が挙げられる。 When preparing an injection, a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous injections are prepared by conventional methods. Can be manufactured. Examples of the pH adjuster and buffer in this case include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride, glucose, D-mannitol, glycerin and the like.
　坐剤を調製する場合は、本発明化合物に当業界において公知の製剤用担体、例えば、ポリエチレングリコール、ラノリン、カカオ脂、脂肪酸トリグリセリド等を、さらに必要に応じてＴｗｅｅｎ８０(登録商標)のような界面活性剤等を加えた後、常法により製造することができる。 When preparing a suppository, a formulation carrier known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., and an interface such as Tween 80 (registered trademark), if necessary, are added to the compound of the present invention. After adding an activator etc., it can manufacture by a conventional method.
　軟膏剤を調製する場合は、本発明化合物に通常使用される基剤、安定剤、湿潤剤、保存剤等が必要に応じて配合され、常法により混合、製剤化される。基剤としては、流動パラフィン、白色ワセリン、サラシミツロウ、オクチルドデシルアルコール、パラフィン等が挙げられる。保存剤としては、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル等が挙げられる。 When preparing an ointment, bases, stabilizers, wetting agents, preservatives and the like that are usually used for the compound of the present invention are blended as necessary, and mixed and formulated by a conventional method. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.
　貼付剤を調製する場合は、通常の支持体に前記軟膏、クリーム、ゲル、ペースト等を常法により塗布すればよい。支持体としては、綿、スフ、化学繊維からなる織布、不織布や軟質塩化ビニル、ポリエチレン、ポリウレタン等のフィルム或いは発泡体シートが適当である。 When preparing a patch, the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method. As the support, a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane film or foam sheet made of cotton, suf, chemical fiber is suitable.
　前記の各投与単位形態中に配合されるべき本発明化合物の量は、これを適用すべき患者の症状により、或いはその剤形等により一定ではないが、一般に投与単位形態あたり、経口剤では約０．０５～１０００ｍｇ、注射剤では約０．０１～５００ｍｇ、坐剤では約１～１０００ｍｇ程度である。
　また、前記投与形態を有する薬剤の１日あたりの投与量は、患者の症状、体重、年齢、性別等によって異なり一概には決定できないが、通常成人（体重５０ｋｇ）１日あたり約０．０５～５０００ｍｇ程度であり、０．１～１０００ｍｇが好ましく、これを１日１回又は２～３回程度に分けて投与するのが好ましい。 The amount of the compound of the present invention to be formulated in each of the above dosage unit forms is not constant depending on the symptoms of the patient to which the compound is to be applied or the dosage form thereof, but is generally about an oral dosage form per dosage unit form. 0.05 to 1000 mg, about 0.01 to 500 mg for injections, and about 1 to 1000 mg for suppositories.
In addition, the daily dose of the drug having the above-mentioned dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally. The dose is about 5000 mg, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into about 2 to 3 times a day.
　本発明化合物を含有する医薬組成物を投与することにより治療できる疾病としては、悪性腫瘍、マラリア、結核等が挙げられ、例えば悪性腫瘍の場合、頭頚部癌、食道癌、胃癌、結腸癌、直腸癌、肝臓癌、胆嚢・胆管癌、膵臓癌、肺癌、乳癌、卵巣癌、子宮頚癌、子宮体癌、腎癌、膀胱癌、前立腺癌、精巣腫瘍、骨・軟部肉腫、白血病、悪性リンパ腫、多発性骨髄腫、皮膚癌、脳腫瘍等が挙げられる。また本発明化合物を抗腫瘍剤に併用することにより、抗腫瘍効果増強剤として用いることも出来る。併用することが出来る抗腫瘍剤としては特に制限はないが、例えば５－Ｆｕ等の代謝拮抗剤や、葉酸代謝拮抗剤のようにチミジレートシンテターゼ阻害作用を有する抗腫瘍剤が好ましい。さらに本発明化合物は、抗ピロリ菌薬、抗寄生虫薬、抗ウイルス薬としても使用できる。 Diseases that can be treated by administering the pharmaceutical composition containing the compound of the present invention include malignant tumors, malaria, tuberculosis, etc. For example, in the case of malignant tumors, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectum Cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular cancer, bone / soft tissue sarcoma, leukemia, malignant lymphoma, Examples include multiple myeloma, skin cancer, brain tumor and the like. Moreover, it can also be used as an antitumor effect enhancer by using this invention compound together with an antitumor agent. The antitumor agent that can be used in combination is not particularly limited, but antitumor agents having an inhibitory action on thymidylate synthetase, such as antimetabolite such as 5-Fu and antifolate, are preferable. Furthermore, the compound of the present invention can be used as an anti-pylori drug, an antiparasitic drug, or an antiviral drug.
　以下に参考例、実施例、試験例及び製剤例を示し、本発明をさらに詳しく説明する。しかしながら、本発明はこれら実施例に制限されるものではない。 Hereinafter, the present invention will be described in more detail with reference examples, examples, test examples and formulation examples. However, the present invention is not limited to these examples.
参考例1
　1-(ペント-4-イニル)ピリミジン-2,4(1H,3H)-ジオンの合成 Reference example 1
Synthesis of 1- (pent-4-ynyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　容易に入手可能な4-ペンチン-1-オール(4.4mL)をジクロロメタン(130mL)に溶解し、0℃でトリエチルアミン(9.8mL)及び塩化メタンスルホニル(4.72mL)を加え室温で40分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(50mL)を加え分液した。有機層を水(50mL)、飽和食塩水(50mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をN,N-ジメチルホルムアミド(以下DMF,200mL)に溶解し、アジ化ナトリウム(6.0g)を加え55℃で8時間撹拌した。反応液を放冷後、水(100mL)を加え酢酸エチル(100mL)で抽出した。有機層を水(100mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(25%酢酸エチル/ヘキサン)で精製した。得られた化合物をテトラヒドロフラン(以下THF,24mL)、水(2.4mL)に溶解し、トリフェニルホスフィン(7.8g)を加え50℃で1時間撹拌した。反応液を減圧濃縮し、クロロホルム(50mL)を加え、希塩酸(1.0M,50mL×2)で抽出した。水層を減圧濃縮し、残渣をトルエン(10mL×3)で共沸した。得られた残渣(1.09g)をDMF(20mL)に溶解し、トリエチルアミン(1.50mL)及びモレキュラーシーブス4A（以下MS4A,1.0g）を加え、文献（J. Heterocyclic Chem., 36, 293(1999)）記載の方法で得られた3-メトキシ-2-プロペノイルイソシアネート（1.27g）のトルエン（10mL）溶液を-40℃でゆっくり加え室温で3時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(25%酢酸エチル/ヘキサン)で精製した。得られた化合物を塩化水素-ジオキサン溶液(4.0M,40mL)に懸濁し、100℃で30分加熱還流した。反応液を放冷後、減圧濃縮し、残渣をトルエン(10mL×5)で共沸することで標記化合物(1.9g)を淡黄色固体として得た。 Easily available 4-pentyn-1-ol (4.4 mL) was dissolved in dichloromethane (130 mL), triethylamine (9.8 mL) and methanesulfonyl chloride (4.72 mL) were added at 0 ° C., and the mixture was stirred at room temperature for 40 minutes. A saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction solution, and the phases were separated. The organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (hereinafter DMF, 200 mL), sodium azide (6.0 g) was added, and the mixture was stirred at 55 ° C. for 8 hours. The reaction mixture was allowed to cool, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate / hexane). The obtained compound was dissolved in tetrahydrofuran (hereinafter THF, 24 mL) and water (2.4 mL), triphenylphosphine (7.8 g) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, chloroform (50 mL) was added, and the mixture was extracted with dilute hydrochloric acid (1.0 M, 50 mL × 2). The aqueous layer was concentrated under reduced pressure, and the residue was azeotroped with toluene (10 mL × 3). The obtained residue (1.09 g) was dissolved in DMF (20 mL), triethylamine (1.50 mL) and molecular sieves 4A (hereinafter MS4A, 1.0 g) were added, and the literature (J. Heterocyclic Chem., 36, 293 (1999) ) A toluene (10 mL) solution of 3-methoxy-2-propenoyl isocyanate (1.27 g) obtained by the method described above was slowly added at −40 ° C. and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (25% ethyl acetate / hexane). The obtained compound was suspended in a hydrogen chloride-dioxane solution (4.0 M, 40 mL) and heated to reflux at 100 ° C. for 30 minutes. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was azeotroped with toluene (10 mL × 5) to give the title compound (1.9 g) as a pale yellow solid.
参考例2
　1-(ヘキス-5-イニル)ピリミジン-2,4(1H,3H)-ジオンの合成 Reference example 2
Synthesis of 1- (hex-5-ynyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　容易に入手可能な5-ヘキシン-1-オール(4.66g)から、参考例1の方法に準じて合成することで、標記化合物(3.5g)を淡黄色固体として得た。 The title compound (3.5 g) was obtained as a pale yellow solid by synthesis according to the method of Reference Example 1 from readily available 5-hexyn-1-ol (4.66 g).
参考例3
　1-(ブト-3-イニル)ピリミジン-2,4(1H,3H)-ジオンの合成 Reference Example 3
Synthesis of 1- (but-3-ynyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　容易に入手可能な3-ブチン-1-オール(3.0g)から、参考例1の方法に準じて合成することで、標記化合物(1.7g)を白色固体として得た。 The title compound (1.7 g) was obtained as a white solid by synthesis according to the method of Reference Example 1 from readily available 3-butyn-1-ol (3.0 g).
参考例4
　1-((ブト-3-イニルオキシ)メチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Reference example 4
Synthesis of 1-((but-3-ynyloxy) methyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　容易に入手可能な3-ブチン-1-オール(1.0g)をジクロロメタン(40mL)に溶解し、N,N-ジイソプロピルアミン(5.21mL)及びクロロメチルメチルエーテル(1.75mL)を加え室温で2時間撹拌した。飽和塩化アンモニウム水溶液(30mL)を加え分液した。有機層を飽和塩化アンモニウム水溶液(30mL×3)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(50%酢酸エチル/ヘキサン)で精製した。得られた化合物をジクロロメタン(20mL)に溶解し、三塩化ホウ素(以下BCl3)のジクロロメタン溶液(1.0M,4.8mL)を氷冷下加え室温で1.5時間撹拌した。反応液を減圧濃縮し、残渣を1,2-ジクロロエタン(以下DCE,20mL)に溶解し、文献（Nucleosides & Nucleotides, 4, 565-585(1985)）記載の方法で得られた2,4－ビス(トリメチルシリルオキシ)ピリミジン(3.68g)及びヨウ素(370mg)を加え、93℃で3時間加熱還流した。放冷後、水（10mL）、飽和チオ硫酸ナトリウム水溶液（1.0mL）を加え分液した。水層を10%メタノール/クロロホルム(100mL)で抽出した。合一した有機層を飽和食塩水(20mL)で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(3%メタノール/クロロホルム)で精製することで標記化合物(500mg)を白色固体として得た。 Easily available 3-butyn-1-ol (1.0 g) is dissolved in dichloromethane (40 mL), and N, N-diisopropylamine (5.21 mL) and chloromethyl methyl ether (1.75 mL) are added for 2 hours at room temperature. Stir. A saturated aqueous ammonium chloride solution (30 mL) was added to separate the layers. The organic layer was washed with a saturated aqueous ammonium chloride solution (30 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in dichloromethane (20 mL), a solution of boron trichloride (hereinafter BCl 3 ) in dichloromethane (1.0 M, 4.8 mL) was added with ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 1,2-dichloroethane (hereinafter DCE, 20 mL) and obtained by the method described in the literature (Nucleosides & Nucleotides, 4, 565-585 (1985)). Bis (trimethylsilyloxy) pyrimidine (3.68 g) and iodine (370 mg) were added, and the mixture was heated to reflux at 93 ° C. for 3 hours. After allowing to cool, water (10 mL) and a saturated aqueous sodium thiosulfate solution (1.0 mL) were added to separate the layers. The aqueous layer was extracted with 10% methanol / chloroform (100 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol / chloroform) to obtain the title compound (500 mg) as a white solid.
参考例5
　1-(4,4-ジメチルヘキス-5-イニル)ピリミジン-2,4(1H,3H)-ジオンの合成 Reference Example 5
Synthesis of 1- (4,4-dimethylhex-5-ynyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　容易に入手可能な3-メチル-1-ブチン(7.5mL)をジエチルエーテル(50mL)に溶解し、氷冷下n-ブチルリチウムのヘキサン溶液(1.6M,92mL)を滴下した。1,2-ビス（ジメチルアミノ）エタン(11.65mL)を加え60℃で16時間加熱還流した。-78℃に冷却し、オキセタン(4.75mL)及び三フッ化ホウ素-ジエチルエーテルコンプレックス(以下BF3・Et2O,9.3mL)を加え、-78℃で6時間撹拌した。室温で希塩酸(1.0M,50mL)を加え分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られたアルコール(690mgの内、100mg)をTHF(3.0mL)に溶解し、文献(J. Med. Chem., 49, 4183-4195(2006))記載の方法で得られたN3-ベンゾイルウラシル(225mg)、トリフェニルホスフィン(416mg)及びアゾジカルボン酸ジイソプロピルのトルエン溶液(1.9M,837μL)加え、室温で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(1.5%メタノール/クロロホルム)で精製した。得られた化合物をメチルアミンのメタノール溶液(40%,4.0mL)に溶解し、室温で30分撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2.5%メタノール/クロロホルム)で精製することで標記化合物(80mg)を白色固体として得た。 Easily available 3-methyl-1-butyne (7.5 mL) was dissolved in diethyl ether (50 mL), and a hexane solution of n-butyllithium (1.6 M, 92 mL) was added dropwise under ice cooling. 1,2-bis (dimethylamino) ethane (11.65 mL) was added and the mixture was heated to reflux at 60 ° C. for 16 hours. After cooling to −78 ° C., oxetane (4.75 mL) and boron trifluoride-diethyl ether complex (hereinafter referred to as BF 3 · Et 2 O, 9.3 mL) were added, and the mixture was stirred at −78 ° C. for 6 hours. Dilute hydrochloric acid (1.0 M, 50 mL) was added at room temperature for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The resulting alcohol (100 mg of 690 mg) was dissolved in THF (3.0 mL), and N 3 -benzoyl obtained by the method described in the literature (J. Med. Chem., 49, 4183-4195 (2006)) A toluene solution (1.9 M, 837 μL) of uracil (225 mg), triphenylphosphine (416 mg) and diisopropyl azodicarboxylate was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1.5% methanol / chloroform). The obtained compound was dissolved in a methanol solution of methylamine (40%, 4.0 mL) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to obtain the title compound (80 mg) as a white solid.
参考例6
　1-(3-エチニルベンジル)ピリミジン-2,4(1H,3H)-ジオンの合成 Reference Example 6
Synthesis of 1- (3-ethynylbenzyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　トリス(ジベンジリデンアセトン)ジパラジウム(0)(78mg)、テトラブチルアンモニウムアセテート(1.93g)をDMF(12mL)に溶解し、容易に入手可能な3-ヨード-ベンジルアルコール(1.0g)を加え、室温で20分撹拌した。反応液にトリメチルシリルアセチレン(590μL)を加え、室温で2時間撹拌した。反応液に水(50mL)を加え、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(20%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(10mL)に溶解し、トリフェニルホスフィン(829mg)、四臭化炭素(1.05g)を加え室温で1時間撹拌した。酢酸エチル(10mL)、ヘキサン(40mL)を加え、生じた白色固体を濾去し、20%酢酸エチル/ヘキサン(50mL)で洗浄し、合一した濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。得られた化合物をDCE(5.0mL)に溶解し、文献（Nucleosides & Nucleotides, 4, 565-585(1985)）記載の方法で得られた2,4－ビス(トリメチルシリルオキシ)ピリミジン(531mg)及びヨウ素(40mg)を加え、93℃で3時間加熱還流した。反応液を放冷後、水（10mL）、飽和チオ硫酸ナトリウム水溶液（1.0mL）を加え分液した。水層を10%メタノール/クロロホルム(20mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/クロロホルム)で精製し、得られた化合物をTHF(3.0mL)に溶解し、テトラブチルアンモニウムフルオリド(以下TBAF)のTHF溶液(1.0M,3.0mL)を加え、室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2.5%メタノール/クロロホルム)で精製することで標記化合物(403mg)を泡状物質として得た。 Tris (dibenzylideneacetone) dipalladium (0) (78 mg), tetrabutylammonium acetate (1.93 g) was dissolved in DMF (12 mL), and readily available 3-iodo-benzyl alcohol (1.0 g) was added, Stir at room temperature for 20 minutes. Trimethylsilylacetylene (590 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane). The obtained compound was dissolved in THF (10 mL), triphenylphosphine (829 mg) and carbon tetrabromide (1.05 g) were added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate (10 mL) and hexane (40 mL) were added, and the resulting white solid was filtered off, washed with 20% ethyl acetate / hexane (50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). The obtained compound was dissolved in DCE (5.0 mL), and 2,4-bis (trimethylsilyloxy) pyrimidine (531 mg) obtained by the method described in the literature (Nucleosides & Nucleotides, 4, 565-585 (1985)) and Iodine (40 mg) was added, and the mixture was heated to reflux at 93 ° C. for 3 hours. The reaction mixture was allowed to cool, and water (10 mL) and saturated aqueous sodium thiosulfate solution (1.0 mL) were added to separate the layers. The aqueous layer was extracted with 10% methanol / chloroform (20 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% methanol / chloroform), the resulting compound was dissolved in THF (3.0 mL), and a THF solution (1.0 M, 3.0 mL) of tetrabutylammonium fluoride (hereinafter TBAF) And stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to give the title compound (403 mg) as a foam.
参考例7
　1-(2-(プロプ-2-イニルオキシ)エチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Reference Example 7
Synthesis of 1- (2- (prop-2-ynyloxy) ethyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
　容易に入手可能なエチレングリコール(2.0g)をTHF(100mL)に溶解し、イミダゾール(3.6g)及びtert-ブチルジメチルシリルクロリド(4.8g)を加え室温で3時間撹拌した。反応液に水(50mL)を加え、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(20％酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(80mL)に溶解し、水素化ナトリウム(55%、1.17g)を氷冷下加え10分撹拌した。反応液にプロパルギルブロミド(1.02mL)を加え、室温で3時間撹拌した。反応液に水(50mL)、を加え、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(30mL)に溶解し、TBAFのTHF溶液(1.0M、46mL)を加え室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物をジクロロメタン(20mL)に溶解した。トリエチルアミン(2.18mL)、塩化メタンスルホニル(975μL)を加え室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(10mL)を加え分液した。有機層を水(10mL)、飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(25mL)に溶解し、アジ化ナトリウム(1.7g)を加え50℃で3時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(20%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(30mL)に溶解し、水(3.0mL)及びトリフェニルホスフィン(2.26g)を加え、50℃で2時間撹拌した。反応液を減圧濃縮し、残渣にクロロホルム(50mL)を加え、1N塩酸(50mL×2)で抽出した。水層を減圧濃縮し、トルエン(10mL×3)で共沸した。得られた残渣(550mgの内、500mg)をDMF(20mL)に溶解し、トリエチルアミン(564μL)、モルキュラーシーブス4Å(1.0g)を加え、-40℃で文献(L.Santanaetal., J. Heterocyclic Chem., 36, 293-295(1999))記載の方法で得られた3-メトキシ-2-プロペノイルイソシアネート(521mg)のトルエン(20mL)溶液を加え、室温で3時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/クロロホルム)で精製した。得られた化合物を塩化水素-ジオキサン溶液(4.0M、4.0mL)に懸濁し、室温で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2.5%メタノール/クロロホルム)で精製することで標記化合物(410mg)を淡黄色固体として得た。 Easily available ethylene glycol (2.0 g) was dissolved in THF (100 mL), imidazole (3.6 g) and tert-butyldimethylsilyl chloride (4.8 g) were added, and the mixture was stirred at room temperature for 3 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane). The obtained compound was dissolved in THF (80 mL), sodium hydride (55%, 1.17 g) was added under ice-cooling, and the mixture was stirred for 10 min. Propargyl bromide (1.02 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane). The obtained compound was dissolved in THF (30 mL), TBAF in THF (1.0 M, 46 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The resulting compound was dissolved in dichloromethane (20 mL). Triethylamine (2.18 mL) and methanesulfonyl chloride (975 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the phases were separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (25 mL), sodium azide (1.7 g) was added, and the mixture was stirred at 50 ° C. for 3 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane). The obtained compound was dissolved in THF (30 mL), water (3.0 mL) and triphenylphosphine (2.26 g) were added, and the mixture was stirred at 50 ° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, chloroform (50 mL) was added to the residue, and the mixture was extracted with 1N hydrochloric acid (50 mL × 2). The aqueous layer was concentrated under reduced pressure and azeotroped with toluene (10 mL × 3). The obtained residue (500 mg of 550 mg) was dissolved in DMF (20 mL), triethylamine (564 μL), 4 μg of molecular sieves (1.0 g) were added, and the literature (L.Santanaetal., J. Heterocyclic Chem., 36, 293-295 (1999)), a solution of 3-methoxy-2-propenoyl isocyanate (521 mg) in toluene (20 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform). The obtained compound was suspended in a hydrogen chloride-dioxane solution (4.0 M, 4.0 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to obtain the title compound (410 mg) as a pale yellow solid.
参考例8
　メチル 7-(tert-ブチルジフェニルシリルオキシ)ヘプト-2-イノエートの合成 Reference Example 8
Synthesis of methyl 7- (tert-butyldiphenylsilyloxy) hept-2-inoate
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
　容易に入手可能な5-ヘキシン-1-オール(1.5g)をDMF(40mL)に溶解し、イミダゾール(1.25g)及びtert-ブチルジフェニルシリルクロリド(3.72mL)を加え、室温で一時間撹拌した。酢酸エチル(80mL)、水(80mL)を加え分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(3%酢酸エチル/ヘキサン)で精製した。得られたシリル体(3.95gの内、1.0g)をTHF(10mL)に溶解し、-78℃でn-ブチルリチウムのヘキサン溶液(2.77M,1.13mL)を滴下し、-78℃で1時間撹拌した。反応液にクロロギ酸メチル(242μL)を加え、室温で2時間撹拌した。反応液に飽和塩化アンモニウム水溶液(5.0mL)を加え分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(3%酢酸エチル/ヘキサン)で精製することで標記化合物(912mg)を無色油状物質として得た。 Easily available 5-hexyn-1-ol (1.5 g) was dissolved in DMF (40 mL), imidazole (1.25 g) and tert-butyldiphenylsilyl chloride (3.72 mL) were added and stirred at room temperature for 1 hour. . Ethyl acetate (80 mL) and water (80 mL) were added for liquid separation. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% ethyl acetate / hexane). The obtained silyl compound (1.05 g of 3.95 g) was dissolved in THF (10 mL), and a hexane solution of n-butyllithium (2.77 M, 1.13 mL) was added dropwise at -78 ° C. Stir for hours. Methyl chloroformate (242 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (5.0 mL) was added to the reaction solution to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (3% ethyl acetate / hexane) to give the title compound (912 mg) as a colorless oil.
参考例9
　メチル6-(tert-ブチルジメチルシリルオキシ)ヘキス-2-イノエートの合成 Reference Example 9
Synthesis of methyl 6- (tert-butyldimethylsilyloxy) hex-2-inoate
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　容易に入手可能な4-ペンチン-1-オール(1.5g)から、参考例8の方法に準じて合成することで、標記化合物(2.1g)を無色油状物質として得た。 The title compound (2.1 g) was obtained as a colorless oil by synthesis from easily available 4-pentyn-1-ol (1.5 g) according to the method of Reference Example 8.
参考例10
メチル5-(メトキシメトキシ)ペント-2-イノエートの合成 Reference Example 10
Synthesis of methyl 5- (methoxymethoxy) pent-2-inoate
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　容易に入手可能な3-ブチン-1-オール(3.0g)をジクロロメタン(40mL)に溶解し、N,N-ジイソプロピルエチルアミン(22.4mL)及びクロロメチルメチルエーテル(4.87mL)を加え、室温で3時間撹拌した。反応液に飽和塩化アンモニウム水溶液(50mL)を加え分液した。有機層を飽和塩化アンモニウム水溶液(40mL×3)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をTHF(20mL×3)で共沸した後、THF(80mL)に溶解し、-78℃でn-ブチルリチウムのヘキサン溶液(2.77M,9.4mL)を滴下し、-78℃で1時間撹拌した。反応液にクロロギ酸メチル(2.0mL)を-78℃で加え、室温で2時間撹拌した。反応液に飽和塩化アンモニウム水溶液(50mL)加え分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製することで標記化合物(2.97g)を無色油状物質として得た。 Easily available 3-butyn-1-ol (3.0 g) is dissolved in dichloromethane (40 mL), N, N-diisopropylethylamine (22.4 mL) and chloromethyl methyl ether (4.87 mL) are added, and 3 at room temperature. Stir for hours. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution to separate the layers. The organic layer was washed with a saturated aqueous ammonium chloride solution (40 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was azeotroped with THF (20 mL × 3), then dissolved in THF (80 mL), and a hexane solution of n-butyllithium (2.77 M, 9.4 mL) was added dropwise at −78 ° C. Stir. Methyl chloroformate (2.0 mL) was added to the reaction solution at −78 ° C., and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution and the phases were separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (2.97 g) as a colorless oil.
参考例11
　メチル5-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)ペント-2-イノエートの合成 Reference Example 11
Synthesis of methyl 5-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) pent-2-inoate
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
　参考例10で得られたメチル5-(メトキシメトキシ)ペント-2-イノエート(15g)をジクロロメタン(70mL)に溶解し、BCl3のジクロロメタン溶液(1.0M,16.9mL)を氷冷下加え室温で1.5時間撹拌した。反応液を減圧濃縮し、残渣をDCE(100mL)に溶解し、文献（Nucleosides & Nucleotides, 4, 565-585(1985)）記載の方法で得られた2,4－ビス(トリメチルシリルオキシ)ピリミジン(21.6g)及びヨウ素(1.2g)を加え、93℃で3時間加熱還流した。反応液を放冷後、水（60mL）、飽和チオ硫酸ナトリウム水溶液（10mL）を加え分液し、水層を10%メタノール/クロロホルム(100mL)で抽出した。合一した有機層を飽和食塩水(80mL)で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(3%メタノール/クロロホルム)で精製することで標記化合物(6.1g)を泡状物質として得た。 Methyl 5- (methoxymethoxy) pent-2-inoate (15 g) obtained in Reference Example 10 was dissolved in dichloromethane (70 mL), and a dichloromethane solution (1.0 M, 16.9 mL) of BCl 3 was added under ice cooling at room temperature. Stir for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCE (100 mL), and 2,4-bis (trimethylsilyloxy) pyrimidine ( 21.6 g) and iodine (1.2 g) were added, and the mixture was heated to reflux at 93 ° C. for 3 hours. The reaction mixture was allowed to cool, water (60 mL) and saturated aqueous sodium thiosulfate solution (10 mL) were added for liquid separation, and the aqueous layer was extracted with 10% methanol / chloroform (100 mL). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol / chloroform) to obtain the title compound (6.1 g) as a foam.
参考例12
　1-((ブト-3-イニルオキシ)メチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Reference Example 12
1-((but-3-ynyloxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　容易に入手可能な3-ブチン-1-オール(2.0g)をジクロロメタン(40mL)に溶解し、N,N-ジイソプロピルアミン(14.9mL)及びクロロメチルメチルエーテル(4.33mL)を加え室温で1.5時間撹拌した。反応液を減圧(>150mmHg)濃縮した後、残渣に飽和塩化アンモニウム水溶液(30mL)を加え、ジエチルエーテル(30mL×2)で抽出した。有機層を飽和塩化アンモニウム水溶液(30mL×5)、飽和食塩水(30mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をジクロロメタン(20mL)に溶解し、BCl3のジクロロメタン溶液(1.0M,9.4mL)を氷冷下加え室温で1.5時間撹拌した。反応液を減圧濃縮した後、残渣をDCE(20mL)に溶解し、容易に入手可能な5-フルオロ-2,4-ビス(トリメチルシリルオキシ)ピリミジン(11.3g)及びヨウ素(734mg)を加え、93℃で12時間加熱還流した。反応液を放冷後、水（20mL）、飽和チオ硫酸ナトリウム水溶液（1.0mL）を加え分液した。水層を10%メタノール/クロロホルム(100mL×2)で抽出した。合一した有機層を飽和食塩水(20mL)で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(80%酢酸エチル/ヘキサン)で精製することで標記化合物(1.2g)を白色固体として得た。 Easily available 3-butyn-1-ol (2.0 g) is dissolved in dichloromethane (40 mL), and N, N-diisopropylamine (14.9 mL) and chloromethyl methyl ether (4.33 mL) are added for 1.5 hours at room temperature. Stir. The reaction solution was concentrated under reduced pressure (> 150 mmHg), a saturated aqueous ammonium chloride solution (30 mL) was added to the residue, and the mixture was extracted with diethyl ether (30 mL × 2). The organic layer was washed with a saturated aqueous ammonium chloride solution (30 mL × 5) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL), a solution of BCl 3 in dichloromethane (1.0 M, 9.4 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hr. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in DCE (20 mL), and easily available 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine (11.3 g) and iodine (734 mg) were added, and 93 The mixture was heated at reflux for 12 hours. The reaction mixture was allowed to cool, and water (20 mL) and saturated aqueous sodium thiosulfate solution (1.0 mL) were added to separate the layers. The aqueous layer was extracted with 10% methanol / chloroform (100 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (80% ethyl acetate / hexane) to give the title compound (1.2 g) as a white solid.
参考例13
　1-(ヘキス-5-イニル)-5-フルオロピリミジン-2,4-(1H,3H)-ジオンの合成 Reference Example 13
Synthesis of 1- (hex-5-ynyl) -5-fluoropyrimidine-2,4- (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
　容易に入手可能な5-ヘキシン-1-オール(1.87mL)にトリフェニルホスフィン(5.35g)、文献(J. Med. Chem., 49, 4183-4195(2006))記載の方法に準じて得られた3-ベンゾイル-5-フルオロピリミジン-2,4(1H,3H)-ジオン(4.33g)及びアゾジカルボン酸ジエチルのトルエン溶液(2.2M、9.3mL)を加え室温で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(50%酢酸エチル/ヘキサン)で精製した。得られた化合物をメチルアミンのメタノール溶液(40%,7.0mL)に溶解し、室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(75%酢酸エチル/ヘキサン)で精製することで、標記化合物(1.3g)を白色固体として得た。 Obtained according to the method described in triphenylphosphine (5.35 g), literature (J. Med. Chem., 49, 4183-4195 (2006)) to easily available 5-hexyn-1-ol (1.87 mL). The obtained 3-benzoyl-5-fluoropyrimidine-2,4 (1H, 3H) -dione (4.33 g) and a toluene solution of diethyl azodicarboxylate (2.2 M, 9.3 mL) were added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in a methanol solution of methylamine (40%, 7.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (75% ethyl acetate / hexane) to give the title compound (1.3 g) as a white solid.
参考例14
　1-(2-アジドエチル)-3-(シクロプロピルメトキシ)ベンゼンの合成 Reference Example 14
Synthesis of 1- (2-azidoethyl) -3- (cyclopropylmethoxy) benzene
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　容易に入手可能な3-(2-ヒドロキシエチル)フェノール(2.5g)をDMF(18mL)に溶解し、炭酸カリウム(5.0g)、ヨウ化ナトリウム(271mg)及びクロロメチルシクロプロパン(1.75mL)を加え、80℃で5時間撹拌した。反応液に水(40mL)を加え、酢酸エチル(40mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(17%酢酸エチル/ヘキサン)で精製した。得られた化合物(3.25gの内、500mg)をジクロロメタン(10mL)に溶解し、トリエチルアミン(540μL)、塩化メタンスルホニル(242μL)を加え室温で30分撹拌した。飽和炭酸水素ナトリウム水溶液(10mL)を加え分液した。有機層を水(10mL)、飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(10mL)に溶解し、アジ化ナトリウム(423mg)を加え50℃で3時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(20mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(17%酢酸エチル/ヘキサン)で精製することで標記化合物(500mg)を淡黄色油状物質として得た。 Easily available 3- (2-hydroxyethyl) phenol (2.5 g) is dissolved in DMF (18 mL) and potassium carbonate (5.0 g), sodium iodide (271 mg) and chloromethylcyclopropane (1.75 mL) are added. The mixture was further stirred at 80 ° C. for 5 hours. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17% ethyl acetate / hexane). The obtained compound (500 mg of 3.25 g) was dissolved in dichloromethane (10 mL), triethylamine (540 μL) and methanesulfonyl chloride (242 μL) were added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added for liquid separation. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (10 mL), sodium azide (423 mg) was added, and the mixture was stirred at 50 ° C. for 3 hr. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17% ethyl acetate / hexane) to give the title compound (500 mg) as a pale yellow oil.
　参考例15～27は、下記表に示す各々の原料から参考例14の方法に準じて合成した。 Reference Examples 15 to 27 were synthesized from the respective raw materials shown in the following table according to the method of Reference Example 14.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
参考例28
　(R)-1-(1-アジドプロパン-2-イル)-3-(シクロプロピルメトキシ)ベンゼンの合成 Reference Example 28
Synthesis of (R) -1- (1-azidopropan-2-yl) -3- (cyclopropylmethoxy) benzene
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　容易に入手可能な2-(3-ヒドロキシフェニル)酢酸(4.6g)をエタノール(75mL)に溶解し、硫酸(1.0mL)を加え、90℃で3時間加熱還流した。反応液を放冷後、減圧濃縮した。残渣に水(10mL)を加えた後、炭酸水素ナトリウムを加えて中和し、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をトルエン(10mL×3)で共沸した。得られた残渣(3.91gの内、1.0g)をDMF(5.0mL)に溶解し、炭酸カリウム(1.5g)、ヨウ化ナトリウム(84mg)及びクロロメチルシクロプロパン(560μL)を加え、80℃で5時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(20mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(17%酢酸エチル/ヘキサン)で精製した。得られたエチル2-(3-(シクロプロピルメトキシ)フェニル)アセテート(1.2gの内、1.0g)をエタノール(2.0mL)、水(1.6mL)に溶解し、水酸化ナトリウム水溶液(4.0M,3.2mL)を加え、50℃で3時間撹拌した。反応液に塩酸(2.0M,10mL)を加え酸性にし、反応液を減圧濃縮した。残渣に水(20mL)を加え、酢酸エチル(20mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した後、残渣をトルエン(10mL×3)で共沸した。残渣(850mgの内、420mg)を塩化チオニル(5.0mL)に溶解し、DMF(10μL)を加え室温で2時間撹拌した。反応液を減圧濃縮し、トルエン(2mL×2)で共沸した。 Easily available 2- (3-hydroxyphenyl) acetic acid (4.6 g) was dissolved in ethanol (75 mL), sulfuric acid (1.0 mL) was added, and the mixture was heated to reflux at 90 ° C. for 3 hours. The reaction solution was allowed to cool and then concentrated under reduced pressure. Water (10 mL) was added to the residue, and the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was azeotroped with toluene (10 mL × 3). The obtained residue (1.01 g of 3.91 g) was dissolved in DMF (5.0 mL), potassium carbonate (1.5 g), sodium iodide (84 mg) and chloromethylcyclopropane (560 μL) were added, and the mixture was heated at 80 ° C. Stir for 5 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17% ethyl acetate / hexane). The obtained ethyl 2- (3- (cyclopropylmethoxy) phenyl) acetate (1.0 g out of 1.2 g) was dissolved in ethanol (2.0 mL) and water (1.6 mL), and an aqueous sodium hydroxide solution (4.0 M, 3.2 mL) was added and the mixture was stirred at 50 ° C. for 3 hours. Hydrochloric acid (2.0 M, 10 mL) was added to the reaction solution to make it acidic, and the reaction solution was concentrated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was azeotroped with toluene (10 mL × 3). The residue (420 mg of 850 mg) was dissolved in thionyl chloride (5.0 mL), DMF (10 μL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure and azeotroped with toluene (2 mL × 2).
　(R)-4-ベンジル-2-オキサゾリジノン(361mg)をTHF(6.0mL)に溶解し、-78℃でn-ブチルリチウムのヘキサン溶液(2.64M,777μL)を滴下し、-78℃で30分撹拌した。反応液にトルエン共沸した残渣のTHF(1.5mL)溶液を加え、-78℃で1.5時間、その後0℃で3時間撹拌した。反応液に飽和塩化アンモニウム水溶液(10mL)を加え分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(17%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(6.0mL)に溶解し、-78℃でビス(トリメチルシリル)アミドナトリウム塩(以下NaHMDS)のTHF溶液(1.0M,1.7mL)を滴下し、-78℃で1.5時間撹拌した。反応液にヨウ化メチル(490μL)のTHF(1.0mL)溶液を滴下し、-78℃で2時間撹拌した。反応液に飽和塩化アンモニウム水溶液(10mL)を室温で加え、分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(14%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(2.0mL)に溶解し、水素化ホウ素リチウムのTHF溶液(2.0M,1.2mL)を加え、室温で12時間撹拌した。反応液に飽和食塩水(10mL)を氷冷下加え、酢酸エチル(10mL×2)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物をジクロロメタン(2.0mL)に溶解し、トリエチルアミン(191μL)及び塩化メタンスルホニル(85μL)を加え室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5.0mL)を加え、有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(3.0mL)に溶解し、アジ化ナトリウム(180mg)を加え50℃で3時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(17%酢酸エチル/ヘキサン)で精製することで、標記化合物(160mg)を淡黄色油状物質として得た。 (R) -4-benzyl-2-oxazolidinone (361 mg) was dissolved in THF (6.0 mL), and a hexane solution of n-butyllithium (2.64 M, 777 μL) was added dropwise at −78 ° C. Stir for minutes. A toluene (1.5 mL) solution of the residue azeotroped with toluene was added to the reaction solution, followed by stirring at −78 ° C. for 1.5 hours and then at 0 ° C. for 3 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17% ethyl acetate / hexane). The obtained compound was dissolved in THF (6.0 mL), and a THF solution (1.0 M, 1.7 mL) of bis (trimethylsilyl) amide sodium salt (hereinafter NaHMDS) was added dropwise at −78 ° C., followed by stirring at −78 ° C. for 1.5 hours. did. A solution of methyl iodide (490 μL) in THF (1.0 mL) was added dropwise to the reaction solution, and the mixture was stirred at −78 ° C. for 2 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution at room temperature, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (14% ethyl acetate / hexane). The obtained compound was dissolved in THF (2.0 mL), a THF solution (2.0 M, 1.2 mL) of lithium borohydride was added, and the mixture was stirred at room temperature for 12 hours. To the reaction solution was added saturated brine (10 mL) under ice-cooling, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound was dissolved in dichloromethane (2.0 mL), triethylamine (191 μL) and methanesulfonyl chloride (85 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution, and the organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (3.0 mL), sodium azide (180 mg) was added, and the mixture was stirred at 50 ° C. for 3 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17% ethyl acetate / hexane) to give the title compound (160 mg) as a pale yellow oil.
参考例29
　(R)-1-(1-アジドブタン-2-イル)-3-(シクロプロピルメトキシ)ベンゼンの合成 Reference Example 29
Synthesis of (R) -1- (1-azidobutan-2-yl) -3- (cyclopropylmethoxy) benzene
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　容易に入手可能な2-(3-ヒドロキシフェニル)酢酸(1.0g)から参考例28の方法に準じて合成することで、標記化合物(190mg)を淡黄色油状物質として得た。 The title compound (190 mg) was obtained as a pale yellow oily substance by synthesis according to the method of Reference Example 28 from readily available 2- (3-hydroxyphenyl) acetic acid (1.0 g).
参考例30
　(S)-1-(1-アジドプロパン-2-イル)-3-(シクロプロピルメトキシ)ベンゼンの合成 Reference Example 30
Synthesis of (S) -1- (1-azidopropan-2-yl) -3- (cyclopropylmethoxy) benzene
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　容易に入手可能な2-(3-ヒドロキシフェニル)酢酸(2.0g)から参考例28の方法に準じて合成することで、標記化合物(252mg)を淡黄色油状物質として得た。 The title compound (252 mg) was obtained as a pale yellow oily substance by synthesis according to the method of Reference Example 28 from readily available 2- (3-hydroxyphenyl) acetic acid (2.0 g).
参考例31
　(S)-1-(1-アジドブタン-2-イル)-3-(シクロプロピルメトキシ)ベンゼンの合成 Reference Example 31
Synthesis of (S) -1- (1-azidobutan-2-yl) -3- (cyclopropylmethoxy) benzene
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　容易に入手可能な2-(3-ヒドロキシフェニル)酢酸(2.0g)から参考例28の方法に準じて合成することで、標記化合物(151mg)を淡黄色油状物質として得た。 The title compound (151 mg) was obtained as a pale yellow oily substance by synthesis according to the method of Reference Example 28 from readily available 2- (3-hydroxyphenyl) acetic acid (2.0 g).
参考例32
　(S)-1-(2-アジドプロピル)-3-(シクロプロピルメトキシ)ベンゼンの合成 Reference Example 32
Synthesis of (S) -1- (2-azidopropyl) -3- (cyclopropylmethoxy) benzene
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　容易に入手可能な3-ブロモフェール(1.0g)をDMF(10mL)に溶解し、炭酸カリウム(1.6g)、ヨウ化ナトリウム(87mg)及びクロロメチルシクロプロパン(587mL)を加え、80℃で5時間撹拌した。反応液に水(30mL)を加え、酢酸エチル(30mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。得られた化合物(1.3gの内、500mg)をTHF(15mL)に溶解し、n-ブチルリチウムのヘキサン溶液(2.64M,795μL)を-78℃で滴下し、同温度で30分撹拌した。反応液に(R)-2-メチルオキシラン(155μL)を-78℃で加え、同温度で10分撹拌した。反応液にBF3・Et2O(361μL)を-78℃で加え、同温度で40分撹拌した。反応液に飽和塩化アンモニウム水溶液(10mL)を室温で加え分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物(300mgの内、260mg)をジクロロメタン(3.0mL)に溶解し,トリエチルアミン(262μL)及び塩化メタンスルホニル(117μL)を加え室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5.0mL)を加え分液した。有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(3.0mL)に溶解し、アジ化ナトリウム(328mg)を加え50℃で3時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製することで、標記化合物(230mg)を淡黄色油状物質として得た。 Easily available 3-bromofehr (1.0 g) is dissolved in DMF (10 mL), potassium carbonate (1.6 g), sodium iodide (87 mg) and chloromethylcyclopropane (587 mL) are added, and 5 ° C. at 5 ° C. Stir for hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). The obtained compound (500 mg out of 1.3 g) was dissolved in THF (15 mL), and a hexane solution of n-butyllithium (2.64 M, 795 μL) was added dropwise at −78 ° C., followed by stirring at the same temperature for 30 minutes. (R) -2-Methyloxirane (155 μL) was added to the reaction solution at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. BF 3 · Et 2 O (361 μL) was added to the reaction solution at −78 ° C., and the mixture was stirred at the same temperature for 40 minutes. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution at room temperature, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound (260 mg of 300 mg) was dissolved in dichloromethane (3.0 mL), triethylamine (262 μL) and methanesulfonyl chloride (117 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (3.0 mL), sodium azide (328 mg) was added, and the mixture was stirred at 50 ° C. for 3 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (230 mg) as a pale yellow oil.
参考例33
　(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-1,2-ジオールの合成 Reference Example 33
Synthesis of (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butane-1,2-diol
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　容易に入手可能な4-フルオロ-3-ヒドロキシ安息香酸(4.7g)をエタノール(80mL)に溶解し、硫酸(1.0mL)を加え90℃で2時間加熱還流した。反応液を放冷後、減圧濃縮した。残渣に水(10mL)を加えた後、炭酸水素ナトリウムを加えて中和し、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水(20mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(30mL)に溶解し、炭酸カリウム(8.0g)、クロロメチルシクロプロパン(2.9mL)及びヨウ化ナトリウム(432mg)を加え、90℃で4時間撹拌した。反応液に水(20mL)を加え、トルエン(20mL)で抽出した。有機層を水(20mL)、飽和食塩水(20mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をエタノール(10mL)、水(10mL)に溶解し、水酸化ナトリウム水溶液(4.0M,22mL)を加え50℃で3時間撹拌した。反応液を減圧濃縮後、希塩酸(1.0M,100mL)で酸性にし、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をDMF(80mL)に溶解し、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩(以下EDC・HCl,8.0g)、1-ヒドロキシ-1H-ベンゾトリアゾール(以下HOBt,5.0g)、N,O-ジメチルヒドロキシルアミン塩酸塩(3.3g)及びトリエチルアミン(4.9mL)を加え、室温で3時間撹拌した。反応液に水(50mL)を加え、トルエン(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(70mL)に溶解し、臭化エチルマグネシウムのTHF溶液(1.0M,22mL)を0℃で滴下し、同温度で2時間撹拌した。反応液に飽和塩化アンモニウム水溶液(100mL)を加え分液した。有機層を水(50mL)、飽和食塩水(100mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%酢酸エチル/ヘキサン)で精製した。 Easily available 4-fluoro-3-hydroxybenzoic acid (4.7 g) was dissolved in ethanol (80 mL), sulfuric acid (1.0 mL) was added, and the mixture was heated to reflux at 90 ° C. for 2 hours. The reaction solution was allowed to cool and then concentrated under reduced pressure. Water (10 mL) was added to the residue, and the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (30 mL), potassium carbonate (8.0 g), chloromethylcyclopropane (2.9 mL) and sodium iodide (432 mg) were added, and the mixture was stirred at 90 ° C. for 4 hr. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with toluene (20 mL). The organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL) and water (10 mL), aqueous sodium hydroxide solution (4.0 M, 22 mL) was added, and the mixture was stirred at 50 ° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, acidified with dilute hydrochloric acid (1.0 M, 100 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in DMF (80 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (hereinafter EDC / HCl, 8.0 g), 1-hydroxy-1H-benzotriazole (hereinafter HOBt, 5.0 g). ), N, O-dimethylhydroxylamine hydrochloride (3.3 g) and triethylamine (4.9 mL) were added, and the mixture was stirred at room temperature for 3 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound was dissolved in THF (70 mL), and a THF solution of ethylmagnesium bromide (1.0 M, 22 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution to separate the layers. The organic layer was washed with water (50 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
　メチルトリフェニルホスホニウムブロミド(10.8g)をTHF(80mL)に懸濁し、0℃でNaHMDSのTHF溶液(1.0M,30mL)を加え、同温度で30分撹拌した。-78℃に冷却し、前反応で得られたケトン体(4.98g)を加え、室温で3時間撹拌した。酢酸(2.0mL)を加え減圧濃縮した後、残渣を10％酢酸エチル/ヘキサン(80mL)に懸濁した。不溶物を濾去し、10％酢酸エチル/ヘキサン(80mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。得られた化合物をtert-ブタノール(90mL)、水(90mL)に溶解し、0℃でAD-mixα(30g)を加え、同温度で3時間撹拌した。反応液に飽和亜硫酸水素ナトリウム水溶液を不溶物がなくなるまで0℃でゆっくり加え、酢酸エチル(100mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製することで、標記化合物(5.2g)を無色油状物質として得た。 Methyltriphenylphosphonium bromide (10.8 g) was suspended in THF (80 mL), a THF solution of NaHMDS (1.0 M, 30 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to −78 ° C., the ketone body (4.98 g) obtained in the previous reaction was added, and the mixture was stirred at room temperature for 3 hours. Acetic acid (2.0 mL) was added and the mixture was concentrated under reduced pressure. The residue was suspended in 10% ethyl acetate / hexane (80 mL). The insoluble material was removed by filtration, washed with 10% ethyl acetate / hexane (80 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). The obtained compound was dissolved in tert-butanol (90 mL) and water (90 mL), AD-mixα (30 g) was added at 0 ° C., and the mixture was stirred at the same temperature for 3 hr. Saturated aqueous sodium hydrogen sulfite solution was slowly added to the reaction mixture at 0 ° C. until no insoluble material disappeared, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane) to give the title compound (5.2 g) as a colorless oil.
参考例34
　(S)-1-アジド-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オールの合成 Reference Example 34
Synthesis of (S) -1-azido-2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butan-2-ol
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
　参考例33で得られた(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-1,2-ジオール(590mg)をジクロロメタン(10mL)に溶解し,トリエチルアミン(472μL)及び塩化メタンスルホニル(193μL)を加え室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(10mL)を加え分液した。有機層を水(10mL)、飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(4.0mL)に溶解し、アジ化ナトリウム(734mg)を加え80℃で12時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製することで、標記化合物(450mg)を無色油状物質として得た。 (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butane-1,2-diol (590 mg) obtained in Reference Example 33 was dissolved in dichloromethane (10 mL), and triethylamine (472 μL) was dissolved. And methanesulfonyl chloride (193 μL) were added and stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the phases were separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (4.0 mL), sodium azide (734 mg) was added, and the mixture was stirred at 80 ° C. for 12 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (450 mg) as a colorless oil.
参考例35
　(S)-2-(3-イソブトキシフェニル)ブタン-1,2-ジオールの合成 Reference Example 35
Synthesis of (S) -2- (3-isobutoxyphenyl) butane-1,2-diol
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　容易に入手可能な3-ヒドロキシ安息香酸エチル(6.6g)をTHF(15mL)に溶解し、トリフェニルホスフィン(21g)及び2-メチルプロパノール(7.4mL)を加えた。反応液にアゾジカルボン酸ジイソプロピルのトルエン溶液(1.9M,42mL)を滴下し、室温で2時間撹拌した。反応液を減圧濃縮し、残渣を10%酢酸エチル/ヘキサン(100mL)に懸濁した後、不溶物を濾去し、10%酢酸エチル/ヘキサン(100mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(4%酢酸エチル/ヘキサン)で精製した。得られた化合物をエタノール(10mL)、水(10mL)に溶解し、水酸化ナトリウム水溶液(4.0M,22mL)を加え50℃で3時間撹拌した。反応液を減圧濃縮した後、希塩酸(1.0M,100mL)で酸性にし、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をDMF(80mL)に溶解し、EDC・HCl(8.0g)、HOBt(5.0g)を加え、N,O-ジメチルヒドロキシルアミン塩酸塩(3.3g)及びトリエチルアミン(4.9mL)を加え、室温で3時間撹拌した。反応液に水(50mL)を加え、トルエン(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(70mL)に溶解し、臭化エチルマグネシウムのTHF溶液(1.0M,25mL)を0℃で滴下し、同温度で2時間撹拌した。反応液に飽和塩化アンモニウム水溶液(100mL)を加え、分液した。有機層を飽和食塩水(100mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%酢酸エチル/ヘキサン)で精製した。 Easily available ethyl 3-hydroxybenzoate (6.6 g) was dissolved in THF (15 mL), and triphenylphosphine (21 g) and 2-methylpropanol (7.4 mL) were added. A toluene solution of diisopropyl azodicarboxylate (1.9 M, 42 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was suspended in 10% ethyl acetate / hexane (100 mL), insolubles were filtered off, washed with 10% ethyl acetate / hexane (100 mL), and the combined filtrate was reduced in vacuo. Concentrated. The residue was purified by silica gel column chromatography (4% ethyl acetate / hexane). The obtained compound was dissolved in ethanol (10 mL) and water (10 mL), aqueous sodium hydroxide solution (4.0 M, 22 mL) was added, and the mixture was stirred at 50 ° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, acidified with dilute hydrochloric acid (1.0 M, 100 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Dissolve the residue in DMF (80 mL), add EDCHCl (8.0 g) and HOBt (5.0 g), add N, O-dimethylhydroxylamine hydrochloride (3.3 g) and triethylamine (4.9 mL), and Stir for 3 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound was dissolved in THF (70 mL), and a THF solution of ethylmagnesium bromide (1.0 M, 25 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and the phases were separated. The organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
　メチルトリフェニルホスホニウムブロミド(10.8g)をTHF(80mL)に懸濁し、0℃でNaHMDSのTHF溶液(1.0M,30mL)を加え、同温度で30分撹拌した。-78℃に冷却し、前反応で得られたケトン体(4.98g)を加え、室温で3時間撹拌した。酢酸(2.0mL)を加え、減圧濃縮した。残渣を10％酢酸エチル/ヘキサン(80mL)に懸濁し、不溶物を濾去し、10％酢酸エチル/ヘキサン(80mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。得られた化合物をtert-ブタノール(90mL)、水(90mL)に溶解し、0℃でAD-mixα(30g)を加え、同温度で3時間撹拌した。飽和亜硫酸水素ナトリウム水溶液を不溶物がなくなるまで0℃でゆっくり加え、酢酸エチル(100mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物(4.9gの内、580mg)をジクロロメタン(10mL)に溶解し,トリエチルアミン(472μL)及び塩化メタンスルホニル(193μL)を加え室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(10mL)を加え分液した。有機層を水(10mL)、飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(4.0mL)に溶解し、アジ化ナトリウム(734mg)を加え80℃で12時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製することで、標記化合物(430mg)を無色油状物質として得た。 Methyltriphenylphosphonium bromide (10.8 g) was suspended in THF (80 mL), a THF solution of NaHMDS (1.0 M, 30 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to −78 ° C., and the ketone body (4.98 g) obtained in the previous reaction was added, followed by stirring at room temperature for 3 hours. Acetic acid (2.0 mL) was added, and the mixture was concentrated under reduced pressure. The residue was suspended in 10% ethyl acetate / hexane (80 mL), insolubles were filtered off, washed with 10% ethyl acetate / hexane (80 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). The obtained compound was dissolved in tert-butanol (90 mL) and water (90 mL), AD-mixα (30 g) was added at 0 ° C., and the mixture was stirred at the same temperature for 3 hr. Saturated aqueous sodium hydrogen sulfite solution was slowly added at 0 ° C. until no insoluble material disappeared, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound (580 mg out of 4.9 g) was dissolved in dichloromethane (10 mL), triethylamine (472 μL) and methanesulfonyl chloride (193 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the phases were separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (4.0 mL), sodium azide (734 mg) was added, and the mixture was stirred at 80 ° C. for 12 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (430 mg) as a colorless oil.
参考例36
　(S)-1-アジド-2-(3-(2,2-ジフルオロエトキシ)フェニル)ブタン-2-オール Reference Example 36
(S) -1-Azido-2- (3- (2,2-difluoroethoxy) phenyl) butan-2-ol
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　容易に入手可能な2,2-ジフルオロエタノール(6.6g)及びトリエチルアミン(16.8mL)をジクロロメタン(200mL)に溶解し、トリフルオロメタンスルホン酸無水物(16mL)を0℃で滴下し、室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(100mL)を加え、分液した。有機層を水(50mL)、飽和食塩水(50mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。 Easily available 2,2-difluoroethanol (6.6 g) and triethylamine (16.8 mL) are dissolved in dichloromethane (200 mL), trifluoromethanesulfonic anhydride (16 mL) is added dropwise at 0 ° C., and 30 minutes at room temperature. Stir. A saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the reaction mixture, and the phases were separated. The organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
　容易に入手可能な3-ヒドロキシ安息香酸エチル(6.6g)をDMF(200mL)に溶解し、炭酸カリウム(16g)及びヨウ化ナトリウム(1.0g)を加え、前反応で得られた残渣のDMF(30mL)溶液を加え、90℃で12時間撹拌した。反応液にトルエン(200mL)、水(200mL)を加え分液した。有機層を水(100mL)、水酸化ナトリウム水溶液(1.0M、100mL)、飽和食塩水(100mL)で洗浄した。無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をエタノール(10mL)、水(10mL)に溶解し、水酸化ナトリウム水溶液(4.0M,22mL)を加え50℃で3時間撹拌した。反応液を減圧濃縮後、希塩酸(1.0M,100mL)で酸性にし、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をDMF(8.0mL)に溶解し、EDC・HCl(8.0g)、HOBt(5.0g)を加え、N,O-ジメチルヒドロキシルアミン塩酸塩(3.3g)及びトリエチルアミン(4.9mL)を加え、室温で3時間撹拌した。反応液に水(50mL)を加え、トルエン(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(70mL)に溶解し、臭化エチルマグネシウムのTHF溶液(1.0M,25mL)を0℃で滴下し、同温度で2時間撹拌した。反応液に飽和塩化アンモニウム水溶液(100mL)を加え分液し、有機層を飽和食塩水(100mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%酢酸エチル/ヘキサン)で精製した。 Easily available ethyl 3-hydroxybenzoate (6.6 g) is dissolved in DMF (200 mL), potassium carbonate (16 g) and sodium iodide (1.0 g) are added, and the DMF ( 30 mL) solution was added and stirred at 90 ° C. for 12 hours. Toluene (200 mL) and water (200 mL) were added to the reaction solution to separate the layers. The organic layer was washed with water (100 mL), aqueous sodium hydroxide solution (1.0 M, 100 mL), and saturated brine (100 mL). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL) and water (10 mL), aqueous sodium hydroxide solution (4.0 M, 22 mL) was added, and the mixture was stirred at 50 ° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, acidified with dilute hydrochloric acid (1.0 M, 100 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Dissolve the residue in DMF (8.0 mL), add EDCHCl (8.0 g) and HOBt (5.0 g), add N, O-dimethylhydroxylamine hydrochloride (3.3 g) and triethylamine (4.9 mL), For 3 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound was dissolved in THF (70 mL), and a THF solution of ethylmagnesium bromide (1.0 M, 25 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
　メチルトリフェニルホスホニウムブロミド(10.8g)をTHF(80mL)に懸濁し、0℃でNaHMDSのTHF溶液(1.0M,30mL)を加え、同温度で30分撹拌した。-78℃に冷却し、前反応で得られたケトン体(4.98g)を加え、室温で3時間撹拌した。酢酸(2.0mL)を加え減圧濃縮し、残渣を10％酢酸エチル/ヘキサン(80mL)に懸濁した。不溶物を濾去し、10％酢酸エチル/ヘキサン(80mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。得られた化合物をtert-ブタノール(90mL)、水(90mL)に溶解し、0℃でAD-mixα(30g)を加え、同温度で3時間撹拌した。反応液に飽和亜硫酸水素ナトリウム水溶液を不溶物がなくなるまで0℃でゆっくり加え、酢酸エチル(100mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物(5.5gの内、595mg)をジクロロメタン(10mL)に溶解し,トリエチルアミン(472μL)、塩化メタンスルホニル(193μL)を加え室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(10mL)を加え分液した。有機層を水(10mL)、飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(4mL)に溶解し、アジ化ナトリウム(734mg)を加え80℃で12時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製することで、標記化合物(470mg)を無色油状物質として得た。 Methyltriphenylphosphonium bromide (10.8 g) was suspended in THF (80 mL), a THF solution of NaHMDS (1.0 M, 30 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to −78 ° C., and the ketone body (4.98 g) obtained in the previous reaction was added, followed by stirring at room temperature for 3 hours. Acetic acid (2.0 mL) was added and the mixture was concentrated under reduced pressure. The residue was suspended in 10% ethyl acetate / hexane (80 mL). The insoluble material was removed by filtration, washed with 10% ethyl acetate / hexane (80 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). The obtained compound was dissolved in tert-butanol (90 mL) and water (90 mL), AD-mixα (30 g) was added at 0 ° C., and the mixture was stirred at the same temperature for 3 hr. Saturated aqueous sodium hydrogen sulfite solution was slowly added to the reaction mixture at 0 ° C. until no insoluble material disappeared, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound (5.5 mg of 5.5 g) was dissolved in dichloromethane (10 mL), triethylamine (472 μL) and methanesulfonyl chloride (193 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the phases were separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (4 mL), sodium azide (734 mg) was added, and the mixture was stirred at 80 ° C. for 12 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (470 mg) as a colorless oil.
　以下の表に示すアジド体は参考例33～35のいずれかの方法に準じて合成した。 The azide compounds shown in the following table were synthesized according to the method of Reference Examples 33 to 35.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　なお、参考例41及び60のアジドはAD-mixαの代わりにAD-mixβを、参考例54のアジドはAD-mixαの代わりに四酸化オスミウムを用いて合成した。 The azides of Reference Examples 41 and 60 were synthesized using AD-mixβ instead of AD-mixα, and the azide of Reference Example 54 using osmium tetroxide instead of AD-mixα.
参考例61
　2-アジド-1,1-ビス(4-フルオロフェニル)エタノールの合成 Reference Example 61
Synthesis of 2-azido-1,1-bis (4-fluorophenyl) ethanol
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　容易に入手可能な2-ヒドロキシ酢酸エチル(3.0g)をDMF(100mL)に溶解し、イミダゾール(2.94g)及びtert-ブチルジメチルシリルクロリド(5.6g)を加え室温で2時間撹拌した。反応液に水(100mL)を加え、酢酸エチル(100mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製した。得られたシリル体(5.2gの内、1.55g)をTHF(25mL)に溶解し、0℃で臭化4-フルオロフェニルマグネシウムのTHF溶液(1.0M,28mL)を滴下し、0℃で3時間撹拌した。反応液に飽和塩化アンモニウム水溶液(20mL)を加え分液した。有機層を飽和食塩水(20mL)で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(20mL)に溶解し、TBAFのTHF溶液(1.0M,20mL)を加え、室温で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られたジオール体(1.3gの内、1.0g)をジクロロメタン(20mL)に溶解し、トリエチルアミン(831μL)及び塩化メタンスルホニル(371μL)を加え室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(10mL)を加え、分液した。有機層を水(10mL)、飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(40mL)に溶解し、アジ化ナトリウム(1.0g)を加え70℃で12時間撹拌した。反応液に水(50mL)を加え、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製することで、標記化合物(300mg)を淡黄色油状物質として得た。 Easily available ethyl 2-hydroxyacetate (3.0 g) was dissolved in DMF (100 mL), imidazole (2.94 g) and tert-butyldimethylsilyl chloride (5.6 g) were added, and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane). The obtained silyl compound (1.55 g out of 5.2 g) was dissolved in THF (25 mL), and a THF solution of 4-fluorophenylmagnesium bromide (1.0 M, 28 mL) was added dropwise at 0 ° C. Stir for hours. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution to separate the layers. The organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane). The obtained compound was dissolved in THF (20 mL), a TBAF solution in THF (1.0 M, 20 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The resulting diol (1.0 g out of 1.3 g) was dissolved in dichloromethane (20 mL), triethylamine (831 μL) and methanesulfonyl chloride (371 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the phases were separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (40 mL), sodium azide (1.0 g) was added, and the mixture was stirred at 70 ° C. for 12 hr. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (300 mg) as a pale yellow oil.
　以下の表に示すアジド体は容易に入手可能な2-ヒドロキシ酢酸エチルを原料とし、容易に入手可能なGrignard試薬又は容易に入手可能なブロモ体から通常公知の方法により調製できるGrignard試薬を用いて参考例61の方法に準じて合成した。 The azide forms shown in the following table are based on easily available 2-hydroxyethyl acetate, and using a readily available Grignard reagent or a Grignard reagent that can be prepared from a readily available bromo form by a generally known method. Synthesized according to the method of Reference Example 61.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
参考例65
　1-(アジドメチル)-3-(シクロプロピルメトキシ)ベンゼンの合成 Reference Example 65
Synthesis of 1- (azidomethyl) -3- (cyclopropylmethoxy) benzene
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　容易に入手可能な3-(ヒドロキシメチル)フェノール(700mg)をDMF(6.0mL)に溶解し、炭酸カリウム(1.56g)、ヨウ化ナトリウム(84mg)及びクロロメチルシクロプロパン(547μL)を加え、80℃で5時間撹拌した。反応液に水(40mL)を加え、酢酸エチル(40mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(17%酢酸エチル/ヘキサン)で精製した。得られた化合物をトルエン(8mL)に溶解し、ジフェニルホスホリルアジド(1.17mL)及び1,8-ジアザビシクロ[5.4.0]-7-ウンデセン(以下DBU,747μL)を0℃で加え室温で5時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を希塩酸(1.0M,10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製することで、標記化合物(850mg)を淡黄色油状物質として得た。 Easily available 3- (hydroxymethyl) phenol (700 mg) is dissolved in DMF (6.0 mL), potassium carbonate (1.56 g), sodium iodide (84 mg) and chloromethylcyclopropane (547 μL) are added, and 80 Stir at 5 ° C. for 5 hours. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17% ethyl acetate / hexane). The obtained compound was dissolved in toluene (8 mL), diphenylphosphoryl azide (1.17 mL) and 1,8-diazabicyclo [5.4.0] -7-undecene (hereinafter DBU, 747 μL) were added at 0 ° C. for 5 hours at room temperature. Stir. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with dilute hydrochloric acid (1.0 M, 10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (850 mg) as a pale yellow oil.
参考例66
　1-(アジドメチル)-2-(シクロプロピルメトキシ)ベンゼンの合成 Reference Example 66
Synthesis of 1- (azidomethyl) -2- (cyclopropylmethoxy) benzene
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　容易に入手可能な2-(ヒドロキシメチル)フェノール(700mg)から参考例65の方法に準じて合成することで、標記化合物(710mg)を淡黄色油状物質として得た。 The title compound (710 mg) was obtained as a pale yellow oily substance by synthesis according to the method of Reference Example 65 from readily available 2- (hydroxymethyl) phenol (700 mg).
参考例67
　rac-1-(1-アジドブタン-2-イル)-3-(シクロプロピルメトキシ)ベンゼンの合成 Reference Example 67
Synthesis of rac-1- (1-azidobutan-2-yl) -3- (cyclopropylmethoxy) benzene
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　マグネシウム(1.5g)をTHF(4.0mL)に懸濁し、ヨウ素(5.0mg)を加えた後、容易に入手可能な3-ブロモフェノールから文献(Eur. J. Org. Chem., 4, 916-923(2006))記載の方法に準じて得られる3-ブロモシクロプロピルメトキシベンゼン(1.5g)のTHF(4.0mL)溶液を滴下し、室温で1時間撹拌した。調製したGrignard試薬を、容易に入手可能な2-ビニルオキシラン(535μL)のTHF(4.0mL)溶液に0℃で滴下し、60℃で2時間撹拌した。反応液に塩化アンモニウム水溶液(10mL)を加え、分液した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(14％酢酸エチル/ヘキサン)で精製した。得られた化合物をメタノール(3.0mL)に溶解し、10%パラジウム-炭素(700mg)を加え、水素雰囲気下、1時間撹拌した。不溶物を濾去し、メタノール(20mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をトルエン(5.0mL)で3回共沸し、得られた残渣をジクロロメタン(4.0mL)に溶解し、トリエチルアミン(149μL)及び塩化メタンスルホニル(77μL)を加え室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5mL)を加え、分液した。有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(4.0mL)に溶解し、アジ化ナトリウム(162mg)を加え50℃で3時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、残渣をシリカゲルカラムクロマトグラフィー(10％酢酸エチル/酢酸エチル)で精製することで、標記化合物(160mg)を淡黄色油状物質として得た。 Magnesium (1.5 g) was suspended in THF (4.0 mL), iodine (5.0 mg) was added, and then readily available 3-bromophenol from literature (Eur. J. Org. Chem., 4, 916- 923 (2006)), a solution of 3-bromocyclopropylmethoxybenzene (1.5 g) obtained in accordance with the method described in THF (4.0 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The prepared Grignard reagent was added dropwise to a readily available solution of 2-vinyloxirane (535 μL) in THF (4.0 mL) at 0 ° C. and stirred at 60 ° C. for 2 hours. Aqueous ammonium chloride solution (10 mL) was added to the reaction solution and the phases were separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (14% ethyl acetate / hexane). The obtained compound was dissolved in methanol (3.0 mL), 10% palladium-carbon (700 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1 hr. The insoluble material was removed by filtration, washed with methanol (20 mL), and the combined filtrate was concentrated under reduced pressure. The residue was azeotroped three times with toluene (5.0 mL), the obtained residue was dissolved in dichloromethane (4.0 mL), triethylamine (149 μL) and methanesulfonyl chloride (77 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the phases were separated. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (4.0 mL), sodium azide (162 mg) was added, and the mixture was stirred at 50 ° C. for 3 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate, and the residue was purified by silica gel column chromatography (10% ethyl acetate / ethyl acetate) to obtain the title compound (160 mg) as a pale yellow oily substance.
参考例68
　4-(2-アジドエチル)-2-(シクロプロピルメトキシ)-1-フルオロベンゼンの合成 Reference Example 68
Synthesis of 4- (2-azidoethyl) -2- (cyclopropylmethoxy) -1-fluorobenzene
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　容易に入手可能な4-フルオロ-3-ヒドロキシ安息香酸(4.7g)をエタノール(8mL)に溶解し、硫酸(1.0mL)を加え90℃で2時間加熱還流した。反応液を減圧濃縮し、残渣に水(10mL)を加えた後、炭酸水素ナトリウムを加えて中和し、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水(20mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(30mL)に溶解し、炭酸カリウム(8.0g)、クロロメチルシクロプロパン(2.9mL)及びヨウ化ナトリウム(432mg)を加え、90℃で4時間撹拌した。反応液を放冷後、水(20mL)を加え、トルエン(20mL)で抽出した。有機層を水(20mL)、飽和食塩水(20mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。
　水素化リチウムアルミニウム(以下LAH)のTHF溶液(2.4M、11.6mL)をTHF(20mL)に溶解し、氷冷下、前反応で得られた残渣(5.7gの内、2.2g)のTHF(5.0mL)溶液を滴下し、室温で3時間撹拌した。反応液に水(5.0mL)を0℃でゆっくり加え、生じた固体を濾去し、酢酸エチル(50mL)及びTHF(50mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をトルエン(10mL×3)で共沸した後、クロロホルム(100mL)に溶解し、二酸化マンガン(7.0g)を加え80℃で2時間加熱還流した。不溶物をセライトを用いて濾去し、クロロホルム(200mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をトルエン(5.0mL×2)で共沸した。 Easily available 4-fluoro-3-hydroxybenzoic acid (4.7 g) was dissolved in ethanol (8 mL), sulfuric acid (1.0 mL) was added, and the mixture was heated to reflux at 90 ° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added to the residue, sodium hydrogen carbonate was added for neutralization, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (30 mL), potassium carbonate (8.0 g), chloromethylcyclopropane (2.9 mL) and sodium iodide (432 mg) were added, and the mixture was stirred at 90 ° C. for 4 hr. The reaction mixture was allowed to cool, water (20 mL) was added, and the mixture was extracted with toluene (20 mL). The organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
A THF solution (2.4 M, 11.6 mL) of lithium aluminum hydride (hereinafter referred to as LAH) was dissolved in THF (20 mL), and the residue obtained from the previous reaction (2.2 g out of 5.7 g, 2.2 g) of THF (under ice cooling) 5.0 mL) solution was added dropwise and stirred at room temperature for 3 hours. Water (5.0 mL) was slowly added to the reaction solution at 0 ° C., and the resulting solid was filtered off, washed with ethyl acetate (50 mL) and THF (50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was azeotroped with toluene (10 mL × 3), dissolved in chloroform (100 mL), manganese dioxide (7.0 g) was added, and the mixture was heated to reflux at 80 ° C. for 2 hours. The insoluble material was filtered off using celite, washed with chloroform (200 mL), and the combined filtrate was concentrated under reduced pressure. The residue was azeotroped with toluene (5.0 mL × 2).
　(メトキシメチル)トリフェニルホスホニウムクロリド(4.62g)をTHF(20mL)に懸濁し、tert-ブトキシカリウム(1.88g)を0℃で加え、室温で30分撹拌した。前反応で得られた残渣を加え、室温で2時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(20mL)で抽出した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(5％酢酸エチル/ヘキサン)で精製した。得られた化合物をアセトン(12mL)に溶解し、12N塩酸(6.0mL)を加え、10分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)に加え、減圧濃縮した。残渣にクロロホルム(20mL)、水(10mL)を加え分液し、有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をエタノール(20mL)に溶解し、水素化ホウ素ナトリウム(383mg)を0℃で加え、室温で2時間撹拌した。反応液に飽和塩化アンモニウム水溶液(50mL)を加え、クロロホルム(100mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(50%酢酸エチル/ヘキサン)で精製した。得られたアルコール体(800mgのうち300mg)をジクロロメタン(3.0mL)に溶解し、トリエチルアミン(296μL)及び塩化メタンスルホニル(132μL)を加え室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5.0mL)を加え分液し、有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(4.0mL)に溶解し、アジ化ナトリウム(277mg)を加え50℃で3時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10％酢酸エチル/ヘキサン)で精製することで、標記化合物(310mg)を淡黄色油状物質として得た。 (Methoxymethyl) triphenylphosphonium chloride (4.62 g) was suspended in THF (20 mL), tert-butoxypotassium (1.88 g) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. The residue obtained in the previous reaction was added and stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane). The obtained compound was dissolved in acetone (12 mL), 12N hydrochloric acid (6.0 mL) was added, and the mixture was stirred for 10 min. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution (20 mL) and concentrated under reduced pressure. Chloroform (20 mL) and water (10 mL) were added to the residue and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (20 mL), sodium borohydride (383 mg) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained alcohol (300 mg out of 800 mg) was dissolved in dichloromethane (3.0 mL), triethylamine (296 μL) and methanesulfonyl chloride (132 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution, and the mixture was partitioned. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (4.0 mL), sodium azide (277 mg) was added, and the mixture was stirred at 50 ° C. for 3 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (310 mg) as a pale yellow oil.
参考例69
　(2-アジドエタン-1,1-ジイル)ジベンゼンの合成 Reference Example 69
Synthesis of (2-azidoethane-1,1-diyl) dibenzene
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　2,2-ジフェニルエタノール(500mg)をTHF(20mL)に溶解し、トリフェニルホスフィン(656mg)、アゾジカルボン酸ジイソプロピルトルエン溶液(1.9M、1.32mL)を加え室温で5分撹拌した。反応液にジフェニルホスホリルアジド(538μL)を滴下し、50℃で12時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製することで、標記化合物(300mg)を淡黄色油状物質として得た。 2,2-diphenylethanol (500 mg) was dissolved in THF (20 mL), triphenylphosphine (656 mg) and azodicarboxylate diisopropyltoluene solution (1.9 M, 1.32 mL) were added, and the mixture was stirred at room temperature for 5 minutes. Diphenylphosphoryl azide (538 μL) was added dropwise to the reaction solution, and the mixture was stirred at 50 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane) to give the title compound (300 mg) as a pale yellow oil.
参考例70
　2-(1-アジドプロパン-2-イル)ビフェニルの合成 Reference Example 70
Synthesis of 2- (1-azidopropan-2-yl) biphenyl
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　2-フェニル安息香酸(1.0g)をDMF(10mL)に溶解し、EDC・HCl(1.44g)、HOBt(810mg)を加え、N,O-ジメチルヒドロキシルアミン塩酸塩(585mg)及びトリエチルアミン(0.9mL)を加え、室温で3時間撹拌した。反応液に水(20mL)を加え、50%酢酸エチル/トルエン溶液(30mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(10mL)に溶解し、臭化メチルマグネシウムのTHF溶液(1.0M,10mL)を0℃で滴下し、同温度で2時間撹拌した。反応液に飽和塩化アンモニウム水溶液(10mL)を加え分液した。有機層を飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%酢酸エチル/ヘキサン)で精製した。 Dissolve 2-phenylbenzoic acid (1.0 g) in DMF (10 mL), add EDCHCl (1.44 g), HOBt (810 mg), N, O-dimethylhydroxylamine hydrochloride (585 mg) and triethylamine (0.9 mL) ) Was added and stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with 50% ethyl acetate / toluene solution (30 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound was dissolved in THF (10 mL), and a THF solution of methylmagnesium bromide (1.0 M, 10 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to separate the layers. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
　メチルトリフェニルホスホニウムブロミド(2.86g)をTHF(30mL)に懸濁し、0℃でNaHMDSのTHF溶液(1.0M,8.0mL)を加え、同温度で30分撹拌した。-78℃に冷却し、前反応で得られたケトン体(550mg)を加え、室温で3時間撹拌した。反応液に酢酸(1.0mL)を加えた後、減圧濃縮した。残渣を10％酢酸エチル/ヘキサン溶液(50mL)に懸濁した。不溶物を濾去し、10％酢酸エチル/ヘキサン溶液(50mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。得られた化合物(500mg)の内、一部(340mg)をTHF(2.0mL)に溶解し、ボラン・THF錯体のTHF溶液(1.0M,2.1mL)を加え、室温で12時間撹拌した。反応液に0℃で水酸化ナトリウム水溶液(3.0M,1.75mL)を加え5分撹拌後、30%過酸化水素水(1.75mL)を加え、室温で1時間撹拌した。反応液に0℃で飽和亜硫酸水素ナトリウム水溶液(2.0mL)を加えた後、塩酸(1.0M,5.0mL)を加え酸性にし、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物(260mg)をジクロロメタン(4.0mL)に溶解し、トリエチルアミン(254μL)を加え、0℃で塩化メタンスルホニル(114μL)を加え、室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5.0mL)を加え分液した。有機層を水(10mL)、飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(4.0mL)に溶解し、アジ化ナトリウム(287mg)を加え、50℃で3時間撹拌した。反応液に酢酸エチル(10mL)、水(10mL)を加え分液した。有機層を水(10mL)、飽和食塩水(10mL)で洗浄した。無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製することで、標記化合物(210mg)を淡黄色油状物質として得た。 Methyltriphenylphosphonium bromide (2.86 g) was suspended in THF (30 mL), a NaHMDS THF solution (1.0 M, 8.0 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to −78 ° C., the ketone body (550 mg) obtained in the previous reaction was added, and the mixture was stirred at room temperature for 3 hours. Acetic acid (1.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was suspended in a 10% ethyl acetate / hexane solution (50 mL). The insoluble material was removed by filtration, washed with a 10% ethyl acetate / hexane solution (50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). A part (340 mg) of the obtained compound (500 mg) was dissolved in THF (2.0 mL), a THF solution (1.0 M, 2.1 mL) of borane / THF complex was added, and the mixture was stirred at room temperature for 12 hours. A sodium hydroxide aqueous solution (3.0 M, 1.75 mL) was added to the reaction solution at 0 ° C., and the mixture was stirred for 5 minutes, 30% aqueous hydrogen peroxide (1.75 mL) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen sulfite solution (2.0 mL) was added to the reaction mixture at 0 ° C., and the mixture was acidified with hydrochloric acid (1.0 M, 5.0 mL), and extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound (260 mg) was dissolved in dichloromethane (4.0 mL), triethylamine (254 μL) was added, methanesulfonyl chloride (114 μL) was added at 0 ° C., and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (4.0 mL), sodium azide (287 mg) was added, and the mixture was stirred at 50 ° C. for 3 hr. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction solution to separate the layers. The organic layer was washed with water (10 mL) and saturated brine (10 mL). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (210 mg) as a pale yellow oil.
参考例71
　(S)-1-アジド-2-(ビフェニル-2-イル)プロパン-2-オールの合成 Reference Example 71
Synthesis of (S) -1-azido-2- (biphenyl-2-yl) propan-2-ol
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　容易に入手可能な2’-ヨードアセトフェノン(1.0g)、フェニルボロン酸(732mg)をエチレングリコールジメチルエーテル(20mL)、水(5.0mL)に溶解し、炭酸ナトリウム(2.54g)、[1,1’-ビス(ジフェニルホスフィノ)-フェロセン]ジクロロパラジウム(II)ジクロロメタン錯体(164mg)を加え、90℃で3時間撹拌した。反応液に酢酸エチル(30mL)、水(30mL)を加え分液した。有機層を飽和食塩水(30mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%酢酸エチル/ヘキサン)で精製した。
　メチルトリフェニルホスホニウムブロミド(2.86g)をTHF(30mL)に懸濁し、0℃でNaHMDSのTHF溶液(1.0M,8.0mL)を加え、同温度で30分撹拌した。-78℃に冷却し、前反応で得られたケトン体(710mg)を加え、室温で3時間撹拌した。反応液に酢酸(1.0mL)を加え減圧濃縮した。残渣を10％酢酸エチル/ヘキサン溶液(50mL)に懸濁した。不溶物を濾去し、10％酢酸エチル/ヘキサン溶液(50mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。得られた化合物(700mg)をtert-ブタノール(26mL)、水(26mL)に溶解し、AD-mixα(8.0g)を加え、75℃で72時間撹拌した。反応液に飽和亜硫酸水素ナトリウム水溶液(20mL)をゆっくり加えた後、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水(40mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(30%酢酸エチル/ヘキサン)で精製した。得られた化合物(120mg)をジクロロメタン(2.0mL)に溶解し、トリエチルアミン(110μL)を加え、0℃で塩化メタンスルホニル(49μL)を加え、室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(2.0mL)を加え分液した。有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をDMF(2.0mL)に溶解し、アジ化ナトリウム(138mg)を加え、90℃で48時間撹拌した。反応液に水(5.0mL)を加えた後、酢酸エチル(5.0mL)で抽出した。有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製することで、標記化合物(52mg)を淡黄色油状物質として得た。 Easily available 2′-iodoacetophenone (1.0 g), phenylboronic acid (732 mg) dissolved in ethylene glycol dimethyl ether (20 mL), water (5.0 mL), sodium carbonate (2.54 g), [1,1 ′ -Bis (diphenylphosphino) -ferrocene] dichloropalladium (II) dichloromethane complex (164 mg) was added and stirred at 90 ° C. for 3 hours. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution and the phases were separated. The organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
Methyltriphenylphosphonium bromide (2.86 g) was suspended in THF (30 mL), a NaHMDS solution in THF (1.0 M, 8.0 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to −78 ° C., the ketone body (710 mg) obtained in the previous reaction was added, and the mixture was stirred at room temperature for 3 hours. Acetic acid (1.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was suspended in a 10% ethyl acetate / hexane solution (50 mL). The insoluble material was removed by filtration, washed with a 10% ethyl acetate / hexane solution (50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). The obtained compound (700 mg) was dissolved in tert-butanol (26 mL) and water (26 mL), AD-mixα (8.0 g) was added, and the mixture was stirred at 75 ° C. for 72 hours. Saturated aqueous sodium hydrogen sulfite solution (20 mL) was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / hexane). The obtained compound (120 mg) was dissolved in dichloromethane (2.0 mL), triethylamine (110 μL) was added, methanesulfonyl chloride (49 μL) was added at 0 ° C., and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added to the reaction solution to separate the layers. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (2.0 mL), sodium azide (138 mg) was added, and the mixture was stirred at 90 ° C. for 48 hr. Water (5.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5.0 mL). The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (52 mg) as a pale yellow oil.
　以下の表に示すアジド体は参考例71の方法に準じて合成した。 The azide compounds shown in the following table were synthesized according to the method of Reference Example 71.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　なお前記表中、参考例72～75で用いた原料は容易に入手可能であり、参考例76～80で用いた原料は文献（Tetrahedron, 20, 2195-2199(1985)）記載の方法により得た。 In the above table, the raw materials used in Reference Examples 72 to 75 are easily available, and the raw materials used in Reference Examples 76 to 80 were obtained by the method described in the literature (Tetrahedron, 20, 2195-2199 (1985)). It was.
参考例81
　(S)-1-(5-(4-(tert-ブチルジフェニルシリルオキシ)ブチル)-4-(ヒドロキシメチル)-1H-1,2,3-トリアゾール-1-イル)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オールの合成 Reference Example 81
(S) -1- (5- (4- (tert-butyldiphenylsilyloxy) butyl) -4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl) -2- (3- Synthesis of (cyclopropylmethoxy) -4-fluorophenyl) butan-2-ol
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　参考例8で得られたメチル7-(tert-ブチルジフェニルシリルオキシ)ヘプト-2-イノエート(660mg)と参考例34で得られた(S)-1-アジド-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オール(700mg)をトルエン(8.0mL)に溶解し、クロロ(ペンタメチルシクロペンタジエニル)(シクロオクタジエン)ルテニウム(II)(63mg)を加え、80℃で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物(1.1gの内、1.0g)をTHF(7.0mL)に溶解し、水素化ホウ素リチウムのTHF溶液(2.0M,1.48mL)を加え80℃で5時間加熱還流した。反応液を放冷後、飽和食塩水(10mL)を加え、分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(50%酢酸エチル/ヘキサン)で精製することで、標記化合物(840mg)を無色油状物質として得た。 Methyl 7- (tert-butyldiphenylsilyloxy) hept-2-inoate (660 mg) obtained in Reference Example 8 and (S) -1-azido-2- (3- (cyclopropyl) obtained in Reference Example 34 Methoxy) -4-fluorophenyl) butan-2-ol (700 mg) is dissolved in toluene (8.0 mL), chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II) (63 mg) is added, Stir at 80 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound (1.0 g out of 1.1 g) was dissolved in THF (7.0 mL), a THF solution of lithium borohydride (2.0 M, 1.48 mL) was added, and the mixture was heated to reflux at 80 ° C. for 5 hours. The reaction mixture was allowed to cool, saturated brine (10 mL) was added, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (840 mg) as a colorless oil.
参考例82
　(S)-1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-5-(4-ヒドロキシブチル)-1H-1,2,3-トリアゾール-4-カルボニトリルの合成 Reference Example 82
(S) -1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -5- (4-hydroxybutyl) -1H-1,2,3-triazole-4 -Synthesis of carbonitrile
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　参考例81で得られた(S)-1-(5-(4-(tert-ブチルジフェニルシリルオキシ)ブチル)-4-(ヒドロキシメチル)-1H-1,2,3-トリアゾール-1-イル)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オール(810mg)をクロロホルム(15mL)に溶解し、二酸化マンガン(1.0g)を加え90℃で2時間加熱還流した。固体をセライトを用いて濾去し、クロロホルム(40mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をトルエン(10mL×2)で共沸し、得られた残渣(700mgの内、400mg)をピリジン(5.0mL)に溶解し、ヒドロキシルアミン塩酸塩(65mg)を加え、室温で6時間撹拌した。反応液を減圧濃縮し、水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をトルエン(5mL×3)で共沸した後、ジクロロメタン(5.0mL)に溶解し、トリエチルアミン(172μL)及び塩化メタンスルホニル(72μL)を0℃で加え室温で3時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5.0mL)を加え分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(25%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(1.3mL)に溶解し、TBAFのTHF溶液(1.0M,1.31mL)を加え室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(5%メタノール/クロロホルム)で精製することで、標記化合物(180mg)を無色油状物質として得た。 (S) -1- (5- (4- (tert-butyldiphenylsilyloxy) butyl) -4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl obtained in Reference Example 81 ) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butan-2-ol (810 mg) was dissolved in chloroform (15 mL), manganese dioxide (1.0 g) was added, and the mixture was heated to reflux at 90 ° C. for 2 hours. did. The solid was filtered off using celite, washed with chloroform (40 mL), and the combined filtrate was concentrated under reduced pressure. The residue was azeotroped with toluene (10 mL × 2), and the obtained residue (400 mg out of 700 mg) was dissolved in pyridine (5.0 mL), hydroxylamine hydrochloride (65 mg) was added, and the mixture was stirred at room temperature for 6 hours. . The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was azeotroped with toluene (5 mL × 3), dissolved in dichloromethane (5.0 mL), triethylamine (172 μL) and methanesulfonyl chloride (72 μL) were added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate / hexane). The obtained compound was dissolved in THF (1.3 mL), a THF solution of TBAF (1.0 M, 1.31 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / chloroform) to give the title compound (180 mg) as a colorless oil.
参考例83
　(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-エチニル-1H-1,2,3-トリアゾール-5-イル)ブタン-1-オールの合成 Reference Example 83
(S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4-ethynyl-1H-1,2,3-triazol-5-yl Synthesis of butan-1-ol
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　参考例81で得られた(S)-1-(5-(4-(tert-ブチルジフェニルシリルオキシ)ブチル)-4-(ヒドロキシメチル)-1H-1,2,3-トリアゾール-1-イル)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オール(810mg)をクロロホルム(15mL)に溶解し、二酸化マンガン(1.0g)を加え90℃で2時間加熱還流した。固体をセライトを用いて濾去し、クロロホルム(40mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をトルエン(10mL×2)で共沸し、得られた残渣(700mgの内、350mg)をメタノール(3.0mL)に溶解し、文献(Eur. J. Org. Chem., 5, 821-832(2003))記載の方法で得られたジメチル1-ジアゾ-2-オキソプロピルホスホネート(136mg)及び炭酸カリウム(149mg)を加え、室温で3時間撹拌した。反応液を減圧濃縮し、残渣に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(25%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(1.5mL)に溶解し、TBAFのTHF溶液(1.0M,1.5mL)を加え室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(3%メタノール/クロロホルム)で精製することで、標記化合物(190mg)を無色油状物質として得た。 (S) -1- (5- (4- (tert-butyldiphenylsilyloxy) butyl) -4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl obtained in Reference Example 81 ) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butan-2-ol (810 mg) was dissolved in chloroform (15 mL), manganese dioxide (1.0 g) was added, and the mixture was heated to reflux at 90 ° C. for 2 hours. did. The solid was filtered off using celite, washed with chloroform (40 mL), and the combined filtrate was concentrated under reduced pressure. The residue was azeotroped with toluene (10 mL × 2), and the resulting residue (350 mg of 700 mg) was dissolved in methanol (3.0 mL), and the literature (Eur. J. Org. Chem., 5, 821-832 (2003)) Dimethyl 1-diazo-2-oxopropylphosphonate (136 mg) and potassium carbonate (149 mg) obtained by the method described above were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate / hexane). The obtained compound was dissolved in THF (1.5 mL), a TBAF solution in THF (1.0 M, 1.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform) to give the title compound (190 mg) as a colorless oil.
参考例84
　(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-(2,2-ジフルオロエチル)-1H-1,2,3-トリアゾール-5-イル)ブタン-1-オールの合成 Reference Example 84
(S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4- (2,2-difluoroethyl) -1H-1,2, Synthesis of 3-triazol-5-yl) butan-1-ol
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　参考例81で得られた(S)-1-(5-(4-(tert-ブチルジフェニルシリルオキシ)ブチル)-4-(ヒドロキシメチル)-1H-1,2,3-トリアゾール-1-イル)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オール(1.6g)をクロロホルム(30mL)に溶解し、二酸化マンガン(2.0g)を加え90℃で2時間加熱還流した。固体をセライトを用いて濾去し、クロロホルム(100mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をトルエン(10mL×2)で共沸し、得られた残渣(1.4gの内、1.2g)をジクロロメタン(5.0mL)に溶解し、0℃でトリメチルシリルトリフルオロメタンスルホネート(505μL)及び2,6-ルチジン(433μL)を加え、室温で1時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5.0mL)を加え分液した。有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られたトリメチルシリル体(1.1gの内、600mg)をDMF(5.0mL)に溶解し、トリフェニルホスフィン(1.32g)、クロロジフルオロ酢酸ナトリウム(921mg)を加え、100℃で3時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(17%酢酸エチル/ヘキサン)で精製した。得られた化合物を酢酸エチル(3.0mL)に溶解し、10%パラジウム-炭素(1.0g)を加え、水素雰囲気下で1時間撹拌した。固体をセライトを用いて濾去し、酢酸エチル(20mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をトルエン(3mL×3)で共沸した後、THF(1.23mL)に溶解し、TBAFのTHF溶液(1.0M,1.23mL)を加え室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/クロロホルム)で精製することで、標記化合物(190mg)を無色油状物質として得た。 (S) -1- (5- (4- (tert-butyldiphenylsilyloxy) butyl) -4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl obtained in Reference Example 81 ) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butan-2-ol (1.6 g) was dissolved in chloroform (30 mL), manganese dioxide (2.0 g) was added, and the mixture was heated at 90 ° C. for 2 hours. Refluxed. The solid was filtered off using celite, washed with chloroform (100 mL), and the combined filtrate was concentrated under reduced pressure. The residue was azeotroped with toluene (10 mL × 2), and the resulting residue (1.2 g out of 1.4 g) was dissolved in dichloromethane (5.0 mL) and trimethylsilyl trifluoromethanesulfonate (505 μL) and 2,6 -Lutidine (433 μL) was added and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained trimethylsilyl form (1.1 mg of 600 mg) was dissolved in DMF (5.0 mL), triphenylphosphine (1.32 g) and sodium chlorodifluoroacetate (921 mg) were added, and the mixture was stirred at 100 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (17% ethyl acetate / hexane). The obtained compound was dissolved in ethyl acetate (3.0 mL), 10% palladium-carbon (1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere for 1 hr. The solid was filtered off using celite, washed with ethyl acetate (20 mL), and the combined filtrate was concentrated under reduced pressure. The residue was azeotroped with toluene (3 mL × 3), dissolved in THF (1.23 mL), TBAF in THF (1.0 M, 1.23 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (190 mg) as a colorless oil.
参考例85
　(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-ビニル-1H-1,2,3-トリアゾール-5-イル)ブタン-1-オールの合成 Reference Example 85
(S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4-vinyl-1H-1,2,3-triazol-5-yl Synthesis of butan-1-ol
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　参考例81で得られた(S)-1-(5-(4-(tert-ブチルジフェニルシリルオキシ)ブチル)-4-(ヒドロキシメチル)-1H-1,2,3-トリアゾール-1-イル)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オール(1.6g)をクロロホルム(30mL)に溶解し、二酸化マンガン(2.0g)を加え90℃で2時間加熱還流した。固体をセライトを用いて濾去し、クロロホルム(100mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をトルエン(10mL×2)で共沸し、得られたアルデヒド体(1.4gの内、1.2g)をジクロロメタン(5.0mL)に溶解し、0℃でトリメチルシリルトリフルオロメタンスルホネート(505μL)及び2,6-ルチジン(433μL)を加え、1時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5.0mL)を加え分液し、有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。
　メチルトリフェニルホスホニウムブロミド(179mg)をTHF(1.0mL)に懸濁し、0℃でNaHMDSのTHF溶液(1.0M,500μL)を加え、同温度で30分撹拌した。-78℃に冷却し、前反応で得られたトリメチルシリル体(1.1gのうち180mg)を加え、室温で3時間撹拌した。反応液に酢酸(200μL)を加え、減圧濃縮した。残渣を10%酢酸エチル/ヘキサン溶液(10mL)に懸濁し、不溶物を濾過し、10%酢酸エチル/ヘキサン溶液(50mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(17%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(1.0mL)に溶解し、TBAFのTHF溶液(1.0M,1.0mL)を加え室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/クロロホルム)で精製することで、標記化合物(45mg)を無色油状物質として得た。 (S) -1- (5- (4- (tert-butyldiphenylsilyloxy) butyl) -4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl obtained in Reference Example 81 ) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butan-2-ol (1.6 g) was dissolved in chloroform (30 mL), manganese dioxide (2.0 g) was added, and the mixture was heated at 90 ° C. for 2 hours. Refluxed. The solid was filtered off using celite, washed with chloroform (100 mL), and the combined filtrate was concentrated under reduced pressure. The residue was azeotroped with toluene (10 mL × 2), and the obtained aldehyde (1.2 g out of 1.4 g) was dissolved in dichloromethane (5.0 mL), and trimethylsilyl trifluoromethanesulfonate (505 μL) and 2, 6-Lutidine (433 μL) was added and stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution, and the mixture was partitioned. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane).
Methyltriphenylphosphonium bromide (179 mg) was suspended in THF (1.0 mL), a NaHMDS solution in THF (1.0 M, 500 μL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to −78 ° C., the trimethylsilyl compound obtained in the previous reaction (180 mg out of 1.1 g) was added, and the mixture was stirred at room temperature for 3 hours. Acetic acid (200 μL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was suspended in a 10% ethyl acetate / hexane solution (10 mL), the insoluble material was filtered, washed with a 10% ethyl acetate / hexane solution (50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17% ethyl acetate / hexane). The obtained compound was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (45 mg) as a colorless oil.
参考例86
　(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-1-(5-(3-ヒドロキシプロピル)-4-(メトキシメチル)-1H-1,2,3-トリアゾール-1-イル)ブタン-2-オールの合成 Reference Example 86
(S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -1- (5- (3-hydroxypropyl) -4- (methoxymethyl) -1H-1,2,3-triazole- Synthesis of 1-yl) butan-2-ol
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　参考例81で得られた(S)-1-(5-(4-(tert-ブチルジフェニルシリルオキシ)ブチル)-4-(ヒドロキシメチル)-1H-1,2,3-トリアゾール-1-イル)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オール(300mg)をTHF(2.0mL)に溶解し、水素化ナトリウム(55%,40mg)を加え0℃で10分撹拌した。反応液にヨウ化メチル(32μL)を加え室温で1.5時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(50%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(1.0mL)に溶解し、TBAFのTHF溶液(1.0M,1.0mL)を加え室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/クロロホルム)で精製することで、標記化合物(105mg)を無色油状物質として得た。 (S) -1- (5- (4- (tert-butyldiphenylsilyloxy) butyl) -4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl obtained in Reference Example 81 ) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butan-2-ol (300 mg) was dissolved in THF (2.0 mL), and sodium hydride (55%, 40 mg) was added at 0 ° C. Stir for 10 minutes. Methyl iodide (32 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (105 mg) as a colorless oil.
参考例87
　(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-(フルオロメチル)-1H-1,2,3-トリアゾール-5-イル)ブタン-1-オールの合成 Reference Example 87
(S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4- (fluoromethyl) -1H-1,2,3-triazole- Synthesis of 5-yl) butan-1-ol
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　参考例81で得られた(S)-1-(5-(4-(tert-ブチルジフェニルシリルオキシ)ブチル)-4-(ヒドロキシメチル)-1H-1,2,3-トリアゾール-1-イル)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オール(300mg)をジクロロメタン(2.0mL)に溶解し、トリエチルアミン(96μL)及び塩化メタンスルホニル(39μL)を加え、室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5.0mL)を加え分液した。有機層を水(2.0mL)、飽和食塩水(2.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をTHF(1.0mL)に溶解し、TBAFのTHF溶液(1.0M、2.88mL)を加え50℃で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/クロロホルム)で精製することで、標記化合物(100mg)を無色油状物質として得た。 (S) -1- (5- (4- (tert-butyldiphenylsilyloxy) butyl) -4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl obtained in Reference Example 81 ) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butan-2-ol (300 mg) was dissolved in dichloromethane (2.0 mL), triethylamine (96 μL) and methanesulfonyl chloride (39 μL) were added, Stir at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers. The organic layer was washed with water (2.0 mL) and saturated brine (2.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 2.88 mL) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (100 mg) as a colorless oil.
参考例88
　メチル1-(2,2-ビス(4-クロロフェニル)-2-ヒドロキシエチル)-5-(3-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-4-カルボキシレートの合成 Reference Example 88
Synthesis of methyl 1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -5- (3-hydroxypropyl) -1H-1,2,3-triazole-4-carboxylate
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　参考例9で得られたメチル6-(tert-ブチルジメチルシリルオキシ)ヘキス-2-イノエート(427mg)と参考例62で得られた2-アジド-1,1-ビス(4-クロロフェニル)エタノール(466mg)をトルエン(7.0mL)に溶解し、クロロ(ペンタメチルシクロペンタジエニル)(シクロオクタジエン)ルテニウム(II)(57mg)を加え、80℃で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物(650mg)の内、一部(200mg)をTHF(1.0mL)に溶解し、TBAFのTHF溶液(1.0M、1.0mL)を加え、室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/クロロホルム)で精製することで、標記化合物(140mg)を無色油状物質として得た。 Methyl 6- (tert-butyldimethylsilyloxy) hex-2-inoate (427 mg) obtained in Reference Example 9 and 2-azido-1,1-bis (4-chlorophenyl) ethanol obtained in Reference Example 62 ( 466 mg) was dissolved in toluene (7.0 mL), chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II) (57 mg) was added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). A part (200 mg) of the obtained compound (650 mg) was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (140 mg) as a colorless oil.
参考例89
　1-(2,2-ビス(4-クロロフェニル)-2-ヒドロキシエチル)-5-(3-ヒドロキシプロピル)-N,N-ジメチル-1H-1,2,3-トリアゾール-4-カルボキサミドの合成 Reference Example 89
Synthesis of 1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -5- (3-hydroxypropyl) -N, N-dimethyl-1H-1,2,3-triazole-4-carboxamide
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　参考例9で得られたメチル6-(tert-ブチルジメチルシリルオキシ)ヘキス-2-イノエート(427mg)と参考例62で得られた2-アジド-1,1-ビス(4-クロロフェニル)エタノール(466mg)をトルエン(7.0mL)に溶解し、クロロ(ペンタメチルシクロペンタジエニル)(シクロオクタジエン)ルテニウム(II)(57mg)を加え、80℃で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(33%酢酸エチル/ヘキサン)で精製した。得られた化合物(650mg)の内、一部(150mg)をメタノール(600μL)、水(100μL)に懸濁し、水酸化ナトリウム水溶液(4.0M,203μL)を加え、50℃で2時間撹拌した。反応液を放冷後、塩酸(1.0M,1.0mL)を加え酸性にし、酢酸エチル(5.0mL)、水(3.0mL)を加え分液した。水層を酢酸エチル(3.0mL)で抽出した。合一した有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた化合物(130mg)をDMF(2.0mL)に溶解し、EDC・HCl(68mg)、HOBt(42mg)を加え、ジメチルアミン水溶液(50%,43mg)を加え、室温で3時間撹拌した。反応液に水(2.0mL)を加え、酢酸エチル(3.0mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(30%酢酸エチル/ヘキサン)で精製した。得られた化合物(100mg)をTHF(500μL)に溶解し、TBAFのTHF溶液(1.0M,500μL)を加え、1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/クロロホルム)で精製することで、標記化合物(70mg)を無色油状物質として得た。 Methyl 6- (tert-butyldimethylsilyloxy) hex-2-inoate (427 mg) obtained in Reference Example 9 and 2-azido-1,1-bis (4-chlorophenyl) ethanol obtained in Reference Example 62 ( 466 mg) was dissolved in toluene (7.0 mL), chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II) (57 mg) was added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). A part (150 mg) of the obtained compound (650 mg) was suspended in methanol (600 μL) and water (100 μL), an aqueous sodium hydroxide solution (4.0 M, 203 μL) was added, and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was allowed to cool, acidified with hydrochloric acid (1.0 M, 1.0 mL), and separated by adding ethyl acetate (5.0 mL) and water (3.0 mL). The aqueous layer was extracted with ethyl acetate (3.0 mL). The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained compound (130 mg) was dissolved in DMF (2.0 mL), EDC.HCl (68 mg) and HOBt (42 mg) were added, dimethylamine aqueous solution (50%, 43 mg) was added, and the mixture was stirred at room temperature for 3 hours. Water (2.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3.0 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / hexane). The obtained compound (100 mg) was dissolved in THF (500 μL), a THF solution of TBAF (1.0 M, 500 μL) was added, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (70 mg) as a colorless oil.
参考例90
　(S)-1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-(トリメチルシリルオキシ)ブチル)-4-(フルオロメチル)-5-(3-(メトキシメトキシ)プロピル)-1H-1,2,3-トリアゾールの合成 Reference Example 90
(S) -1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2- (trimethylsilyloxy) butyl) -4- (fluoromethyl) -5- (3- (methoxymethoxy) propyl ) -1H-1,2,3-Triazole Synthesis
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
　参考例10で得られたメチル5-(メトキシメトキシ)ペント-2-イノエート(1.53g)と参考例34で得られた(S)-1-アジド-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オール(2.07g)をトルエン(40mL)に溶解し、クロロ(ペンタメチルシクロペンタジエニル)(シクロオクタジエン)ルテニウム(II)(281mg)を加え、80℃で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(50%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(25mL)に溶解し、水素化ホウ素リチウムのTHF溶液(2.0M,8.8mL)を加え80℃で10時間撹拌した。反応液に飽和食塩水(30mL)を0℃で加え分液し、有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2.5%メタノール/クロロホルム)で精製した。得られたジオール体(1.73gの内、400mg)をジクロロメタン(4.0mL)に溶解し、トリエチルアミン(198μL)及び塩化メタンスルホニル(80μL)を加え室温で30分撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5.0mL)を加え分液した。有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をTHF(2.0mL)に溶解し、TBAFのTHF溶液(1.0M,5.0mL)を加え50℃で4時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(50%酢酸エチル/ヘキサン)で精製した。得られた化合物をジクロロメタン(1.2mL)に溶解し、0℃でトリメチルシリルトリフルオロメタンスルホネート(64μL)、2,6-ルチジン(109μL)を加え、1時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(5.0mL)を加え分液した。有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(50%酢酸エチル/ヘキサン)で精製することで、標記化合物(95mg)を無色油状物質として得た。 Methyl 5- (methoxymethoxy) pent-2-inoate (1.53 g) obtained in Reference Example 10 and (S) -1-azido-2- (3- (cyclopropylmethoxy)- 4-Fluorophenyl) butan-2-ol (2.07 g) was dissolved in toluene (40 mL), and chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II) (281 mg) was added at 80 ° C. Stir for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in THF (25 mL), a solution of lithium borohydride in THF (2.0 M, 8.8 mL) was added, and the mixture was stirred at 80 ° C. for 10 hr. To the reaction solution was added saturated brine (30 mL) at 0 ° C., and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2.5% methanol / chloroform). The obtained diol (1.73 g, 400 mg) was dissolved in dichloromethane (4.0 mL), triethylamine (198 μL) and methanesulfonyl chloride (80 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (2.0 mL), TBAF in THF (1.0 M, 5.0 mL) was added, and the mixture was stirred at 50 ° C. for 4 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in dichloromethane (1.2 mL), trimethylsilyl trifluoromethanesulfonate (64 μL) and 2,6-lutidine (109 μL) were added at 0 ° C., and the mixture was stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (95 mg) as a colorless oil.
参考例91
　4-(1-(3-(シクロプロピルメトキシ)フェネチル)-4-メチル-1H-1,2,3-トリアゾール-5-イル)ブタン-1-オール、及び4-(1-(3-(シクロプロピルメトキシ)フェネチル)-5-メチル-1H-1,2,3-トリアゾール-4-イル)ブタン-1-オール（混合物）の合成 Reference Example 91
4- (1- (3- (cyclopropylmethoxy) phenethyl) -4-methyl-1H-1,2,3-triazol-5-yl) butan-1-ol, and 4- (1- (3- ( Synthesis of cyclopropylmethoxy) phenethyl) -5-methyl-1H-1,2,3-triazol-4-yl) butan-1-ol (mixture)
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　文献(J. Chem. Soc., Perkin Trans. 1, 22, 3779-3785(2000))記載の方法で得られたtert-ブチル(ヘキス-5-イニルオキシ)ジメチルシラン(453mg)、参考例14から得られた1-(2-アジドエチル)-3-(シクロプロピルメトキシ)ベンゼン(320mg)をトルエン(10mL)に溶解し、120℃で96時間加熱還流した。反応液を減圧濃縮し、DMF(7.0mL)を加え145℃で48時間加熱還流した。反応液を放冷後、酢酸エチル(20mL)、ヘキサン(20mL)及び水(20mL)を加え分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧乾燥した。残渣をシリカゲルカラムクロマトグラフィー(25%酢酸エチル/ヘキサン)で精製した。得られた位置異性体混合物(279mg)をTHF(1.0mL)に溶解し、TBAFのTHF溶液(1.0M,1.0mL)を加え、50℃で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/酢酸エチル)で精製し、標記化合物(188mg)を無色油状物質として得た。 Tert-butyl (hex-5-ynyloxy) dimethylsilane (453 mg) obtained by the method described in the literature (J.JChem. Soc., Perkin Trans. 1, 22, 3779-3785 (2000)), from Reference Example 14 The obtained 1- (2-azidoethyl) -3- (cyclopropylmethoxy) benzene (320 mg) was dissolved in toluene (10 mL) and heated to reflux at 120 ° C. for 96 hours. The reaction solution was concentrated under reduced pressure, DMF (7.0 mL) was added, and the mixture was heated to reflux at 145 ° C. for 48 hours. The reaction solution was allowed to cool, and ethyl acetate (20 mL), hexane (20 mL) and water (20 mL) were added to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and dried under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate / hexane). The obtained regioisomer mixture (279 mg) was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / ethyl acetate) to give the title compound (188 mg) as a colorless oil.
参考例92
　1-(ブト-3-イニル)-3-(シクロプロピルメトキシ)ベンゼンの合成 Reference Example 92
Synthesis of 1- (but-3-ynyl) -3- (cyclopropylmethoxy) benzene
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　容易に入手可能な3-(ヒドロキシメチル)フェノール(1.0g)をDMF(8.0mL)に溶解し、炭酸カリウム(2.21g)及びブロモメチルシクロプロパン(1.2g)を加え、100℃で5時間撹拌した。反応液を放冷後、水(20mL)を加え、酢酸エチル(20mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(25%酢酸エチル/ヘキサン)で精製した。得られたモノアルコール体をTHF(20mL)に溶解し、四臭化炭素(3.29g)及びトリフェニルホスフィン(2.6g)を加え、室温で2時間撹拌した。反応液を減圧濃縮し、残渣にヘキサン(10mL)、酢酸エチル(1.0mL)を加えた。生じた固体を濾去し、10%酢酸エチル/ヘキサン(30mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。 Easily available 3- (hydroxymethyl) phenol (1.0 g) is dissolved in DMF (8.0 mL), potassium carbonate (2.21 g) and bromomethylcyclopropane (1.2 g) are added, and the mixture is stirred at 100 ° C. for 5 hours. did. The reaction mixture was allowed to cool, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate / hexane). The obtained monoalcohol was dissolved in THF (20 mL), carbon tetrabromide (3.29 g) and triphenylphosphine (2.6 g) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and hexane (10 mL) and ethyl acetate (1.0 mL) were added to the residue. The resulting solid was removed by filtration, washed with 10% ethyl acetate / hexane (30 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
　1-トリメチルシリル-1-プロピン(1.38mL)をTHF(7.0mL)に溶解し、氷冷下、n-ブチルリチウムのヘキサン溶液(2.68M,3.48mL)を滴下し、0℃で3時間撹拌した。前反応で得られたブロモ体のTHF(3.0mL)溶液を反応液に滴下し、室温で10時間撹拌した。反応液に飽和塩化アンモニウム水溶液(20mL)を加え分液した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。得られたトリメチルシリル体をエタノール(4.0mL)に溶解し、水酸化ナトリウム(420mg)を加え、室温で3時間撹拌した。反応液を減圧濃縮し、残渣に水(20mL)を加え、酢酸エチル(20mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(3%酢酸エチル/ヘキサン)で精製することで、標記化合物(660mg)を淡黄色油状物質として得た。 1-Trimethylsilyl-1-propyne (1.38 mL) was dissolved in THF (7.0 mL), and hexane solution of n-butyllithium (2.68M, 3.48 mL) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 3 hours. . A THF (3.0 mL) solution of the bromo compound obtained in the previous reaction was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 10 hours. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). The obtained trimethylsilyl compound was dissolved in ethanol (4.0 mL), sodium hydroxide (420 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% ethyl acetate / hexane) to give the title compound (660 mg) as a pale yellow oil.
参考例93
　1,1-ビス(4-クロロフェニル)ブト-3-イン-1-オールの合成 Reference Example 93
Synthesis of 1,1-bis (4-chlorophenyl) but-3-in-1-ol
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　容易に入手可能なエチル3-クロロプロパノエート(500mg)をTHF(6.0mL)に溶解し、0℃で4-クロロフェニルマグネシウムブロミドのTHF溶液(1.0M,10.98mL)を滴下し、同温度で3時間撹拌した。反応液に0℃で飽和塩化アンモニウム水溶液(10mL)を加え分液した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%酢酸エチル/ヘキサン)で精製した。得られた化合物(890mg)をDMF(10mL)に溶解し、酢酸ナトリウム(900mg)、ヨウ化ナトリウム(549mg)を加え、90℃で12時間撹拌した。反応液に水(20mL)、酢酸エチル(20mL)を加え分液した。有機層を水(10mL)、飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製した。得られた化合物(198mg)をメチルアミンのメタノール溶液(40%,2.0mL)に溶解し、室温で1時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(5%酢酸エチル/ヘキサン)で精製した。得られた化合物(140mg)をジメチルスルホキシド(2.0mL)、トルエン(1.0mL)に溶解し、EDC・HCl(270mg)、ピリジン(38μL)、トリフルオロ酢酸(20μL)を加え、室温で1時間撹拌した。水(5.0mL)、酢酸エチル(5.0mL)を加え分液した。有機層を水(5.0mL)、飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をメタノール(2.0mL)に溶解し、文献(Eur. J. Org. Chem., 5, 821-832(2003))記載の方法で得られたジメチル1-ジアゾ-2-オキソプロピルホスホネート(108mg)及び炭酸カリウム(130mg)を加え、室温で3時間撹拌した。反応液を減圧濃縮した後、残渣に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%酢酸エチル/ヘキサン)で精製することで、標記化合物(80mg)を淡黄色油状物質として得た。 Easily available ethyl 3-chloropropanoate (500 mg) is dissolved in THF (6.0 mL), and 4-chlorophenylmagnesium bromide in THF (1.0 M, 10.98 mL) is added dropwise at 0 ° C. at the same temperature. Stir for 3 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution at 0 ° C., and the phases were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane). The obtained compound (890 mg) was dissolved in DMF (10 mL), sodium acetate (900 mg) and sodium iodide (549 mg) were added, and the mixture was stirred at 90 ° C. for 12 hours. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution and the phases were separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane). The obtained compound (198 mg) was dissolved in a methanol solution of methylamine (40%, 2.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane). The obtained compound (140 mg) was dissolved in dimethyl sulfoxide (2.0 mL) and toluene (1.0 mL), EDC / HCl (270 mg), pyridine (38 μL), trifluoroacetic acid (20 μL) were added, and the mixture was stirred at room temperature for 1 hour. did. Water (5.0 mL) and ethyl acetate (5.0 mL) were added for liquid separation. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (2.0 mL), and dimethyl 1-diazo-2-oxopropylphosphonate (108 mg) obtained by the method described in the literature (Eur. J. Org. Chem., 5, 821-832 (2003)). ) And potassium carbonate (130 mg) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane) to give the title compound (80 mg) as a pale yellow oil.
参考例94
　1-(4-アジドブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Reference Example 94
Synthesis of 1- (4-azidobutyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　文献(J. Med. Chem., 49, 4183-4195(2006))記載の方法で得られた1-(4-ヒドロキシブチル)ピリミジン-2,4(1H,3H)-ジオン(2.1g)をピリジン(50mL)に溶解し、塩化メタンスルホニル(900μL)を加え、室温で30分撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(5%メタノール/クロロホルム)で精製した。得られた化合物をDMF(50mL)に溶解した。アジ化ナトリウム(1.57g)を加え、50℃で10時間撹拌した。反応液に水(50mL)を加え、酢酸エチル(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2.5%メタノール/クロロホルム)で精製することで、標記化合物(1.43g)を無色油状物質として得た。 1- (4-hydroxybutyl) pyrimidine-2,4 (1H, 3H) -dione (2.1 g) obtained by the method described in the literature (J. Med. Chem., 49, 3 4183-4195 (2006)) Dissolved in pyridine (50 mL), methanesulfonyl chloride (900 μL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / chloroform). The obtained compound was dissolved in DMF (50 mL). Sodium azide (1.57 g) was added and stirred at 50 ° C. for 10 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to obtain the title compound (1.43 g) as a colorless oily substance.
参考例95
　1-(3-アジドプロピル)ピリミジン-2,4(1H,3H)-ジオンの合成 Reference Example 95
Synthesis of 1- (3-azidopropyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　文献(J. Med. Chem., 49, 4183-4195(2006))記載の方法で得られた1-(4-ヒドロキシプロピル)ピリミジン-2,4(1H,3H)-ジオン(2.0g)から参考例94の方法に準じて合成することで、標記化合物(1.21g)を淡黄色油状物質として得た。 From 1- (4-hydroxypropyl) pyrimidine-2,4 (1H, 3H) -dione (2.0 g) obtained by the method described in the literature (J. Med. Chem., 49, 4183-4195 (2006)) The title compound (1.21 g) was obtained as a pale yellow oil by synthesis according to the method of Reference Example 94.
参考例96
　N-(2-((3-ベンゾイル-2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)エチル)-3-(3-(シクロプロピルメトキシ)フェニル)プロパンアミドの合成 Reference Example 96
N- (2-((3-benzoyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) ethyl) -3- (3- (cyclopropylmethoxy) phenyl) propanamide Synthesis of
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　容易に入手可能な3-ヒドロキシベンズアルデヒド(1.0g)をDMF(8.0mL)に溶解し、クロロメチルシクロプロパン(794μL)、炭酸カリウム(2.26g)及びヨウ化ナトリウム(123mg)を加え、90℃で6時間撹拌した。反応液を放冷後、水(50mL)を加え、トルエン(50mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製した。
　水素化ナトリウム(55%inoil、220mg)をTHF(3.0mL)に懸濁し、氷冷下、トリエチルホスホノアセテート(991μL)を滴下し、0℃で1時間撹拌した。前反応で得られたアルデヒド体(1.1gの内、870mg)のTHF(3.0mL)溶液を0℃で滴下し、室温で3時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(20mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。得られた化合物をメタノール(20mL)に溶解し、10%パラジウム-炭素(2.0g)を加え、水素雰囲気下室温で2時間撹拌した。不溶物を濾去し、メタノール(50mL)で洗浄後、合一した濾液を減圧濃縮した。残渣をエタノール(1.6mL)、水(1.6mL)に溶解し、水酸化ナトリウム水溶液(4.0M,3.2mL)を加え、50℃で2時間撹拌した。塩酸(2.0M,10mL)で酸性にし、反応液を減圧濃縮した。残渣に水(20mL)を加え、酢酸エチル(20mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られたカルボン酸(285mg)をDMF(7.0mL)に溶解し、EDC・HCl(370mg)、HOBt(209mg)及び文献(J. Heterocyclic Chem. 18, 947-951(1981))記載の方法で得られた1-((2-アミノエトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン(240mg)を加え、室温で10時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2.5%メタノール/クロロホルム)で精製した。得られた化合物をジクロロメタン(3.0mL)に溶解し、N,N-ジイソプロピルエチルアミン(595μL)、塩化ベンゾイル(244μL)を加え室温で2時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(10mL)を加え、クロロホルム(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(1.5%メタノール/クロロホルム)で精製することで、標記化合物(350mg)を無色油状物質として得た。 Easily available 3-hydroxybenzaldehyde (1.0 g) is dissolved in DMF (8.0 mL), chloromethylcyclopropane (794 μL), potassium carbonate (2.26 g) and sodium iodide (123 mg) are added, at 90 ° C. Stir for 6 hours. The reaction mixture was allowed to cool, water (50 mL) was added, and the mixture was extracted with toluene (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10% ethyl acetate / hexane).
Sodium hydride (55% inoil, 220 mg) was suspended in THF (3.0 mL), and triethylphosphonoacetate (991 μL) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 1 hour. A solution of the aldehyde obtained in the previous reaction (1.1 mg, 870 mg) in THF (3.0 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). The obtained compound was dissolved in methanol (20 mL), 10% palladium-carbon (2.0 g) was added, and the mixture was stirred at room temperature for 2 hr in a hydrogen atmosphere. The insoluble material was removed by filtration, washed with methanol (50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (1.6 mL) and water (1.6 mL), aqueous sodium hydroxide solution (4.0 M, 3.2 mL) was added, and the mixture was stirred at 50 ° C. for 2 hr. The mixture was acidified with hydrochloric acid (2.0 M, 10 mL), and the reaction mixture was concentrated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained carboxylic acid (285 mg) was dissolved in DMF (7.0 mL), and EDC-HCl (370 mg), HOBt (209 mg) and literature (J. Heterocyclic Chem. 18, 947-951 (1981)) were used. The obtained 1-((2-aminoethoxy) methyl) pyrimidine-2,4 (1H, 3H) -dione (240 mg) was added and stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform). The obtained compound was dissolved in dichloromethane (3.0 mL), N, N-diisopropylethylamine (595 μL) and benzoyl chloride (244 μL) were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1.5% methanol / chloroform) to obtain the title compound (350 mg) as a colorless oily substance.
参考例97
　(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-(トリメチルシリルオキシ)ブタン-1-オールの合成 Reference Example 97
Synthesis of (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2- (trimethylsilyloxy) butan-1-ol
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　参考例33で得られた(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-1,2-ジオール(129mg)をジクロロメタン(1.5mL)に溶解し、2,6-ルチジン(291μL)及びトリメチルシリルトリフルオロメタンスルホネート(300μL)を加え、室温で1時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(20mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(1.5mL)、水(300μL)に溶解し、酢酸(300μL)を加え、室温で3.5時間撹拌した。飽和炭酸水素ナトリウム水溶液(5.0mL)で中和し、酢酸エチル(10mL)で抽出した。有機層を飽和食塩水(5.0mL)で洗浄し、無水硫酸マグネシウムで乾燥した。残渣をシリカゲルカラムクロマトグラフィー(2.5%酢酸エチル/ヘキサン)で精製することで、標記化合物(96mg)を無色油状物質として得た。 (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butane-1,2-diol (129 mg) obtained in Reference Example 33 was dissolved in dichloromethane (1.5 mL), and 2,6 -Lutidine (291 μL) and trimethylsilyl trifluoromethanesulfonate (300 μL) were added and stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). The obtained compound was dissolved in THF (1.5 mL) and water (300 μL), acetic acid (300 μL) was added, and the mixture was stirred at room temperature for 3.5 hours. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution (5.0 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (5.0 mL) and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (2.5% ethyl acetate / hexane) to give the title compound (96 mg) as a colorless oil.
参考例98
　(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-（トリメチルシリルオキシ）ブチルメタンスルホネートの合成 Reference Example 98
Synthesis of (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2- (trimethylsilyloxy) butylmethanesulfonate
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　参考例97で得られた(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-(トリメチルシリルオキシ)ブタン-1-オール（327mg）をジクロロメタン（4.0mL）に溶解し、0℃でトリエチルアミン(181μL)及び塩化メタンスルホニル（85μL）を加え室温で30分撹拌した。反応液に水（10mL）を加え、酢酸エチル（15mL）で抽出した。有機層を飽和食塩水（10mL）で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮することで、標記化合物（405mg）を無色油状物質として得た。 Dissolve (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2- (trimethylsilyloxy) butan-1-ol (327 mg) obtained in Reference Example 97 in dichloromethane (4.0 mL) Then, triethylamine (181 μL) and methanesulfonyl chloride (85 μL) were added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (405 mg) as a colorless oil.
参考例99
　(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-1H-ピロール2-イル)ブタン-1-オールの合成 Reference Example 99
Synthesis of (S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -1H-pyrrol-2-yl) butan-1-ol
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　塩化メチルマグネシウムのTHF溶液（3.0M,6.67mL）をトルエン（20mL）に溶解し、0℃でピロール（1.66g）をゆっくり滴下し50℃で1時間撹拌した。反応液にγ-ブチロラクトン（0.762mL）のトルエン（20mL）溶液を加え105℃で1.5時間撹拌した。反応液を放冷後、飽和塩化アンモニウム水（50mL）を加え、THF（150mL）で抽出した。有機層を飽和食塩水（30mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（3%メタノール/クロロホルム）で精製した。得られた濃紫色油状物質（1.10g）をトルエン（5.0mL×3）で共沸した。 A THF solution (3.0 M, 6.67 mL) of methylmagnesium chloride was dissolved in toluene (20 mL), pyrrole (1.66 g) was slowly added dropwise at 0 ° C., and the mixture was stirred at 50 ° C. for 1 hour. To the reaction solution, a solution of γ-butyrolactone (0.762 mL) in toluene (20 mL) was added and stirred at 105 ° C. for 1.5 hours. The reaction mixture was allowed to cool, saturated aqueous ammonium chloride (50 mL) was added, and the mixture was extracted with THF (150 mL). The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol / chloroform). The obtained dark purple oily substance (1.10 g) was azeotroped with toluene (5.0 mL × 3).
　塩化アルミニウム（2.87g）をジクロロメタン（100mL）に懸濁し、0℃でボラン-tert-ブチルアミン複合体（3.75g）をゆっくり加え0℃で20分撹拌した。反応液に0℃でトルエン共沸した濃紫色油状物質（1.10g）のジクロロメタン（5.0mL）溶液を滴下し、0℃で1.5時間撹拌した。反応液に0℃で水（10mL）をゆっくり滴下し、室温で希塩酸水（30mL）を加え、ガスの発生が終わるまで（30分）室温で撹拌した。THF（100mL×3）で抽出し、有機層を飽和食塩水（50mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（2%メタノール/クロロホルム）で精製した。 Aluminum chloride (2.87 g) was suspended in dichloromethane (100 mL), borane-tert-butylamine complex (3.75 g) was slowly added at 0 ° C., and the mixture was stirred at 0 ° C. for 20 minutes. To the reaction solution was added dropwise a solution of dark purple oily substance (1.10 g) azeotroped with toluene at 0 ° C. in dichloromethane (5.0 mL) and stirred at 0 ° C. for 1.5 hours. Water (10 mL) was slowly added dropwise to the reaction solution at 0 ° C., dilute aqueous hydrochloric acid (30 mL) was added at room temperature, and the mixture was stirred at room temperature until gas evolution ceased (30 minutes). The mixture was extracted with THF (100 mL × 3), and the organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% methanol / chloroform).
　得られた淡黄色油状物質（345mg）をDMF（6.0mL）に溶解し、イミダゾール（371mg）及びtert-ブチルジメチルシリルクロリド（411mg）を加え室温で1時間撹拌した。反応液に水（10mL）を加え、酢酸エチル（15mL）で抽出した。有機層を水（10mL）、飽和食塩水（10mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（15%酢酸エチル/ヘキサン）で精製した。得られた淡黄色油状物質（577mgの内、253mg）をトルエン（5.0mL×3）で共沸した後、DMF（4.0mL）に溶解し、0℃で水素化ナトリウム（55%,52mg）を加え50℃で30分撹拌した。反応液に参考例98で得られた(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-（トリメチルシリルオキシ）ブチルメタンスルホネート（405mg）のDMF（3.0mL）を0℃で加え、室温で12時間撹拌した。反応液に飽和塩化アンモニウム水（4.0mL）を加え、50%酢酸エチル/ヘキサン（10mL）で抽出した。有機層を水（5.0mL）、飽和食塩水（5.0mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（10%酢酸エチル/ヘキサン）で精製した。 The obtained pale yellow oily substance (345 mg) was dissolved in DMF (6.0 mL), imidazole (371 mg) and tert-butyldimethylsilyl chloride (411 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / hexane). The obtained pale yellow oily substance (253 mg of 577 mg) was azeotroped with toluene (5.0 mL × 3), dissolved in DMF (4.0 mL), and sodium hydride (55%, 52 mg) was added at 0 ° C. The mixture was further stirred at 50 ° C. for 30 minutes. DMF (3.0 mL) of (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2- (trimethylsilyloxy) butylmethanesulfonate (405 mg) obtained in Reference Example 98 was added to the reaction solution. It added at 0 degreeC and stirred at room temperature for 12 hours. Saturated aqueous ammonium chloride (4.0 mL) was added to the reaction mixture, and the mixture was extracted with 50% ethyl acetate / hexane (10 mL). The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane).
　得られた橙色油状物質（153mg）をTHF（1.0mL）に溶解し、TBAFのTHF溶液（1.0M,0.465mL）を加え室温で30分、50℃で30分撹拌した。反応液を減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（50%酢酸エチル/ヘキサン）で精製することで、標記化合物（110mg）を淡黄色油状物質として得た。 The obtained orange oily substance (153 mg) was dissolved in THF (1.0 mL), a THF solution of TBAF (1.0 M, 0.465 mL) was added, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (110 mg) as a pale yellow oil.
参考例100
　(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-3-メチル-1H-1,2,4-トリアゾール-5-イル)ブタン-1-オールの合成 Reference Example 100
(S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -3-methyl-1H-1,2,4-triazol-5-yl Synthesis of butan-1-ol
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　文献(SynLett, 20, 3160-3162(2005))記載の方法で得られた5-(tert-ブチルジフェニルシリルオキシ)ペンタンニトリル(3.0g)、アセトヒドラジド(222mg)、炭酸カリウム(207mg)をn-ブタノール(6.0mL)に溶解し、スチール封管中、150℃で3時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(3%メタノール/クロロホルム)で精製した。得られた化合物をDMF(4.0mL)に溶解し、水素化ナトリウム(55%inoil、110mg)を0℃で加え、室温で1時間撹拌した。反応液に参考例98で得られた(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-（トリメチルシリルオキシ）ブチルメタンスルホネート(500mg)を加え、60℃で4時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(25%酢酸エチル/ヘキサン)で精製した。得られた化合物をTHF(1.0mL)に溶解し、TBAFのTHF溶液(1.0M,1.0mL)を加え、室温で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(3%メタノール/クロロホルム)で精製することで、標記化合物(120mg)を無色油状物質として得た。 5- (tert-butyldiphenylsilyloxy) pentanenitrile (3.0 g), acetohydrazide (222 mg), potassium carbonate (207 mg) obtained by the method described in the literature (SynLett, 20, 3160-3162 (2005)) -Dissolved in butanol (6.0 mL) and stirred in a steel sealed tube at 150 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform). The obtained compound was dissolved in DMF (4.0 mL), sodium hydride (55% inoil, 110 mg) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hr. (S) -2- (3- (Cyclopropylmethoxy) -4-fluorophenyl) -2- (trimethylsilyloxy) butylmethanesulfonate (500 mg) obtained in Reference Example 98 was added to the reaction solution, and the mixture was heated at 60 ° C. for 4 hours. Stir for hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate / hexane). The obtained compound was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform) to give the title compound (120 mg) as a colorless oil.
参考例101
　8-(tert-ブチルジフェニルシリルオキシ)オクト-3-イン-2-オンの合成 Reference Example 101
Synthesis of 8- (tert-butyldiphenylsilyloxy) oct-3-in-2-one
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　文献(Tetrahedron, 61(5), 1127-1140(2005))記載の方法で得られたtert-ブチル(ヘキス-5-イニルオキシ)ジフェニルシラン(1.5g)をTHF(20mL)に溶解し、-78℃でn-ブチルリチウムのヘキサン溶液(2.77M,1.69mL)を滴下し、-78℃で10分撹拌した。N-メトキシ-N-メチルアセトアミド(478μL)を加え、室温で2時間撹拌した。反応液に飽和塩化アンモニウム水溶液(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(2%酢酸エチル/ヘキサン)で精製することで、標記化合物(1.52g)を無色油状物質として得た。 Tert-butyl (hex-5-ynyloxy) diphenylsilane (1.5 g) obtained by the method described in the literature (Tetrahedron, 61 (5), 1127-1140 (2005)) was dissolved in THF (20 mL), and -78 A hexane solution of n-butyllithium (2.77 M, 1.69 mL) was added dropwise at ° C and the mixture was stirred at -78 ° C for 10 minutes. N-methoxy-N-methylacetamide (478 μL) was added and stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (10 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane) to give the title compound (1.52 g) as a colorless oil.
参考例102
　(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-3-メチル-1H-ピラゾール-5-イル)ブタン-1-オールの合成 Reference Example 102
(S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -3-methyl-1H-pyrazol-5-yl) butan-1-ol Synthesis of
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　参考例97で得られた(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-(トリメチルシリルオキシ)ブタン-1-オール(300mg)をトルエン(2.1mL)、DMSO(2.4mL)に溶解し、EDC・HCl(520mg)、ピリジン(65μL)及びトリフルオロ酢酸(30μL)を加え室温で1時間撹拌した。反応液に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮後、トルエン(5.0mL×3)で共沸した。残渣をメタノール(2.4mL)に溶解し、0℃でtert-ブチルカーバゼート(250mg)のメタノール(2.4mL)溶液を加え、室温で2時間撹拌した。反応液に酢酸(60μL)、水素化ホウ素シアノナトリウム(300mg)を加え、室温で1時間、50℃で1時間撹拌した。反応液を減圧濃縮し、残渣に水(10mL)を加え、酢酸エチル(10mL)で抽出した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(10%酢酸エチル/ヘキサン)で精製した。得られた化合物を塩化水素-ジオキサン溶液(4.0M,3.0mL)に溶解し、室温で1時間撹拌した。反応液を減圧濃縮し、トルエン(2.0mL×3)で共沸した。エタノール(2.0mL)に溶解し、参考例101で得られた8-(tert-ブチルジフェニルシリルオキシ)オクト-3-イン-2-オン(203mg)、トリエチルアミン(68μL)及び酢酸(84μL)を加え、90℃で3時間加熱還流した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(16%酢酸エチル/ヘキサン)で精製した。 (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2- (trimethylsilyloxy) butan-1-ol (300 mg) obtained in Reference Example 97 was added to toluene (2.1 mL), DMSO (2.4 mL), EDC.HCl (520 mg), pyridine (65 μL) and trifluoroacetic acid (30 μL) were added, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and azeotroped with toluene (5.0 mL × 3). The residue was dissolved in methanol (2.4 mL), a solution of tert-butylcarbazate (250 mg) in methanol (2.4 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hr. Acetic acid (60 μL) and sodium cyanoborohydride (300 mg) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and at 50 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10% ethyl acetate / hexane). The obtained compound was dissolved in a hydrogen chloride-dioxane solution (4.0 M, 3.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and azeotroped with toluene (2.0 mL × 3). Dissolve in ethanol (2.0 mL) and add 8- (tert-butyldiphenylsilyloxy) oct-3-in-2-one (203 mg), triethylamine (68 μL) and acetic acid (84 μL) obtained in Reference Example 101. The mixture was heated to reflux at 90 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (16% ethyl acetate / hexane).
　得られた化合物をTHF(1.0mL)に溶解し、TBAFのTHF溶液(1.0M,1.0mL)を加え、室温で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2.5%メタノール/クロロホルム)で精製することで、標記化合物(71mg)を無色油状物質として得た。 The obtained compound was dissolved in THF (1.0 mL), a TBAF solution in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to give the title compound (71 mg) as a colorless oil.
参考例103
　tert-ブチル4-(2,2-ビス(4-クロロフェニル)エチル)-3-(3-ヒドロキシプロピル)-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾール-1-カルボキシレートの合成 Reference Example 103
tert-butyl 4- (2,2-bis (4-chlorophenyl) ethyl) -3- (3-hydroxypropyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazole-1- Carboxylate synthesis
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　文献（J. Am. Chem. Soc., 105, 3183-3188(1983)）記載の方法で得られた2,2-ビス4-クロロフェニル)エタンアミン（320mg）をトルエン（6.5mL）に溶解し、トリエチルアミン(335μL)を加え0℃に冷却した。反応液にトリホスゲン(132mg)を加え、0℃で1.5時間撹拌した。生じた析出物を濾去し、トルエン(10mL×5)で洗浄後、合一した濾液を減圧濃縮した。残渣をトルエン(6.0mL)に溶解した。 2,2-bis4-chlorophenyl) ethanamine (320 mg) obtained by the method described in the literature (J. Am. Chem. Soc., 105, 3183-3188 (1983)) was dissolved in toluene (6.5 mL), Triethylamine (335 μL) was added and cooled to 0 ° C. Triphosgene (132 mg) was added to the reaction mixture, followed by stirring at 0 ° C. for 1.5 hours. The resulting precipitate was filtered off, washed with toluene (10 mL × 5), and the combined filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (6.0 mL).
　容易に入手可能な4-ヒドロキシブタンヒドラジド(709mg)をDMF(20mL)に溶解し、イミダゾール(817mg)及びtert-ブチルジフェニルシリルクロリド（1.7mL）を加え室温で2時間撹拌した。反応液に飽和炭酸ナトリウム水溶液（60mL）を加え、酢酸エチル（100mL）で抽出した。有機層を水（100mL×2）及び飽和食塩水（100mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（70%酢酸エチル/ヘキサン）で精製した。得られた化合物(1.29g)の内、一部(513mg)をアセトニトリル(6.5mL)に溶解し、トリエチルアミン(251μL)及び前記残渣のトルエン溶液を加え、50℃で3時間撹拌した。反応液に水(20mL)を加え、酢酸エチル(20mL)で抽出した。有機層を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（60%酢酸エチル/ヘキサン）で精製した。得られた化合物(179mg)をジオキサン(2.5mL)に溶解し、水酸化ナトリウム水溶液(4.0M,2.5mL)を加え、100℃で5時間加熱還流した。反応液を放冷後、塩酸(6.0M,1.7mL)で中和し、酢酸エチル(15mL×2)で抽出した。有機層を飽和食塩水(10mL)で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（5%メタノール/クロロホルム）で精製した。得られた化合物(92mg)をDMF(500μL)に溶解し、イミダゾール(32mg)及びtert-ブチルジフェニルシリルクロリド（66μL）を加え室温で1.5時間撹拌した。反応液に水(5.0mL)を加え、酢酸エチル(10mL)で抽出した。有機層を水(5.0mL×2)及び飽和食塩水(5.0mL)で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（60%酢酸エチル/ヘキサン）で精製した。得られた化合物(120mg)をジクロロメタン(2.0mL)に溶解し、トリエチルアミン(53μL),N,N-ジメチルアミノ-4-ピリジン(4.6mg)及び二炭酸-ジ-tert-ブチル（62mg）を加え室温で14時間撹拌した。反応液を減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（20%酢酸エチル/ヘキサン）で精製した。得られた化合物(131mg)をTHF(1.0mL)に溶解し、TBAFのTHF溶液（1.0M,270μL）を加え50℃で1.5時間撹拌した。反応液を減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（2%メタノール/クロロホルム）で精製することで、標記化合物(77mg)を泡状物質として得た。 Easily available 4-hydroxybutane hydrazide (709 mg) was dissolved in DMF (20 mL), imidazole (817 mg) and tert-butyldiphenylsilyl chloride (1.7 mL) were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium carbonate solution (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (70% ethyl acetate / hexane). A part (513 mg) of the obtained compound (1.29 g) was dissolved in acetonitrile (6.5 mL), triethylamine (251 μL) and a toluene solution of the residue were added, and the mixture was stirred at 50 ° C. for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% ethyl acetate / hexane). The obtained compound (179 mg) was dissolved in dioxane (2.5 mL), an aqueous sodium hydroxide solution (4.0 M, 2.5 mL) was added, and the mixture was heated to reflux at 100 ° C. for 5 hr. The reaction mixture was allowed to cool, neutralized with hydrochloric acid (6.0 M, 1.7 mL), and extracted with ethyl acetate (15 mL × 2). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol / chloroform). The obtained compound (92 mg) was dissolved in DMF (500 μL), imidazole (32 mg) and tert-butyldiphenylsilyl chloride (66 μL) were added, and the mixture was stirred at room temperature for 1.5 hours. Water (5.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with water (5.0 mL × 2) and saturated brine (5.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% ethyl acetate / hexane). The obtained compound (120 mg) was dissolved in dichloromethane (2.0 mL), and triethylamine (53 μL), N, N-dimethylamino-4-pyridine (4.6 mg) and di-tert-butyl dicarbonate (62 mg) were added. Stir at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate / hexane). The obtained compound (131 mg) was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 270 μL) was added, and the mixture was stirred at 50 ° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (77 mg) as a foam.
参考例104
　1-((2-(2-アジドエチル)ベンジルオキシ)メチル)ピリミジン-2,4-(1H,3H)-ジオンの合成 Reference Example 104
Synthesis of 1-((2- (2-azidoethyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　文献（J. Org. Chem., 52, 1027-1035(1987)）記載の方法で得られた2-(2-(ヒドロキシメチル)フェニル)エタノール（11.5g）をピリジン（300mL）に溶解し、tert-ブチルジフェニルシリルクロリド（20.3mL）を加え室温で2時間撹拌した。反応液にメタノール（20mL）を加え減圧濃縮した後、残渣に水（200mL）を加え、酢酸エチル（200mL）で抽出した。有機層を水（150mL）、飽和食塩水（150mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をトルエン（30mL×3）で共沸した後、ジクロロメタン（250mL）に溶解し、N,N-ジイソプロピルエチルアミン（31.6mL）及びクロロメチルメチルエーテル（6.89mL）を加え室温で12時間撹拌した。反応液にメタノール（20mL）を加え減圧濃縮した後、残渣に水（150mL）を加え、酢酸エチル（200mL）で抽出した。有機層を水（150mL）、飽和食塩水（150mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（5%酢酸エチル/ヘキサン）で精製した。得られた無色油状物質（14.6g）をジクロロメタン（300mL）に溶解し、0℃でBCl3のジクロロメタン溶液（1.0M,11.2mL）をゆっくり加え室温で2時間撹拌した。反応液を減圧濃縮した後、残渣をDCE（300mL）に溶解し、文献（Nucleosides & Nucleotides, 4, 565-585(1985)）記載の方法で得られた2,4-ビス(トリメチルシリルオキシ)ピリミジン（10.3g）及びヨウ素（886mg）を加え93℃で1.5時間加熱還流した。反応液を放冷後、飽和亜硫酸ナトリウム水溶液（100mL）及び水（500mL）を加え、酢酸エチル(600mL)で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（1%メタノール/クロロホルム）で精製した。 2- (2- (hydroxymethyl) phenyl) ethanol (11.5 g) obtained by the method described in the literature (J. Org. Chem., 52, 1027-1035 (1987)) was dissolved in pyridine (300 mL), tert-Butyldiphenylsilyl chloride (20.3 mL) was added and stirred at room temperature for 2 hours. Methanol (20 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water (200 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (150 mL) and saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene (30 mL × 3), dissolved in dichloromethane (250 mL), N, N-diisopropylethylamine (31.6 mL) and chloromethyl methyl ether (6.89 mL) were added, and the mixture was stirred at room temperature for 12 hours. Methanol (20 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water (150 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (150 mL) and saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane). The obtained colorless oil (14.6 g) was dissolved in dichloromethane (300 mL), and a solution of BCl 3 in dichloromethane (1.0 M, 11.2 mL) was slowly added at 0 ° C., followed by stirring at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in DCE (300 mL), and 2,4-bis (trimethylsilyloxy) pyrimidine obtained by the method described in the literature (Nucleosides & Nucleotides, 4, 565-585 (1985)) (10.3 g) and iodine (886 mg) were added, and the mixture was heated to reflux at 93 ° C. for 1.5 hours. The reaction mixture was allowed to cool, saturated aqueous sodium sulfite solution (100 mL) and water (500 mL) were added, and the mixture was extracted with ethyl acetate (600 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol / chloroform).
　得られた無色泡状物質（7.47g）をTHF（100mL）に溶解し、TBAFのTHF溶液（1.0M,15.2mL）を加え室温で1時間撹拌した。反応液を減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（5%メタノール/クロロホルム）で精製した。 The obtained colorless foam (7.47 g) was dissolved in THF (100 mL), a THF solution of TBAF (1.0 M, 15.2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / chloroform).
　得られた白色固体（3.93g）をピリジン（70mL）に溶解し、塩化メタンスルホニル（1.20mL）を加え室温で1時間撹拌した。反応液にメタノール（5.0mL）を加え減圧濃縮した後、残渣に水（50mL）を加え、酢酸エチル（100mL）で抽出した。有機層を飽和食塩水（50mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（4%メタノール/クロロホルム）で精製した。得られた無色泡状物質（3.90g）をDMF（60mL）に溶解し、アジ化ナトリウム（1.07g）を加え70℃で2時間撹拌した。反応液に水（100mL）を加え、酢酸エチル（100mL）で抽出した。有機層を水（100mL×2）、飽和食塩水（100mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮することで、標記化合物（3.28g）を無色油状物質として得た。 The obtained white solid (3.93 g) was dissolved in pyridine (70 mL), methanesulfonyl chloride (1.20 mL) was added, and the mixture was stirred at room temperature for 1 hour. Methanol (5.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (4% methanol / chloroform). The obtained colorless foam (3.90 g) was dissolved in DMF (60 mL), sodium azide (1.07 g) was added, and the mixture was stirred at 70 ° C. for 2 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (3.28 g) as a colorless oil.
参考例105
　1-((2-(2-アジドエチル)ベンジルチオ)メチル)ピリミジン-2,4-(1H,3H)-ジオンの合成 Reference Example 105
Synthesis of 1-((2- (2-azidoethyl) benzylthio) methyl) pyrimidine-2,4- (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　文献（J. Org. Chem., 52, 1027-1035(1987)）記載の方法で得られた2-(2-(ヒドロキシメチル)フェニル)エタノール（1.62g）をピリジン（30mL）に溶解し、tert-ブチルジフェニルシリルクロリド（2.77mL）を加え室温で2時間撹拌した。反応液にメタノール（5.0mL）を加え減圧濃縮した後、残渣に水（50mL）を加え、酢酸エチル（50mL）で抽出した。有機層を水（50mL）、飽和食塩水（50mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（20%酢酸エチル/ヘキサン）で精製した。得られた無色ガム状物質（1.86g）をTHF（20mL）に溶解し、トリフェニルホスフィン（1.87g）及び四臭化炭素（2.36g）を加え室温で30分撹拌した。反応液に生じた不溶物を濾過し、酢酸エチル（50mL×3）で洗浄した後、合一した濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（5%酢酸エチル/ヘキサン）で精製した。 2- (2- (hydroxymethyl) phenyl) ethanol (1.62 g) obtained by the method described in the literature (J. Org. Chem., 52, 1027-1035 (1987)) was dissolved in pyridine (30 mL), tert-Butyldiphenylsilyl chloride (2.77 mL) was added and stirred at room temperature for 2 hours. Methanol (5.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane). The obtained colorless gum (1.86 g) was dissolved in THF (20 mL), triphenylphosphine (1.87 g) and carbon tetrabromide (2.36 g) were added, and the mixture was stirred at room temperature for 30 min. Insoluble matter generated in the reaction solution was filtered and washed with ethyl acetate (50 mL × 3), and then the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
　得られた淡黄色ガム状物質（2.27g）をDMF（20mL）に溶解し、炭酸カリウム（2.0g）、チオ酢酸（680μL）を加え室温で30分撹拌した。反応液に水（50mL）を加え、酢酸エチル（50mL）で抽出した。有機層を水（50mLx3）、飽和食塩水（50mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をメタノール（12mL）、THF（3.0mL）に溶解し、ナトリウムメトキシド（443mg）を加え室温で30分撹拌した。反応液を減圧濃縮した後、飽和塩化アンモニウム水溶液（20mL）を加え、酢酸エチル（30mL）で抽出した。有機層を飽和食塩水（20mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をジクロロメタン（12mL）に溶解し、N,N-ジイソプロピルエチルアミン（2.14mL）及びクロロメチルメチルエーテル（780μL）を加え室温で5時間撹拌した。反応液に水（20mL）を加え、酢酸エチル（30mL）で抽出した。有機層を水（15mL）、飽和食塩水（15mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（5%酢酸エチル/ヘキサン）で精製した。 The obtained pale yellow gum (2.27 g) was dissolved in DMF (20 mL), potassium carbonate (2.0 g) and thioacetic acid (680 μL) were added, and the mixture was stirred at room temperature for 30 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (12 mL) and THF (3.0 mL), sodium methoxide (443 mg) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (12 mL), N, N-diisopropylethylamine (2.14 mL) and chloromethyl methyl ether (780 μL) were added, and the mixture was stirred at room temperature for 5 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
　得られた無色油状物質（745mg）をジクロロメタン（1.6mL）に溶解し、0℃でBCl3のジクロロメタン溶液（1.0M,550μL）をゆっくり加え室温で1.5時間撹拌した。反応液を減圧濃縮した後、残渣をDCE（16mL）に溶解し、文献（Nucleosides & Nucleotides, 4, 565-585(1985)）記載の方法で得られた2,4-ビス(トリメチルシリルオキシ)ピリミジン（635mg）及びヨウ素（16mg）を加え93℃で48時間加熱還流した。反応液を放冷後、飽和亜硫酸ナトリウム水溶液（10mL）及び水（50mL）を加え、酢酸エチル(60mL)で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（70%酢酸エチル/ヘキサン）で精製した。得られた淡黄色ガム状物質（381mg）をTHF（4.0mL）に溶解し、TBAFのTHF溶液（1.0M,1.0mL）を加え室温で1時間撹拌した。反応液を減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（5%メタノール/クロロホルム）で精製した。 The obtained colorless oily substance (745 mg) was dissolved in dichloromethane (1.6 mL), BCl 3 in dichloromethane (1.0 M, 550 μL) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hr. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in DCE (16 mL) and 2,4-bis (trimethylsilyloxy) pyrimidine obtained by the method described in the literature (Nucleosides & Nucleotides, 4, 565-585 (1985)) (635 mg) and iodine (16 mg) were added, and the mixture was heated to reflux at 93 ° C. for 48 hours. The reaction mixture was allowed to cool, saturated aqueous sodium sulfite solution (10 mL) and water (50 mL) were added, and the mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (70% ethyl acetate / hexane). The obtained pale yellow gum (381 mg) was dissolved in THF (4.0 mL), TBAF in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / chloroform).
　得られた無色ガム状物質（200mg）をピリジン（4.0mL）に溶解し、塩化メタンスルホニル（63μL）を加え室温で1時間撹拌した。反応液を減圧濃縮し、残渣をトルエン（5.0mL×1）で共沸した後、シリカゲルカラムクロマトグラフィー（3%メタノール/クロロホルム）で精製した。得られた淡黄色ガム状物質（221mg）をDMF（4.0mL）に溶解し、アジ化ナトリウム（117mg）を加え55℃で16時間撹拌した。反応液に水（10mL）を加え、酢酸エチル（15mL）で抽出した。有機層を水（10mL×2）、飽和食塩水（10mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（70%酢酸エチル/ヘキサン）で精製することで、標記化合物（183mg）を白色固体として得た。 The obtained colorless gum-like substance (200 mg) was dissolved in pyridine (4.0 mL), methanesulfonyl chloride (63 μL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene (5.0 mL × 1) and purified by silica gel column chromatography (3% methanol / chloroform). The obtained pale yellow gum (221 mg) was dissolved in DMF (4.0 mL), sodium azide (117 mg) was added, and the mixture was stirred at 55 ° C. for 16 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL × 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (70% ethyl acetate / hexane) to give the title compound (183 mg) as a white solid.
参考例106
　1-((2-(2-アジドプロピル)ベンジルオキシ)メチル)ピリミジン-2,4-(1H,3H)-ジオンの合成 Reference Example 106
Synthesis of 1-((2- (2-azidopropyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　文献（J. Org. Chem., 52, 1027-1035(1987)）記載の方法で得られた2-(2-(ヒドロキシメチル)フェニル)エタノール（3.88g）をピリジン（40mL）に溶解し、tert-ブチルジフェニルシリルクロリド（6.63mL）を加え室温で2時間撹拌した。反応液にメタノール（5.0mL）を加え減圧濃縮した後、残渣に水（50mL）を加え、酢酸エチル（50mL）で抽出した。有機層を水（50mL）、飽和食塩水（50mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（20%酢酸エチル/ヘキサン）で精製した。得られた無色ガム状物質（5.30g）をジクロロメタン（30mL）に溶解し、N.N-ジイソプロピルエチルアミン（5.92mL）及びクロロメチルメチルエーテル（2.07mL）を加え室温で14時間撹拌した。反応液に飽和塩化アンモニウム水（50mL）を加え、酢酸エチル（90mL）で抽出した。有機層を飽和塩化アンモニウム水（50mLx3）、飽和食塩水（50mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（10%酢酸エチル/ヘキサン）で精製した。 2- (2- (hydroxymethyl) phenyl) ethanol (3.88 g) obtained by the method described in the literature (J. Org. Chem., 52, 1027-1035 (1987)) was dissolved in pyridine (40 mL), tert-Butyldiphenylsilyl chloride (6.63 mL) was added and stirred at room temperature for 2 hours. Methanol (5.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane). The obtained colorless gum (5.30 g) was dissolved in dichloromethane (30 mL), N.N-diisopropylethylamine (5.92 mL) and chloromethyl methyl ether (2.07 mL) were added, and the mixture was stirred at room temperature for 14 hr. Saturated aqueous ammonium chloride (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (90 mL). The organic layer was washed with saturated aqueous ammonium chloride (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane).
　得られた無色油状物質（5.62g内、1.74g）をTHF（5.0mL）に溶解し、TBAFのTHF溶液（1.0M,5.0mL）を加え室温で1時間撹拌した。反応液を減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（50%酢酸エチル/ヘキサン）で精製した。得られた無色油状物質（771mgの内、393mg）をトルエン(4.0mL)、DMSO(4.0mL)に溶解し、ピリジン（243μL）、トリフルオロ酢酸(111μL)及びEDC・HCl(1.15g)を加え室温で1時間撹拌した。反応液に水（20mL）を加え、酢酸エチル（20mL）で抽出した。有機層を水（15mL）、飽和食塩水（10mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をトルエン（5.0mLx3）で共沸した後、ジエチルエーテル（10mL）に溶解し、-78℃でヨウ化メチルマグネシウムのジエチルエーテル溶液（3.0M,1.0mL）を加え-78℃で2時間撹拌した。反応液に飽和塩化アンモニウム水（10mL）を加え室温で30分撹拌した後、酢酸エチル（15mL）で抽出した。有機層を水（15mL）及び飽和食塩水（10mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(40%酢酸エチル/ヘキサン)で精製した。 The obtained colorless oily substance (5.62 g, 1.74 g) was dissolved in THF (5.0 mL), TBAF in THF (1.0 M, 5.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained colorless oily substance (393 mg of 771 mg) was dissolved in toluene (4.0 mL) and DMSO (4.0 mL), and pyridine (243 μL), trifluoroacetic acid (111 μL) and EDC · HCl (1.15 g) were added. Stir at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with water (15 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene (5.0 mL x 3), dissolved in diethyl ether (10 mL), methylmagnesium iodide in diethyl ether (3.0 M, 1.0 mL) was added at -78 ° C, and the mixture was stirred at -78 ° C for 2 hours. did. Saturated aqueous ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate (15 mL). The organic layer was washed with water (15 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate / hexane).
　得られた無色油状物質(300mg)をアセトニトリル(5.0mL)に溶解し、トリエチルアミン(400μL)、DMAP(35mg)及び無水安息香酸(485mg)を加え50℃で1時間撹拌した。反応液にメタノール(5.0mL)を加え室温で30分撹拌した後、減圧濃縮した。残渣に水（10mL）を加え、酢酸エチル（15mL）で抽出した。有機層を水（10mL）及び飽和食塩水（10mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（15%酢酸エチル/ヘキサン）で精製した。得られた無色油状物質（390mg）をジクロロメタン（1.0mL）に溶解し、0℃でBCl3のジクロロメタン溶液（1.0M,410μL）をゆっくり加え室温で2時間撹拌した。反応液を減圧濃縮した後、残渣をDCE（12mL）に溶解し、文献（Bailey, S. etal. Nucleosides & Nucleotides, 4, 565-585(1985)）記載の方法で得られた2,4-ビス(トリメチルシリルオキシ)ピリミジン（477mg）及びヨウ素（12mg）を加え93℃で3.0時間加熱還流した。 The obtained colorless oily substance (300 mg) was dissolved in acetonitrile (5.0 mL), triethylamine (400 μL), DMAP (35 mg) and benzoic anhydride (485 mg) were added, and the mixture was stirred at 50 ° C. for 1 hr. Methanol (5.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. Water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / hexane). The obtained colorless oily substance (390 mg) was dissolved in dichloromethane (1.0 mL), a solution of BCl 3 in dichloromethane (1.0 M, 410 μL) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 2 hr. After concentrating the reaction solution under reduced pressure, the residue was dissolved in DCE (12 mL) and obtained by the method described in the literature (Bailey, S. etal. Nucleosides & Nucleotides, 4, 565-585 (1985)). Bis (trimethylsilyloxy) pyrimidine (477 mg) and iodine (12 mg) were added, and the mixture was heated to reflux at 93 ° C. for 3.0 hours.
　反応液を放冷した後、飽和亜硫酸ナトリウム水溶液（10mL）及び水（40mL）を加え、酢酸エチル(40mL)で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（85%酢酸エチル/ヘキサン）で精製した。 After allowing the reaction solution to cool, a saturated aqueous sodium sulfite solution (10 mL) and water (40 mL) were added, and the mixture was extracted with ethyl acetate (40 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (85% ethyl acetate / hexane).
　得られた無色ガム状物質（220mg）をメタノール（3.0mL）に溶解し、ナトリウムメトキシド（61mg）を加え45℃で12時間撹拌した。塩酸（6.0M,約9滴）で中和後、反応液を減圧濃縮した。残渣をトルエン（5.0mL）で共沸した後、シリカゲルカラムクロマトグラフィー（4%メタノール/クロロホルム）で精製した。得られた無色ガム状物質（148mg）をピリジン（3.0mL）に溶解し、塩化メタンスルホニル（44μL）を加え室温で3.5時間撹拌した。反応液にメタノール（1.0mL）を加え減圧濃縮し、残渣をトルエン（5.0mL×2）で共沸した後、シリカゲルカラムクロマトグラフィー（2%メタノール/クロロホルム）で精製した。得られた無色ガム状物質（180mg）をDMF（4.0mL）に溶解し、アジ化ナトリウム（96mg）を加え70℃で3時間撹拌した。反応液に水（10mL）を加え、酢酸エチル（10mL）で抽出した。有機層を水（10mL×2）、飽和食塩水（10mL）で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（75%酢酸エチル/ヘキサン）で精製して標記化合物（148mg）を無色ガム状物質として得た。 The obtained colorless gum-like substance (220 mg) was dissolved in methanol (3.0 mL), sodium methoxide (61 mg) was added, and the mixture was stirred at 45 ° C. for 12 hours. After neutralization with hydrochloric acid (6.0 M, about 9 drops), the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (5.0 mL) and purified by silica gel column chromatography (4% methanol / chloroform). The resulting colorless gum (148 mg) was dissolved in pyridine (3.0 mL), methanesulfonyl chloride (44 μL) was added, and the mixture was stirred at room temperature for 3.5 hours. Methanol (1.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (5.0 mL × 2) and then purified by silica gel column chromatography (2% methanol / chloroform). The obtained colorless gum (180 mg) was dissolved in DMF (4.0 mL), sodium azide (96 mg) was added, and the mixture was stirred at 70 ° C. for 3 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with water (10 mL × 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (75% ethyl acetate / hexane) to give the title compound (148 mg) as a colorless gum.
実施例1
　1-(4-(1-(3-(シクロプロピルメトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 1
Synthesis of 1- (4- (1- (3- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　参考例2で得られた1-(ヘキス-5-イニル)ピリミジン-2,4(1H,3H)-ジオン(48mg)と、参考例14で得られた1-(2-アジドエチル)-3-(シクロプロピルメトキシ)ベンゼン(65mg)を1,4-ジオキサン(2.5mL)に溶解し、クロロ(ペンタメチルシクロペンタジエニル)(シクロオクタジエン)ルテニウム(II)(9.5mg)加え、60℃で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/クロロホルム)で精製することで、標記化合物(90mg、収率88%)を泡状物質として得た。 1- (Hex-5-ynyl) pyrimidine-2,4 (1H, 3H) -dione (48 mg) obtained in Reference Example 2 and 1- (2-azidoethyl) -3-yl obtained in Reference Example 14 (Cyclopropylmethoxy) benzene (65 mg) was dissolved in 1,4-dioxane (2.5 mL), chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II) (9.5 mg) was added, and the mixture was heated at 60 ° C. Stir for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (90 mg, yield 88%) as a foam.
1H-NMR(CDCl3)δ(ppm):
0.29-0.35(2H,m),0.60-0.67(2H,m),1.16-1.24(1H,m),1.38-1.49(2H,m),1.55-1.66(2H,m),2.28(2H,t,J=7.6Hz),3.18(2H,t,J=7.0Hz),3.65(2H,t,J=7.0Hz),3.71(2H,d,J=7.0Hz),4,41(2H,t,J=7.0Hz),5.70(1H,dd,J=2.2,7.8Hz),6.52(1H,t,J=1.9Hz),6.61(1H,d,J=7.6Hz),6.76(1H,dd,J=1.6,7.3Hz),7.09(1H,d,J=7.8Hz),7.17(1H,t,J=7.8Hz),7.37(1H,s),8.41(1H,brs) 1 H-NMR (CDCl 3 ) δ (ppm):
0.29-0.35 (2H, m), 0.60-0.67 (2H, m), 1.16-1.24 (1H, m), 1.38-1.49 (2H, m), 1.55-1.66 (2H, m), 2.28 (2H, t , J = 7.6Hz), 3.18 (2H, t, J = 7.0Hz), 3.65 (2H, t, J = 7.0Hz), 3.71 (2H, d, J = 7.0Hz), 4,41 (2H, t , J = 7.0Hz), 5.70 (1H, dd, J = 2.2,7.8Hz), 6.52 (1H, t, J = 1.9Hz), 6.61 (1H, d, J = 7.6Hz), 6.76 (1H, dd , J = 1.6,7.3Hz), 7.09 (1H, d, J = 7.8Hz), 7.17 (1H, t, J = 7.8Hz), 7.37 (1H, s), 8.41 (1H, brs)
　実施例2～118はそれぞれ、以下の表に示すアルキンとアジドから実施例1の方法に準じて合成した。 Examples 2 to 118 were synthesized according to the method of Example 1 from alkynes and azides shown in the following table, respectively.
実施例2
　1-((2-(1-(3-(シクロプロピルメトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 2
1-((2- (1- (3- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) pyrimidine-2,4 (1H, 3H) -dione
実施例3
　1-(2-((1-(3-(シクロプロピルメトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)メトキシ)エチル)ピリミジン-2,4(1H,3H)-ジオン Example 3
1- (2-((1- (3- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) methoxy) ethyl) pyrimidine-2,4 (1H, 3H) -dione
実施例4
　1-(3-(1-(3-(シクロプロピルメトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)ベンジル)ピリミジン-2,4(1H,3H)-ジオン Example 4
1- (3- (1- (3- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) benzyl) pyrimidine-2,4 (1H, 3H) -dione
実施例5
　1-(3-(1-(3-(シクロペンチルオキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 5
1- (3- (1- (3- (cyclopentyloxy) phenethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例6
　1-(3-(1-(2-(シクロプロピルメトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 6
1- (3- (1- (2- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例7
　1-(3-(1-(2-(シクロブチルメトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 7
1- (3- (1- (2- (cyclobutylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例8
　1-(3-(1-(2-(シクロペンチルオキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 8
1- (3- (1- (2- (cyclopentyloxy) phenethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例9
　(R)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)フェニル)プロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 9
(R) -1- (4- (1- (2- (3- (cyclopropylmethoxy) phenyl) propyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 ( 1H, 3H) -Dione
実施例10
　(R)-1-((2-(1-(2-(3-(シクロプロピルメトキシ)フェニル)プロピル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 10
(R) -1-((2- (1- (2- (3- (cyclopropylmethoxy) phenyl) propyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) pyrimidine-2 , 4 (1H, 3H) -Dione
実施例11
　(R)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)フェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 11
(R) -1- (4- (1- (2- (3- (cyclopropylmethoxy) phenyl) butyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 ( 1H, 3H) -Dione
実施例12
　(R)-1-((2-(1-(2-(3-(シクロプロピルメトキシ)フェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 12
(R) -1-((2- (1- (2- (3- (cyclopropylmethoxy) phenyl) butyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) pyrimidine-2 , 4 (1H, 3H) -Dione
実施例13
　(S)-1-(4-(1-(1-(3-(シクロプロピルメトキシ)フェニル)プロパン-2-イル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 13
(S) -1- (4- (1- (1- (3- (cyclopropylmethoxy) phenyl) propan-2-yl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine- 2,4 (1H, 3H) -dione
実施例14
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 14
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) (Butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例15
　(S)-1-((2-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 15
(S) -1-((2- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl ) Ethoxy) methyl) pyrimidine-2,4 (1H, 3H) -dione
実施例16
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)-4-メチルペンチル)ピリミジン-2,4(1H,3H)-ジオン Example 16
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) -4-methylpentyl) pyrimidine-2,4 (1H, 3H) -dione
実施例17
　(S)-1-(3-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ベンジル)ピリミジン-2,4(1H,3H)-ジオン Example 17
(S) -1- (3- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) (Benzyl) pyrimidine-2,4 (1H, 3H) -dione
実施例18
　(S)-1-(4-(1-(2-ヒドロキシ-2-(3-イソブトキシフェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 18
(S) -1- (4- (1- (2-hydroxy-2- (3-isobutoxyphenyl) butyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -Dione
実施例19
　(S)-1-(4-(1-(2-(3-(2,2-ジフルオロエトキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 19
(S) -1- (4- (1- (2- (3- (2,2-difluoroethoxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl Pyrimidine-2,4 (1H, 3H) -dione
実施例20
　(S)-1-(4-(1-(2-(3-(シクロペンチルオキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 20
(S) -1- (4- (1- (2- (3- (cyclopentyloxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2 , 4 (1H, 3H) -Dione
実施例21
　(S)-1-((2-(1-(2-(3-(シクロペンチルオキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 21
(S) -1-((2- (1- (2- (3- (cyclopentyloxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) Pyrimidine-2,4 (1H, 3H) -dione
実施例22
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 22
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine- 2,4 (1H, 3H) -dione
実施例23
　(S)-1-((2-(1-(2-(3-(シクロプロピルメトキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 23
(S) -1-((2- (1- (2- (3- (cyclopropylmethoxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl Pyrimidine-2,4 (1H, 3H) -dione
実施例24
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)フェニル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 24
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) phenyl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine- 2,4 (1H, 3H) -dione
実施例25
　(S)-1-((2-(1-(2-(3-(シクロプロピルメトキシ)フェニル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 25
(S) -1-((2- (1- (2- (3- (cyclopropylmethoxy) phenyl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl Pyrimidine-2,4 (1H, 3H) -dione
実施例26
　(R)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)フェニル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 26
(R) -1- (4- (1- (2- (3- (cyclopropylmethoxy) phenyl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine- 2,4 (1H, 3H) -dione
実施例27
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシ-3-メチルブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 27
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxy-3-methylbutyl) -1H-1,2,3-triazole-5 -Yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例28
　1-(4-(1-((S)-2-(3-(R)-sec-ブトキシフェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 28
1- (4- (1-((S) -2- (3- (R) -sec-butoxyphenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) Pyrimidine-2,4 (1H, 3H) -dione
実施例29
　1-(4-(1-((S)-2-(3-(S)-sec-ブトキシフェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 29
1- (4- (1-((S) -2- (3- (S) -sec-butoxyphenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) Pyrimidine-2,4 (1H, 3H) -dione
実施例30
　(S)-1-(4-(1-(2-ヒドロキシ-2-(3-((1-メチルシクロプロピル)メトキシ)フェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 30
(S) -1- (4- (1- (2-hydroxy-2- (3-((1-methylcyclopropyl) methoxy) phenyl) butyl) -1H-1,2,3-triazol-5-yl ) Butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例31
　1-(4-(1-((S)-2-ヒドロキシ-2-(3-((R)-テトラヒドロフラン-3-イルオキシ)フェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 31
1- (4- (1-((S) -2-hydroxy-2- (3-((R) -tetrahydrofuran-3-yloxy) phenyl) butyl) -1H-1,2,3-triazole-5- Yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例32
　(S)-1-(4-(1-(2-ヒドロキシ-2-(3-(テトラヒドロ-2H-ピラン-4-イルオキシ)フェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 32
(S) -1- (4- (1- (2-hydroxy-2- (3- (tetrahydro-2H-pyran-4-yloxy) phenyl) butyl) -1H-1,2,3-triazole-5- Yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例33
　(S)-1-(4-(1-(2-(3-シクロブトキシフェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 33
(S) -1- (4- (1- (2- (3-Cyclobutoxyphenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -Dione
実施例34
　(S)-1-(4-(1-(2-(3-エトキシフェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 34
(S) -1- (4- (1- (2- (3-Ethoxyphenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 ( 1H, 3H) -Dione
実施例35
　1-(4-(1-((2S)-2-(3-(1-シクロプロピルエトキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 35
1- (4- (1-((2S) -2- (3- (1-cyclopropylethoxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) Pyrimidine-2,4 (1H, 3H) -dione
実施例36
　(S)-1-(4-(1-(2-(3-(シクロブチルメトキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 36
(S) -1- (4- (1- (2- (3- (cyclobutylmethoxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine- 2,4 (1H, 3H) -dione
実施例37
　(S)-1-(4-(1-(2-ヒドロキシ-2-(3-(2,2,2-トリフルオロエトキシ)フェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 37
(S) -1- (4- (1- (2-hydroxy-2- (3- (2,2,2-trifluoroethoxy) phenyl) butyl) -1H-1,2,3-triazole-5- Yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例38
　(S)-1-(4-(1-(2-(3-(ジシクロプロピルメトキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 38
(S) -1- (4- (1- (2- (3- (dicyclopropylmethoxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine -2,4 (1H, 3H) -dione
実施例39
　1-((2-(1-(2-(3-(シクロプロピルメトキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 39
1-((2- (1- (2- (3- (cyclopropylmethoxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) pyrimidine-2 , 4 (1H, 3H) -Dione
実施例40
　1-(3-(1-(2,2-ビス(4-フルオロフェニル)-2-ヒドロキシエチル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 40
1- (3- (1- (2,2-bis (4-fluorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H , 3H) -Dione
実施例41
　1-(4-(1-(2,2-ビス(4-フルオロフェニル)-2-ヒドロキシエチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 41
1- (4- (1- (2,2-bis (4-fluorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H , 3H) -Dione
実施例42
　1-(4-(1-(3-(シクロプロピルメトキシ)ベンジル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 42
1- (4- (1- (3- (cyclopropylmethoxy) benzyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例43
　1-(4-(1-(2-(シクロプロピルメトキシ)ベンジル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 43
1- (4- (1- (2- (cyclopropylmethoxy) benzyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例44
　1-(4-(1-(2-(3-(シクロプロピルメトキシ)フェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 44
1- (4- (1- (2- (3- (cyclopropylmethoxy) phenyl) butyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -Zeon
実施例45
　1-(4-(1-(3-(シクロプロピルメトキシ)-4-フルオロフェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 45
1- (4- (1- (3- (cyclopropylmethoxy) -4-fluorophenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H)- Dione
実施例46
　1-(2-((1-(3-(シクロプロピルメトキシ)-4-フルオロフェネチル)-1H-1,2,3-トリアゾール-5-イル)メトキシ)エチル)ピリミジン-2,4(1H,3H)-ジオン Example 46
1- (2-((1- (3- (cyclopropylmethoxy) -4-fluorophenethyl) -1H-1,2,3-triazol-5-yl) methoxy) ethyl) pyrimidine-2,4 (1H, 3H) -Dione
実施例47
　1-(3-(1-(2,2-ジフェニルエチル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 47
1- (3- (1- (2,2-diphenylethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例48
　1-(3-(1-ベンズヒドリル-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 48
1- (3- (1-Benzhydryl-1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例49
　1-(4-(1-ベンズヒドリル-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 49
1- (4- (1-Benzhydryl-1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例50
　1-(3-(1-フェネチル-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 50
1- (3- (1-phenethyl-1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例51
　(S)-1-(4-(1-(2-(4-クロロフェニル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 51
(S) -1- (4- (1- (2- (4-Chlorophenyl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H , 3H) -Dione
実施例52
　(S)-1-(4-(1-(2-(2-フルオロフェニル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 52
(S) -1- (4- (1- (2- (2-Fluorophenyl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 ( 1H, 3H) -Dione
実施例53
　1-(4-(1-(2,2-ジフェニルエチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 53
1- (4- (1- (2,2-diphenylethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例54
　1-(4-(1-(2-メトキシフェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 54
1- (4- (1- (2-methoxyphenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例55
　1-(4-(1-(3-メトキシフェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 55
1- (4- (1- (3-methoxyphenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例56
　1-(4-(1-(4-メトキシフェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 56
1- (4- (1- (4-Methoxyphenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例57
　(S)-1-(4-(1-(2-(2-(シクロプロピルメトキシ)フェニル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 57
(S) -1- (4- (1- (2- (2- (cyclopropylmethoxy) phenyl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine- 2,4 (1H, 3H) -dione
実施例58
　1-(2-(1-(2,2-ビス(4-クロロフェニル)-2-ヒドロキシエチル)-1H-1,2,3-トリアゾール-5-イル)エチル)ピリミジン-2,4(1H,3H)-ジオン Example 58
1- (2- (1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) ethyl) pyrimidine-2,4 (1H, 3H) -Dione
実施例59
　(S)-1-(3-(1-(2-(4-クロロフェニル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 59
(S) -1- (3- (1- (2- (4-Chlorophenyl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H , 3H) -Dione
実施例60
　1-(2-(1-(2,2-ビス(4-フルオロフェニル)-2-ヒドロキシエチルl)-1H-1,2,3-トリアゾール-5-イル)エチル)ピリミジン-2,4(1H,3H)-ジオン Example 60
1- (2- (1- (2,2-bis (4-fluorophenyl) -2-hydroxyethyl l) -1H-1,2,3-triazol-5-yl) ethyl) pyrimidine-2,4 ( 1H, 3H) -Dione
実施例61
　1-(4-(1-フェネチル-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 61
1- (4- (1-Phenethyl-1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例62
　1-((2-(1-ベンズヒドリル-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 62
1-((2- (1-Benzhydryl-1H-1,2,3-triazol-5-yl) ethoxy) methyl) pyrimidine-2,4 (1H, 3H) -dione
実施例63
　(S)-1-(4-(1-(2-ヒドロキシ-2-フェニルプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 63
(S) -1- (4- (1- (2-hydroxy-2-phenylpropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H)- Dione
実施例64
　1-(3-(1-(2,2-ビス(4-クロロフェニル)-2-ヒドロキシエチル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 64
1- (3- (1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -Dione
実施例65
　1-(4-(1-(2,2-ビス(4-クロロフェニル)-2-ヒドロキシエチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 65
1- (4- (1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -Dione
実施例66
　1-(3-(1-(2,2-ビス(4-クロロ-3-メトキシフェニル)-2-ヒドロキシエチル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 66
1- (3- (1- (2,2-bis (4-chloro-3-methoxyphenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2 , 4 (1H, 3H) -Dione
実施例67
　1-(3-(1-(2-(ビフェニル-2-イル)プロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 67
1- (3- (1- (2- (biphenyl-2-yl) propyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例68
　1-(4-(1-(2-ヒドロキシ-2,2-ビス(3-メトキシフェニル)エチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 68
1- (4- (1- (2-hydroxy-2,2-bis (3-methoxyphenyl) ethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H , 3H) -Dione
実施例69
　1-(4-(1-(2-(ビフェニル-2-イル)プロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 69
1- (4- (1- (2- (biphenyl-2-yl) propyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例70
　(S)-1-(3-(1-(2-(4'-フルオロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 70
(S) -1- (3- (1- (2- (4'-Fluorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine -2,4 (1H, 3H) -dione
実施例71
　(S)-1-(3-(1-(2-(ビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 71
(S) -1- (3- (1- (2- (biphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -Dione
実施例72
　(S)-1-(3-(1-(2-ヒドロキシ-2-(2-(チオフェン-3-イル)フェニル)プロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 72
(S) -1- (3- (1- (2-hydroxy-2- (2- (thiophen-3-yl) phenyl) propyl) -1H-1,2,3-triazol-5-yl) propyl) Pyrimidine-2,4 (1H, 3H) -dione
実施例73
　(S)-1-(3-(1-(2-(4'-クロロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 73
(S) -1- (3- (1- (2- (4'-Chlorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine -2,4 (1H, 3H) -dione
実施例74
　(S)-1-(4-(1-(2-ヒドロキシ-2-(2-(チオフェン-3-イル)フェニル)プロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 74
(S) -1- (4- (1- (2-hydroxy-2- (2- (thiophen-3-yl) phenyl) propyl) -1H-1,2,3-triazol-5-yl) butyl) Pyrimidine-2,4 (1H, 3H) -dione
実施例75
　(S)-1-(4-(1-(2-(4'-クロロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 75
(S) -1- (4- (1- (2- (4'-Chlorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine -2,4 (1H, 3H) -dione
実施例76
　(S)-1-(4-(1-(2-(4'-フルオロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 76
(S) -1- (4- (1- (2- (4'-Fluorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine -2,4 (1H, 3H) -dione
実施例77
　(S)-1-(3-(1-(2-(3'-フルオロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 77
(S) -1- (3- (1- (2- (3'-Fluorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine -2,4 (1H, 3H) -dione
実施例78
　(S)-1-(4-(1-(2-(ビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 78
(S) -1- (4- (1- (2- (biphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -Dione
実施例79
　(S)-1-(4-(1-(2-(3'-フルオロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 79
(S) -1- (4- (1- (2- (3'-Fluorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine -2,4 (1H, 3H) -dione
実施例80
　1-(3-(1-(2-(ビフェニル-2-イル)エチル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 80
1- (3- (1- (2- (biphenyl-2-yl) ethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例81
　(S)-1-(4-(1-(2-(2-クロロフェニル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 81
(S) -1- (4- (1- (2- (2-Chlorophenyl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H , 3H) -Dione
実施例82
　1-(3-(1-(2-ヒドロキシ-2,2-ビス(3-メトキシフェネチル)エチル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 82
1- (3- (1- (2-hydroxy-2,2-bis (3-methoxyphenethyl) ethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H , 3H) -Dione
実施例83
　1-(4-(1-(2-(シクロプロピルメトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 83
1- (4- (1- (2- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例84
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)フェニル)プロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 84
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) phenyl) propyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 ( 1H, 3H) -Dione
実施例85
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)フェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 85
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) phenyl) butyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 ( 1H, 3H) -Dione
実施例86
　(R)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 86
(R) -1- (4- (1- (2- (3- (cyclopropylmethoxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine- 2,4 (1H, 3H) -dione
実施例87
　(S)-1-(3-(1-(2-(5-クロロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 87
(S) -1- (3- (1- (2- (5-chlorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine- 2,4 (1H, 3H) -dione
実施例88
　(S)-1-(3-(1-(2-(5-クロロ-3'-フルオロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 88
(S) -1- (3- (1- (2- (5-Chloro-3'-fluorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl ) Propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例89
　(S)-1-(3-(1-(2-(5-クロロ-4'-フルオロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 89
(S) -1- (3- (1- (2- (5-Chloro-4'-fluorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl ) Propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例90
　(S)-1-(3-(1-(2-(4',5-ジクロロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 90
(S) -1- (3- (1- (2- (4 ', 5-dichlorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) propyl Pyrimidine-2,4 (1H, 3H) -dione
実施例91
　(S)-1-(3-(1-(2-(4-クロロ-2-(チオフェン-3-イル)フェニル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオン Example 91
(S) -1- (3- (1- (2- (4-Chloro-2- (thiophen-3-yl) phenyl) -2-hydroxypropyl) -1H-1,2,3-triazole-5- Yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
実施例92
　(S)-1-(4-(1-(2-(5-クロロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 92
(S) -1- (4- (1- (2- (5-chlorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine- 2,4 (1H, 3H) -dione
実施例93
　(S)-1-(4-(1-(2-(5-クロロ-3'-フルオロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 93
(S) -1- (4- (1- (2- (5-Chloro-3'-fluorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl ) Butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例94
　(S)-1-(4-(1-(2-(5-クロロ-4'-フルオロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 94
(S) -1- (4- (1- (2- (5-Chloro-4'-fluorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl ) Butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例95
　(S)-1-(4-(1-(2-(4',5-ジクロロビフェニル-2-イル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 95
(S) -1- (4- (1- (2- (4 ', 5-dichlorobiphenyl-2-yl) -2-hydroxypropyl) -1H-1,2,3-triazol-5-yl) butyl Pyrimidine-2,4 (1H, 3H) -dione
実施例96
　(S)-1-(4-(1-(2-(4-クロロ-2-(チオフェン-3-イル)フェニル)-2-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 96
(S) -1- (4- (1- (2- (4-Chloro-2- (thiophen-3-yl) phenyl) -2-hydroxypropyl) -1H-1,2,3-triazole-5- Yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例97
　(S)-1-((2-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 97
(S) -1-((2- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl ) Ethoxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione
実施例98
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 98
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) Butyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione
実施例99
　1-((2-(1-(3-(シクロペンチルオキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 99
1-((2- (1- (3- (cyclopentyloxy) phenethyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H ) -Dione
実施例100
　1-((2-(1-(3-(シクロプロピルメトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 100
1-((2- (1- (3- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -Dione
実施例101
　1-((2-(1-(3-(2,2-ジフルオロエトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 101
1-((2- (1- (3- (2,2-difluoroethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -Dione
実施例102
　1-(4-(1-(3-(シクロペンチルオキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 102
1- (4- (1- (3- (cyclopentyloxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione
実施例103
　1-(4-(1-(3-(シクロプロピルメトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 103
1- (4- (1- (3- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) -5-fluoropyrimidine-2,4 (1H, 3H)- Dione
実施例104
　1-(4-(1-(3-(2,2-ジフルオロエトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 104
1- (4- (1- (3- (2,2-difluoroethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) -5-fluoropyrimidine-2,4 (1H, 3H) -Dione
実施例105
　5-フルオロ-1-((2-(1-(3-イソブトキシフェネチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 105
5-Fluoro-1-((2- (1- (3-isobutoxyphenethyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) pyrimidine-2,4 (1H, 3H)- Dione
実施例106
　5-フルオロ-1-((2-(1-(3-(2,2,2-トリフルオロエトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 106
5-fluoro-1-((2- (1- (3- (2,2,2-trifluoroethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) pyrimidine- 2,4 (1H, 3H) -dione
実施例107
　(S)-5-フルオロ-1-((2-(1-(3-(2-メチルブトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 107
(S) -5-Fluoro-1-((2- (1- (3- (2-methylbutoxy) phenethyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) pyrimidine-2 , 4 (1H, 3H) -Dione
実施例108
　5-フルオロ-1-(4-(1-(3-イソブトキシフェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 108
5-Fluoro-1- (4- (1- (3-isobutoxyphenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例109
　5-フルオロ-1-(4-(1-(3-(2,2,2-トリフルオロエトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 109
5-fluoro-1- (4- (1- (3- (2,2,2-trifluoroethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -Dione
実施例110
　(S)-5-フルオロ-1-(4-(1-(3-(2-メチルブトキシ)フェネチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 110
(S) -5-Fluoro-1- (4- (1- (3- (2-methylbutoxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 ( 1H, 3H) -Dione
実施例111
　(S)-1-((2-(1-(2-(3-(シクロペンチルオキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 111
(S) -1-((2- (1- (2- (3- (cyclopentyloxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) -5-Fluoropyrimidine-2,4 (1H, 3H) -dione
実施例112
　(S)-1-((2-(1-(2-(3-(2,2-ジフルオロエトキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 112
(S) -1-((2- (1- (2- (3- (2,2-difluoroethoxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) Ethoxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione
実施例113
　(S)-1-(4-(1-(2-(3-(シクロペンチルオキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 113
(S) -1- (4- (1- (2- (3- (cyclopentyloxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl) -5- Fluoropyrimidine-2,4 (1H, 3H) -dione
実施例114
　(S)-1-(4-(1-(2-(3-(2,2-ジフルオロエトキシ)フェニル)-2-ヒドロキシブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)-5-フルオロピリミジン-2,4(1H,3H)-ジオン Example 114
(S) -1- (4- (1- (2- (3- (2,2-difluoroethoxy) phenyl) -2-hydroxybutyl) -1H-1,2,3-triazol-5-yl) butyl ) -5-Fluoropyrimidine-2,4 (1H, 3H) -dione
実施例115
　(S)-5-フルオロ-1-((2-(1-(2-ヒドロキシ-2-(3-(2,2,2-トリフルオロエトキシ)フェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 115
(S) -5-Fluoro-1-((2- (1- (2-hydroxy-2- (3- (2,2,2-trifluoroethoxy) phenyl) butyl) -1H-1,2,3 -Triazol-5-yl) ethoxy) methyl) pyrimidine-2,4 (1H, 3H) -dione
実施例116
　(S)-5-フルオロ-1-((2-(1-(2-ヒドロキシ-2-(3-イソブトキシフェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオン Example 116
(S) -5-Fluoro-1-((2- (1- (2-hydroxy-2- (3-isobutoxyphenyl) butyl) -1H-1,2,3-triazol-5-yl) ethoxy) Methyl) pyrimidine-2,4 (1H, 3H) -dione
実施例117
　(S)-5-フルオロ-1-(4-(1-(2-ヒドロキシ-2-(3-(2,2,2-トリフルオロエトキシ)フェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 117
(S) -5-Fluoro-1- (4- (1- (2-hydroxy-2- (3- (2,2,2-trifluoroethoxy) phenyl) butyl) -1H-1,2,3- Triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
実施例118
　(S)-5-フルオロ-1-(4-(1-(2-ヒドロキシ-2-(3-イソブトキシフェニル)ブチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 118
(S) -5-Fluoro-1- (4- (1- (2-hydroxy-2- (3-isobutoxyphenyl) butyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine -2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
　なお前記表中、実施例48、49、62の合成で用いるアジドは文献(TetrahedronLett.,48,7109-7172(2007))記載の方法で得た。 In the above table, the azide used in the synthesis of Examples 48, 49 and 62 was obtained by the method described in the literature (Tetrahedron Lett., 48, 7109-7172 (2007)).
実施例119
　(S)-1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-5-(4-(2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)ブチル)-1H-1,2,3-トリアゾール-4-カルボニトリルの合成 Example 119
(S) -1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -5- (4- (2,4-dioxo-3,4-dihydropyrimidine-1 Synthesis of (2H) -yl) butyl) -1H-1,2,3-triazole-4-carbonitrile
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　参考例82で得られた(S)-1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-5-(4-ヒドロキシブチル)-1H-1,2,3-トリアゾール-4-カルボニトリル(180mg)をTHF(2.2mL)に溶解し、トリフェニルホスフィン(236mg)、文献(J.Med.Chem.,49,4183-4195(2006))記載の方法で得られたN3-ベンゾイルウラシル(145mg)及びアゾカルボン酸ジイソプロピルのトルエン溶液(1.9M、473μL)を加え室温で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2%メタノール/クロロホルム)で精製した。得られた化合物をメチルアミンのメタノール溶液(40%,5.0mL)に溶解し、室温で30分撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(3%メタノール/クロロホルム)で精製することで、標記化合物(110mg、収率49%)を泡状物質として得た。 (S) -1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -5- (4-hydroxybutyl) -1H-1, obtained in Reference Example 82 2,3-triazole-4-carbonitrile (180 mg) was dissolved in THF (2.2 mL) and triphenylphosphine (236 mg) described in the literature (J. Med. Chem., 49, 4183-4195 (2006)). N3-benzoyluracil (145 mg) obtained by the method and a toluene solution (1.9 M, 473 μL) of diisopropyl azocarboxylate were added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform). The obtained compound was dissolved in a methanol solution of methylamine (40%, 5.0 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform) to give the title compound (110 mg, yield 49%) as a foam.
1H-NMR(DMSO-d6)δ(ppm):
0.29-0.34(2H,m),0.54-0.60(2H,m),0.67(3H,t,J=7.0Hz),1.14-1.23(1H,m),1.59(4H,brs),1.73-1.81(1H,m),1.98-2.06(1H,m),2.76(2H,brs),3.66(2H,brs),3.83(2H,d,J=7.0Hz),4.61(2H,dd,J=14,22Hz),5.41(1H,s),5.54(1H,d,J=7.8Hz),6.88-7.15(3H,m),7.62(1H,d,J=7.6Hz),11.2(1H,brs) 1 H-NMR (DMSO-d 6 ) δ (ppm):
0.29-0.34 (2H, m), 0.54-0.60 (2H, m), 0.67 (3H, t, J = 7.0Hz), 1.14-1.23 (1H, m), 1.59 (4H, brs), 1.73-1.81 ( 1H, m), 1.98-2.06 (1H, m), 2.76 (2H, brs), 3.66 (2H, brs), 3.83 (2H, d, J = 7.0Hz), 4.61 (2H, dd, J = 14, 22Hz), 5.41 (1H, s), 5.54 (1H, d, J = 7.8Hz), 6.88-7.15 (3H, m), 7.62 (1H, d, J = 7.6Hz), 11.2 (1H, brs)
実施例120
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-エチニル-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 120
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4-ethynyl-1H-1,2,3-triazole- Synthesis of 5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　参考例83で得られた(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-エチニル-1H-1,2,3-トリアゾール-5-イル)ブタン-1-オール(190mg)から実施例119の方法に準じて合成することで、標記化合物(82mg、50%)を泡状物質として得た。 (S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4-ethynyl-1H-1,2, obtained in Reference Example 83 The title compound (82 mg, 50%) was obtained as a foam by synthesis from 3-triazol-5-yl) butan-1-ol (190 mg) according to the method of Example 119.
1H-NMR(CDCl3)δ(ppm):
0.32-0.37(2H,m),0.58-0.67(2H,m),0.82(3H,t,J=7.3Hz),1.18-1.29(1H,m),1.43-1.69(4H,m),1.77-2.12(2H,m),2.53(2H,t,J=7.8Hz),3.30(1H,s),3.71(2H,t,J=6.8Hz),3.80(2H,d,J=7.0Hz),3.85(1H,brs),4.42(2H,dd,J=14,33Hz),5.71(1H,dd,J=2.2,7.8Hz),6.80(2H,m),7.02(1H,dd,J=8.4,11Hz),7.13(1H,d,J=7.8Hz),8.75(1H,brs) 1 H-NMR (CDCl 3 ) δ (ppm):
0.32-0.37 (2H, m), 0.58-0.67 (2H, m), 0.82 (3H, t, J = 7.3Hz), 1.18-1.29 (1H, m), 1.43-1.69 (4H, m), 1.77- 2.12 (2H, m), 2.53 (2H, t, J = 7.8Hz), 3.30 (1H, s), 3.71 (2H, t, J = 6.8Hz), 3.80 (2H, d, J = 7.0Hz), 3.85 (1H, brs), 4.42 (2H, dd, J = 14,33Hz), 5.71 (1H, dd, J = 2.2,7.8Hz), 6.80 (2H, m), 7.02 (1H, dd, J = 8.4 , 11Hz), 7.13 (1H, d, J = 7.8Hz), 8.75 (1H, brs)
実施例121
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-(2,2-ジフルオロエチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 121
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4- (2,2-difluoroethyl) -1H-1 , 2,3-Triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
　参考例84で得られた(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-(2,2-ジフルオロエチル)-1H-1,2,3-トリアゾール-5-イル)ブタン-1-オール(190mg)から実施例119の方法に準じて合成することで、標記化合物(108mg、49%)を泡状物質として得た。 (S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4- (2,2-difluoroethyl) obtained in Reference Example 84 -1H-1,2,3-triazol-5-yl) butan-1-ol (190 mg) was synthesized according to the method of Example 119 to give the title compound (108 mg, 49%) as a foam. Obtained.
1H-NMR(CDCl3)δ(ppm):
0.32-0.36(2H,m),0.59-0.66(2H,m),0.82(3H,t,J=7.3Hz),1.21-1.40(3H,m),1.62-1.69(2H,m),1.78-2.08(2H,m),2.41-2.48(2H,m),3.05-3.18(2H,m),3.68-3.75(2H,m),3.81(2H,d,J=6.8Hz),4.23(1H,brs),4.40(2H,dd,J=14,18Hz),5.72(1H,dd,J=2.2,7.8Hz),5.79-6.24(1H,m),6.78-6.83(1H,m),6.94-6.99(2H,m),7.11(1H,d,J=7.8Hz),8.72(1H,brs) 1 H-NMR (CDCl 3 ) δ (ppm):
0.32-0.36 (2H, m), 0.59-0.66 (2H, m), 0.82 (3H, t, J = 7.3Hz), 1.21-1.40 (3H, m), 1.62-1.69 (2H, m), 1.78- 2.08 (2H, m), 2.41-2.48 (2H, m), 3.05-3.18 (2H, m), 3.68-3.75 (2H, m), 3.81 (2H, d, J = 6.8Hz), 4.23 (1H, brs), 4.40 (2H, dd, J = 14,18Hz), 5.72 (1H, dd, J = 2.2,7.8Hz), 5.79-6.24 (1H, m), 6.78-6.83 (1H, m), 6.94 6.99 (2H, m), 7.11 (1H, d, J = 7.8Hz), 8.72 (1H, brs)
実施例122
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-ビニル-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 122
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4-vinyl-1H-1,2,3-triazole- Synthesis of 5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　参考例85で得られた(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-ビニル-1H-1,2,3-トリアゾール-5-イル)ブタン-1-オール(45mg)から実施例119の方法に準じて合成することで、標記化合物(29mg、収率53%)を泡状物質として得た。 (S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4-vinyl-1H-1,2, obtained in Reference Example 85 The title compound (29 mg, 53% yield) was obtained as a foam by synthesis from 3-triazol-5-yl) butan-1-ol (45 mg) according to the method of Example 119.
1H-NMR(CDCl3)δ(ppm):
0.29-0.34(2H,m),0.58-0.65(2H,m),0.83(3H,t,J=7.0Hz),1.16-1.43(3H,m),1.56-1.67(2H,m),1.79-2.08(2H,m),2.42-2.49(2H,m),3.65-3.71(2H,m),3.77(2H,d,J=7.0Hz),4.33(1H,s),4.40(2H,dd,J=14.3,27Hz),5.32(1H,dd,J=1.6,11Hz),5.71(1H,dd,J=1.9,7.8Hz),5.98(1H,dd,J=18,1.6Hz),6.47(1H,dd,J=11,18Hz),6.81-6.90(2H,m),7.01(1H,dd,J=11,8.4Hz),7.12(1H,d,J=8.1Hz),9.17(1H,brs) 1 H-NMR (CDCl 3 ) δ (ppm):
0.29-0.34 (2H, m), 0.58-0.65 (2H, m), 0.83 (3H, t, J = 7.0Hz), 1.16-1.43 (3H, m), 1.56-1.67 (2H, m), 1.79- 2.08 (2H, m), 2.42-2.49 (2H, m), 3.65-3.71 (2H, m), 3.77 (2H, d, J = 7.0Hz), 4.33 (1H, s), 4.40 (2H, dd, J = 14.3,27Hz), 5.32 (1H, dd, J = 1.6,11Hz), 5.71 (1H, dd, J = 1.9,7.8Hz), 5.98 (1H, dd, J = 18,1.6Hz), 6.47 ( 1H, dd, J = 11,18Hz), 6.81-6.90 (2H, m), 7.01 (1H, dd, J = 11,8.4Hz), 7.12 (1H, d, J = 8.1Hz), 9.17 (1H, brs)
実施例123
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-(メトキシメチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン Example 123
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4- (methoxymethyl) -1H-1,2,3 -Triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　参考例86で得られた(S)-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-1-(5-(3-ヒドロキシプロピル)-4-(メトキシメチル)-1H-1,2,3-トリアゾール-1-イル)ブタン-2-オール(105mg)から実施例119の方法に準じて合成することで、標記化合物(57mg、44%)を泡状物質として得た。 (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -1- (5- (3-hydroxypropyl) -4- (methoxymethyl) -1H-1 obtained in Reference Example 86 , 2,3-Triazol-1-yl) butan-2-ol (105 mg) according to the method of Example 119 to give the title compound (57 mg, 44%) as a foam.
1H-NMR(CDCl3)δ(ppm):
0.29-0.35(2H,m),0.58-0.65(2H,m),0.81(3H,t,J=7.3Hz),1.20-1.27(1H,m),1.37-1.48(2H,m),1.59-1.67(2H,m),1.79-2.07(2H,m),2.45-2.52(2H,m),3.28(3H,s),3.66-3.72(2H,m),3.79(2H,d,J=7.0Hz),4.36-4.49(5H,m),5.69(1H,d,J=7.8Hz),6.79-6.85(1H,m),6.92-7.03(2H,m),7.17(1H,d,J=7.8Hz),9.89(1H,brs) 1 H-NMR (CDCl 3 ) δ (ppm):
0.29-0.35 (2H, m), 0.58-0.65 (2H, m), 0.81 (3H, t, J = 7.3Hz), 1.20-1.27 (1H, m), 1.37-1.48 (2H, m), 1.59- 1.67 (2H, m), 1.79-2.07 (2H, m), 2.45-2.52 (2H, m), 3.28 (3H, s), 3.66-3.72 (2H, m), 3.79 (2H, d, J = 7.0 Hz), 4.36-4.49 (5H, m), 5.69 (1H, d, J = 7.8Hz), 6.79-6.85 (1H, m), 6.92-7.03 (2H, m), 7.17 (1H, d, J = 7.8Hz), 9.89 (1H, brs)
実施例124
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-(フルオロメチル)-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 124
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4- (fluoromethyl) -1H-1,2,3 -Triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　参考例87で得られた(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-(フルオロメチル)-1H-1,2,3-トリアゾール-5-イル)ブタン-1-オール(100mg)から実施例119の方法に準じて合成することで、標記化合物(60mg、50%)を泡状物質として得た。 (S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4- (fluoromethyl) -1H-1 obtained in Reference Example 87 , 2,3-Triazol-5-yl) butan-1-ol (100 mg) was synthesized according to the method of Example 119 to give the title compound (60 mg, 50%) as a foam.
1H-NMR(DMSO-d6)δ(ppm):
0.27-0.33(2H,m),0.52-0.59(2H,m),0.67(3H,t,J=7.0Hz),1.13-1.22(1H,m),1.33-1.59(4H,m),1.73-1.81(1H,m),1.97-2.05(1H,m),2.55-2.62(2H,m),3.63(2H,t,J=6.8Hz),3.78(2H,d,J=7.3Hz),4.48(2H,dd,J=14,17Hz),5.34(1H,s),5.37(2H,d,J=49Hz),5.52(1H,d,J=8.1Hz),6.86-6.91(1H,m),6.96-7.00(1H,m),7.09(1H,dd,J=8.4,11Hz),7.59(1H,d,J=7.8Hz),11.2(1H,brs) 1 H-NMR (DMSO-d 6 ) δ (ppm):
0.27-0.33 (2H, m), 0.52-0.59 (2H, m), 0.67 (3H, t, J = 7.0Hz), 1.13-1.22 (1H, m), 1.33-1.59 (4H, m), 1.73- 1.81 (1H, m), 1.97-2.05 (1H, m), 2.55-2.62 (2H, m), 3.63 (2H, t, J = 6.8Hz), 3.78 (2H, d, J = 7.3Hz), 4.48 (2H, dd, J = 14,17Hz), 5.34 (1H, s), 5.37 (2H, d, J = 49Hz), 5.52 (1H, d, J = 8.1Hz), 6.86-6.91 (1H, m) , 6.96-7.00 (1H, m), 7.09 (1H, dd, J = 8.4,11Hz), 7.59 (1H, d, J = 7.8Hz), 11.2 (1H, brs)
実施例125
　(S)-1-((2-(1-(2-(3-(シクロペンチルオキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-(ヒドロキシメチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 125
(S) -1-((2- (1- (2- (3- (cyclopentyloxy) -4-fluorophenyl) -2-hydroxybutyl) -4- (hydroxymethyl) -1H-1,2,3 Of -Triazol-5-yl) ethoxy) methyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　参考例37で得られた(S)-1-アジド-2-(3-(シクロペンチルオキシ)-4-フルオロフェニル)ブタン-2-オール(1.0g)と参考例11で得られたメチル5-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)ペント-2-イノエート(882mg)を1,4-ジオキサン(2.0mL)に溶解し、クロロ(ペンタメチルシクロペンタジエニル)(シクロオクタジエン)ルテニウム(II)(129mg)加え、80℃で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(3%メタノール/クロロホルム)で精製した。得られたメチルエステル体(1.2gの内、500mg)をTHF(4.0mL)に溶解し、水素化ホウ素リチウムのTHF溶液(2.0M,1.38mL)を加え、50℃で3時間撹拌した。反応液に飽和食塩水(10mL)を加え分液し、有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(5%メタノール/クロロホルム)で精製することで、標記化合物(120mg、収率25%)を泡状物質として得た。 (S) -1-azido-2- (3- (cyclopentyloxy) -4-fluorophenyl) butan-2-ol (1.0 g) obtained in Reference Example 37 and methyl 5- ((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) pent-2-inoate (882 mg) was dissolved in 1,4-dioxane (2.0 mL) and chloro (pentamethyl Cyclopentadienyl) (cyclooctadiene) ruthenium (II) (129 mg) was added, and the mixture was stirred at 80 ° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform). The obtained methyl ester compound (500 mg out of 1.2 g) was dissolved in THF (4.0 mL), a THF solution of lithium borohydride (2.0 M, 1.38 mL) was added, and the mixture was stirred at 50 ° C. for 3 hours. Saturated brine (10 mL) was added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol / chloroform) to give the title compound (120 mg, yield 25%) as a foam.
1H-NMR(DMSO-d6)δ(ppm):
0.65(3H,t,J=7.3Hz),1.56-2.04(10H,m),2.93-3.03(2H,m),3.64(2H,t,J=6.2Hz),4.47-4.68(4H,m),4.75-4.80(1H,m),4.99(2H,s),5.27(1H,t,J=5.1Hz),5.48(1H,s),5.54(1H,dd,J=2.2,8.1Hz),6.89-7.13(3H,m),7.55(1H,d,J=8.1Hz),11.3(1H,brs) 1 H-NMR (DMSO-d 6 ) δ (ppm):
0.65 (3H, t, J = 7.3Hz), 1.56-2.04 (10H, m), 2.93-3.03 (2H, m), 3.64 (2H, t, J = 6.2Hz), 4.47-4.68 (4H, m) , 4.75-4.80 (1H, m), 4.99 (2H, s), 5.27 (1H, t, J = 5.1Hz), 5.48 (1H, s), 5.54 (1H, dd, J = 2.2,8.1Hz), 6.89-7.13 (3H, m), 7.55 (1H, d, J = 8.1Hz), 11.3 (1H, brs)
実施例126
　(S)-1-((2-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-4-(フルオロメチル)-1H-1,2,3-トリアゾール-5-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 126
(S) -1-((2- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4- (fluoromethyl) -1H-1,2, Synthesis of 3-triazol-5-yl) ethoxy) methyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
　参考例90で得られた(S)-1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-(トリメチルシリルオキシ)ブチル)-4-(フルオロメチル)-5-(3-(メトキシメトキシ)プロピル)-1H-1,2,3-トリアゾール(35mg)から参考例11の方法に準じて合成することで、標記化合物(17mg、収率17％)を泡状物質として得た。 (S) -1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2- (trimethylsilyloxy) butyl) -4- (fluoromethyl) -5- ( Synthesis from 3- (methoxymethoxy) propyl) -1H-1,2,3-triazole (35 mg) according to the method of Reference Example 11 gave the title compound (17 mg, 17% yield) as a foam. Obtained.
1H-NMR(CDCl3)δ(ppm):
0.30-0.36(2H,m),0.59-0.67(2H,m),0.79(3H,t,J=7.0Hz),1.19-1.29(1H,m),1.71-1.84(1H,m),1.97-2.10(1H,m),2.80(2H,t,J=6.2Hz),3.61-3.71(2H,m),3.80(2H,d,J=7.0Hz),3.90(1H,s),4.48(2H,dd,J=14,30Hz),5.03(2H,s),5.38(2H,d,J=49Hz),5.71(1H,d,J=7.8Hz),6.80-7.02(3H,m),7.07(1H,d,J=8.1Hz),8.90(1H,brs) 1 H-NMR (CDCl 3 ) δ (ppm):
0.30-0.36 (2H, m), 0.59-0.67 (2H, m), 0.79 (3H, t, J = 7.0Hz), 1.19-1.29 (1H, m), 1.71-1.84 (1H, m), 1.97- 2.10 (1H, m), 2.80 (2H, t, J = 6.2Hz), 3.61-3.71 (2H, m), 3.80 (2H, d, J = 7.0Hz), 3.90 (1H, s), 4.48 (2H , dd, J = 14,30Hz), 5.03 (2H, s), 5.38 (2H, d, J = 49Hz), 5.71 (1H, d, J = 7.8Hz), 6.80-7.02 (3H, m), 7.07 (1H, d, J = 8.1Hz), 8.90 (1H, brs)
実施例127
　(S)-1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-5-(2-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)エチル)-N,N-ジメチル-1H-1,2,3-トリアゾール-4-カルボキサミドの合成 Example 127
(S) -1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -5- (2-((2,4-dioxo-3,4-dihydropyrimidine- Synthesis of 1 (2H) -yl) methoxy) ethyl) -N, N-dimethyl-1H-1,2,3-triazole-4-carboxamide
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　参考例34で得られた(S)-1-アジド-2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)ブタン-2-オール(3.68g)と参考例11から得られるメチル5-((2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)ペント-2-イノエート(3.0g)を1,4-ジオキサン(70mL)に溶解し、クロロ(ペンタメチルシクロペンタジエニル)(シクロオクタジエン)ルテニウム(II)(456mg)加え、80℃で2時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2.5%メタノール/クロロホルム)で精製した。得られたメチルエステル体(5.8g)をメタノール(7.0mL)、水(5.0mL)に溶解し、水酸化ナトリウム水溶液(4.0M,8.1mL)を加え、50℃で4時間撹拌した。強酸性陽イオン交換樹脂(DIAIONPK212,H+form)を加え反応液を酸性にした後、樹脂を濾去し、メタノール(50mL)及び水(50mL)で洗浄後、合一した濾液を減圧濃縮し、残渣をトルエン(20mL×4)で共沸した。 (S) -1-azido-2- (3- (cyclopropylmethoxy) -4-fluorophenyl) butan-2-ol (3.68 g) obtained in Reference Example 34 and methyl 5- ((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) pent-2-inoate (3.0 g) was dissolved in 1,4-dioxane (70 mL) and chloro (pentamethyl Cyclopentadienyl) (cyclooctadiene) ruthenium (II) (456 mg) was added, and the mixture was stirred at 80 ° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform). The obtained methyl ester (5.8 g) was dissolved in methanol (7.0 mL) and water (5.0 mL), an aqueous sodium hydroxide solution (4.0 M, 8.1 mL) was added, and the mixture was stirred at 50 ° C. for 4 hr. After strongly acidic cation exchange resin (DIAIONPK212, H + form) was added to acidify the reaction solution, the resin was filtered off, washed with methanol (50 mL) and water (50 mL), and the combined filtrate was concentrated under reduced pressure. The residue was azeotroped with toluene (20 mL × 4).
　得られたカルボン酸(4.3g)をDMF(30mL)に溶解し、EDC・HCl(2.4g)、HOBt(1.46g)、トリエチルアミン(2.42mL)及び容易に入手可能なジメチルアミン塩酸塩(1.35g)を加え、室温で3時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(5%メタノール/クロロホルム)で精製することで、標記化合物(3.8g、収率84%)を泡状物質として得た。 The resulting carboxylic acid (4.3 g) was dissolved in DMF (30 mL), EDCHCl (2.4 g), HOBt (1.46 g), triethylamine (2.42 mL) and readily available dimethylamine hydrochloride (1.35 g). ) Was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / chloroform) to give the title compound (3.8 g, yield 84%) as a foam.
1H-NMR(CDCl3)δ(ppm):
0.30-0.36(2H,m),0.60-0.67(2H,m),0.80(3H,t,J=7.3Hz),1.19-1.30(1H,m),1.70-2.08(2H,m),2.91-3.11(5H,m),3.39(3H,s),3.75-3.88(4H,m),4.52(2H,dd,J=14,18Hz),5.02(2H,s),5.66(1H,dd,J=2.2,7.8Hz),6.80-6.86(1H,m),6.97-7.09(3H,m),8.71(1H,brs) 1 H-NMR (CDCl 3 ) δ (ppm):
0.30-0.36 (2H, m), 0.60-0.67 (2H, m), 0.80 (3H, t, J = 7.3Hz), 1.19-1.30 (1H, m), 1.70-2.08 (2H, m), 2.91- 3.11 (5H, m), 3.39 (3H, s), 3.75-3.88 (4H, m), 4.52 (2H, dd, J = 14,18Hz), 5.02 (2H, s), 5.66 (1H, dd, J = 2.2,7.8Hz), 6.80-6.86 (1H, m), 6.97-7.09 (3H, m), 8.71 (1H, brs)
実施例128
　1-(2,2-ビス(4-クロロフェニル)-2-ヒドロキシエチル)-5-(3-(2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)プロピル)-N-メチルl-1H-1,2,3-トリアゾール-4-カルボキサミドの合成 Example 128
1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -5- (3- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) propyl) -N Of 2-methyll-1H-1,2,3-triazole-4-carboxamide
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　参考例88により得られるメチル1-(2,2-ビス(4-クロロフェニル)-2-ヒドロキシエチル)-5-(3-ヒドロキシプロピル)-1H-1,2,3-トリアゾール-4-カルボキシレート(80mg)から実施例119の方法に準じて合成することで、標記化合物(53mg、55%)を泡状物質として得た。 Methyl 1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -5- (3-hydroxypropyl) -1H-1,2,3-triazole-4-carboxylate obtained by Reference Example 88 The title compound (53 mg, 55%) was obtained as a foam by synthesis from (80 mg) according to the method of Example 119.
1H-NMR(DMSO-d6)δ(ppm):
1.79-1.91(2H,m),2.70(3H,d,J=4.6Hz),2.89-2.95(2H,m),3.69(2H,t,J=6.8Hz),5.12(2H,s),5.56(1H,d,J=7.9Hz),6.50(1H,s),7.34-7.42(8H,m),7.61(1H,d,J=7.9Hz),8.27(1H,q,J=4.6Hz),11.23(1H,brs) 1 H-NMR (DMSO-d 6 ) δ (ppm):
1.79-1.91 (2H, m), 2.70 (3H, d, J = 4.6Hz), 2.89-2.95 (2H, m), 3.69 (2H, t, J = 6.8Hz), 5.12 (2H, s), 5.56 (1H, d, J = 7.9Hz), 6.50 (1H, s), 7.34-7.42 (8H, m), 7.61 (1H, d, J = 7.9Hz), 8.27 (1H, q, J = 4.6Hz) , 11.23 (1H, brs)
実施例129
　1-(2,2-ビス(4-クロロフェニル)-2-ヒドロキシエチル)-5-(3-(2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)プロピル)-N,N-ジメチル-1H-1,2,3-トリアゾール-4-カルボキサミドの合成 Example 129
1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -5- (3- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) propyl) -N Of N, N-dimethyl-1H-1,2,3-triazole-4-carboxamide
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　参考例89により得られる1-(2,2-ビス(4-クロロフェニル)-2-ヒドロキシエチル)-5-(3-ヒドロキシプロピル)-N,N-ジメチル-1H-1,2,3-トリアゾール-4-カルボキサミド(80mg)から実施例119の方法に準じて合成することで、標記化合物(61mg、63%)を泡状物質として得た。 1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -5- (3-hydroxypropyl) -N, N-dimethyl-1H-1,2,3-triazole obtained by Reference Example 89 The title compound (61 mg, 63%) was obtained as a foam by synthesis from 4-carboxamide (80 mg) according to the method of Example 119.
1H-NMR(DMSO-d6)δ(ppm):
1.70-1.85(2H,m),2.71-2.78(2H,m),2.93(3H,s),3.09(3H,s),3.64(2H,t,J=7.0Hz),5.08(2H,s),5.55(1H,d,J=7.8Hz),6.49(1H,brs),7.31-7.42(8H,m),7.57(1H,d,J=7.8Hz) 1 H-NMR (DMSO-d 6 ) δ (ppm):
1.70-1.85 (2H, m), 2.71-2.78 (2H, m), 2.93 (3H, s), 3.09 (3H, s), 3.64 (2H, t, J = 7.0Hz), 5.08 (2H, s) , 5.55 (1H, d, J = 7.8Hz), 6.49 (1H, brs), 7.31-7.42 (8H, m), 7.57 (1H, d, J = 7.8Hz)
実施例130及び131
　1-(4-(1-(3-(シクロプロピルメトキシ)フェネチル)-4-メチル-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオン及び1-(4-(1-(3-(シクロプロピルメトキシ)フェネチル)-4-メチル-1H-1,2,3-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Examples 130 and 131
1- (4- (1- (3- (cyclopropylmethoxy) phenethyl) -4-methyl-1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H)- Dione and 1- (4- (1- (3- (cyclopropylmethoxy) phenethyl) -4-methyl-1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H ) -Dione synthesis
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
　参考例91で得られた4-(1-(3-(シクロプロピルメトキシ)フェネチル)-4-メチル-1H-1,2,3-トリアゾール-5-イル)ブタン-1-オールと4-(1-(3-(シクロプロピルメトキシ)フェネチル)-5-メチル-1H-1,2,3-トリアゾール-4-イル)ブタン-1-オールの位置異性体混合物(151mg)から実施例119の方法に準じて合成し、得られた位置異性体混合物を逆相カラムクロマトグラフィー(RP-18,50%メタノール水溶液)で分離することで、標記化合物(実施例130：54mg,収率39%、実施例131：40mg,収率29%)をそれぞれ泡状物質として得た。 4- (1- (3- (cyclopropylmethoxy) phenethyl) -4-methyl-1H-1,2,3-triazol-5-yl) butan-1-ol obtained in Reference Example 91 and 4- ( The method of Example 119 from a regioisomer mixture (151 mg) of 1- (3- (cyclopropylmethoxy) phenethyl) -5-methyl-1H-1,2,3-triazol-4-yl) butan-1-ol The title compound (Example 130: 54 mg, 39% yield) was obtained by separating the regioisomer mixture obtained by reverse phase column chromatography (RP-18, 50% aqueous methanol solution). Example 131: 40 mg, 29% yield) was obtained as foam.
実施例130
1H-NMR(DMSO-d6)δ(ppm):
0.26-0.28(2H,m),0.52-0.56(2H,m),1.10-1.30(3H,m),1.46-1.51(2H,m),2.11(3H,s),2.43-2.50(2H,m),3.04(2H,t,J=7.3Hz),3.59(2H,t,J=7.0Hz),3.71(2H,d,J=7.0Hz),4.39(2H,t,J=7.0Hz),5.51(1H,d,J=8.1Hz),6.66-6.76(3H,m),7.13(1H,t,J=7.6Hz),7.57(1H,d,J=7.8Hz),11.2(1H,brs) Example 130
1 H-NMR (DMSO-d 6 ) δ (ppm):
0.26-0.28 (2H, m), 0.52-0.56 (2H, m), 1.10-1.30 (3H, m), 1.46-1.51 (2H, m), 2.11 (3H, s), 2.43-2.50 (2H, m ), 3.04 (2H, t, J = 7.3Hz), 3.59 (2H, t, J = 7.0Hz), 3.71 (2H, d, J = 7.0Hz), 4.39 (2H, t, J = 7.0Hz), 5.51 (1H, d, J = 8.1Hz), 6.66-6.76 (3H, m), 7.13 (1H, t, J = 7.6Hz), 7.57 (1H, d, J = 7.8Hz), 11.2 (1H, brs )
実施例131
1H-NMR(DMSO-d6)δ(ppm):
0.27-0.31(2H,m),0.51-0.56(2H,m),1.10-1.26(1H,m),1.51(4H,m),1.94(3H,s),2.47-2.50(2H,m),3.00(2H,t,J=7.3Hz),3.63(2H,t,J=6.5Hz),3.72(2H,d,J=6.7Hz),4.40(2H,t,J=7.0Hz),5.48(1H,d,J=7.8Hz),6.60-6.75(3H,m),7.12(1H,t,J=7.8Hz),7.56(1H,d,J=7.8Hz),11.1(1H,brs) Example 131
1 H-NMR (DMSO-d 6 ) δ (ppm):
0.27-0.31 (2H, m), 0.51-0.56 (2H, m), 1.10-1.26 (1H, m), 1.51 (4H, m), 1.94 (3H, s), 2.47-2.50 (2H, m), 3.00 (2H, t, J = 7.3Hz), 3.63 (2H, t, J = 6.5Hz), 3.72 (2H, d, J = 6.7Hz), 4.40 (2H, t, J = 7.0Hz), 5.48 ( 1H, d, J = 7.8Hz), 6.60-6.75 (3H, m), 7.12 (1H, t, J = 7.8Hz), 7.56 (1H, d, J = 7.8Hz), 11.1 (1H, brs)
実施例132
　1-(4-(5-(3-(シクロプロピルメトキシ)フェネチル)-1H-1,2,3-トリアゾール-1-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 132
Synthesis of 1- (4- (5- (3- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-1-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　参考例92で得られた1-(ブト-3-イニル)-3-(シクロプロピルメトキシ)ベンゼン(60mg)と参考例94から得られる1-(4-アジドブチル)ピリミジン-2,4(1H,3H)-ジオン(40mg)から実施例1の方法に準じて合成することで、標記化合物(53mg、収率65%)を泡状物質として得た。 1- (but-3-ynyl) -3- (cyclopropylmethoxy) benzene (60 mg) obtained in Reference Example 92 and 1- (4-azidobutyl) pyrimidine-2,4 (1H, obtained from Reference Example 94 Synthesis from 3H) -dione (40 mg) according to the method of Example 1 gave the title compound (53 mg, 65% yield) as a foam.
1H-NMR(CDCl3)δ(ppm):
0.31-0.37(2H,m),0.61-0.68(2H,m),1.18-1.32(1H,m),1.60-1.70(2H,m),1.77-1.87(2H,m),2.93(4H,s),3.69(2H,t,J=7.3Hz),3.77(2H,d,J=7.0Hz),4.15(2H,t,J=6.5Hz),5.69(1H,dd,J=2.2,7.8Hz),6.70-6.79(3H,m),7.12(1H,d,J=7.8Hz),7.20(1H,t,J=7.8Hz),7.49(1H,s),8.61(1H,brs) 1 H-NMR (CDCl 3 ) δ (ppm):
0.31-0.37 (2H, m), 0.61-0.68 (2H, m), 1.18-1.32 (1H, m), 1.60-1.70 (2H, m), 1.77-1.87 (2H, m), 2.93 (4H, s ), 3.69 (2H, t, J = 7.3Hz), 3.77 (2H, d, J = 7.0Hz), 4.15 (2H, t, J = 6.5Hz), 5.69 (1H, dd, J = 2.2, 7.8Hz) ), 6.70-6.79 (3H, m), 7.12 (1H, d, J = 7.8Hz), 7.20 (1H, t, J = 7.8Hz), 7.49 (1H, s), 8.61 (1H, brs)
実施例133
　1-(3-(5-(2,2-ビス(4-クロロフェニル)-2-ヒドロキシエチル)-1H-1,2,3-トリアゾール-1-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 133
1- (3- (5- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-1-yl) propyl) pyrimidine-2,4 (1H, Synthesis of (3H) -dione
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　参考例93で得られた1,1-ビス(4-クロロフェニル)ブト-3-イン-1-オール(80mg)と参考例95で得られた1-(3-アジドプロピル)ピリミジン-2,4(1H,3H)-ジオン(54mg)から実施例1の方法に準じて合成することで、標記化合物(60mg、収率46%)を泡状物質として得た。 1,1-bis (4-chlorophenyl) but-3-yn-1-ol (80 mg) obtained in Reference Example 93 and 1- (3-azidopropyl) pyrimidine-2,4 obtained in Reference Example 95 The title compound (60 mg, 46% yield) was obtained as a foam by synthesis from (1H, 3H) -dione (54 mg) according to the method of Example 1.
1H-NMR(DMSO-d6)δ(ppm):
1.97-2.06(2H,m),3.64-3.69(4H,m),4.22(2H,t,J=7.3Hz),5.55(1H,d,J=7.8Hz),6.29(1H,brs),6.95(1H,s),7.34(4H,d,J=8.4Hz),7.44(4H,d,J=8.4Hz),7.58(1H,d,J=7.8Hz) 1 H-NMR (DMSO-d 6 ) δ (ppm):
1.97-2.06 (2H, m), 3.64-3.69 (4H, m), 4.22 (2H, t, J = 7.3Hz), 5.55 (1H, d, J = 7.8Hz), 6.29 (1H, brs), 6.95 (1H, s), 7.34 (4H, d, J = 8.4Hz), 7.44 (4H, d, J = 8.4Hz), 7.58 (1H, d, J = 7.8Hz)
実施例134
　1-((2-(5-(3-(シクロプロピルメトキシ)フェネチル)-1H-テトラゾール-1-イル)エトキシ)メチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 134
Synthesis of 1-((2- (5- (3- (cyclopropylmethoxy) phenethyl) -1H-tetrazol-1-yl) ethoxy) methyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　参考例96で得られたN-(2-((3-ベンゾイル-2,4-ジオキソ-3,4-ジヒドロピリミジン-1(2H)-イル)メトキシ)エチル)-3-(3-(シクロプロピルメトキシ)フェニル)プロパンアミド(350mg)をTHF(10mL)に溶解し、トリフェニルホスフィン(374mg)、アゾジカルボン酸ジイソプロピルのトルエン溶液(1.9M,747μL)及びトリメチルシリルアジド(186μL)を加え50℃で10時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(1.5%メタノール/クロロホルム)で精製した。得られた化合物をメチルアミンのメタノール溶液(40%,3.0mL)に溶解し、室温で30分撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(2.5%メタノール/クロロホルム)で精製することで、標記化合物(150mg、収率51%)を無色ガム状物質として得た。 N- (2-((3-benzoyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) ethyl) -3- (3- (cyclo (cyclohexane)) obtained in Reference Example 96 Propylmethoxy) phenyl) propanamide (350 mg) was dissolved in THF (10 mL), triphenylphosphine (374 mg), toluene solution of diisopropyl azodicarboxylate (1.9 M, 747 μL) and trimethylsilyl azide (186 μL) were added at 50 ° C. Stir for 10 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1.5% methanol / chloroform). The obtained compound was dissolved in a methanol solution of methylamine (40%, 3.0 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to give the title compound (150 mg, yield 51%) as a colorless gum.
1H-NMR(CDCl3)δ(ppm):
0.31-0.37(2H,m),0.61-0.68(2H,m),1.19-1.29(1H,m),3.14(4H,s),3.76(2H,d,J=7.0Hz),3.91(2H,t,J=5.4Hz),4.17(2H,t,J=5.4Hz),4.99(2H,s),5.70(1H,d,J=8.1Hz),6.68-6.78(3H,m),6.98(1H,d,J=7.8Hz),7.19(1H,t,J=7.8Hz),8.20(1H,brs) 1 H-NMR (CDCl 3 ) δ (ppm):
0.31-0.37 (2H, m), 0.61-0.68 (2H, m), 1.19-1.29 (1H, m), 3.14 (4H, s), 3.76 (2H, d, J = 7.0Hz), 3.91 (2H, t, J = 5.4Hz), 4.17 (2H, t, J = 5.4Hz), 4.99 (2H, s), 5.70 (1H, d, J = 8.1Hz), 6.68-6.78 (3H, m), 6.98 ( 1H, d, J = 7.8Hz), 7.19 (1H, t, J = 7.8Hz), 8.20 (1H, brs)
実施例135
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-1H-ピロール-2-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 135
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -1H-pyrrol-2-yl) butyl) pyrimidine-2, Synthesis of 4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　参考例99で得られた(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-1H-ピロール2-イル)ブタン-1-オール(105mg)から実施例119の方法に準じて合成することで、標記化合物(94mg、収率75%)を泡状物質として得た。 (S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -1H-pyrrol-2-yl) butane-1 obtained in Reference Example 99 The title compound (94 mg, yield 75%) was obtained as a foam by synthesis from -ol (105 mg) according to the method of Example 119.
1H-NMR(DMSO-d6)δ(ppm):
0.25-0.26(2H,m),0.52-0.55(2H,m),0.67(3H,t,J=7.3Hz),1.11-1.20(1H,m),1.31-1.35(2H,m),1.48-1.51(2H,m),1.60-1.72(1H,m),1.90-1.97(1H,m),2.07-2.10(2H,m),3.60(2H,t,J=6.8Hz),3.71(2H,d,J=7.0Hz),3.88(2H,s),5.05(1H,s),5.51(1H,d,J=7.8Hz),5.56-5.57(1H,m),5.78(1H,t,J=3.2Hz),6.51-6.53(1H,m),6.78-6.85(2H,m),7.01-7.10(1H,m),7.59(1H,d,J=7.8Hz),11.2(1H,brs) 1 H-NMR (DMSO-d 6 ) δ (ppm):
0.25-0.26 (2H, m), 0.52-0.55 (2H, m), 0.67 (3H, t, J = 7.3Hz), 1.11-1.20 (1H, m), 1.31-1.35 (2H, m), 1.48- 1.51 (2H, m), 1.60-1.72 (1H, m), 1.90-1.97 (1H, m), 2.07-2.10 (2H, m), 3.60 (2H, t, J = 6.8Hz), 3.71 (2H, d, J = 7.0Hz), 3.88 (2H, s), 5.05 (1H, s), 5.51 (1H, d, J = 7.8Hz), 5.56-5.57 (1H, m), 5.78 (1H, t, J = 3.2Hz), 6.51-6.53 (1H, m), 6.78-6.85 (2H, m), 7.01-7.10 (1H, m), 7.59 (1H, d, J = 7.8Hz), 11.2 (1H, brs)
実施例136
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-3-メチル-1H-1,2,4-トリアゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 136
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -3-methyl-1H-1,2,4-triazole- Synthesis of 5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
　参考例100で得られた(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-3-メチル-1H-1,2,4-トリアゾール-5-イル)ブタン-1-オール(120mg)から実施例119の方法に準じて合成することで、標記化合物(80mg、収率53%)を泡状物質として得た。 (S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -3-methyl-1H-1,2, obtained in Reference Example 100 Synthesis from 4-triazol-5-yl) butan-1-ol (120 mg) according to the method of Example 119 gave the title compound (80 mg, 53% yield) as a foam.
1H-NMR(DMSO-d6)δ(ppm):
0.29-0.33(2H,m),0.52-0.59(2H,m),0.66(3H,t,J=7.0Hz),1.13-1.23(1H,m),1.46-1.48(4H,m),1.73-1.83(1H,m),1.90-2.00(1H,m),2.14(3H,s),2.29-2.33(2H,m),3.69(2H,t,J=6.8Hz),3.78(2H,d,J=7.3Hz),4.15(2H,d,J=4.6Hz),5.29(1H,s),5.53(1H,d,J=7.8Hz),6.90-7.12(3H,m),7.59(1H,d,J=7.8Hz),11.2(1H,brs) 1 H-NMR (DMSO-d 6 ) δ (ppm):
0.29-0.33 (2H, m), 0.52-0.59 (2H, m), 0.66 (3H, t, J = 7.0Hz), 1.13-1.23 (1H, m), 1.46-1.48 (4H, m), 1.73- 1.83 (1H, m), 1.90-2.00 (1H, m), 2.14 (3H, s), 2.29-2.33 (2H, m), 3.69 (2H, t, J = 6.8Hz), 3.78 (2H, d, J = 7.3Hz), 4.15 (2H, d, J = 4.6Hz), 5.29 (1H, s), 5.53 (1H, d, J = 7.8Hz), 6.90-7.12 (3H, m), 7.59 (1H, d, J = 7.8Hz), 11.2 (1H, brs)
実施例137
　(S)-1-(4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-3-メチル-1H-ピラゾール-5-イル)ブチル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 137
(S) -1- (4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -3-methyl-1H-pyrazol-5-yl) butyl) Synthesis of pyrimidine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
　参考例102で得られた(S)-4-(1-(2-(3-(シクロプロピルメトキシ)-4-フルオロフェニル)-2-ヒドロキシブチル)-3-メチル-1H-ピラゾール-5-イル)ブタン-1-オール(71mg)から実施例119の方法に準じて合成することで、標記化合物(70mg、収率80%)を泡状物質として得た。 (S) -4- (1- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -3-methyl-1H-pyrazole-5- obtained in Reference Example 102 Synthesis from yl) butan-1-ol (71 mg) according to the method of Example 119 gave the title compound (70 mg, 80% yield) as a foam.
1H-NMR(DMSO-d6)δ(ppm):
0.27-0.29(2H,m),0.53-0.57(2H,m),0.66(3H,t,J=7.0Hz),1.10-1.60(4H,m),1.65-1.75(1H,m),1.88-2.01(1H,m),2.08(3H,s),2.17(1H,t,J=8.4Hz),3.59(2H,t,J=7.3Hz),3.74(2H,d,J=7.0Hz),4.07(2H,dd,J=14,47Hz),5.52(2H,d,J=7.8Hz),5.67-5.69(2H,m),6.81-6.86(2H,m),7.00-7.07(1H,m),7.58(1H,d,J=7.5Hz),11.2(1H,brs) 1 H-NMR (DMSO-d 6 ) δ (ppm):
0.27-0.29 (2H, m), 0.53-0.57 (2H, m), 0.66 (3H, t, J = 7.0Hz), 1.10-1.60 (4H, m), 1.65-1.75 (1H, m), 1.88- 2.01 (1H, m), 2.08 (3H, s), 2.17 (1H, t, J = 8.4Hz), 3.59 (2H, t, J = 7.3Hz), 3.74 (2H, d, J = 7.0Hz), 4.07 (2H, dd, J = 14,47Hz), 5.52 (2H, d, J = 7.8Hz), 5.67-5.69 (2H, m), 6.81-6.86 (2H, m), 7.00-7.07 (1H, m ), 7.58 (1H, d, J = 7.5Hz), 11.2 (1H, brs)
実施例138
　1-(3-(4-(2,2-ビス(4-クロロフェニル)エチル)-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾール-3-イル)プロピル)ピリミジン-2,4(1H,3H)-ジオンの合成 Example 138
1- (3- (4- (2,2-bis (4-chlorophenyl) ethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) propyl) pyrimidine- Synthesis of 2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　参考例103で得られたtert-ブチル4-(2,2-ビス(4-クロロフェニル)エチル)-3-(3-ヒドロキシプロピル)-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾール-1-カルボキシレート(73mg)をTHF(1.5mL)に溶解し、トリフェニルホスフィン(51mg)、文献(J. Med. Chem., 49, 4183-4195(2006))記載の方法で得られたN3-ベンゾイルウラシル(35mg)及びアゾカルボン酸ジイソプロピルのトルエン溶液(1.9M、101μL)を加え室温で45分撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(70%酢酸エチル/ヘキサン)で精製した。得られた化合物をメチルアミンのメタノール溶液(40%,1.5mL)に溶解し、室温で1時間撹拌した。反応液を減圧濃縮し、残渣をトルエン(2.0mL×2)で共沸した。残渣を塩化水素-ジオキサン溶液(4.0M,1.5mL)に溶解し、室温で1時間撹拌した。反応液を減圧濃縮し、残渣をトルエン(2.0mL×3)で共沸した後、シリカゲルカラムクロマトグラフィー(8%メタノール/クロロホルム)で精製することで、標記化合物(48mg、収率66%)を泡状物質として得た。 Tert-butyl 4- (2,2-bis (4-chlorophenyl) ethyl) -3- (3-hydroxypropyl) -5-oxo-4,5-dihydro-1H-1,2 obtained in Reference Example 103 1,4-triazole-1-carboxylate (73 mg) dissolved in THF (1.5 mL), triphenylphosphine (51 mg), a method described in the literature (J. Med. Chem., 49, 4183-4195 (2006)) N3-benzoyluracil (35 mg) obtained in (1) and a toluene solution (1.9 M, 101 μL) of diisopropyl azocarboxylate were added and stirred at room temperature for 45 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (70% ethyl acetate / hexane). The obtained compound was dissolved in a methanol solution of methylamine (40%, 1.5 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene (2.0 mL × 2). The residue was dissolved in a hydrogen chloride-dioxane solution (4.0 M, 1.5 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene (2.0 mL × 3) and purified by silica gel column chromatography (8% methanol / chloroform) to give the title compound (48 mg, 66% yield). Obtained as a foam.
1H-NMR(DMSO-d6)δ(ppm):
1.66-1.77(2H,m),2.14-2.19(2H,m),3.62(2H,t,J=6.9Hz),4.13(2H,d,J=8.1Hz),4.51(1H,t,J=8.7Hz),5.54(1H,d,J=7.9Hz),7.29-7.37(8H,m),7.54(1H,d,J=7.9Hz),11.23(1H,brs),11.39(1H,brs) 1 H-NMR (DMSO-d 6 ) δ (ppm):
1.66-1.77 (2H, m), 2.14-2.19 (2H, m), 3.62 (2H, t, J = 6.9Hz), 4.13 (2H, d, J = 8.1Hz), 4.51 (1H, t, J = 8.7Hz), 5.54 (1H, d, J = 7.9Hz), 7.29-7.37 (8H, m), 7.54 (1H, d, J = 7.9Hz), 11.23 (1H, brs), 11.39 (1H, brs)
実施例139
　1-((2-(2-(1H-1,2,3-トリアゾール-1-イル)エチル)ベンジルオキシ)メチル)ピリミジン-2,4-(1H,3H)-ジオンの合成 Example 139
Synthesis of 1-((2- (2- (1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
　参考例104で得られた化合物（49mg）をトルエン（4.0mL）に溶解し、容易に入手可能なトリメチルシリルアセチレン（1.1mL）を加え120℃で60時間撹拌した。反応液を放冷後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（2%メタノール/クロロホルム）で精製した。得られた無色泡状物質（60mg）の内、一部（42mg）をTHF（2.0mL）に溶解し、TBAFのTHF溶液（1.0M,158μL）を加え70℃で4時間撹拌した。反応液を減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（4%メタノール/クロロホルム）で精製することで、標記化合物（33mg,収率96%）を泡状物質として得た。 The compound (49 mg) obtained in Reference Example 104 was dissolved in toluene (4.0 mL), and readily available trimethylsilylacetylene (1.1 mL) was added, and the mixture was stirred at 120 ° C. for 60 hours. The reaction solution was allowed to cool and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform). A part (42 mg) of the obtained colorless foamy substance (60 mg) was dissolved in THF (2.0 mL), a THF solution of TBAF (1.0 M, 158 μL) was added, and the mixture was stirred at 70 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (4% methanol / chloroform) to give the title compound (33 mg, yield 96%) as a foam.
1H-NMR(DMSO-d6)δ(ppm):
3.13-3.18(2H,m),4.56-4.61(4H,m),5.17(2H,s),5.58(1H,d,J=7.9Hz),7.06-7.33(4H,m),7.67(1H,d,J=0.9Hz),7.72(1H,d,J=7.9Hz),7.99(1H,d,J=0.9Hz),11.33(1H,brs) 1 H-NMR (DMSO-d 6 ) δ (ppm):
3.13-3.18 (2H, m), 4.56-4.61 (4H, m), 5.17 (2H, s), 5.58 (1H, d, J = 7.9Hz), 7.06-7.33 (4H, m), 7.67 (1H, d, J = 0.9Hz), 7.72 (1H, d, J = 7.9Hz), 7.99 (1H, d, J = 0.9Hz), 11.33 (1H, brs)
実施例140～142
　以下の化合物は参考例104～106の化合物と容易に入手可能若しくは文献（実施例140：J. Org. Chem., 53, 2489-2496(1988)）記載の方法で得られたアセチレン化合物から、実施例139の方法に準じて合成した。 Examples 140-142
The following compounds are readily available from the compounds of Reference Examples 104 to 106 or from acetylene compounds obtained by the method described in the literature (Example 140: J. Org. Chem., 53, 2489-2496 (1988)). Synthesized according to the method of Example 139.
実施例140
　1-((2-(2-(5-(チアゾール-2-イル)-(1H-1,2,3-トリアゾール-1-イル)エチル)ベンジルオキシ)メチル)ピリミジン-2,4-(1H,3H)-ジオン Example 140
1-((2- (2- (5- (thiazol-2-yl)-(1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H , 3H) -Dione
実施例141
　1-((2-(2-(5-フェニル-1H-1,2,3-トリアゾール-1-イル)エチル)ベンジルチオ)メチル)ピリミジン-2,4-(1H,3H)-ジオン Example 141
1-((2- (2- (5-phenyl-1H-1,2,3-triazol-1-yl) ethyl) benzylthio) methyl) pyrimidine-2,4- (1H, 3H) -dione
実施例142
　1-((2-(2-(5-フェニル-(1H-1,2,3-トリアゾール-1-イル)プロピル)ベンジルオキシ)メチル)ピリミジン-2,4-(1H,3H)-ジオン Example 142
1-((2- (2- (5-Phenyl- (1H-1,2,3-triazol-1-yl) propyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
実施例143及び144
　1-((2-(2-(5-フェニル-1H-1,2,3-トリアゾール-1-イル)エチル)ベンジルオキシ)メチル)ピリミジン-2,4-(1H,3H)-ジオン及び1-((2-(2-(4-フェニル-1H-1,2,3-トリアゾール-1-イル)エチル)ベンジルオキシ)メチル)ピリミジン-2,4-(1H,3H)-ジオンの合成 Examples 143 and 144
1-((2- (2- (5-phenyl-1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione and 1 Synthesis of-((2- (2- (4-phenyl-1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
　参考例104で得られた化合物（200mg）をトルエン（10mL）に溶解し、容易に入手可能なフェニルアセチレン（203μL）を加え120℃で72時間撹拌した。反応液を放冷後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（2%メタノール/クロロホルム）、及びC18逆相カラムクロマトグラフィー（50%メタノール/水）で精製することで、標記化合物（実施例143：88mg,収率33%、実施例144：92mg,収率34%）を泡状物質として得た。 The compound (200 mg) obtained in Reference Example 104 was dissolved in toluene (10 mL), easily available phenylacetylene (203 μL) was added, and the mixture was stirred at 120 ° C. for 72 hours. The reaction solution is allowed to cool and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (2% methanol / chloroform) and C18 reverse phase column chromatography (50% methanol / water) to give the title compound (Example). 143: 88 mg, yield 33%, Example 144: 92 mg, yield 34%) was obtained as a foam.
実施例143
1H-NMR(CDCl3)δ(ppm):
3.26(2H,t,J=7.3Hz),4.56(2H,s),4.62(2H,t,J=7.3Hz),5.16(2H,s),5.69(1H,d,J=8.1Hz),7.10-7.13(1H,m),7.24-7.40(7H,m),7.54(1H,s),7.75(2H,d,J=8.1Hz),9.69(1H,brs) Example 143
1 H-NMR (CDCl 3 ) δ (ppm):
3.26 (2H, t, J = 7.3Hz), 4.56 (2H, s), 4.62 (2H, t, J = 7.3Hz), 5.16 (2H, s), 5.69 (1H, d, J = 8.1Hz), 7.10-7.13 (1H, m), 7.24-7.40 (7H, m), 7.54 (1H, s), 7.75 (2H, d, J = 8.1Hz), 9.69 (1H, brs)
実施例144
1H-NMR(DMSO-d6)δ(ppm):
3.08(2H,t,J=7.3Hz),4.38(2H,s),4.57(2H,t,J=7.3Hz),5.03(2H,s),5.57(1H,dd,J=2.2,7.9Hz),6.81-6.85(1H,m),7.09-7.30(5H,m),7.43-7.46(3H,m),7.62(1H,d,J=7.9Hz),7.80(1H,s),11.31(1H,brs) Example 144
1 H-NMR (DMSO-d 6 ) δ (ppm):
3.08 (2H, t, J = 7.3Hz), 4.38 (2H, s), 4.57 (2H, t, J = 7.3Hz), 5.03 (2H, s), 5.57 (1H, dd, J = 2.2,7.9Hz) ), 6.81-6.85 (1H, m), 7.09-7.30 (5H, m), 7.43-7.46 (3H, m), 7.62 (1H, d, J = 7.9Hz), 7.80 (1H, s), 11.31 ( 1H, brs)
実施例145
　1-((2-(2-(4,5-ジフェニル-1H-1,2,3-トリアゾール-1-イル)エチル)ベンジルオキシ)メチル)ピリミジン-2,4-(1H,3H)-ジオンの合成 Example 145
1-((2- (2- (4,5-diphenyl-1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione Synthesis of
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　参考例104で得られた化合物（30mg）をトルエン（2.0mL）に溶解し、容易に入手可能なジフェニルアセチレン（54mg）を加え120℃で96時間撹拌した。反応液を放冷後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（1%メタノール/クロロホルム）で精製することで、標記化合物（33mg,収率69%）を無色泡状物質として得た。 The compound (30 mg) obtained in Reference Example 104 was dissolved in toluene (2.0 mL), readily available diphenylacetylene (54 mg) was added, and the mixture was stirred at 120 ° C. for 96 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol / chloroform) to give the title compound (33 mg, yield 69%) as a colorless foam.
1H-NMR(DMSO-d6)δ(ppm):
3.08(2H,t,J=7.3Hz),4.33-4.39(4H,m),5.02(2H,s),5.58(1H,d,J=7.9Hz),6.80-6.83(1H,m),7.11-7.31(8H,m),7.38-7.51(5H,m),7.63(1H,d,J=7.9Hz),11.31(1H,brs) 1 H-NMR (DMSO-d 6 ) δ (ppm):
3.08 (2H, t, J = 7.3Hz), 4.33-4.39 (4H, m), 5.02 (2H, s), 5.58 (1H, d, J = 7.9Hz), 6.80-6.83 (1H, m), 7.11 -7.31 (8H, m), 7.38-7.51 (5H, m), 7.63 (1H, d, J = 7.9Hz), 11.31 (1H, brs)
比較例１
　1-((2-トリチルオキシ)エトキシ)メチル)ピリミジン-2,4-(1H,3H)-ジオン Comparative Example 1
1-((2-trityloxy) ethoxy) methyl) pyrimidine-2,4- (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
　前記化合物は国際公開2005-065689号に、最もヒトデオキシウリジントリホスファターゼ（以下、dUTPase）阻害活性の強い化合物として記載されており、本発明化合物と活性の比較をするため国際公開WO2005-065689号記載の方法で合成した。 The compound is described in International Publication No. 2005-065689 as a compound having the strongest human deoxyuridine triphosphatase (hereinafter referred to as dUTPase) inhibitory activity, and described in International Publication No. WO2005-065689 in order to compare the activity with the compound of the present invention. The method was synthesized.
試験例１　ヒトdUTPase阻害作用
　本発明化合物のヒトdUTPaseに対する阻害活性を、下記方法により[5-3H]デオキシウリジントリホスフェート(以下、[5-3H]dUTP)からの[5-3H]デオキシウリジンモノホスフェート (以下、[5-3H]dUMP)の生成を測定することにより求めた。
　すなわち、1μMdUTP（588Bq/mLの[5-3H]dUTPを含む）0.02mL、0.2Mトリス緩衝液（pH7.4）0.05mL、16mM塩化マグネシウム0.05mL、20mM2-メルカプトエタノール0.02mL、1%ウシ胎児血清由来アルブミン水溶液0.02mL、種々濃度の被検化合物溶液又は対照として純水0.02mL及び大腸菌を用いて発現させ精製したヒトdUTPase溶液0.02mLの計0.2mLを37℃で15分間反応させた。反応後直ちに100℃の水浴中で1分間加熱して反応を停止させ、15000rpmで2分間遠心分離した。遠心分離後、得られた上清の一部（150μL）をAtlantisdC18カラム（Waters社製、4.6×250mm）を用いて高速液体クロマトグラフ（島津製作所製、Prominence）にて分析した。流速0.8mL/minで移動相A（10mMリン酸二水素カリウム（pH6.7）、10mMテトラブチルアンモニウム、0.25％メタノール）と移動相B（50mMリン酸二水素カリウム（pH6.7）、5.6mMテトラブチルアンモニウム、30％メタノール）の4:6混液から移動相Bへの30分間濃度勾配により溶離した。溶離液に1:2の比率でシンチレーター（パーキンエルマー社製、Ultima-FloAP）を混和し、RadiomaticFlowScintillationAnalyzer（パーキンエルマー社製、525TR）にて生成した[5-3H]dUMP（RT10.2min）の放射活性を測定した。 The inhibitory activity against human dUTPase Test Example 1 Human dUTPase inhibitory activity present compound, the following methods [5- 3 H] deoxyuridine triphosphate (hereinafter, [5- 3 H] dUTP) [5- 3 H] from It was determined by measuring the production of deoxyuridine monophosphate (hereinafter referred to as [5- 3 H] dUMP).
1 μM dUTP (containing 588 Bq / mL [5- 3 H] dUTP) 0.02 mL, 0.2 M Tris buffer (pH 7.4) 0.05 mL, 16 mM magnesium chloride 0.05 mL, 20 mM 2-mercaptoethanol 0.02 mL, 1% bovine A total of 0.2 mL of 0.02 mL of fetal serum-derived albumin aqueous solution, test compound solutions of various concentrations or 0.02 mL of pure water as a control and 0.02 mL of human dUTPase solution expressed and purified using E. coli were reacted at 37 ° C. for 15 minutes. Immediately after the reaction, the reaction was stopped by heating in a water bath at 100 ° C. for 1 minute, followed by centrifugation at 15000 rpm for 2 minutes. After centrifugation, a part of the obtained supernatant (150 μL) was analyzed with a high performance liquid chromatograph (Shimadzu Corporation, Prominence) using an AtlantisdC18 column (Waters, 4.6 × 250 mm). Mobile phase A (10 mM potassium dihydrogen phosphate (pH 6.7), 10 mM tetrabutylammonium, 0.25% methanol) and mobile phase B (50 mM potassium dihydrogen phosphate (pH 6.7), 5.6 mM at a flow rate of 0.8 mL / min Elution was performed with a 30-minute concentration gradient from a 4: 6 mixture of tetrabutylammonium, 30% methanol) to mobile phase B. The scintillator (Perkin Elmer, Ultima-FloAP) was mixed with the eluent at a ratio of 1: 2, and [5- 3 H] dUMP (RT10.2min) generated by RadiomaticFlowScintillationAnalyzer (PerkinElmer, 525TR) Radioactivity was measured.
　被検化合物の阻害活性は次式により求め、ヒトdUTPaseによって生成する[5-3H]dUMPの量を50％阻害する被検液の濃度をIC50（μM）として表４７に示した。 The inhibitory activity of the test compound was determined by the following equation, and the concentration of the test solution that inhibits the amount of [5- 3 H] dUMP produced by human dUTPase by 50% is shown in Table 47 as IC 50 (μM).
Figure JPOXMLDOC01-appb-M000001
Figure JPOXMLDOC01-appb-M000001
　以下の表にヒトdUTPase阻害活性データを示す。 The following table shows human dUTPase inhibitory activity data.
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047

Claims (11)

  1. 　一般式（Ｉ）
    Figure JPOXMLDOC01-appb-C000099
     〔一般式（Ｉ）中、Ｘは、炭素原子間又は末端にヘテロ原子を有していてもよい２価の炭化水素基を示し、Ｙは水素原子又はフッ素原子を示し、
    Ａは置換基を有していてもよい含窒素不飽和複素環基を示し、
    Ｒ１及びＲ２は、同一又は相異なって、水素原子、シアノ基、置換基を有していてもよい炭素数１～６のアルキル基、置換基を有していてもよい炭素数２～６のアルケニル基、置換基を有していてもよい炭素数２～６のアルキニル基、モノアルキルアミノカルボニル基、ジアルキルアミノカルボニル基、アリール基、不飽和複素環基、又は置換基を有していてもよいアラルキル基を示す。〕
    で表されるウラシル化合物又はその塩。     Formula (I)
    Figure JPOXMLDOC01-appb-C000099
     [In General Formula (I), X represents a divalent hydrocarbon group which may have a hetero atom between carbon atoms or at the terminal, Y represents a hydrogen atom or a fluorine atom,
    A represents a nitrogen-containing unsaturated heterocyclic group which may have a substituent,
    R 1 and R 2 are the same or different and are a hydrogen atom, a cyano group, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon atom having 2 to An alkenyl group having 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms which may have a substituent, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group, an aryl group, an unsaturated heterocyclic group, or a substituent. The aralkyl group which may be sufficient is shown. ]
    Or a salt thereof.
  2. 　Ｘが、炭素原子間又は末端に酸素原子を有していてもよい炭素数１～６のアルキレン基、炭素数６～１４の２価のアリール基、又は炭素原子間若しくは末端に酸素原子若しくは硫黄原子を有していてもよい炭素数６～２０の２価のアルキル－フェニル－アルキル基を示し、
    Ｙが水素原子又はフッ素原子を示し、
    Ａが置換基を有していてもよい３～６員環の含窒素不飽和複素環基を示し、
    Ｒ１及びＲ２は、同一又は相異なって、水素原子、シアノ基、置換基を有していてもよい炭素数１～６のアルキル基、置換基を有していてもよい炭素数２～６のアルケニル基、置換基を有していてもよい炭素数２～６のアルキニル基、モノアルキルアミノカルボニル基、ジアルキルアミノカルボニル基、、炭素数６～１４のアリール基、不飽和複素環基、又は置換基を有していてもよい炭素数７～２４のアラルキル基を示す請求項１記載のウラシル化合物又はその塩。     X is an alkylene group having 1 to 6 carbon atoms which may have an oxygen atom between or at carbon atoms, a divalent aryl group having 6 to 14 carbon atoms, or an oxygen atom or sulfur at or between carbon atoms A divalent alkyl-phenyl-alkyl group having 6 to 20 carbon atoms which may have an atom;
    Y represents a hydrogen atom or a fluorine atom,
    A represents a 3- to 6-membered nitrogen-containing unsaturated heterocyclic group which may have a substituent,
    R 1 and R 2 are the same or different and are a hydrogen atom, a cyano group, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon atom having 2 to An alkenyl group having 6 carbon atoms, an optionally substituted alkynyl group having 2 to 6 carbon atoms, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group, an aryl group having 6 to 14 carbon atoms, an unsaturated heterocyclic group, 2. The uracil compound or a salt thereof according to claim 1, which represents an aralkyl group having 7 to 24 carbon atoms which may have a substituent.
  3. 　Ｘが、炭素原子間又は末端に酸素原子を有していてもよい炭素数２～３の直鎖状のアルキレン基、炭素数４～６の分岐状のアルキレン基、フェニレン基又は下記一般式（II）
    Figure JPOXMLDOC01-appb-C000100
     （式（II）中、Ｚは酸素原子又は硫黄原子を示し、Ｒ３は、水素原子又は炭素数1～６のアルキル基を示し、式（II）中のＺ末端は式（Ｉ）中のメチレン基と結合し、式（II）中の炭素末端は、式（Ｉ）中のＡと結合する。）
    で表される基を示し、
    Ｙが水素原子又はフッ素原子を示し、
    Ａがオキソ基を有していてもよい５員環の含窒素不飽和複素環基を示し、
    Ｒ１及びＲ２が、同一又は相異なって、水素原子、シアノ基、置換基として、ハロゲン原子、ヒドロキシル基、又は炭素数１～６のアルコキシ基のいずれかを有していてもよい炭素数１～６のアルキル基、ビニル基、エチニル基、モノメチルアミノカルボニル基、ジメチルアミノカルボニル基、フェニル基、不飽和複素環基、置換基として、置換基を有していてもよい炭素数１～６のアルコキシ基、又はフェニル基のいずれかを有していてもよいベンジル基、又は置換基として、ヒドロキシル基、炭素数１～６のアルキル基、置換基を有していてもよい炭素数１～６アルコキシ基、炭素原子間に酸素原子を有していてもよい炭素数３～７のシクロアルコキシ基、置換基を有していてもよいフェニル基、又は置換基を有していてもよいチエニル基のいずれかを有していてもよいフェニルエチル基を示す請求項１又は２記載のウラシル化合物又はその塩。     X is a linear alkylene group having 2 to 3 carbon atoms which may have an oxygen atom between carbon atoms or at the terminal, a branched alkylene group having 4 to 6 carbon atoms, a phenylene group or the following general formula ( II)
    Figure JPOXMLDOC01-appb-C000100
     (In Formula (II), Z represents an oxygen atom or a sulfur atom, R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the Z terminal in Formula (II) is the same as in Formula (I)). (It binds to a methylene group, and the carbon terminal in formula (II) binds to A in formula (I).)
    Represents a group represented by
    Y represents a hydrogen atom or a fluorine atom,
    A represents a 5-membered nitrogen-containing unsaturated heterocyclic group optionally having an oxo group,
    R 1 and R 2 may be the same or different and each may have a hydrogen atom, a cyano group, a substituent, a halogen atom, a hydroxyl group, or an alkoxy group having 1 to 6 carbon atoms. 1 to 6 alkyl groups, vinyl group, ethynyl group, monomethylaminocarbonyl group, dimethylaminocarbonyl group, phenyl group, unsaturated heterocyclic group, and optionally having 1 to 6 carbon atoms as a substituent A benzyl group optionally having either an alkoxy group or a phenyl group, or a substituent such as a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon group having 1 to 6 an alkoxy group, a C3-C7 cycloalkoxy group optionally having an oxygen atom between carbon atoms, an optionally substituted phenyl group, or an optionally substituted thieni Uracil compound or a salt thereof according to claim 1 or 2, wherein represents an phenylethyl group which may have any group.
  4. 　Ｘが、炭素原子間又は末端に酸素原子を有していてもよい炭素数２～３の直鎖状のアルキレン基、炭素数４～６の分岐状のアルキレン基、フェニレン基又は下記一般式（II）
    Figure JPOXMLDOC01-appb-C000101
     （式（II）中、Ｚは酸素原子又は硫黄原子を示し、Ｒ３は、水素原子又はメチル基を示し、式（II）中のＺ末端は式（Ｉ）中のメチレン基と結合し、式（II）中の炭素末端は、式（Ｉ）中のＡと結合する。）
    で表される基を示し、
    Ｙが水素原子又はフッ素原子を示し、
    Ａがオキソ基を有していてもよい５員環の含窒素不飽和複素環基を示し、
    Ｒ１が、水素原子、シアノ基、置換基としてハロゲン原子、ヒドロキシル基、又は炭素数１～６のアルコキシ基のいずれかを有していてもよい炭素数１～６のアルキル基、ビニル基、エチニル基、モノメチルアミノカルボニル基、ジメチルアミノカルボニル基、フェニル基を示し、
    Ｒ２が、置換基として、置換基を有していてもよい炭素数１～６のアルコキシ基、又はフェニル基のいずれかを有していてもよいベンジル基を示すか、置換基としてヒドロキシル基、炭素数１～６のアルキル基、置換基を有していてもよい炭素数１～６アルコキシ基、炭素原子間に酸素原子を有していてもよい炭素数３～７のシクロアルコキシ基、置換基を有していてもよいフェニル基、チアゾリル基、又は置換基を有していてもよいチエニル基のいずれかを有していてもよいフェニルエチル基を示す請求項１～３のいずれかに記載のウラシル化合物又はその塩。     X is a linear alkylene group having 2 to 3 carbon atoms which may have an oxygen atom between carbon atoms or at the terminal, a branched alkylene group having 4 to 6 carbon atoms, a phenylene group or the following general formula ( II)
    Figure JPOXMLDOC01-appb-C000101
     (In the formula (II), Z represents an oxygen atom or a sulfur atom, R 3 represents a hydrogen atom or a methyl group, the Z terminal in the formula (II) is bonded to the methylene group in the formula (I), (The carbon terminal in the formula (II) is bonded to A in the formula (I).)
    Represents a group represented by
    Y represents a hydrogen atom or a fluorine atom,
    A represents a 5-membered nitrogen-containing unsaturated heterocyclic group optionally having an oxo group,
    R 1 may be any one of a hydrogen atom, a cyano group, a halogen atom as a substituent, a hydroxyl group, or an alkoxy group having 1 to 6 carbon atoms, a C 1-6 alkyl group, a vinyl group, Ethynyl group, monomethylaminocarbonyl group, dimethylaminocarbonyl group, phenyl group,
    R 2 represents, as a substituent, an optionally substituted alkoxy group having 1 to 6 carbon atoms or a benzyl group optionally having a phenyl group, or a hydroxyl group as a substituent. An alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms which may have a substituent, a cycloalkoxy group having 3 to 7 carbon atoms which may have an oxygen atom between carbon atoms, 4. The phenylethyl group optionally having any one of a phenyl group optionally having a substituent, a thiazolyl group, and a thienyl group optionally having a substituent. Or a salt thereof.
  5. 　Ｘが、炭素原子間又は末端に酸素原子を有していてもよいエチレン基、炭素原子間又は末端に酸素原子を有していてもよいトリメチレン基、ジメチルトリメチレン基、フェニレン基を示し、
    Ｙが水素原子又はフッ素原子を示し、
    Ａは、ピロリル基、ピラゾリニル基、オキソ基を有していてもよいトリアゾリル基又はテトラゾリル基を示し、
    Ｒ１が、水素原子、シアノ基、メチル基、モノフルオロメチル基、ジフルオロエチル基、ヒドロキシメチル基、メトキシメチル基、ビニル基、エチニル基、モノメチルアミノカルボニル基、ジメチルアミノカルボニル基又はフェニル基を示し、
    Ｒ２が、水素原子、フェニル基、又は下記一般式（III）
    Figure JPOXMLDOC01-appb-C000102
     （ｎは０又は１を示し、
    ｎ＝０のとき、Ｒ6及びＲ7は、同一又は相異なって、水素原子又はフェニル基を示し、Ｒ8及びＲ9は、同一又は相異なって、水素原子又は置換基を有していてもよい炭素数１～６のアルコキシ基を示し、
    ｎ＝１のとき、Ｒ4及びＲ5は、同一又は相異なって、水素原子又は炭素数１～６のアルキル基を示し、
    Ｒ6及びＲ7は、同一又は相異なって、水素原子、ヒドロキシル基、炭素数１～６のアルキル基又は置換基を有していてもよいフェニル基を示し、
    Ｒ8及びＲ9は、同一又は相異なって、水素原子、ハロゲン原子、置換基を有していてもよい炭素数１～７のアルコキシ基、炭素原子間に酸素原子を有していてもよい炭素数３～７のシクロアルコキシ基、置換基を有していてもよいフェニル基、又は置換基を有していてもよいチエニル基を示す。）で表されるベンジル基若しくはフェニルエチル基を示す請求項１～４のいずれか１項に記載のウラシル化合物又はその塩。     X represents an ethylene group which may have an oxygen atom between or at the ends of a carbon atom, a trimethylene group which may have an oxygen atom between or at the ends of a carbon atom, a dimethyltrimethylene group and a phenylene group;
    Y represents a hydrogen atom or a fluorine atom,
    A represents a pyrrolyl group, a pyrazolinyl group, a triazolyl group or a tetrazolyl group which may have an oxo group,
    R 1 represents a hydrogen atom, a cyano group, a methyl group, a monofluoromethyl group, a difluoroethyl group, a hydroxymethyl group, a methoxymethyl group, a vinyl group, an ethynyl group, a monomethylaminocarbonyl group, a dimethylaminocarbonyl group or a phenyl group. ,
    R 2 is a hydrogen atom, a phenyl group, or the following general formula (III)
    Figure JPOXMLDOC01-appb-C000102
     (N represents 0 or 1,
    When n = 0, R 6 and R 7 are the same or different and represent a hydrogen atom or a phenyl group, and R 8 and R 9 are the same or different and have a hydrogen atom or a substituent. An alkoxy group having 1 to 6 carbon atoms,
    when n = 1, R 4 and R 5 are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
    R 6 and R 7 are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, or an optionally substituted phenyl group;
    R 8 and R 9 may be the same or different and each may have a hydrogen atom, a halogen atom, an optionally substituted alkoxy group having 1 to 7 carbon atoms, or an oxygen atom between carbon atoms. A cycloalkoxy group having 3 to 7 carbon atoms, a phenyl group which may have a substituent, or a thienyl group which may have a substituent is shown. The uracil compound or a salt thereof according to any one of claims 1 to 4, which represents a benzyl group or a phenylethyl group represented by
  6. 　Ｘが、エチレン基、トリメチレン基、下記式（IV）～（VII）
    Figure JPOXMLDOC01-appb-C000103
     （式（IV）中の酸素末端は式（Ｉ）中のメチレン基と結合し、式（IV）中のメチレン末端は、式（Ｉ）中のＡと結合し、式（VII）中のメチレン末端は式（Ｉ）中のメチレン基と結合し、式（VII）中のジメチルメチレン末端は、式（Ｉ）中のＡと結合する。）
    で表される基、及び一般式（II）で表される基から選ばれるいずれかの基を示し、
    Ｙが水素原子又はフッ素原子を示し、
    Ａが、下記式(VIII)～(XV)
    Figure JPOXMLDOC01-appb-C000104
     から選ばれるいずれかの含窒素不飽和複素環基を示し、
    Ｒ１が、水素原子、シアノ基、メチル基、モノフルオロメチル基、ジフルオロエチル基、ヒドロキシメチル基、メトキシメチル基、ビニル基、エチニル基、モノメチルアミノカルボニル基、ジメチルアミノカルボニル基又はフェニル基を示し、
    Ｒ２が、水素原子、又は下記一般式（III）
    Figure JPOXMLDOC01-appb-C000105
     （ｎは０又は１を示し、
    ｎ＝０のとき、Ｒ6及びＲ7は、同一又は相異なって、水素原子又はフェニル基を示し、Ｒ8及びＲ9は、同一又は相異なって、水素原子、又は置換基としてハロゲン原子、若しくは炭素数３～７のシクロアルキル基のいずれかを有していてもよい炭素数１～６のアルコキシ基を示し、
    ｎ＝１のとき、Ｒ4及びＲ5は、同一又は相異なって、水素原子又は炭素数１～６のアルキル基を示し、
    Ｒ6及びＲ7は、同一又は相異なって、水素原子、ヒドロキシル基、炭素数１～６のアルキル基、又は置換基としてハロゲン原子、若しくは炭素数１～６のアルコキシ基のいずれかを有していてもよいフェニル基を示し、
    Ｒ8及びＲ9は、同一又は相異なって、水素原子、ハロゲン原子、置換基としてハロゲン原子、若しくは炭素数３～７のシクロアルキル基のいずれかを有していてもよい炭素数１～７のアルコキシ基、炭素原子間に酸素原子を有していてもよい炭素数３～７のシクロアルコキシ基、置換基としてハロゲン原子、若しくは炭素数１～６のアルコキシ基のいずれかを有していてもよいフェニル基、又はチエニル基を示す。）で表されるベンジル基若しくはフェニルエチル基を示す請求項１～５のいずれか１項に記載のウラシル化合物又はその塩。     X represents an ethylene group, a trimethylene group, and the following formulas (IV) to (VII)
    Figure JPOXMLDOC01-appb-C000103
     (The oxygen end in formula (IV) is bonded to the methylene group in formula (I), the methylene end in formula (IV) is bonded to A in formula (I), and the methylene group in formula (VII) The terminal is bonded to the methylene group in formula (I), and the dimethylmethylene terminal in formula (VII) is bonded to A in formula (I).
    And any group selected from the group represented by general formula (II),
    Y represents a hydrogen atom or a fluorine atom,
    A represents the following formulas (VIII) to (XV)
    Figure JPOXMLDOC01-appb-C000104
     A nitrogen-containing unsaturated heterocyclic group selected from
    R 1 represents a hydrogen atom, a cyano group, a methyl group, a monofluoromethyl group, a difluoroethyl group, a hydroxymethyl group, a methoxymethyl group, a vinyl group, an ethynyl group, a monomethylaminocarbonyl group, a dimethylaminocarbonyl group or a phenyl group. ,
    R 2 is a hydrogen atom, or the following general formula (III)
    Figure JPOXMLDOC01-appb-C000105
     (N represents 0 or 1,
    when n = 0, R 6 and R 7 are the same or different and each represents a hydrogen atom or a phenyl group; R 8 and R 9 are the same or different and each represents a hydrogen atom or a halogen atom as a substituent; Or an alkoxy group having 1 to 6 carbon atoms which may have any of a cycloalkyl group having 3 to 7 carbon atoms,
    when n = 1, R 4 and R 5 are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
    R 6 and R 7 are the same or different and each has a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, a halogen atom as a substituent, or an alkoxy group having 1 to 6 carbon atoms. An optionally substituted phenyl group,
    R 8 and R 9 are the same or different and each has a hydrogen atom, a halogen atom, a halogen atom as a substituent, or a cycloalkyl group having 3 to 7 carbon atoms, which may have 1 to 7 carbon atoms. An alkoxy group having 3 to 7 carbon atoms which may have an oxygen atom between carbon atoms, a halogen atom as a substituent, or an alkoxy group having 1 to 6 carbon atoms. It may be a phenyl group or a thienyl group. The uracil compound or a salt thereof according to any one of claims 1 to 5, which represents a benzyl group or a phenylethyl group represented by
  7. 　Ｘが、エチレン基、トリメチレン基又は式（IV）で表される基を示し、
    Ｙが水素原子又はフッ素原子を示し、
    Ａが、式（X)～(XII) 又は式 (XV) から選ばれるいずれかの含窒素不飽和複素環基を示し、
    Ｒ1が、水素原子、メチル基、エチニル基、又はモノフルオロメチル基を示し、
    Ｒ2が、下記一般式（III）
    Figure JPOXMLDOC01-appb-C000106
     （ｎ＝１を示し、Ｒ4及びＲ5は水素原子を示し、
    Ｒ6は、水素原子又はヒドロキシル基を示し
    Ｒ7は、水素原子、炭素数１～６のアルキル基又は置換基としてフッ素原子、塩素原子、メトキシ基を有していてもよいフェニル基を示し、
    Ｒ8及びＲ9は、同一又は相異なって、水素原子、フッ素原子、塩素原子、炭素数１～６の直鎖状又は分枝状のアルコキシ基（当該アルコキシ基は、置換基としてハロゲン原子、炭素数３～７のシクロアルキル基若しくはシクロアルキリデン構造を有していてもよい）、シクロブチルオキシ基、シクロペンチルオキシ基、テトラヒドロフリルオキシ基、テトラヒドロピリルオキシ基、置換基としてフッ素原子及び塩素原子を有していてもよいフェニル基、又はチエニル基を示す。）で表されるフェニルエチル基を示す請求項６に記載のウラシル化合物又はその塩。     X represents an ethylene group, a trimethylene group or a group represented by the formula (IV),
    Y represents a hydrogen atom or a fluorine atom,
    A represents any nitrogen-containing unsaturated heterocyclic group selected from formulas (X) to (XII) or formula (XV);
    R 1 represents a hydrogen atom, a methyl group, an ethynyl group, or a monofluoromethyl group,
    R 2 represents the following general formula (III)
    Figure JPOXMLDOC01-appb-C000106
     (N = 1 is shown, R 4 and R 5 are hydrogen atoms,
    R 6 represents a hydrogen atom or a hydroxyl group, R 7 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a phenyl group which may have a fluorine atom, a chlorine atom or a methoxy group as a substituent,
    R 8 and R 9 are the same or different and are a hydrogen atom, a fluorine atom, a chlorine atom, a linear or branched alkoxy group having 1 to 6 carbon atoms (the alkoxy group is a halogen atom, (It may have a cycloalkyl group having 3 to 7 carbon atoms or a cycloalkylidene structure), cyclobutyloxy group, cyclopentyloxy group, tetrahydrofuryloxy group, tetrahydropyryloxy group, fluorine atom and chlorine atom as a substituent A phenyl group or a thienyl group which may have The uracil compound or its salt of Claim 6 which shows the phenylethyl group represented by this.
  8. 　請求項１～７のいずれか１項に記載のウラシル化合物又はその塩を含有する医薬組成物。 A pharmaceutical composition comprising the uracil compound or a salt thereof according to any one of claims 1 to 7.
  9. 　請求項１～７のいずれか１項に記載のウラシル化合物又はその塩を含有するヒトdUTPase阻害剤。 A human dUTPase inhibitor comprising the uracil compound or a salt thereof according to any one of claims 1 to 7.
  10. 　請求項１～７のいずれか１項に記載のウラシル化合物又はその塩の、ヒトdUTPase阻害剤製造のための使用。 Use of the uracil compound or a salt thereof according to any one of claims 1 to 7 for producing a human dUTPase inhibitor.
  11. 　請求項１～７のいずれか一項に記載のウラシル化合物又はその塩を投与することを特徴とするヒトdUTPase阻害方法。 A method for inhibiting human dUTPase, comprising administering the uracil compound or a salt thereof according to any one of claims 1 to 7.
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