WO2021095091A1 - Aminoaryl derivative, intermediate of same, method for producing said aminoaryl derivative, and method for producing said intermediate - Google Patents

Aminoaryl derivative, intermediate of same, method for producing said aminoaryl derivative, and method for producing said intermediate Download PDF

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Publication number
WO2021095091A1
WO2021095091A1 PCT/JP2019/044117 JP2019044117W WO2021095091A1 WO 2021095091 A1 WO2021095091 A1 WO 2021095091A1 JP 2019044117 W JP2019044117 W JP 2019044117W WO 2021095091 A1 WO2021095091 A1 WO 2021095091A1
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compound
group
silylating agent
mmol
production method
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PCT/JP2019/044117
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French (fr)
Japanese (ja)
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英彰 梅本
小川　晃一
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藤本化学製品株式会社
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Priority to PCT/JP2019/044117 priority Critical patent/WO2021095091A1/en
Publication of WO2021095091A1 publication Critical patent/WO2021095091A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/68—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the present invention uses, for example, an intermediate capable of further reacting with an electrophilic reagent or the like as a nucleophilic reaction reagent to obtain the aminoaryl derivative without isolation as an intermediate protected by an amino group, and an intermediate using the same.
  • the present invention relates to the obtained aminoaryl derivatives, methods for producing them, and the like.
  • the present invention is an intermediate in which the above aminoaryl derivative can be obtained by further reacting with an electrophile or the like as a nucleophilic reaction reagent without isolating it as an intermediate having an amino group protected.
  • An object of the present invention is to provide a body and a method for producing the same.
  • the present invention also relates to aminoaryl derivatives obtained using the above intermediates, methods for producing them, and the like.
  • the method for producing the compound (A) of the present invention is an aromatic compound (a1) or a heteroaromatic compound having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring.
  • the step (1) of reacting the compound (a2) with the silylating agent (b) in the presence of an organic metal reagent is included.
  • the silylating agent (b) is added to the amino group on the aromatic ring or the heteroaromatic ring of the aromatic compound (a1) or the heteroaromatic compound (a2).
  • the compound (A) reacted as one protective group is obtained.
  • the aminoaryl derivative is obtained by further reacting with an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate in which an amino group is protected. This makes it possible to suppress side reactions, and is excellent in terms of process, time, and raw material cost.
  • the organometallic reagent contains an alkyllithium, an aryllithium, or a Grignard reagent.
  • the compound (A) may be an organic lithium compound or an organic magnesium compound.
  • the amino group may be a primary amino group.
  • the silylating agent (b) is a monovalent silylating agent.
  • the silylating agent (b) is a divalent silylating agent.
  • the silylating agent is used in an equal amount of 0.25 to 0.75 with respect to the amino group.
  • the silylating agent (b) is an n-valent silylating agent (n is an integer from 3 to 9).
  • n is an integer from 3 to 9.
  • the silylating agent is used in an equal amount of [(1 / n) ⁇ 0.1] to [(1 / n) +0.1] with respect to the amino group. It can be given as an example.
  • the monovalent silylating agent is used in an amount of 0.75 to 1.25 equal to the amino group.
  • the aromatic compound (a1) has a skeleton selected from the group consisting of benzene, naphthalene, anthracene, tetracene, pyrene, benzopyrene, perylene, tetracene, azulene, and tropone. ..
  • a preferable example is that the aromatic compound (a1) contains 1 to 100 benzene rings.
  • the heterocyclic compound (a2) includes furan, thiophene, pyridine, oxazole, isoxazole, thiazole, isothiazole, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,3,5-triazine, 1, 2,4-Triazine, quinoline, isothiazole, benzothiophene, benzofuran, cinnoline, quinazoline, quinoxaline, phthalazine, benzoxazole, 1,2-benzoisoxazole, benzothiazole, 1,2-benzoisothiazole, 1,2-benzo Isothiazole-3 (2H) -one, 2,1-benzoisothiazole-3 (1H) -one, pteridine, aclysine, xanthene, benzo-C-cinnoline, and N-H group
  • the heterocyclic compound (a2) contains 1 to 100 heterocycles.
  • the method for producing the compound (B) of the present invention is: The step (2) of reacting the compound (A) obtained by the above production method with an electrophile is included.
  • the other production method of the compound (B) of the present invention is An aromatic compound (a1) or a heteroaromatic compound (a2) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring, and a silylating agent (b) are added.
  • the step of reacting in the presence of an organic metal reagent (1), and The step (2) of reacting the compound (A) obtained in the step (1) with the electrophile is included.
  • the method for producing the compound (B) of the present invention by passing through the compound (A), it reacts with an electrophile as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group.
  • the compound (B) such as the aminoaryl derivative can be obtained, which is excellent in terms of suppression of side reactions, process, time and raw material cost.
  • the electrophile is a ketone, an aldehyde, an ester, an amide, an acid halide, a halogen, a haloalkane, a halogirate, a carbamoyl halide, an epoxide, an imine, a nitrile, or an acid anhydride.
  • Preferable examples include having one or more groups selected from the group consisting of substances and sulfonyl halides.
  • the compound (B) is an alcohol compound, a silyl ether compound, a ketone compound, an aldehyde compound, an imine compound, an amine compound, an ester compound, a carbamate compound, a sulfonyl compound, or , Alcan compound can be given as a preferable example.
  • the compound (A) of the present invention has one or more metallized N-silylamino groups on the aromatic ring or heteroaromatic ring, and one or more metalized nitrogen atoms [(M) N ().
  • SiR 1 R 2 R 3 represent a chain or cyclic alkyl group having 1 to 10 carbon atoms, an alkenyl group, an alkynyl group, or an aryl group, which may be substituted independently of each other.
  • M represents a metal atom.
  • the compound (A) of the present invention comprises an aromatic compound (a1) or a heteroaromatic compound (a2) substituted with one or more halogen groups and one or more amino groups, and a silylating agent.
  • (B) is a compound obtained by reacting with an organic metal reagent.
  • the compound (A) of the present invention by passing through the compound (A), for example, it further reacts with an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group.
  • an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group.
  • the silylating agent (b) is applied to the amino group on the aromatic ring or the heteroaromatic ring of the aromatic compound (a1) or the heteroaromatic compound (a2). ) Reacted as one protective group to easily obtain the compound (A). Then, by passing through the compound (A), the aminoaryl derivative is obtained by further reacting with an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate in which an amino group is protected. This makes it possible to suppress side reactions, and is excellent in terms of process, time, and raw material cost.
  • the compound (A) is reacted with an electrophile as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group.
  • the compound (B) such as the aminoaryl derivative can be obtained, which is excellent in terms of suppression of side reactions, process, time and raw material cost.
  • the above aminoaryl derivative is obtained by further reacting with an electrophile or the like as a nucleophilic reaction reagent without isolation as an intermediate having an amino group protected. This makes it possible to suppress side reactions, and is excellent in terms of process, time, and raw material cost.
  • the method for producing the compound (A) of the present invention is an aromatic compound (a1) or a heteroaromatic compound (a1) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring.
  • the step (1) of reacting the a2) and the silylating agent (b) in the presence of an organic metal reagent is included.
  • the method for producing the compound (B) of the present invention is as follows.
  • the step (2) of reacting the compound (A) obtained in the step (1) with the electrophile is included.
  • the derivatives in the present invention broadly include those in which the chemical structure of each of the above compounds is partially substituted, as long as the effects of the present invention are not impaired.
  • an aromatic ring and / or a heterocycle Includes a case where a substituent is contained in, or a case where a part or all of the molecular skeleton is substituted with another atom or a substituent.
  • the hydrogen atom on the aromatic ring and / or heterocyclic ring, alkyl group, functional group, etc. is another alkyl group, hydroxyl group, amino group, ester group, carboxyl group, carbonyl group, cyano group, ether group, F, Cl. , Br, I and other halogen atoms, protectors, and metal salt forms can be given as examples, but the present invention is not limited to these.
  • the method for producing the compound (A) of the present invention is an aromatic compound (a1) or a heteroaromatic compound (a1) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring.
  • the step (1) of reacting the a2) and the silylating agent (b) in the presence of an organic metal reagent is included.
  • the silylating agent (the above-mentioned silylating agent (a1) or the heteroaromatic compound (a2) has an amino group on the aromatic ring or the heteroaromatic ring.
  • the compound (A) in which b) has reacted as one protective group can be easily obtained.
  • the aminoaryl derivative is obtained by further reacting with an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate in which an amino group is protected. This makes it possible to suppress side reactions, and is excellent in terms of process, time, and raw material cost.
  • the step (1) is a step of reacting the aromatic compound (a1) or the heteroaromatic compound (a2) with the silylating agent (b) in the presence of the organometallic reagent. If there is, it can be used without particular limitation.
  • the order of adding the aromatic compound (a1) or the heteroaromatic compound (a2), the silylating agent (b), and the organometallic reagent to the reaction system is determined in the reaction step. It may be done as appropriate. For example, a method in which the aromatic compound (a1) or the heteroaromatic compound (a2) is present in the reaction system, then the silylating agent (b) is added to the reaction system, and then the organometallic reagent is added is given. be able to.
  • the aromatic compound (a1) is newly synthesized as long as it is an aromatic compound having one or more halogen groups and one or more amino groups, even if it is known. Even if it is a product, it can be used as appropriate.
  • the aromatic compound (a1) preferably has, for example, an amino group on the aromatic ring, and the amino group reacts with the silylating agent (b) so that the amino group is on the amino group. It can be protected by a silyl group.
  • the compound (A) in which one silyl group is protected against the amino group can be mentioned as preferable.
  • the amino group may be a primary amino group.
  • one hydrogen atom of the primary amino group is substituted with a silyl group, and the other hydrogen atom on the amino group is substituted with a metal derived from an organic metal reagent, for example, lithium.
  • the aromatic compound (a1) for example, it is preferable to have a halogen group on the aromatic ring, and the halogen group reacts with the organic metal reagent to become the compound (A) which is an aryl anionic intermediate. sell.
  • the aromatic compound (a1) may contain 1 to 100 benzene rings as a preferable example, and may be, for example, 1 to 80 or 1 to 50. It may be 2 to 30, 3 to 20, 4 to 15, 5 to 10, or 6 to 9. It may be 7 to 8 pieces.
  • the aromatic compound (a1) has a skeleton selected from the group consisting of benzene, naphthalene, anthracene, tetracene, pyrene, benzopyrene, perylene, tetracene, azulene, and tropone. I can give it. Moreover, these skeletons may have two or more kinds.
  • the heteroaromatic compound (a2) is newly synthesized as long as it is a known heteroaromatic compound having one or more halogen groups and one or more amino groups. Even if it is a product, it can be used as appropriate.
  • the heteroaromatic compound (a2) preferably has, for example, an amino group on the heterocycle, and the amino group reacts with the silylating agent (b) on the amino group. Is protected by a silyl group.
  • the compound (A) in which one silyl group is protected against the amino group can be mentioned as preferable.
  • the amino group may be a primary amino group.
  • one hydrogen atom of the primary amino group is substituted with a silyl group, and the other hydrogen atom on the amino group is substituted with a metal derived from an organic metal reagent, for example, lithium.
  • heteroaromatic compound (a2) for example, it is preferable to have a halogen group on the heterocycle, and the halogen group reacts with the organometallic reagent to form a heteroaryl anionic intermediate (A). ) Can be.
  • the heterocyclic compound (a2) may contain 1 to 100 heterocycles as a preferable example, and may be, for example, 1 to 80 or 1 to 50. It may be 2 to 30, 3 to 20, 4 to 15, 5 to 10, or 6 to 9. It may be 7 to 8 pieces.
  • the heterocyclic compound (a2) is furan, thiophene, pyridine, oxazole, isoxazole, thiazole, isothiazole, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,3,5-.
  • skeleton selected from the group consisting of pyrrol, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, indole, isothiazole, benzimidazole, indazole, benzotriazole, and purine. This can be given as a preferable example. Moreover, these skeletons may have two or more kinds.
  • the silylating agent (b) may be a known one or a newly synthesized one as long as it can react with and protect the amino group. It can be done.
  • the silylating agent (b) is a monovalent silylating agent.
  • the silylating agent (b) is a monovalent silylating agent
  • the silylating agent is 0.75 to 1.25 or the like with respect to the amino group. It can be mentioned as a preferable example that it is used in a quantity.
  • the silylating agent may be used, for example, in an equal amount of 0.80 to 1.20, may be used in an equal amount of 0.85 to 1.10, and may be used in an equal amount of 0.90 to 1.05. Equal amounts may be used, 0.95 to 1.00 equal amounts may be used, and 1.0 equal amounts may be used.
  • the amino group is a primary amino group
  • the compound (A) in which one silyl group is protected against the amino group can be easily obtained.
  • the silylating agent (b) is a divalent silylating agent
  • the silylating agent is used in an equal amount of 0.25 to 0.75 with respect to the amino group.
  • the silylating agent may be used, for example, in an equal amount of 0.28 to 0.72, or in an equal amount of 0.30 to 0.70, or 0.35 to 0.65. Equal amounts may be used, 0.40 to 0.60 equal amounts may be used, 0.45 to 0.55 equal amounts may be used, and 0.5 equal amounts may be used.
  • the amino group is a primary amino group
  • the compound (A) in which one silyl group is protected against the amino group can be easily obtained.
  • the silylating agent (b) is an n-valent silylating agent (n is an integer from 3 to 9).
  • the silylating agent is used in an equal amount of [(1 / n) ⁇ 0.1] to [(1 / n) +0.1] with respect to the amino group. It can be given as an example.
  • the amino group is a primary amino group, it is preferable that the compound (A) in which one silyl group is protected against the amino group can be easily obtained.
  • the organometallic reagent contains an alkyllithium, an aryllithium, or a Grignard reagent.
  • the alkyllithium, the aryllithium, and the Grignard reagent known ones can be appropriately used. These may be used alone or in combination of two or more.
  • the compound (A) may be an organic lithium compound or an organic magnesium compound.
  • the organic lithium compound and the organic magnesium compound known ones can be appropriately used. These may be used alone or in combination of two or more.
  • the compound (A) in the present invention for example, Can be given.
  • it is the compound (A) obtained when a compound having an aminopyridine skeleton is used as a starting material.
  • R 3 to R 5 are the same as the alkyl group in this specification.
  • a silylating agent for example, 1.0 mol equal amount
  • n-butyllithium as an organometallic reagent for example, 3.0 mol equal amount
  • the reaction is carried out at (room temperature to ⁇ 100 ° C.) to form a compound (A) having an N-silylamino group in which a nitrogen atom is metallized (lithiumized).
  • the obtained compound (A) can be obtained by adding an electrophile to the system and subjecting it to a nucleophilic substitution reaction or the like to obtain an aminopyridine derivative having a skeleton that has reacted with the electrophile. ..
  • aminobromopyridine derivative for example, As described above, a pyridine lithium derivative having an N-silylamino group in which a nitrogen atom is lithium can be obtained.
  • R 3 to R 5 are the same as the alkyl group in this specification.
  • R 3 to R 5 are the same as the alkyl group in this specification.
  • a silylating agent for example, 1.0 mol equal amount
  • s-butyllithium as an organometallic reagent for example, 3.2 mol equal amount
  • the reaction is carried out at ⁇ 70 ° C.) to form a compound (A) having an N-silylamino group in which a nitrogen atom is metallized (lithiumized).
  • the obtained compound (A) can be obtained by adding an electrophile to the system and subjecting it to a nucleophilic substitution reaction or the like to obtain an aniline derivative having a skeleton that has reacted with the electrophile.
  • Method for producing compound (B), etc. Further, the method for producing the compound (B) of the present invention is as follows. The step (2) of reacting the compound (A) obtained by the above production method with an electrophile is included.
  • the other production method of the compound (B) of the present invention is An aromatic compound (a1) or a heteroaromatic compound (a2) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring, and a silylating agent (b) are added.
  • the step of reacting in the presence of an organic metal reagent (1), and The step (2) of reacting the compound (A) obtained in the step (1) with the electrophile is included.
  • the compound (A) is reacted with an electrophile as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group. It becomes possible to obtain a compound (B) such as an aminoaryl derivative, which is excellent in terms of suppression of side reactions, process, time and raw material cost.
  • the matters described in the section of the method for producing the compound (A) may be used as appropriate for the matters not described in this section.
  • step (2) can be used without particular limitation as long as it is a step of reacting the compound (A) obtained in the step (1) with an electrophile.
  • the electrophile comprises a group consisting of ketones, aldehydes, esters, amides, acid halides, halogens, haloalkanes, halograte esters, carbamoyl halides, epoxides, imines, nitriles, acid anhydrides, and sulfonyl halides. Having one or more groups of choice can be given as a preferred example.
  • known ones or newly synthesized ones can be appropriately used.
  • these skeletons may have two or more kinds.
  • the compound (B) is an alcohol compound, a silyl ether compound, a ketone compound, an aldehyde compound, an imine compound, an amine compound, an ester compound, a carbamate compound, a sulfonyl compound, or an alkane compound. It can be given as a preferable example.
  • the compound (B) for example, Can be given.
  • it is a compound (B) obtained when a compound having an aminopyridine skeleton is used as a starting material.
  • Ele is a skeleton derived from an electrophile.
  • the compound (B) is, for example, Can be.
  • R 1 , R 2, etc. are the same as the alkyl group in this specification.
  • the compound (B) is, for example, Can be.
  • R and the like are the same as those of the alkyl group and the like in the present specification.
  • the compound (B) for example, Can be given.
  • it is a compound (B) obtained when a compound having an aniline skeleton is used as a starting material.
  • Ele is a skeleton derived from an electrophile.
  • the compound (B) is, for example, Can be.
  • R 1 , R 2, etc. are the same as the alkyl group in this specification.
  • R 3 to R 5 are the same as the alkyl group in this specification.
  • Ele is a skeleton derived from an electrophile.
  • a silylating agent for example, 1.0 mol equal amount
  • n-butyllithium as an organometallic reagent for example, 3.0 mol equal amount
  • the reaction is carried out at (room temperature to -100 ° C.) to form an intermediate compound (A) having an N-silylamino group in which a nitrogen atom is metallized (lithiumized).
  • an electrophile can be further added to the system, and an aminopyridine derivative having a skeleton that has reacted with the electrophile can be obtained by a nucleophilic substitution reaction or the like.
  • a ketone is used as the electrophile
  • a hydroxyalkylaminopyridine derivative can be obtained.
  • R 1 to R 5 are the same as the alkyl group in this specification.
  • Ele is a skeleton derived from an electrophile.
  • R 3 to R 5 are the same as the alkyl group in this specification.
  • Ele is a skeleton derived from an electrophile.
  • a silylating agent for example, 1.0 mol equal amount
  • s-butyllithium as an organometallic reagent for example, 3.2 mol equal amount
  • a THF solvent for example, in an equal amount of 3.2 mol.
  • the reaction is carried out at ⁇ 70 ° C.) to form an intermediate compound (A) having an N-silylamino group in which a nitrogen atom is metallized (lithiumized).
  • an electrophile can be further added to the system, and an aniline derivative having a skeleton that has reacted with the electrophile can be obtained by a nucleophilic substitution reaction or the like.
  • a ketone is used as the electrophile
  • a hydroxyalkylaniline derivative can be obtained.
  • R 1 to R 5 are the same as the alkyl group in this specification.
  • Ele is a skeleton derived from an electrophile.
  • An aromatic compound (a1) or a heteroaromatic compound (a2) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring, and a silylating agent (b) are added.
  • the step of reacting in the presence of an organic metal reagent (1), and A step (2) of reacting the compound (A) obtained in the step (1) with an electrophile is included, and the step (2) is included in the system without working up after the reaction of the step (1). ), And then the reaction treatment and purification treatment (for example, as a one-pot reaction) after performing the step (2) can be given as a particularly preferable example.
  • compound (A) which is a reaction intermediate obtained by adding a silylating agent and n-butyllithium as an organometallic reagent, is further prepared without isolation or purification.
  • a preferable example is to add a ketone as an electrophile to the system to obtain a 5- (hydroxyalkyl) -2-aminopyridine derivative as compound (B).
  • R 1 to R 5 are the same as the alkyl group in this specification.
  • the compound (A) of the present invention has one or more metallized N-silylamino groups [(M) N () in which one or more nitrogen atoms are metallized on the aromatic ring or heteroaromatic ring.
  • SiR 1 R 2 R 3 represent a chain or cyclic alkyl group having 1 to 10 carbon atoms, an alkenyl group, an alkynyl group, or an aryl group, which may be substituted independently of each other.
  • M represents a metal atom.
  • the compound (A) and the like of the present invention are silylated with an aromatic compound (a1) or a heteroaromatic compound (a2) substituted with one or more halogen groups and one or more amino groups. It is a compound obtained by reacting the agent (b) with an organic metal reagent.
  • the compound (A) of the present invention by passing through the compound (A), for example, it further reacts with an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group.
  • an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group.
  • the items described in the above-mentioned method for producing the compound (A) and the method for producing the compound (B) may be appropriately used in the same manner. ..
  • the compound (A) of the present invention can be obtained, for example, by the above-mentioned method for producing the compound (A).
  • the compound (A) of the present invention has one or more metallized N-silylamino groups [(M) N () in which one or more nitrogen atoms are metallized on the aromatic ring or heteroaromatic ring.
  • SiR 1 R 2 R 3 represent a chain or cyclic alkyl group having 1 to 10 carbon atoms, an alkenyl group, an alkynyl group, or an aryl group, which may be substituted independently of each other.
  • M represents a metal atom. ].
  • R 1 to R 3 may be independently substituted, respectively, and may be a chain or cyclic alkyl group having 1 to 10 carbon atoms, an alkenyl group, an alkynyl group, or an alkynyl group. , Represents an aryl group.
  • the chain or cyclic alkyl group, alkenyl group, alkynyl group, or aryl group having 1 to 10 carbon atoms includes, for example, a methyl group, an ethyl group, a 1-propyl group, a 1-methyl-1-ethyl group, and the like.
  • 1-butyl group 1-methyl-1-propyl group, 1,1-dimethyl-1-ethyl group, 2-methyl-1-propyl group, 1-pentyl group, 2-pentyl group, 1-heptyl group, 2 -Heptyl group, 1-octyl group, 2-octyl group, 1-nonyl group, 2-nonyl group, 1-decanyl group, 2-decanyl group, cyclopentyl group, cyclobutenyl group, ethenyl group, 1-propenyl group, 2- Propenyl group, 1-butenyl group, 2-butenyl group, 1-pentenyl group, 2-pentenyl group, 1-heptenyl group, 2-heptenyl group, 1-octenyl group, 2-octenyl group, 1-nonenyl group, 2- Examples thereof include a nonenyl group, a 1-decanenyl group, a 2-decanenyl group, a phen
  • M represents a metal atom.
  • the above M is, for example, a metal derived from an organometallic reagent usually used in the step (1) when the compound (A) is obtained by the step (1), and for example, alkali lithium such as n-BuLi or aryl lithium is used.
  • M becomes Li
  • a Grignard reagent such as an organomagnesium reagent is used, it becomes Mg.
  • a plurality of metallized N-silylamino groups having different Ms may be contained in the same reaction system.
  • the compound (A) for example, Can be given.
  • it is the compound (A) obtained when a compound having an aminopyridine skeleton such as 5-bromo-2-aminopyridine is used as a raw material.
  • one lithium ion can be a counter cation of an aryl anion on an aromatic ring or a heterocycle, and can contain a lithium N-silylamino group on the amino group.
  • R 3 to R 5 are the same as the alkyl group in this specification.
  • the compound (A) for example, Can be given.
  • it is the compound (A) obtained when a compound having an aminobenzene skeleton such as 4-bromo-1-aminobenzene is used as a raw material.
  • one lithium ion can be a counter cation of an aryl anion on an aromatic ring or a heterocycle, and can contain a lithium N-silylamino group on the amino group.
  • R 3 to R 5 are the same as the alkyl group in this specification.
  • the compound (A) of the present invention is preferably carried out as a sequential reaction or a continuous reaction with the compound (B) following the compound (A), including a synthetic reaction with the compound (B), but other methods.
  • the reaction product which has been isolated or has not been purified, may be used as an intermediate in the next reaction.
  • 2-Amino-5-bromopyridine (21.000 g, 121.4 mmol, 1.0 eq) was dissolved in 210 ml of THF at room temperature and in a nitrogen atmosphere and cooled to ⁇ 70 ° C. At the same temperature, chlorotrimethylsilane (13.187 g, 121.4 mmol, 1.00 eq) and 1.6 M n-BuLihexane solution (227.9 ml, 370.2 mmol, 3.05 eq) were added to 0. After stirring for 5 hours, acetone (17.624 g, 303.5 mmol, 2.5 eq) was added and the mixture was stirred for 30 minutes.
  • reaction solution was heated to room temperature, city water (46 ml) and primary hydrochloric acid (20.5 ml) were added, and the mixture was stirred and then the aqueous layer was separated. A 50% aqueous NaOH solution (12 ml) was added to the aqueous layer, and the mixture was extracted 3 times with toluene and 4 times with THF. The obtained organic layer was concentrated under reduced pressure, and then the residue was recrystallized from THF / hexane to obtain Compound 1 (10.256 g, 56%).
  • Example 2 Synthesis of Compound 1 using various silylating agents
  • the silylating agent was added to a THF solution (0.6M) of 2-amino-5-bromopyridine at room temperature under an Ar atmosphere. Subsequently, the solution was ice-cooled, n-BuLi (1.20 equivalent) was added, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. The reaction mixture was cooled to ⁇ 70 ° C., n-BuLi (2.00 equivalents) was added, and the mixture was stirred for 0.5 hours, acetone was added, and the mixture was stirred for 10 minutes. The temperature was raised to room temperature, and city water and primary hydrochloric acid were added to obtain a solution containing compound 1. For this solution, the compound 1 synthesized in Example 1 was used as a standard product, and the compound 1 contained in this solution was quantified by quantifying under the following HPLC conditions.
  • Example 3 Synthesis of compound 1 using Grignard reagent Under an Ar atmosphere, 2-amino-5-bromopyridine (0.200 g, 1.16 mmol, 1.00 equivalent) was dissolved in 2 ml of THF at room temperature. It was cooled to -5 ° C. At the same temperature, add chlorotrimethylsilane (0.126 g, 1.16 mmol, 1.00 eq) and a THF solution of 1.3 M i-PrMgCl / LiCl (3.1 ml, 4.05 mmol, 3.50 eq). , The temperature was raised to 50 ° C., and the mixture was stirred overnight.
  • Example 4 A general procedure for synthesizing alcohols, silyl ethers, ketones, and alkanes by reacting a halogenated pyridylamine or a halogenated phenylamine with an electrophile using chlorotrimethylsilane.
  • a THF solution (0.1M to 0.6M) of pyridyl amine halide and phenyl amine halide was prepared at room temperature under an Ar atmosphere, and cooled to ⁇ 70 ° C. to ⁇ 100 ° C.
  • chlorotrimethylsilane (1.00 eq), n-BuLi or s-BuLi (3.05 eq) is added and stirred for 0.5 to 2 hours, and then the electrophile or the electrophile THF.
  • the solution was added and the mixture was stirred for 0 to 2 hours.
  • city water and NaCl were added to separate the organic layer, and the aqueous layer was further extracted twice with THF.
  • the organic layers were mixed , dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by column chromatography [Silica gel 60N (spherical, nutral), chloroform / methanol] to obtain the desired compound.
  • 2-amino-5-bromopyridine 1.000 g, 5.78 mmol, 1.00 equivalent
  • 10 ml of THF 10 ml
  • chlorotrimethylsilane 0.28 g, 5.78 mmol, 1.00 eq
  • 1.6 M n-BuLihexane solution 11.0 ml, 17.63 mmol, 3.05 eq
  • the obtained solution was added dropwise to 4,4'-dimethoxybenzophenone (1.400 g, 5.78 mmol, 1.00 eq) suspended in 2 ml of THF, stirred for 0.5 hours, and then heated to room temperature.
  • Example 6 A general procedure for alcohol synthesis by reacting a halogenated pyridylamine with an electrophile using chlorot-butyldimethylsilane. Chloro-t-butyldimethylsilane (1.00 equivalent) was added to a THF solution (0.6 M) of pyridylamine halide at room temperature under an Ar atmosphere. Subsequently, the solution was ice-cooled, n-BuLi (1.05 eq) was added, the temperature was raised to room temperature, and the mixture was stirred for about 0.5 to 2 hours.
  • the reaction mixture was cooled to ⁇ 100 ° C., n-BuLi (2.00 equivalents) was added, the mixture was stirred for 0.5 hours, and a THF solution of an electrophile was added. After stirring the reaction solution for 0 to 10 minutes, the temperature was raised to room temperature, and city water and primary hydrochloric acid were added to separate the aqueous layer. After adding an aqueous NaOH solution (50%) to the aqueous layer to adjust the pH to about 10, extraction was performed three times with THF, and the obtained organic layer was dried over Na 2 SO 4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography [Silica gel 60N (spherical, nutral), chloroform / methanol] to obtain the desired compound.
  • 2-Amino-5-bromopyridine (0.200 g, 1.16 mmol, 1.00 eq) was dissolved in 2 ml of THF under an Ar atmosphere at room temperature, and chloro t-butyldimethylsilane (0.174 g, 1. 16 mmol, 1.00 eq) was added. Subsequently, the solution was ice-cooled, a 14.6% (w / w) n-BuLihexane solution (0.609 g, 1.39 mmol, 1.20 equivalents) was added, and then the temperature was raised to room temperature. The mixture was stirred for 5 hours.
  • compound 22 purchased from Fuji Film Wako Pure Chemical Industries, Ltd. was used as a standard product, and analysis was performed under the following HPLC conditions. Since the retention times were the same, the formation of compound 22 was confirmed. Moreover, as a result of determining the content of compound 22 by HPLC quantification, it was confirmed that the yield was 82%.
  • 2-amino-5-bromopyridine (1.00 g, 5.78 mmol, 1.00 equivalent) was dissolved in 10 ml of THF at room temperature, and chloro t-butyldimethylsilane (0.871 g, 5. 78 mmol, 1.00 eq) was added. Subsequently, the solution was ice-cooled, a 1.6 M n-BuLihexane solution (3.8 ml, 6.07 mmol, 1.05 eq) was added, the temperature was raised to room temperature, and the mixture was stirred for 2 hours.

Abstract

The present invention relates to provision of: an intermediate which enables, for example, the achievement of an aminoaryl derivative by being reacted, as a nucleophilic reaction reagent, with an electrophilic reagent or the like, without being isolated as an amino group-protected intermediate; an aminoaryl derivative which is obtained using this intermediate; a method for producing this intermediate; a method for producing this aminoaryl derivative; and the like.　A method for producing a compound (A), said method comprising a step (1) for reacting an aromatic compound (a1) or a heteroaromatic compound (a2), which has one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring, with a silylating agent (b) in the presence of an organic metal reagent.

Description

アミノアリール誘導体及びその中間体、並びにそれらの製造方法Aminoaryl derivatives and their intermediates, and methods for producing them
　本発明は、アミノ基の保護した中間体として単離することなく、例えば、さらに求核反応試薬として求電子試薬等と反応して上記アミノアリール誘導体を得うる中間体、及び、それを用いて得られたアミノアリール誘導体、並びにそれらの製造方法等に関する。 The present invention uses, for example, an intermediate capable of further reacting with an electrophilic reagent or the like as a nucleophilic reaction reagent to obtain the aminoaryl derivative without isolation as an intermediate protected by an amino group, and an intermediate using the same. The present invention relates to the obtained aminoaryl derivatives, methods for producing them, and the like.
　これまで、アミノアリール誘導体等の合成において、例えば、当該芳香環上に有機金属試薬を用いケトン等と反応させてヒドロキシアルキル基等を導入する場合、アミノ基上の水素原子を全て有機シリル基で保護してから行う方法が提案されている（たとえば、特許文献１、２参照）。 So far, in the synthesis of aminoaryl derivatives and the like, for example, when an organic metal reagent is used on the aromatic ring to react with a ketone or the like to introduce a hydroxyalkyl group or the like, all hydrogen atoms on the amino group are represented by an organic silyl group. A method has been proposed in which protection is performed (see, for example, Patent Documents 1 and 2).
　しかしながら、上記提案では、各原料化合物が過剰量必要となる上、特に２つ目のシリル基保護の反応時間が長く、各操作自体も煩雑となってしまう。 However, in the above proposal, an excessive amount of each raw material compound is required, and in particular, the reaction time for protecting the second silyl group is long, and each operation itself becomes complicated.
国際公開第２０１４／１８２９２９号International Publication No. 2014/182929 国際公開第２０１４／１６０８７３号International Publication No. 2014/168073
　また、発明者らの研究により、上記アミノアリール誘導体等の合成において、例えば、当該芳香環上に有機金属試薬を用いケトン等と反応させてヒドロキシアルキル基等を導入する場合、アミノ基を保護せずに行うと、副反応も多く生じ、ほとんど目的化合物が得られないことが判明した。 In addition, according to the research by the inventors, in the synthesis of the aminoaryl derivative and the like, for example, when an organic metal reagent is used on the aromatic ring and a hydroxyalkyl group or the like is introduced by reacting with a ketone or the like, the amino group is protected. It was found that if it was performed without this, many side reactions occurred and the target compound could hardly be obtained.
　そこで本発明は、このような事情に照らし、アミノ基の保護した中間体として単離することなく、例えば、さらに求核反応試薬として求電子試薬等と反応して上記アミノアリール誘導体を得うる中間体、及び、その製造方法等を提供することを目的とする。 Therefore, in light of these circumstances, the present invention is an intermediate in which the above aminoaryl derivative can be obtained by further reacting with an electrophile or the like as a nucleophilic reaction reagent without isolating it as an intermediate having an amino group protected. An object of the present invention is to provide a body and a method for producing the same.
　また、本発明は、上記中間体を用いて得られたアミノアリール誘導体、並びにそれらの製造方法等に関する。 The present invention also relates to aminoaryl derivatives obtained using the above intermediates, methods for producing them, and the like.
　本発明者らは、上記課題を解決するため鋭意検討した結果、以下に示す新規のアミノアリール誘導体の中間体化合物ないしそれを経由する新規のアミノアリール誘導体の製造方法等の創製に成功し、上記中間体化合物ないし上記製造方法等により上記目的を達成できることを見出して、本発明を完成するに至った。 As a result of diligent studies to solve the above problems, the present inventors have succeeded in creating an intermediate compound of a novel aminoaryl derivative shown below or a method for producing a novel aminoaryl derivative via the intermediate compound, and described above. The present invention has been completed by finding that the above object can be achieved by using an intermediate compound or the above production method.
　すなわち、本発明の化合物（Ａ）の製造方法は、芳香環または複素芳香環上に、１つ以上のハロゲン基と、１つ以上のアミノ基を有する、芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬の存在下で反応させる工程（１）を含む。 That is, the method for producing the compound (A) of the present invention is an aromatic compound (a1) or a heteroaromatic compound having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring. The step (1) of reacting the compound (a2) with the silylating agent (b) in the presence of an organic metal reagent is included.
　本発明の化合物（Ａ）の製造方法によると、上記芳香族化合物（ａ１）または複素芳香族化合物（ａ２）の芳香環または複素芳香環上のアミノ基に対し、上記シリル化剤（ｂ）が１つ保護基として反応した化合物（Ａ）が得られる。そして、上記化合物（Ａ）を経由することにより、アミノ基の保護した中間体として単離することなく、例えば、さらに求核反応試薬として求電子試薬等と反応して上記アミノアリール誘導体を得ることが可能となり、副反応の抑制や、工程面、時間的・原料コスト的において優れたものとなる。 According to the method for producing the compound (A) of the present invention, the silylating agent (b) is added to the amino group on the aromatic ring or the heteroaromatic ring of the aromatic compound (a1) or the heteroaromatic compound (a2). The compound (A) reacted as one protective group is obtained. Then, by passing through the compound (A), the aminoaryl derivative is obtained by further reacting with an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate in which an amino group is protected. This makes it possible to suppress side reactions, and is excellent in terms of process, time, and raw material cost.
　また、本発明の化合物（Ａ）の製造方法において、上記有機金属試薬が、アルキルリチウム、アリールリチウム、又は、グリニャール試薬を含むことを、好ましい例としてあげることができる。 Further, in the method for producing the compound (A) of the present invention, it can be mentioned as a preferable example that the organometallic reagent contains an alkyllithium, an aryllithium, or a Grignard reagent.
　また、本発明の化合物（Ａ）の製造方法において、上記化合物（Ａ）が、有機リチウム化合物、又は、有機マグネシウム化合物であってもよい。 Further, in the method for producing the compound (A) of the present invention, the compound (A) may be an organic lithium compound or an organic magnesium compound.
　また、本発明の化合物（Ａ）の製造方法において、上記アミノ基が、１級アミノ基であってもよい。 Further, in the method for producing the compound (A) of the present invention, the amino group may be a primary amino group.
　また、本発明の化合物（Ａ）の製造方法において、上記シリル化剤（ｂ）が、１価のシリル化剤であることを、好ましい例としてあげることができる。 Further, in the method for producing the compound (A) of the present invention, it can be mentioned as a preferable example that the silylating agent (b) is a monovalent silylating agent.
　また、本発明の化合物（Ａ）の製造方法において、
　上記シリル化剤（ｂ）が、２価のシリル化剤であって、
　上記工程（１）において、上記シリル化剤は、上記アミノ基に対して、０．２５～０．７５等量用いられることを、好ましい例としてあげることができる。 Further, in the method for producing the compound (A) of the present invention,
The silylating agent (b) is a divalent silylating agent.
In the step (1), it can be mentioned as a preferable example that the silylating agent is used in an equal amount of 0.25 to 0.75 with respect to the amino group.
　また、本発明の化合物（Ａ）の製造方法において、
　上記シリル化剤（ｂ）が、ｎ価のシリル化剤（ｎは３～９までの整数）であって、
　上記工程（１）において、上記シリル化剤は、上記アミノ基に対して、[（１／ｎ）－０．１]～[（１／ｎ）＋０．１]等量用いられることを、好ましい例としてあげることができる。 Further, in the method for producing the compound (A) of the present invention,
The silylating agent (b) is an n-valent silylating agent (n is an integer from 3 to 9).
In the step (1), it is preferable that the silylating agent is used in an equal amount of [(1 / n) −0.1] to [(1 / n) +0.1] with respect to the amino group. It can be given as an example.
　また、本発明の化合物（Ａ）の製造方法において、
　上記工程（１）において、上記１価のシリル化剤は、上記アミノ基に対して、０．７５～１．２５等量用いられることを、好ましい例としてあげることができる。 Further, in the method for producing the compound (A) of the present invention,
In the step (1), it can be mentioned as a preferable example that the monovalent silylating agent is used in an amount of 0.75 to 1.25 equal to the amino group.
　また、本発明の化合物（Ａ）の製造方法において、
　上記芳香族化合物（ａ１）は、ベンゼン、ナフタレン、アントラセン、テトラセン、ピレン、ベンゾピレン、ペリレン、テトラセン、アズレン、及び、トロポンからなる群より選択される骨格を有することを、好ましい例としてあげることができる。 Further, in the method for producing the compound (A) of the present invention,
A preferred example is that the aromatic compound (a1) has a skeleton selected from the group consisting of benzene, naphthalene, anthracene, tetracene, pyrene, benzopyrene, perylene, tetracene, azulene, and tropone. ..
　また、本発明の化合物（Ａ）の製造方法において、
　上記芳香族化合物（ａ１）は、ベンゼン環を１～１００個を含むことを、好ましい例としてあげることができる。 Further, in the method for producing the compound (A) of the present invention,
A preferable example is that the aromatic compound (a1) contains 1 to 100 benzene rings.
　また、本発明の化合物（Ａ）の製造方法において、
　上記複素環式化合物（ａ２）は、フラン、チオフェン、ピリジン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、ピリダジン、ピリミジン、ピラジン、１，２，３－トリアジン、１，３，５－トリアジン、１，２，４－トリアジン、キノリン、イソキノリン、ベンゾチオフェン、ベンゾフラン、シンノリン、キナゾリン、キノキサリン、フタラジン、ベンゾオキサゾール、１，２－ベンゾイソオキサゾール、ベンゾチアゾール、１，２－ベンゾイソチアゾール、１，２－ベンゾイソチアゾール－３（２Ｈ）－オン、２，１－ベンゾイソチアゾール－３（１Ｈ）－オン、プテリジン、アクリジン、キサンテン、ベンゾ－Ｃ－シンノリン、並びに、Ｎ－Ｈ基が保護ざれた、ピロール、イミダゾール、ピラゾール、１，２，３－トリアゾール、１，２，４－トリアゾール、インドール、イソインドール、ベンゾイミダゾール、インダゾール、ベンゾトリアゾール、及び、プリンからなる群より選択される骨格を有することを、好ましい例としてあげることができる。 Further, in the method for producing the compound (A) of the present invention,
The heterocyclic compound (a2) includes furan, thiophene, pyridine, oxazole, isoxazole, thiazole, isothiazole, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,3,5-triazine, 1, 2,4-Triazine, quinoline, isothiazole, benzothiophene, benzofuran, cinnoline, quinazoline, quinoxaline, phthalazine, benzoxazole, 1,2-benzoisoxazole, benzothiazole, 1,2-benzoisothiazole, 1,2-benzo Isothiazole-3 (2H) -one, 2,1-benzoisothiazole-3 (1H) -one, pteridine, aclysine, xanthene, benzo-C-cinnoline, and N-H group protected pyrrol, It is preferable to have a skeleton selected from the group consisting of imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, indole, isothiazole, benzimidazole, indazole, benzotriazole, and purine. It can be given as an example.
　また、本発明の化合物（Ａ）の製造方法において、
　上記複素環式化合物（ａ２）は、複素環を１～１００個を含むことを、好ましい例としてあげることができる。 Further, in the method for producing the compound (A) of the present invention,
It can be mentioned as a preferable example that the heterocyclic compound (a2) contains 1 to 100 heterocycles.
　一方、本発明の化合物（Ｂ）の製造方法は、
　上記製造方法で得られた化合物（Ａ）と、求電子剤とを反応させる工程（２）を含む。 On the other hand, the method for producing the compound (B) of the present invention is:
The step (2) of reacting the compound (A) obtained by the above production method with an electrophile is included.
　また、本発明の化合物（Ｂ）の他の製造方法は、
　芳香環または複素芳香環上に、１つ以上のハロゲン基と、１つ以上のアミノ基を有する、芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬の存在下で反応させる工程（１）、並びに、
　前記工程（１）で得られた化合物（Ａ）と、求電子剤とを反応させる工程（２）を含む。 Further, the other production method of the compound (B) of the present invention is
An aromatic compound (a1) or a heteroaromatic compound (a2) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring, and a silylating agent (b) are added. , The step of reacting in the presence of an organic metal reagent (1), and
The step (2) of reacting the compound (A) obtained in the step (1) with the electrophile is included.
　本発明の化合物（Ｂ）の製造方法によると、上記化合物（Ａ）を経由することにより、アミノ基の保護した中間体として単離することなく、求核反応試薬として求電子剤と反応して上記アミノアリール誘導体等の化合物（Ｂ）を得ることが可能となり、副反応の抑制や、工程面、時間的・原料コスト的において優れたものとなる。 According to the method for producing the compound (B) of the present invention, by passing through the compound (A), it reacts with an electrophile as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group. The compound (B) such as the aminoaryl derivative can be obtained, which is excellent in terms of suppression of side reactions, process, time and raw material cost.
　また、本発明の化合物（Ｂ）の製造方法において、上記求電子剤が、ケトン、アルデヒド、エステル、アミド、酸ハライド、ハロゲン、ハロアルカン、ハロギ酸エステル、カルバモイルハライド、エポキシド、イミン、ニトリル、酸無水物、及び、スルホニルハライドからなる群より選択される１つ以上の基を有することを、好ましい例としてあげることができる。 Further, in the method for producing the compound (B) of the present invention, the electrophile is a ketone, an aldehyde, an ester, an amide, an acid halide, a halogen, a haloalkane, a halogirate, a carbamoyl halide, an epoxide, an imine, a nitrile, or an acid anhydride. Preferable examples include having one or more groups selected from the group consisting of substances and sulfonyl halides.
　また、本発明の化合物（Ｂ）の製造方法において、上記化合物（Ｂ）が、アルコール化合物、シリルエーテル化合物、ケトン化合物、アルデヒド化合物、イミン化合物、アミン化合物、エステル化合物、カーバメート化合物、スルホニル化合物、又は、アルカン化合物であることを、好ましい例としてあげることができる。 Further, in the method for producing the compound (B) of the present invention, the compound (B) is an alcohol compound, a silyl ether compound, a ketone compound, an aldehyde compound, an imine compound, an amine compound, an ester compound, a carbamate compound, a sulfonyl compound, or , Alcan compound can be given as a preferable example.
　他方、本発明の化合物（Ａ）は、芳香環または複素芳香環上の1か所以上がメタル化され、1つ以上の，窒素原子をメタル化されたＮ－シリルアミノ基［（Ｍ）Ｎ（ＳｉＲ１Ｒ２Ｒ３）。Ｒ１～Ｒ３は、それぞれ独立して置換されていてもよい、炭素数１～１０の鎖状または環状のアルキル基、アルケニル基、アルキニル基、又は、アリール基を表す。Ｍは、金属原子を表す。］を有する。 On the other hand, the compound (A) of the present invention has one or more metallized N-silylamino groups on the aromatic ring or heteroaromatic ring, and one or more metalized nitrogen atoms [(M) N (). SiR 1 R 2 R 3 ). R 1 to R 3 represent a chain or cyclic alkyl group having 1 to 10 carbon atoms, an alkenyl group, an alkynyl group, or an aryl group, which may be substituted independently of each other. M represents a metal atom. ].
　また、本発明の化合物（Ａ）は、１つ以上のハロゲン基と、１つ以上のアミノ基とにより置換されている芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬で反応させて得られる化合物である。 Further, the compound (A) of the present invention comprises an aromatic compound (a1) or a heteroaromatic compound (a2) substituted with one or more halogen groups and one or more amino groups, and a silylating agent. (B) is a compound obtained by reacting with an organic metal reagent.
　本発明の化合物（Ａ）によると、上記化合物（Ａ）を経由することにより、アミノ基の保護した中間体として単離することなく、例えば、さらに求核反応試薬として求電子試薬等と反応して上記アミノアリール誘導体を得ることが可能となり、副反応の抑制や、工程面、時間的・原料コスト的において優れたものとなる。 According to the compound (A) of the present invention, by passing through the compound (A), for example, it further reacts with an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group. As a result, the above-mentioned aminoaryl derivative can be obtained, which is excellent in terms of suppression of side reactions, process, time and raw material cost.
　本発明の化合物（Ａ）の製造方法を用いることにより、上記芳香族化合物（ａ１）または複素芳香族化合物（ａ２）の芳香環または複素芳香環上のアミノ基に対し、上記シリル化剤（ｂ）が１つ保護基として反応した化合物（Ａ）を簡便に得ることができる。そして、上記化合物（Ａ）を経由することにより、アミノ基の保護した中間体として単離することなく、例えば、さらに求核反応試薬として求電子試薬等と反応して上記アミノアリール誘導体を得ることが可能となり、副反応の抑制や、工程面、時間的・原料コスト的において優れたものとなる。 By using the method for producing the compound (A) of the present invention, the silylating agent (b) is applied to the amino group on the aromatic ring or the heteroaromatic ring of the aromatic compound (a1) or the heteroaromatic compound (a2). ) Reacted as one protective group to easily obtain the compound (A). Then, by passing through the compound (A), the aminoaryl derivative is obtained by further reacting with an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate in which an amino group is protected. This makes it possible to suppress side reactions, and is excellent in terms of process, time, and raw material cost.
　また、本発明の化合物（Ｂ）の製造方法を用いることにより、上記化合物（Ａ）を、アミノ基の保護した中間体として単離することなく、求核反応試薬として求電子剤と反応して上記アミノアリール誘導体等の化合物（Ｂ）を得ることが可能となり、副反応の抑制や、工程面、時間的・原料コスト的において優れたものとなる。 Further, by using the method for producing the compound (B) of the present invention, the compound (A) is reacted with an electrophile as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group. The compound (B) such as the aminoaryl derivative can be obtained, which is excellent in terms of suppression of side reactions, process, time and raw material cost.
　また、本発明の化合物（Ａ）を用いることにより、アミノ基の保護した中間体として単離することなく、例えば、さらに求核反応試薬として求電子試薬等と反応して上記アミノアリール誘導体を得ることが可能となり、副反応の抑制や、工程面、時間的・原料コスト的において優れたものとなる。 Further, by using the compound (A) of the present invention, the above aminoaryl derivative is obtained by further reacting with an electrophile or the like as a nucleophilic reaction reagent without isolation as an intermediate having an amino group protected. This makes it possible to suppress side reactions, and is excellent in terms of process, time, and raw material cost.
　以下、本発明の実施の形態について詳細に説明する。 Hereinafter, embodiments of the present invention will be described in detail.
　本発明の化合物（Ａ）の製造方法は、芳香環または複素芳香環上に、１つ以上のハロゲン基と、１つ以上のアミノ基を有する、芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬の存在下で反応させる工程（１）を含む。 The method for producing the compound (A) of the present invention is an aromatic compound (a1) or a heteroaromatic compound (a1) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring. The step (1) of reacting the a2) and the silylating agent (b) in the presence of an organic metal reagent is included.
　また、本発明の化合物（Ｂ）の製造方法は、
　工程（１）で得られた化合物（Ａ）と、求電子剤とを反応させる工程（２）を含む。 Further, the method for producing the compound (B) of the present invention is as follows.
The step (2) of reacting the compound (A) obtained in the step (1) with the electrophile is included.
　なお、本発明における各誘導体とは、本発明の作用効果を損なわないものであれば、上記各化合物の化学構造を一部置換したものが広く含まれ、たとえば、芳香環及び／又は複素環上に置換基が含まれる場合や、分子骨格上の一部又は全部が他原子や置換基に置換されている場合等を含む。例えば、芳香環及び／又は複素環上やアルキル基、官能基上の水素原子等が他のアルキル基や水酸基、アミノ基、エステル基、カルボキシル基、カルボニル基、シアノ基、エーテル基、Ｆ、Ｃｌ、Ｂｒ、Ｉ等のハロゲン原子や保護体、金属塩形態のものを一例としてあげることができるが、これらに限定するものではない。 The derivatives in the present invention broadly include those in which the chemical structure of each of the above compounds is partially substituted, as long as the effects of the present invention are not impaired. For example, on an aromatic ring and / or a heterocycle. Includes a case where a substituent is contained in, or a case where a part or all of the molecular skeleton is substituted with another atom or a substituent. For example, the hydrogen atom on the aromatic ring and / or heterocyclic ring, alkyl group, functional group, etc. is another alkyl group, hydroxyl group, amino group, ester group, carboxyl group, carbonyl group, cyano group, ether group, F, Cl. , Br, I and other halogen atoms, protectors, and metal salt forms can be given as examples, but the present invention is not limited to these.
　〔化合物（Ａ）及びその製造方法等〕
　本発明の化合物（Ａ）の製造方法は、芳香環または複素芳香環上に、１つ以上のハロゲン基と、１つ以上のアミノ基を有する、芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬の存在下で反応させる工程（１）を含む。 [Compound (A) and its production method, etc.]
The method for producing the compound (A) of the present invention is an aromatic compound (a1) or a heteroaromatic compound (a1) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring. The step (1) of reacting the a2) and the silylating agent (b) in the presence of an organic metal reagent is included.
　本発明の化合物（Ａ）の製造方法等を用いることにより、上記芳香族化合物（ａ１）または複素芳香族化合物（ａ２）の芳香環または複素芳香環上のアミノ基に対し、上記シリル化剤（ｂ）が１つ保護基として反応した化合物（Ａ）を簡便に得ることができる。そして、上記化合物（Ａ）を経由することにより、アミノ基の保護した中間体として単離することなく、例えば、さらに求核反応試薬として求電子試薬等と反応して上記アミノアリール誘導体を得ることが可能となり、副反応の抑制や、工程面、時間的・原料コスト的において優れたものとなる。 By using the method for producing the compound (A) of the present invention, the silylating agent (the above-mentioned silylating agent (a1) or the heteroaromatic compound (a2) has an amino group on the aromatic ring or the heteroaromatic ring. The compound (A) in which b) has reacted as one protective group can be easily obtained. Then, by passing through the compound (A), the aminoaryl derivative is obtained by further reacting with an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate in which an amino group is protected. This makes it possible to suppress side reactions, and is excellent in terms of process, time, and raw material cost.
　本発明において、上記工程（１）は、上記芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、上記シリル化剤（ｂ）とを、上記有機金属試薬の存在下で反応させる工程であれば、特に制限されずに用いることができる。 In the present invention, the step (1) is a step of reacting the aromatic compound (a1) or the heteroaromatic compound (a2) with the silylating agent (b) in the presence of the organometallic reagent. If there is, it can be used without particular limitation.
　また、上記工程（１）において、上記芳香族化合物（ａ１）または複素芳香族化合物（ａ２）、上記シリル化剤（ｂ）、並びに上記有機金属試薬の反応系への添加順序は、反応工程上適宜行ってよい。例えば、上記芳香族化合物（ａ１）または複素芳香族化合物（ａ２）を反応系に存在させ、次いで上記シリル化剤（ｂ）を反応系に添加した後に、上記有機金属試薬を添加する方法をあげることができる。 Further, in the step (1), the order of adding the aromatic compound (a1) or the heteroaromatic compound (a2), the silylating agent (b), and the organometallic reagent to the reaction system is determined in the reaction step. It may be done as appropriate. For example, a method in which the aromatic compound (a1) or the heteroaromatic compound (a2) is present in the reaction system, then the silylating agent (b) is added to the reaction system, and then the organometallic reagent is added is given. be able to.
　また、本発明において、上記芳香族化合物（ａ１）は、１つ以上のハロゲン基と、１つ以上のアミノ基を有する芳香族化合物であれば、公知のものであっても、新たに合成されたものであっても、適宜用いることができる。 Further, in the present invention, the aromatic compound (a1) is newly synthesized as long as it is an aromatic compound having one or more halogen groups and one or more amino groups, even if it is known. Even if it is a product, it can be used as appropriate.
　本発明において、上記芳香族化合物（ａ１）において、例えば、上記芳香環上にアミノ基を有していることが好ましく、当該アミノ基が上記シリル化剤（ｂ）と反応し、アミノ基上がシリル基により保護されたものとなりうる。例えば、１級アミノ基の場合、当該アミノ基に対して1つのシリル基保護がなされた化合物（Ａ）が好ましいものとしてあげることができる。 In the present invention, the aromatic compound (a1) preferably has, for example, an amino group on the aromatic ring, and the amino group reacts with the silylating agent (b) so that the amino group is on the amino group. It can be protected by a silyl group. For example, in the case of a primary amino group, the compound (A) in which one silyl group is protected against the amino group can be mentioned as preferable.
　なお、本発明の化合物（Ａ）の製造方法において、この項に記載がない事項について、上記化合物（Ａ）や化合物（Ｂ）の製造方法の項における記載事項等を同様に適宜用いてもよい。 In the method for producing the compound (A) of the present invention, with respect to the matters not described in this section, the items described in the above-mentioned compound (A) and the method for producing the compound (B) may be appropriately used in the same manner. ..
　また、本発明において、上記アミノ基が、１級アミノ基であってもよい。この場合、１級アミノ基の1つの水素原子がシリル基により置換されるとともに、アミノ基上のもう一方の水素原子は有機金属試薬由来の金属、例えば、リチウムに置換される。 Further, in the present invention, the amino group may be a primary amino group. In this case, one hydrogen atom of the primary amino group is substituted with a silyl group, and the other hydrogen atom on the amino group is substituted with a metal derived from an organic metal reagent, for example, lithium.
　上記芳香族化合物（ａ１）において、例えば、上記芳香環上にハロゲン基を有していることが好ましく、当該ハロゲン基が上記有機金属試薬と反応し、アリールアニオン中間体である化合物（Ａ）となりうる。 In the aromatic compound (a1), for example, it is preferable to have a halogen group on the aromatic ring, and the halogen group reacts with the organic metal reagent to become the compound (A) which is an aryl anionic intermediate. sell.
　また、本発明において、上記芳香族化合物（ａ１）は、ベンゼン環を１～１００個を含むことを、好ましい例としてあげることができ、例えば、１～８０個でもよく、１～５０個であってもよく、２～３０個であってもよく、３～２０個であってもよく、４～１５個であってもよく、５～１０個であってもよく、６～９個であってもよく、７～８個であってもよい。 Further, in the present invention, the aromatic compound (a1) may contain 1 to 100 benzene rings as a preferable example, and may be, for example, 1 to 80 or 1 to 50. It may be 2 to 30, 3 to 20, 4 to 15, 5 to 10, or 6 to 9. It may be 7 to 8 pieces.
　本発明において、上記芳香族化合物（ａ１）は、ベンゼン、ナフタレン、アントラセン、テトラセン、ピレン、ベンゾピレン、ペリレン、テトラセン、アズレン、及び、トロポンからなる群より選択される骨格を有することを、好ましい例としてあげることができる。また、これらの骨格は２種以上を有していてもよい。 In the present invention, it is preferable that the aromatic compound (a1) has a skeleton selected from the group consisting of benzene, naphthalene, anthracene, tetracene, pyrene, benzopyrene, perylene, tetracene, azulene, and tropone. I can give it. Moreover, these skeletons may have two or more kinds.
　本発明において、上記複素芳香族化合物（ａ２）は、１つ以上のハロゲン基と、１つ以上のアミノ基を有する複素芳香族化合物であれば、公知のものであっても、新たに合成されたものであっても、適宜用いることができうる。 In the present invention, the heteroaromatic compound (a2) is newly synthesized as long as it is a known heteroaromatic compound having one or more halogen groups and one or more amino groups. Even if it is a product, it can be used as appropriate.
　本発明において、上記複素芳香族化合物（ａ２）において、例えば、上記複素環上にアミノ基を有していることが好ましく、当該アミノ基が上記シリル化剤（ｂ）と反応し、アミノ基上がシリル基により保護されたものとなる。例えば、１級アミノ基の場合、当該アミノ基に対して1つのシリル基保護がなされた化合物（Ａ）が好ましいものとしてあげることができる。 In the present invention, the heteroaromatic compound (a2) preferably has, for example, an amino group on the heterocycle, and the amino group reacts with the silylating agent (b) on the amino group. Is protected by a silyl group. For example, in the case of a primary amino group, the compound (A) in which one silyl group is protected against the amino group can be mentioned as preferable.
　また、本発明において、上記アミノ基が、１級アミノ基であってもよい。この場合、１級アミノ基の1つの水素原子がシリル基により置換されるとともに、アミノ基上のもう一方の水素原子は有機金属試薬由来の金属、例えば、リチウムに置換される。 Further, in the present invention, the amino group may be a primary amino group. In this case, one hydrogen atom of the primary amino group is substituted with a silyl group, and the other hydrogen atom on the amino group is substituted with a metal derived from an organic metal reagent, for example, lithium.
　上記複素芳香族化合物（ａ２）において、例えば、上記複素環上にハロゲン基を有していることが好ましく、当該ハロゲン基が上記有機金属試薬と反応し、ヘテロアリールアニオン中間体である化合物（Ａ）となりうる。 In the heteroaromatic compound (a2), for example, it is preferable to have a halogen group on the heterocycle, and the halogen group reacts with the organometallic reagent to form a heteroaryl anionic intermediate (A). ) Can be.
　本発明において、上記複素環式化合物（ａ２）は、複素環を１～１００個を含むことを、好ましい例としてあげることができ、例えば、１～８０個でもよく、１～５０個であってもよく、２～３０個であってもよく、３～２０個であってもよく、４～１５個であってもよく、５～１０個であってもよく、６～９個であってもよく、７～８個であってもよい。 In the present invention, the heterocyclic compound (a2) may contain 1 to 100 heterocycles as a preferable example, and may be, for example, 1 to 80 or 1 to 50. It may be 2 to 30, 3 to 20, 4 to 15, 5 to 10, or 6 to 9. It may be 7 to 8 pieces.
　本発明において、上記複素環式化合物（ａ２）は、フラン、チオフェン、ピリジン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、ピリダジン、ピリミジン、ピラジン、１，２，３－トリアジン、１，３，５－トリアジン、１，２，４－トリアジン、キノリン、イソキノリン、ベンゾチオフェン、ベンゾフラン、シンノリン、キナゾリン、キノキサリン、フタラジン、ベンゾオキサゾール、１，２－ベンゾイソオキサゾール、ベンゾチアゾール、１，２－ベンゾイソチアゾール、１，２－ベンゾイソチアゾール－３（２Ｈ）－オン、２，１－ベンゾイソチアゾール－３（１Ｈ）－オン、プテリジン、アクリジン、キサンテン、ベンゾ－Ｃ－シンノリン、並びに、Ｎ－Ｈ基が保護ざれた、ピロール、イミダゾール、ピラゾール、１，２，３－トリアゾール、１，２，４－トリアゾール、インドール、イソインドール、ベンゾイミダゾール、インダゾール、ベンゾトリアゾール、及び、プリンからなる群より選択される骨格を有することを、好ましい例としてあげることができる。また、これらの骨格は２種以上を有していてもよい。 In the present invention, the heterocyclic compound (a2) is furan, thiophene, pyridine, oxazole, isoxazole, thiazole, isothiazole, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,3,5-. Triazine, 1,2,4-triazine, quinoline, isoquinoline, benzothiophene, benzofuran, cinnoline, quinazoline, quinoxaline, phthalazine, benzoxazole, 1,2-benzoisoxazole, benzothiazole, 1,2-benzoisothiazole, 1 , 2-Benzisothiazole-3 (2H) -one, 2,1-benzoisothiazole-3 (1H) -one, pteridine, aclysine, xanthene, benzo-C-sinnoline, and N-H groups are protected. It also has a skeleton selected from the group consisting of pyrrol, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, indole, isothiazole, benzimidazole, indazole, benzotriazole, and purine. This can be given as a preferable example. Moreover, these skeletons may have two or more kinds.
　本発明において、上記シリル化剤（ｂ）は、上記アミノ基と反応し保護し得るものであれば、公知のものであっても、新たに合成されたものであっても、適宜用いることができうる。 In the present invention, the silylating agent (b) may be a known one or a newly synthesized one as long as it can react with and protect the amino group. It can be done.
　本発明において、上記シリル化剤（ｂ）が、１価のシリル化剤であることを、好ましい例としてあげることができる。上記シリル化剤（ｂ）が、１価のシリル化剤である場合、上記工程（１）において、上記１価のシリル化剤は、上記アミノ基に対して、０．７５～１．２５等量用いられることを、好ましい例としてあげることができる。また、この場合、上記シリル化剤は、例えば、０．８０～１．２０等量用いられてもよく、０．８５～１．１０等量用いられてもよく、０．９０～１．０５等量用いられてもよく、０．９５～１．００等量用いられてもよく、１．０等量用いられてもよい。上記構成を有することにより、例えば、上記アミノ基が１級アミノ基の場合、当該アミノ基に対して1つのシリル基保護がなされた化合物（Ａ）が得られやすくなり好ましい。 In the present invention, a preferred example is that the silylating agent (b) is a monovalent silylating agent. When the silylating agent (b) is a monovalent silylating agent, in the step (1), the monovalent silylating agent is 0.75 to 1.25 or the like with respect to the amino group. It can be mentioned as a preferable example that it is used in a quantity. Further, in this case, the silylating agent may be used, for example, in an equal amount of 0.80 to 1.20, may be used in an equal amount of 0.85 to 1.10, and may be used in an equal amount of 0.90 to 1.05. Equal amounts may be used, 0.95 to 1.00 equal amounts may be used, and 1.0 equal amounts may be used. By having the above structure, for example, when the amino group is a primary amino group, it is preferable that the compound (A) in which one silyl group is protected against the amino group can be easily obtained.
　また、本発明において、上記シリル化剤（ｂ）が、２価のシリル化剤である場合、
　上記工程（１）において、上記シリル化剤は、上記アミノ基に対して、０．２５～０．７５等量用いられることを、好ましい例としてあげることができる。また、この場合、上記シリル化剤は、例えば、０．２８～０．７２等量用いられてもよく、０．３０～０．７０等量用いられてもよく、０．３５～０．６５等量用いられてもよく、０．４０～０．６０等量用いられてもよく、０．４５～０．５５等量用いられてもよく、０．５等量用いられてもよい。上記構成を有することにより、例えば、上記アミノ基が１級アミノ基の場合、当該アミノ基に対して1つのシリル基保護がなされた化合物（Ａ）が得られやすくなり好ましい。 Further, in the present invention, when the silylating agent (b) is a divalent silylating agent,
In the step (1), it can be mentioned as a preferable example that the silylating agent is used in an equal amount of 0.25 to 0.75 with respect to the amino group. Further, in this case, the silylating agent may be used, for example, in an equal amount of 0.28 to 0.72, or in an equal amount of 0.30 to 0.70, or 0.35 to 0.65. Equal amounts may be used, 0.40 to 0.60 equal amounts may be used, 0.45 to 0.55 equal amounts may be used, and 0.5 equal amounts may be used. By having the above structure, for example, when the amino group is a primary amino group, it is preferable that the compound (A) in which one silyl group is protected against the amino group can be easily obtained.
　また、本発明において、上記シリル化剤（ｂ）が、ｎ価のシリル化剤（ｎは３～９までの整数）であって、
　上記工程（１）において、上記シリル化剤は、上記アミノ基に対して、[（１／ｎ）－０．１]～[（１／ｎ）＋０．１]等量用いられることを、好ましい例としてあげることができる。上記構成を有することにより、例えば、上記アミノ基が１級アミノ基の場合、当該アミノ基に対して1つのシリル基保護がなされた化合物（Ａ）が得られやすくなり好ましい。　 Further, in the present invention, the silylating agent (b) is an n-valent silylating agent (n is an integer from 3 to 9).
In the step (1), it is preferable that the silylating agent is used in an equal amount of [(1 / n) −0.1] to [(1 / n) +0.1] with respect to the amino group. It can be given as an example. By having the above structure, for example, when the amino group is a primary amino group, it is preferable that the compound (A) in which one silyl group is protected against the amino group can be easily obtained.
　また、本発明において、上記有機金属試薬が、アルキルリチウム、アリールリチウム、又は、グリニャール試薬を含むことを、好ましい例としてあげることができる。上記アルキルリチウム、上記アリールリチウム、及び、上記グリニャール試薬は、いずれも、公知のものを適宜用いることができる。これらは単独で使用してもよく、また２種以上を混合して使用してもよい。 Further, in the present invention, it can be mentioned as a preferable example that the organometallic reagent contains an alkyllithium, an aryllithium, or a Grignard reagent. As the alkyllithium, the aryllithium, and the Grignard reagent, known ones can be appropriately used. These may be used alone or in combination of two or more.
　また、本発明において、上記化合物（Ａ）が、有機リチウム化合物、又は、有機マグネシウム化合物であってもよい。上記有機リチウム化合物、及び、上記有機マグネシウム化合物は、いずれも、公知のものを適宜用いることができる。これらは単独で使用してもよく、また２種以上を混合して使用してもよい。 Further, in the present invention, the compound (A) may be an organic lithium compound or an organic magnesium compound. As the organic lithium compound and the organic magnesium compound, known ones can be appropriately used. These may be used alone or in combination of two or more.
　また、本発明における化合物（Ａ）の製造方法として、例えば、
Figure JPOXMLDOC01-appb-C000001
 をあげることができる。上記の例では、例えば、アミノピリジン骨格を有する化合物を出発原料とした際に得られる化合物（Ａ）である。なお、Ｒ3～Ｒ５は、本明細書中のアルキル基と同様である。 Further, as a method for producing the compound (A) in the present invention, for example,
Figure JPOXMLDOC01-appb-C000001
 Can be given. In the above example, for example, it is the compound (A) obtained when a compound having an aminopyridine skeleton is used as a starting material. In addition, R 3 to R 5 are the same as the alkyl group in this specification.
　上記の合成例では、アミノブロモピリジン誘導体に対し、シリル化剤（例えば、１．０モル等量）と有機金属試薬としてのｎ－ブチルリチウム（例えば、３．０モル等量）をＴＨＦ溶媒下（室温～－１００℃下）で反応させ、窒素原子をメタル化（リチウム化）されたＮ－シリルアミノ基を有する化合物（Ａ）が形成される。得られた化合物（Ａ）は、好適な例としては当該系中に、さらに求電子試薬を加え、求核置換反応等により、求電子剤と反応した骨格を有するアミノピリジン誘導体を得ることができる。 In the above synthesis example, a silylating agent (for example, 1.0 mol equal amount) and n-butyllithium as an organometallic reagent (for example, 3.0 mol equal amount) are added to the aminobromopyridine derivative under a THF solvent. The reaction is carried out at (room temperature to −100 ° C.) to form a compound (A) having an N-silylamino group in which a nitrogen atom is metallized (lithiumized). As a suitable example, the obtained compound (A) can be obtained by adding an electrophile to the system and subjecting it to a nucleophilic substitution reaction or the like to obtain an aminopyridine derivative having a skeleton that has reacted with the electrophile. ..
　また、上記アミノブロモピリジン誘導体として５－ブロモ－２－アミノピリジンを用いた場合、例えば、
Figure JPOXMLDOC01-appb-C000002
 のように、窒素原子をリチウム化されたＮ－シリルアミノ基を有するピリジンリチウム誘導体を得ることができる。なお、Ｒ３～Ｒ５は、本明細書中のアルキル基と同様である。 When 5-bromo-2-aminopyridine is used as the aminobromopyridine derivative, for example,
Figure JPOXMLDOC01-appb-C000002
 As described above, a pyridine lithium derivative having an N-silylamino group in which a nitrogen atom is lithium can be obtained. In addition, R 3 to R 5 are the same as the alkyl group in this specification.
　また、本発明における他の化合物（Ａ）の製造方法として、例えば、
Figure JPOXMLDOC01-appb-C000003
 をあげることができる。なお、Ｒ3～Ｒ５は、本明細書中のアルキル基と同様である。 Further, as a method for producing another compound (A) in the present invention, for example,
Figure JPOXMLDOC01-appb-C000003
 Can be given. In addition, R 3 to R 5 are the same as the alkyl group in this specification.
　上記の合成例では、ブロモアニリン誘導体に対し、シリル化剤（例えば、１．０モル等量）と有機金属試薬としてのｓ－ブチルリチウム（例えば、３．２モル等量）をＴＨＦ溶媒下（－７０℃下）で反応させ、窒素原子をメタル化（リチウム化）されたＮ－シリルアミノ基を有する化合物（Ａ）が形成される。得られた化合物（Ａ）は、好適な例としては当該系中に、さらに求電子試薬を加え、求核置換反応等により、求電子剤と反応した骨格を有するアニリン誘導体を得ることができる。 In the above synthesis example, a silylating agent (for example, 1.0 mol equal amount) and s-butyllithium as an organometallic reagent (for example, 3.2 mol equal amount) are added to the bromoaniline derivative under a THF solvent (for example, 3.2 mol equal amount). The reaction is carried out at −70 ° C.) to form a compound (A) having an N-silylamino group in which a nitrogen atom is metallized (lithiumized). As a suitable example, the obtained compound (A) can be obtained by adding an electrophile to the system and subjecting it to a nucleophilic substitution reaction or the like to obtain an aniline derivative having a skeleton that has reacted with the electrophile.
　〔化合物（Ｂ）の製造方法等〕
　また、本発明の化合物（Ｂ）の製造方法は、
　上記製造方法で得られた化合物（Ａ）と、求電子剤とを反応させる工程（２）を含む。 [Method for producing compound (B), etc.]
Further, the method for producing the compound (B) of the present invention is as follows.
The step (2) of reacting the compound (A) obtained by the above production method with an electrophile is included.
　また、本発明の化合物（Ｂ）の他の製造方法は、
　芳香環または複素芳香環上に、１つ以上のハロゲン基と、１つ以上のアミノ基を有する、芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬の存在下で反応させる工程（１）、並びに、
　前記工程（１）で得られた化合物（Ａ）と、求電子剤とを反応させる工程（２）を含む。 Further, the other production method of the compound (B) of the present invention is
An aromatic compound (a1) or a heteroaromatic compound (a2) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring, and a silylating agent (b) are added. , The step of reacting in the presence of an organic metal reagent (1), and
The step (2) of reacting the compound (A) obtained in the step (1) with the electrophile is included.
　本発明の化合物（Ｂ）の製造方法等を用いることにより、上記化合物（Ａ）を、アミノ基の保護した中間体として単離することなく、求核反応試薬として求電子剤と反応して上記アミノアリール誘導体等の化合物（Ｂ）を得ることが可能となり、副反応の抑制や、工程面、時間的・原料コスト的において優れたものとなる。 By using the method for producing the compound (B) of the present invention, the compound (A) is reacted with an electrophile as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group. It becomes possible to obtain a compound (B) such as an aminoaryl derivative, which is excellent in terms of suppression of side reactions, process, time and raw material cost.
　なお、本発明の化合物（Ａ）において、この項に記載がない事項について、上記化合物（Ａ）の製造方法の項における記載事項等を同様に適宜用いてもよい。 In the compound (A) of the present invention, the matters described in the section of the method for producing the compound (A) may be used as appropriate for the matters not described in this section.
　また、上記工程（２）は、前記工程（１）で得られた化合物（Ａ）と、求電子剤とを反応させる工程であれば、特に制限されずに用いることができる。 Further, the step (2) can be used without particular limitation as long as it is a step of reacting the compound (A) obtained in the step (1) with an electrophile.
　本発明において、上記求電子剤が、ケトン、アルデヒド、エステル、アミド、酸ハライド、ハロゲン、ハロアルカン、ハロギ酸エステル、カルバモイルハライド、エポキシド、イミン、ニトリル、酸無水物、及び、スルホニルハライドからなる群より選択される１つ以上の基を有することを、好ましい例としてあげることができる。上記ケトン、上記アルデヒド、上記エステル、上記アミド、上記酸ハライド、上記ハロゲン、上記ハロアルカン、上記ハロギ酸エステル、上記カルバモイルハライド、上記エポキシド、上記イミン、上記ニトリル、上記酸無水物、及び、上記スルホニルハライドは、いずれも、公知のものないし新たに合成されたものを適宜用いることができる。また、これらの骨格は２種以上を有していてもよい。 In the present invention, the electrophile comprises a group consisting of ketones, aldehydes, esters, amides, acid halides, halogens, haloalkanes, halograte esters, carbamoyl halides, epoxides, imines, nitriles, acid anhydrides, and sulfonyl halides. Having one or more groups of choice can be given as a preferred example. The ketone, the aldehyde, the ester, the amide, the acid halide, the halogen, the haloalkane, the halograte, the carbamoyl halide, the epoxide, the imine, the nitrile, the acid anhydride, and the sulfonyl halide. As for all, known ones or newly synthesized ones can be appropriately used. Moreover, these skeletons may have two or more kinds.
　また、本発明において、上記化合物（Ｂ）が、アルコール化合物、シリルエーテル化合物、ケトン化合物、アルデヒド化合物、イミン化合物、アミン化合物、エステル化合物、カーバメート化合物、スルホニル化合物、又は、アルカン化合物であることを、好ましい例としてあげることができる。 Further, in the present invention, the compound (B) is an alcohol compound, a silyl ether compound, a ketone compound, an aldehyde compound, an imine compound, an amine compound, an ester compound, a carbamate compound, a sulfonyl compound, or an alkane compound. It can be given as a preferable example.
　また、上記化合物（Ｂ）として、例えば、
Figure JPOXMLDOC01-appb-C000004
 をあげることができる。上記の例では、例えば、アミノピリジン骨格を有する化合物を出発原料とした際に得られる化合物（Ｂ）である。なお、Ｅｌｅとは求電子剤由来の骨格である。 Further, as the compound (B), for example,
Figure JPOXMLDOC01-appb-C000004
 Can be given. In the above example, for example, it is a compound (B) obtained when a compound having an aminopyridine skeleton is used as a starting material. Ele is a skeleton derived from an electrophile.
　また、上記求電子剤がケトンの場合、化合物（Ｂ）は、例えば、
Figure JPOXMLDOC01-appb-C000005
 となりうる。なお、Ｒ１、Ｒ２等は、本明細書中のアルキル基と同様である。 When the electrophile is a ketone, the compound (B) is, for example,
Figure JPOXMLDOC01-appb-C000005
 Can be. In addition, R 1 , R 2, etc. are the same as the alkyl group in this specification.
　そして、例えば、出発原料である上記アミノピリジン骨格を有する化合物が５－ブロモ－２－アミノピリジンの場合には、化合物（Ｂ）として、例えば、
Figure JPOXMLDOC01-appb-C000006
 が得られうる。なお、Ｒ１、Ｒ２等は、本明細書中のアルキル基と同様である。 Then, for example, when the compound having the aminopyridine skeleton as a starting material is 5-bromo-2-aminopyridine, as compound (B), for example,
Figure JPOXMLDOC01-appb-C000006
 Can be obtained. In addition, R 1 , R 2, etc. are the same as the alkyl group in this specification.
　また、上記求電子剤がハロゲン化アルキル等の場合、化合物（Ｂ）は、例えば、
Figure JPOXMLDOC01-appb-C000007
 となりうる。なお、Ｒ等は、本明細書中のアルキル基等と同様である。 When the electrophile is an alkyl halide or the like, the compound (B) is, for example,
Figure JPOXMLDOC01-appb-C000007
 Can be. R and the like are the same as those of the alkyl group and the like in the present specification.
　また、上記化合物（Ｂ）として、例えば、
Figure JPOXMLDOC01-appb-C000008
 をあげることができる。上記の例では、例えば、アニリン骨格を有する化合物を出発原料とした際に得られる化合物（Ｂ）である。なお、Ｅｌｅとは求電子剤由来の骨格である。 Further, as the compound (B), for example,
Figure JPOXMLDOC01-appb-C000008
 Can be given. In the above example, for example, it is a compound (B) obtained when a compound having an aniline skeleton is used as a starting material. Ele is a skeleton derived from an electrophile.
　また、上記求電子剤がケトンの場合、化合物（Ｂ）は、例えば、
Figure JPOXMLDOC01-appb-C000009
 となりうる。なお、Ｒ１、Ｒ２等は、本明細書中のアルキル基と同様である。 When the electrophile is a ketone, the compound (B) is, for example,
Figure JPOXMLDOC01-appb-C000009
 Can be. In addition, R 1 , R 2, etc. are the same as the alkyl group in this specification.
　また、本発明における化合物（Ｂ）の製造方法として、例えば、
Figure JPOXMLDOC01-appb-C000010
 をあげることができる。なお、Ｒ3～Ｒ５は、本明細書中のアルキル基と同様である。Ｅｌｅとは求電子剤由来の骨格である。 Further, as a method for producing the compound (B) in the present invention, for example,
Figure JPOXMLDOC01-appb-C000010
 Can be given. In addition, R 3 to R 5 are the same as the alkyl group in this specification. Ele is a skeleton derived from an electrophile.
　上記の合成例では、アミノブロモピリジン誘導体に対し、シリル化剤（例えば、１．０モル等量）と有機金属試薬としてのｎ－ブチルリチウム（例えば、３．０モル等量）をＴＨＦ溶媒下（室温～－１００℃下）で反応させ、中間体である、窒素原子をメタル化（リチウム化）されたＮ－シリルアミノ基を有する化合物（Ａ）が形成される。そして、好適な例としては当該系中に、さらに求電子試薬を加え、求核置換反応等により、求電子剤と反応した骨格を有するアミノピリジン誘導体を得ることができる。 In the above synthesis example, a silylating agent (for example, 1.0 mol equal amount) and n-butyllithium as an organometallic reagent (for example, 3.0 mol equal amount) are added to the aminobromopyridine derivative under a THF solvent. The reaction is carried out at (room temperature to -100 ° C.) to form an intermediate compound (A) having an N-silylamino group in which a nitrogen atom is metallized (lithiumized). Then, as a preferable example, an electrophile can be further added to the system, and an aminopyridine derivative having a skeleton that has reacted with the electrophile can be obtained by a nucleophilic substitution reaction or the like.
　また、上記求電子剤としてケトンを用いた場合、例えば、
Figure JPOXMLDOC01-appb-C000011
 のように、ヒドロキシアルキルアミノピリジン誘導体を得ることができる。なお、Ｒ１～Ｒ５は、本明細書中のアルキル基と同様である。Ｅｌｅとは求電子剤由来の骨格である。 When a ketone is used as the electrophile, for example,
Figure JPOXMLDOC01-appb-C000011
 As in, a hydroxyalkylaminopyridine derivative can be obtained. In addition, R 1 to R 5 are the same as the alkyl group in this specification. Ele is a skeleton derived from an electrophile.
　また、本発明における他の化合物（Ｂ）の製造方法として、例えば、
Figure JPOXMLDOC01-appb-C000012
 をあげることができる。なお、Ｒ3～Ｒ５は、本明細書中のアルキル基と同様である。Ｅｌｅとは求電子剤由来の骨格である。 Further, as a method for producing another compound (B) in the present invention, for example,
Figure JPOXMLDOC01-appb-C000012
 Can be given. In addition, R 3 to R 5 are the same as the alkyl group in this specification. Ele is a skeleton derived from an electrophile.
　上記の合成例では、ブロモアニリン誘導体に対し、シリル化剤（例えば、１．０モル等量）と有機金属試薬としてのｓ－ブチルリチウム（例えば、３．２モル等量）をＴＨＦ溶媒下（－７０℃下）で反応させ、中間体である、窒素原子をメタル化（リチウム化）されたＮ－シリルアミノ基を有する化合物（Ａ）が形成される。そして、好適な例としては当該系中に、さらに求電子試薬を加え、求核置換反応等により、求電子剤と反応した骨格を有するアニリン誘導体を得ることができる。 In the above synthesis example, a silylating agent (for example, 1.0 mol equal amount) and s-butyllithium as an organometallic reagent (for example, 3.2 mol equal amount) are added to the bromoaniline derivative in a THF solvent (for example, in an equal amount of 3.2 mol). The reaction is carried out at −70 ° C.) to form an intermediate compound (A) having an N-silylamino group in which a nitrogen atom is metallized (lithiumized). Then, as a preferable example, an electrophile can be further added to the system, and an aniline derivative having a skeleton that has reacted with the electrophile can be obtained by a nucleophilic substitution reaction or the like.
　また、上記求電子剤としてケトンを用いた場合、例えば、
Figure JPOXMLDOC01-appb-C000013
 のように、ヒドロキシアルキルアニリン誘導体を得ることができる。なお、Ｒ１～Ｒ５は、本明細書中のアルキル基と同様である。Ｅｌｅとは求電子剤由来の骨格である。 When a ketone is used as the electrophile, for example,
Figure JPOXMLDOC01-appb-C000013
 As in, a hydroxyalkylaniline derivative can be obtained. In addition, R 1 to R 5 are the same as the alkyl group in this specification. Ele is a skeleton derived from an electrophile.
　本発明の化合物（Ｂ）の製造方法において、
　芳香環または複素芳香環上に、１つ以上のハロゲン基と、１つ以上のアミノ基を有する、芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬の存在下で反応させる工程（１）、並びに、
　前記工程（１）で得られた化合物（Ａ）と、求電子剤とを反応させる工程（２）を含み、上記工程（１）の反応後にワークアップせずに、当該系中に工程（２）における求電子剤等を加えて工程（２）を行った後に反応処理や精製処理を行うこと（例えば、ワンポット反応として）が、特に好適な例としてあげることができる。 In the method for producing the compound (B) of the present invention.
An aromatic compound (a1) or a heteroaromatic compound (a2) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring, and a silylating agent (b) are added. , The step of reacting in the presence of an organic metal reagent (1), and
A step (2) of reacting the compound (A) obtained in the step (1) with an electrophile is included, and the step (2) is included in the system without working up after the reaction of the step (1). ), And then the reaction treatment and purification treatment (for example, as a one-pot reaction) after performing the step (2) can be given as a particularly preferable example.
　例えば、複素芳香族化合物（ａ２）の場合の例として、下記反応式に示すように、
Figure JPOXMLDOC01-appb-C000014
 　２－アミノ－５－ブロモピリジンを出発原料として、シリル化剤と有機金属試薬としてのｎ－ブチルリチウムを加えて得られる反応中間体たる化合物（Ａ）を単離や精製を行わずに、さらに当該系中に求電子剤としてのケトンを加えて化合物（Ｂ）たる５－（ヒドロキシアルキル）－２－アミノピリジン誘導体をえることが好適な例としてあげることができる。なお、Ｒ１～Ｒ５は、本明細書中のアルキル基と同様である。 For example, as an example in the case of the heteroaromatic compound (a2), as shown in the following reaction formula,
Figure JPOXMLDOC01-appb-C000014
 Using 2-amino-5-bromopyridine as a starting material, compound (A), which is a reaction intermediate obtained by adding a silylating agent and n-butyllithium as an organometallic reagent, is further prepared without isolation or purification. A preferable example is to add a ketone as an electrophile to the system to obtain a 5- (hydroxyalkyl) -2-aminopyridine derivative as compound (B). In addition, R 1 to R 5 are the same as the alkyl group in this specification.
　〔化合物（Ａ）等〕
　また、本発明の化合物（Ａ）は、芳香環または複素芳香環上の1か所以上がメタル化され、1つ以上の，窒素原子をメタル化されたＮ－シリルアミノ基［（Ｍ）Ｎ（ＳｉＲ１Ｒ２Ｒ３）。Ｒ１～Ｒ３は、それぞれ独立して置換されていてもよい、炭素数１～１０の鎖状または環状のアルキル基、アルケニル基、アルキニル基、又は、アリール基を表す。Ｍは、金属原子を表す。］を有する。 [Compound (A), etc.]
In addition, the compound (A) of the present invention has one or more metallized N-silylamino groups [(M) N () in which one or more nitrogen atoms are metallized on the aromatic ring or heteroaromatic ring. SiR 1 R 2 R 3 ). R 1 to R 3 represent a chain or cyclic alkyl group having 1 to 10 carbon atoms, an alkenyl group, an alkynyl group, or an aryl group, which may be substituted independently of each other. M represents a metal atom. ].
　また、本発明の化合物（Ａ）等は、１つ以上のハロゲン基と、１つ以上のアミノ基とにより置換されている芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬で反応させて得られる化合物である。 Further, the compound (A) and the like of the present invention are silylated with an aromatic compound (a1) or a heteroaromatic compound (a2) substituted with one or more halogen groups and one or more amino groups. It is a compound obtained by reacting the agent (b) with an organic metal reagent.
　本発明の化合物（Ａ）によると、上記化合物（Ａ）を経由することにより、アミノ基の保護した中間体として単離することなく、例えば、さらに求核反応試薬として求電子試薬等と反応して上記アミノアリール誘導体を得ることが可能となり、副反応の抑制や、工程面、時間的・原料コスト的において優れたものとなる。 According to the compound (A) of the present invention, by passing through the compound (A), for example, it further reacts with an electrophile or the like as a nucleophilic reaction reagent without being isolated as an intermediate protected by an amino group. As a result, the above-mentioned aminoaryl derivative can be obtained, which is excellent in terms of suppression of side reactions, process, time and raw material cost.
　なお、本発明の化合物（Ａ）において、この項に記載がない事項について、上記化合物（Ａ）の製造方法や化合物（Ｂ）の製造方法の項における記載事項等を同様に適宜用いてもよい。 Regarding the matters not described in this section of the compound (A) of the present invention, the items described in the above-mentioned method for producing the compound (A) and the method for producing the compound (B) may be appropriately used in the same manner. ..
　本発明の化合物（Ａ）は、例えば、上述の化合物（Ａ）の製造方法によって得ることができる。 The compound (A) of the present invention can be obtained, for example, by the above-mentioned method for producing the compound (A).
　また、本発明の化合物（Ａ）は、芳香環または複素芳香環上の1か所以上がメタル化され、1つ以上の，窒素原子をメタル化されたＮ－シリルアミノ基［（Ｍ）Ｎ（ＳｉＲ１Ｒ２Ｒ３）。Ｒ１～Ｒ３は、それぞれ独立して置換されていてもよい、炭素数１～１０の鎖状または環状のアルキル基、アルケニル基、アルキニル基、又は、アリール基を表す。Ｍは、金属原子を表す。］を有する。 In addition, the compound (A) of the present invention has one or more metallized N-silylamino groups [(M) N () in which one or more nitrogen atoms are metallized on the aromatic ring or heteroaromatic ring. SiR 1 R 2 R 3 ). R 1 to R 3 represent a chain or cyclic alkyl group having 1 to 10 carbon atoms, an alkenyl group, an alkynyl group, or an aryl group, which may be substituted independently of each other. M represents a metal atom. ].
　上記メタル化されたＮ－シリルアミノ基において、Ｒ１～Ｒ３は、それぞれ独立して置換されていてもよい、炭素数１～１０の鎖状または環状のアルキル基、アルケニル基、アルキニル基、又は、アリール基を表す。 In the metallized N-silylamino group, R 1 to R 3 may be independently substituted, respectively, and may be a chain or cyclic alkyl group having 1 to 10 carbon atoms, an alkenyl group, an alkynyl group, or an alkynyl group. , Represents an aryl group.
　上記炭素数１～１０の鎖状または環状のアルキル基、アルケニル基、アルキニル基、又は、アリール基とは、例えば、メチル基、エチル基、１－プロピル基、１－メチル－１－エチル基、１－ブチル基、１－メチル－１－プロピル基、１，１－ジメチル－１－エチル基、２－メチル－１－プロピル基、１－ペンチル基、２－ペンチル基、１－ヘプチル基、２－ヘプチル基、１－オクチル基、２－オクチル基、１－ノニル基、２－ノニル基、１－デカニル基、２－デカニル基、シクロペンチル基、シクロブテニル基、エテニル基、１－プロペニル基、２－プロペニル基、１－ブテニル基、２－ブテニル基、１－ペンテニル基、２－ペンテニル基、１－ヘプテニル基、２－ヘプテニル基、１－オクテニル基、２－オクテニル基、１－ノネニル基、２－ノネニル基、１－デカネニル基、２－デカネニル基、フェニル基、ナフチル基、アントラセニル基、ならびに、これらの置換体をあげることができる。また、置換体として、例えば、炭素数１～４の鎖状または環状のアルキル基、ハロゲン基、水酸基、アルコキシ基などをあげることができる。 The chain or cyclic alkyl group, alkenyl group, alkynyl group, or aryl group having 1 to 10 carbon atoms includes, for example, a methyl group, an ethyl group, a 1-propyl group, a 1-methyl-1-ethyl group, and the like. 1-butyl group, 1-methyl-1-propyl group, 1,1-dimethyl-1-ethyl group, 2-methyl-1-propyl group, 1-pentyl group, 2-pentyl group, 1-heptyl group, 2 -Heptyl group, 1-octyl group, 2-octyl group, 1-nonyl group, 2-nonyl group, 1-decanyl group, 2-decanyl group, cyclopentyl group, cyclobutenyl group, ethenyl group, 1-propenyl group, 2- Propenyl group, 1-butenyl group, 2-butenyl group, 1-pentenyl group, 2-pentenyl group, 1-heptenyl group, 2-heptenyl group, 1-octenyl group, 2-octenyl group, 1-nonenyl group, 2- Examples thereof include a nonenyl group, a 1-decanenyl group, a 2-decanenyl group, a phenyl group, a naphthyl group, an anthrasenyl group, and substitutions thereof. Further, as the substituent, for example, a chain or cyclic alkyl group having 1 to 4 carbon atoms, a halogen group, a hydroxyl group, an alkoxy group and the like can be mentioned.
　上記メタル化されたＮ－シリルアミノ基において、Ｍは、金属原子を表す。上記Ｍは、例えば、工程（１）により化合物（Ａ）を得る場合には、通常、工程（１）で用いる有機金属試薬由来の金属となり、例えば、ｎ－ＢｕＬｉ等のアルカリリチウムやアリールリチウムを用いた場合には、ＭはＬｉとなり、有機マグネシウム試薬等のグリニャール試薬を用いた場合には、Ｍｇとなる。また、例えば、上記有機金属試薬が複数種用いた場合、Ｍが相違する複数のメタル化されたＮ－シリルアミノ基が同一反応系に含まれていてもよい。 In the metallized N-silylamino group, M represents a metal atom. The above M is, for example, a metal derived from an organometallic reagent usually used in the step (1) when the compound (A) is obtained by the step (1), and for example, alkali lithium such as n-BuLi or aryl lithium is used. When used, M becomes Li, and when a Grignard reagent such as an organomagnesium reagent is used, it becomes Mg. Further, for example, when a plurality of kinds of the above-mentioned organometallic reagents are used, a plurality of metallized N-silylamino groups having different Ms may be contained in the same reaction system.
　上記化合物（Ａ）として、例えば、
Figure JPOXMLDOC01-appb-C000015
 をあげることができる。上記の例では、例えば、５－ブロモ－２－アミノピリジン等のアミノピリジン骨格を有する化合物を原料とした際に得られる化合物（Ａ）である。上記化合物（Ａ）１分子に対して、１つのリチウムイオンが芳香環又は複素環上でアリールアニオンのカウンターカチオンとなり得、アミノ基上にリチウム化されたＮ－シリルアミノ基を含みうる。なお、Ｒ3～Ｒ５は、本明細書中のアルキル基と同様である。 As the compound (A), for example,
Figure JPOXMLDOC01-appb-C000015
 Can be given. In the above example, it is the compound (A) obtained when a compound having an aminopyridine skeleton such as 5-bromo-2-aminopyridine is used as a raw material. For one molecule of the compound (A), one lithium ion can be a counter cation of an aryl anion on an aromatic ring or a heterocycle, and can contain a lithium N-silylamino group on the amino group. In addition, R 3 to R 5 are the same as the alkyl group in this specification.
　また、上記化合物（Ａ）として、例えば、
Figure JPOXMLDOC01-appb-C000016
 をあげることができる。上記の例では、例えば、４－ブロモ－１－アミノベンゼン等のアミノベンゼン骨格を有する化合物を原料とした際に得られる化合物（Ａ）である。上記化合物（Ａ）１分子に対して、１つのリチウムイオンが芳香環又は複素環上でアリールアニオンのカウンターカチオンとなり得、アミノ基上にリチウム化されたＮ－シリルアミノ基を含みうる。なお、Ｒ3～Ｒ５は、本明細書中のアルキル基と同様である。 Further, as the compound (A), for example,
Figure JPOXMLDOC01-appb-C000016
 Can be given. In the above example, it is the compound (A) obtained when a compound having an aminobenzene skeleton such as 4-bromo-1-aminobenzene is used as a raw material. For one molecule of the compound (A), one lithium ion can be a counter cation of an aryl anion on an aromatic ring or a heterocycle, and can contain a lithium N-silylamino group on the amino group. In addition, R 3 to R 5 are the same as the alkyl group in this specification.
　また、本発明の化合物（Ａ）は、化合物（Ｂ）への合成反応を含めた、化合物（Ａ）に次いで化合物（Ｂ）のでの順次反応、連続反応として行うことが好ましいが、他の方法として、例えば、可能な場合は単離したり、精製しないままの反応物を中間体として次反応に用いてもよい。 Further, the compound (A) of the present invention is preferably carried out as a sequential reaction or a continuous reaction with the compound (B) following the compound (A), including a synthetic reaction with the compound (B), but other methods. For example, if possible, the reaction product, which has been isolated or has not been purified, may be used as an intermediate in the next reaction.
　以下、本発明の構成と効果を具体的に示す実施例等について説明する。以下、実施例における濃縮操作は特に指定のない限り、減圧下で行った。なお、実施例等における評価項目は下記のようにして測定を行った。 Hereinafter, examples and the like that specifically show the configuration and effects of the present invention will be described. Hereinafter, the concentration operation in the examples was carried out under reduced pressure unless otherwise specified. The evaluation items in the examples and the like were measured as follows.
　＜１Ｈ－ＮＭＲスペクトルの測定＞
　１Ｈ－ＮＭＲスペクトルの測定は、核磁気共鳴装置（日本電子社製、製品名ＡＬ４００）を用い、内部標準としてテトラメチルシランを用いて行った。 < 1 Measurement of 1 H-NMR spectrum>
1 The H-NMR spectrum was measured using a nuclear magnetic resonance apparatus (manufactured by JEOL Ltd., product name AL400) and tetramethylsilane as an internal standard.
　＜１３Ｃ－ＮＭＲスペクトルの測定＞
　１３Ｃ－ＮＭＲスペクトルの測定は、核磁気共鳴装置（日本電子社製、製品名ＡＬ４００）を用い、内部標準としてテトラメチルシランを用いて行った。 < Measurement of 13 C-NMR spectrum>
13 The C-NMR spectrum was measured using a nuclear magnetic resonance apparatus (manufactured by JEOL Ltd., product name AL400) and tetramethylsilane as an internal standard.
　＜高分解ＭＳスペクトルの測定＞
　高分解ＭＳスペクトル（ＨＲＭＳ）の測定は、飛行時間型質量分析計（Ｗａｔｅｒｓ社製、製品名ＬＣＴ－ＰｒｅｍｉｅｒＸＥ、大気圧固体試料分析プローブ法：ＡＳＡＰ）を用いて行った。 <Measurement of high resolution MS spectrum>
The measurement of the highly decomposed MS spectrum (HRMS) was performed using a time-of-flight mass spectrometer (manufactured by Waters, product name LCT-PremierXE, atmospheric pressure solid sample analysis probe method: ASAP).
　〔実施例１〕化合物１：２－（６－アミノピリジン－３－イル）プロパン－２－オールの合成
Figure JPOXMLDOC01-appb-C000017
 [Example 1] Synthesis of compound 1: 2- (6-aminopyridine-3-yl) propan-2-ol
Figure JPOXMLDOC01-appb-C000017
　室温、窒素雰囲気下で、２－アミノ－５－ブロモピリジン（２１．０００ｇ、１２１．４ｍｍｏｌ、１．０当量）を２１０ｍｌのＴＨＦに溶液し、－７０℃まで冷却した。同温度にてクロロトリメチルシラン（１３．１８７ｇ、１２１．４ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（２２７．９ｍｌ、３７０．２ｍｍｏｌ、３．０５当量）を加えて０．５時間攪拌した後に、アセトン（１７．６２４ｇ、３０３．５ｍｍｏｌ、２．５当量）を加えて３０分攪拌した。反応液を室温まで昇温し、市水（４６ｍｌ）、１級塩酸（２０．５ｍｌ）を加えて攪拌後、水層を分液した。水層に５０％ＮａＯＨ水溶液（１２ｍｌ）を加え、トルエンで３回、ＴＨＦで４回抽出した。得られた有機層を減圧濃縮した後に、残渣をＴＨＦ／ヘキサンで再結晶化し化合物１（１０．２５６ｇ、５６％）を得た。
白色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）δ７．９８（ｄ、Ｊ＝２．０Ｈｚ、１Ｈ）、７．４４（ｄｄ、Ｊ＝２．４、８．４、１Ｈ）、６．３８（ｄ、Ｊ＝８．８、１Ｈ）、５．６９（ｂｒ、２Ｈ）、４．８５（ｂｒ、１Ｈ）、１．３７（ｓ、６Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤ３ＯＤ）δ１５９．３、１４３．８、１３６．８、１３５．２、１０９．８、７１．４、３１．６。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ８Ｈ１３Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：１５３．１０２８、実測値１５３．１０２０。 2-Amino-5-bromopyridine (21.000 g, 121.4 mmol, 1.0 eq) was dissolved in 210 ml of THF at room temperature and in a nitrogen atmosphere and cooled to −70 ° C. At the same temperature, chlorotrimethylsilane (13.187 g, 121.4 mmol, 1.00 eq) and 1.6 M n-BuLihexane solution (227.9 ml, 370.2 mmol, 3.05 eq) were added to 0. After stirring for 5 hours, acetone (17.624 g, 303.5 mmol, 2.5 eq) was added and the mixture was stirred for 30 minutes. The reaction solution was heated to room temperature, city water (46 ml) and primary hydrochloric acid (20.5 ml) were added, and the mixture was stirred and then the aqueous layer was separated. A 50% aqueous NaOH solution (12 ml) was added to the aqueous layer, and the mixture was extracted 3 times with toluene and 4 times with THF. The obtained organic layer was concentrated under reduced pressure, and then the residue was recrystallized from THF / hexane to obtain Compound 1 (10.256 g, 56%).
White crystals;
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ7.98 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 2.4, 8.4, 1H), 6.38 ( d, J = 8.8, 1H), 5.69 (br, 2H), 4.85 (br, 1H), 1.37 (s, 6H).
13 C-NMR (100 MHz, CD 3 OD) δ159.3, 143.8, 136.8, 135.2, 109.8, 71.4, 31.6.
HRMS (ASAP): C 8 H 13 N 2 O [M + H] + calculated value: 153.1028, measured value 153.1020.
　〔実施例２〕様々なシリル化剤を用いた化合物１の合成
　Ａｒ雰囲気下、室温にて２－アミノ－５－ブロモピリジンのＴＨＦ溶液（０．６Ｍ）にシリル化剤を加えた。続いて溶液を氷冷してｎ－ＢｕＬｉ（１．２０当量）を加えた後に、室温まで昇温して２時間攪拌した。反応液を－７０℃に冷却してｎ－ＢｕＬｉ（２．００当量）を加えて０．５時間攪拌し、アセトンを加えて１０分間攪拌した。室温まで昇温し、市水と一級塩酸を加え、化合物１を含有する溶液を得た。この溶液について、実施例１で合成した化合物１を標準品として用い、下記のＨＰＬＣ条件で定量することにより、この溶液に含まれる化合物１を定量した。 [Example 2] Synthesis of Compound 1 using various silylating agents The silylating agent was added to a THF solution (0.6M) of 2-amino-5-bromopyridine at room temperature under an Ar atmosphere. Subsequently, the solution was ice-cooled, n-BuLi (1.20 equivalent) was added, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. The reaction mixture was cooled to −70 ° C., n-BuLi (2.00 equivalents) was added, and the mixture was stirred for 0.5 hours, acetone was added, and the mixture was stirred for 10 minutes. The temperature was raised to room temperature, and city water and primary hydrochloric acid were added to obtain a solution containing compound 1. For this solution, the compound 1 synthesized in Example 1 was used as a standard product, and the compound 1 contained in this solution was quantified by quantifying under the following HPLC conditions.
　＜ＨＰＬＣ条件＞
カラム        ：ｓｃｈｅｒｚｏ　ＳＳ－Ｃ１８　１００×３ｍｍ
カラム温度    ：４０℃
注入量        ：５μｌ
検出波長      ：２８０ｎｍ
流速          ：０．５ｍｌ／ｍｉｎ
移動相Ａ      ：ｐＨ＝４．７に調整した１００ｍＭギ酸アンモニウム水溶液
移動相Ｂ      ：ＭｅＣＮ／ｍｉｌｌｉＱ水＝７／３
グラジエント  ：Ｂ：５％→１００％（０～１２分）
Ｂ：１００％（１２～１５分）
Ｂ：１００％→５％（１５～１６分）
Ｂ：５％（１６～２０分）
化合物１の保持時間:４．５分 <HPLC conditions>
Column: scherzo SS-C18 100 x 3 mm
Column temperature: 40 ° C
Injection volume: 5 μl
Detection wavelength: 280 nm
Flow velocity: 0.5 ml / min
Mobile phase A: 100 mM ammonium formate aqueous solution adjusted to pH = 4.7 Mobile phase B: MeCN / milliQ water = 7/3
Gradient: B: 5% → 100% (0-12 minutes)
B: 100% (12 to 15 minutes)
B: 100% → 5% (15-16 minutes)
B: 5% (16 to 20 minutes)
Retention time of compound 1: 4.5 minutes
　（１）クロロトリエチルシランを用いた化合物１の合成
　２－アミノ－５－ブロモピリジン（０．２００ｇ、１．１６ｍｍｏｌ、１．００当量）、クロロトリエチルシラン（０．１７４ｇ、１．１６ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１回目：０．９ｍｌ、１．３９ｍｍｏｌ、１．２０当量、２回目：１．４ｍｌ、２．３１ｍｍｏｌ、２．００当量）、アセトン（０．１６８ｇ、２．８９ｍｍｏｌ、２．５０当量）を用いて化合物１を合成した。得られた溶液に含まれる化合物１を定量し、収率６０％を算出した。 (1) Synthesis of Compound 1 using chlorotriethylsilane 2-amino-5-bromopyridine (0.200 g, 1.16 mmol, 1.00 equivalent), chlorotriethylsilane (0.174 g, 1.16 mmol, 1. 00 equivalents), 1.6 M n-BuLihexane solution (1st time: 0.9 ml, 1.39 mmol, 1.20 equivalents), 2nd time: 1.4 ml, 2.31 mmol, 2.00 equivalents), acetone (0) Compound 1 was synthesized using .168 g, 2.89 mmol, 2.50 eq). Compound 1 contained in the obtained solution was quantified, and the yield was calculated to be 60%.
　（２）クロロｔ－ブチルジメチルシランを用いた化合物１の合成
　２－アミノ－５－ブロモピリジン（０．２００ｇ、１．１６ｍｍｏｌ、１．００当量）、クロロｔ－ブチルジメチルシラン（０．１７４ｇ、１．１６ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１回目：０．９ｍｌ、１．３９ｍｍｏｌ、１．２０当量、２回目：１．４ｍｌ、２．３１ｍｍｏｌ、２．００当量）、アセトン（０．１６８ｇ、２．８９ｍｍｏｌ、２．５０当量）を用いて化合物１を合成した。得られた溶液に含まれる化合物１を定量し、収率７４％を算出した。 (2) Synthesis of Compound 1 using chloro t-butyl dimethyl silane 2-amino-5-bromopyridine (0.200 g, 1.16 mmol, 1.00 equivalent), chloro t-butyl dimethyl silane (0.174 g, 1.16 mmol, 1.00 eq), 1.6 M n-BuLihexane solution (1st: 0.9 ml, 1.39 mmol, 1.20 eq), 2nd: 1.4 ml, 2.31 mmol, 2.00 Compound 1 was synthesized using (equivalent) and acetone (0.168 g, 2.89 mmol, 2.50 equivalent). Compound 1 contained in the obtained solution was quantified, and the yield was calculated to be 74%.
　（３）ジクロロジメチルシランを用いた化合物１の合成
　２－アミノ－５－ブロモピリジン（０．２００ｇ、１．１６ｍｍｏｌ、１．００当量）、ジクロロジメチルシラン（０．０７５ｇ、０．５８ｍｍｏｌ、０．５０当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１回目：０．９ｍｌ、１．３９ｍｍｏｌ、１．２０当量、２回目：１．４ｍｌ、２．３１ｍｍｏｌ、２．００当量）、アセトン（０．１６８ｇ、２．８９ｍｍｏｌ、２．５０当量）を用いて化合物１を合成した。得られた溶液に含まれる化合物１を定量し、収率５５％を算出した。 (3) Synthesis of Compound 1 using dichlorodimethylsilane 2-amino-5-bromopyridine (0.200 g, 1.16 mmol, 1.00 equivalent), dichlorodimethylsilane (0.075 g, 0.58 mmol, 0. 50 equivalents), 1.6 M n-BuLihexane solution (1st time: 0.9 ml, 1.39 mmol, 1.20 equivalents), 2nd time: 1.4 ml, 2.31 mmol, 2.00 equivalents), acetone (0) Compound 1 was synthesized using .168 g, 2.89 mmol, 2.50 eq). Compound 1 contained in the obtained solution was quantified, and a yield of 55% was calculated.
　〔実施例３〕グリニャール試薬を用いた化合物１の合成
　Ａｒ雰囲気下、室温にて２－アミノ－５－ブロモピリジン（０．２００ｇ、１．１６ｍｍｏｌ、１．００当量）を２ｍｌのＴＨＦに溶解し－５℃に冷却した。同温度にてクロロトリメチルシラン（０．１２６ｇ、１．１６ｍｍｏｌ、１．００当量）、１．３Ｍのｉ－ＰｒＭｇＣｌ・ＬｉＣｌのＴＨＦ溶液（３．１ｍｌ、４．０５ｍｍｏｌ、３．５０当量）を加え、５０℃に昇温して一晩攪拌した。続いてアセトン（０．２６９ｇ、４．６２ｍｍｏｌ、４．００当量）を加えて０．５時間攪拌し、市水１．２ｍｌを加えて室温まで冷却した。同温度で一級塩酸０．３ｇを加え、化合物１を含有する溶液を得た。この溶液に含まれる化合物１の含量を、実施例２と同じ方法にて定量し、収率１９％を算出した。 [Example 3] Synthesis of compound 1 using Grignard reagent Under an Ar atmosphere, 2-amino-5-bromopyridine (0.200 g, 1.16 mmol, 1.00 equivalent) was dissolved in 2 ml of THF at room temperature. It was cooled to -5 ° C. At the same temperature, add chlorotrimethylsilane (0.126 g, 1.16 mmol, 1.00 eq) and a THF solution of 1.3 M i-PrMgCl / LiCl (3.1 ml, 4.05 mmol, 3.50 eq). , The temperature was raised to 50 ° C., and the mixture was stirred overnight. Subsequently, acetone (0.269 g, 4.62 mmol, 4.00 equivalent) was added, the mixture was stirred for 0.5 hours, 1.2 ml of city water was added, and the mixture was cooled to room temperature. 0.3 g of primary hydrochloric acid was added at the same temperature to obtain a solution containing compound 1. The content of compound 1 contained in this solution was quantified by the same method as in Example 2, and the yield was calculated to be 19%.
　〔実施例４〕クロロトリメチルシランを用いたハロゲン化ピリジルアミンまたはハロゲン化フェニルアミンと求電子剤との反応によるアルコール、シリルエーテル、ケトン、アルカン合成の一般的手順．
　Ａｒ雰囲気下、室温にてハロゲン化ピリジルアミンおよびハロゲン化フェニルアミンのＴＨＦ溶液（０．１Ｍ～０．６Ｍ）を調製し、－７０℃～－１００℃に冷却した。同温度にてクロロトリメチルシラン（１．００当量）、ｎ－ＢｕＬｉまたはｓ－ＢｕＬｉ（３．０５当量）を加えて０．５～２時間攪拌した後に、求電子剤、または求電子剤のＴＨＦ溶液を加えて０～２時間攪拌した。反応液を室温まで昇温した後に市水、ＮａＣｌを加えて有機層を分液し、さらに水層をＴＨＦで２回抽出した。有機層を混合してＮａ２ＳＯ４で乾燥した後にろ過し、ろ液を減圧濃縮した。濃縮残渣をカラムクロマトグラフィー［Ｓｉｌｉｃａｇｅｌ　６０Ｎ（ｓｐｈｅｒｉｃａｌ、ｎｕｔｒａｌ）、クロロホルム／メタノール］にて精製して目的の化合物を得た。 [Example 4] A general procedure for synthesizing alcohols, silyl ethers, ketones, and alkanes by reacting a halogenated pyridylamine or a halogenated phenylamine with an electrophile using chlorotrimethylsilane.
A THF solution (0.1M to 0.6M) of pyridyl amine halide and phenyl amine halide was prepared at room temperature under an Ar atmosphere, and cooled to −70 ° C. to −100 ° C. At the same temperature, chlorotrimethylsilane (1.00 eq), n-BuLi or s-BuLi (3.05 eq) is added and stirred for 0.5 to 2 hours, and then the electrophile or the electrophile THF. The solution was added and the mixture was stirred for 0 to 2 hours. After the reaction solution was heated to room temperature, city water and NaCl were added to separate the organic layer, and the aqueous layer was further extracted twice with THF. The organic layers were mixed , dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by column chromatography [Silica gel 60N (spherical, nutral), chloroform / methanol] to obtain the desired compound.
　上記の手順に従い化合物２～１７を得た。 Compounds 2 to 17 were obtained according to the above procedure.
　（１）化合物２：２－（６－アミノピリジン－３－イル）ヘプタン－２－オール
Figure JPOXMLDOC01-appb-C000018
 (1) Compound 2: 2- (6-aminopyridine-3-yl) heptane-2-ol
Figure JPOXMLDOC01-appb-C000018
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、２－ヘプタノン（２．３１０ｇ、２０．２ｍｍｏｌ、３．５０当量）より化合物２（０．９７３ｇ、８１％）を得た。
白色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ８．０８（ｄｄ、Ｊ＝０．８、２．４Ｈｚ、１Ｈ）、７．５２（ｄｄ、Ｊ＝２．４、８．８Ｈｚ、１Ｈ）、６．４７（ｄｄ、Ｊ＝０．８、８．４Ｈｚ、１Ｈ）、４．４２（ｂｒ、２Ｈ）、２．２５（ｂｒ、１Ｈ）、１．７８－１．７０（ｍ、２Ｈ）、１．５２（ｓ、３Ｈ）、１．３０－１．１４（ｍ、６Ｈ）、０．８４（ｔ、Ｊ＝６．８Ｈｚ、３Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１５７．０、１４４．７、１３５．３、１３３．５、１０８．１、７３．３、４４．１、３２．１、２９．７、２３．７、２２．６、１４．０。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１２Ｈ２１Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算：２０９．１６５４、実測値：２０９．１６４０。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLihexane solution Compound 2 (0.973 g, 81%) was obtained from 2-heptanone (2.310 g, 20.2 mmol, 3.50 eq) (11.0 ml, 17.63 mmol, 3.05 eq).
White crystals;
1 1 H-NMR (400 MHz, CDCl 3 ) δ8.08 (dd, J = 0.8, 2.4 Hz, 1H), 7.52 (dd, J = 2.4, 8.8 Hz, 1H), 6. 47 (dd, J = 0.8, 8.4Hz, 1H), 4.42 (br, 2H), 2.25 (br, 1H), 1.78-1.70 (m, 2H), 1. 52 (s, 3H), 1.30-1.14 (m, 6H), 0.84 (t, J = 6.8Hz, 3H).
13 C-NMR (100 MHz, CDCl 3 ) δ157.0, 144.7, 135.3, 133.5, 108.1, 73.3, 44.1, 32.1, 29.7, 23.7, 22.6, 14.0.
HRMS (ASAP): C 12 H 21 N 2 O [M + H] + calculation: 209.1654, measured value: 209.1640.
　（２）化合物３：２－（６－アミノピリジン－３－イル）－３，３－ジメチルブタン－２－オール
Figure JPOXMLDOC01-appb-C000019
 (2) Compound 3: 2- (6-aminopyridine-3-yl) -3,3-dimethylbutan-2-ol
Figure JPOXMLDOC01-appb-C000019
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、ピナコリン（１．１８７ｇ、１１．８ｍｍｏｌ、２．０５当量）より化合物３（０．８８２ｇ、７９％）を得た。
白色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ８．０９（ｄ、Ｊ＝２．４Ｈｚ、１Ｈ）、７．５４（ｄｄ、Ｊ＝２．４、８．４Ｈｚ、１Ｈ）、６．４５（ｄ、Ｊ＝８．４Ｈｚ、１Ｈ）、４．４１（ｂｒ、２Ｈ）、２．０１（ｂｒ、１Ｈ）、１．５６（ｓ、３Ｈ）、０．９１（ｓ、９Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１５６．８、１４６．４、１３７．１、１３１．７、１０７．１、７７．３、３８．１、２５．６、２５．０。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１１Ｈ１９Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：１９５．１４９７、実測値：１９５．１４７９。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLi hexane solution Compound 3 (0.882 g, 79%) was obtained from (11.0 ml, 17.63 mmol, 3.05 eq) and pinacolin (1.187 g, 11.8 mmol, 2.05 eq).
White crystals;
1 1 H-NMR (400 MHz, CDCl 3 ) δ8.09 (d, J = 2.4 Hz, 1H), 7.54 (dd, J = 2.4, 8.4 Hz, 1H), 6.45 (d, J = 8.4Hz, 1H), 4.41 (br, 2H), 2.01 (br, 1H), 1.56 (s, 3H), 0.91 (s, 9H).
13 C-NMR (100 MHz, CDCl 3 ) δ156.8, 146.4, 137.1, 131.7, 107.1, 77.3, 38.1, 25.6, 25.0.
HRMS (ASAP): C 11 H 19 N 2 O [M + H] + calculated value: 195.1497, measured value: 195.1479.
　（３）化合物４：１－（６－アミノピリジン－３－イル）－シクロペンタン－１－オール
Figure JPOXMLDOC01-appb-C000020
 (3) Compound 4: 1- (6-aminopyridine-3-yl) -cyclopentane-1-ol
Figure JPOXMLDOC01-appb-C000020
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、シクロペンタノン（０．９９７ｇ、１１．８ｍｍｏｌ、２．０５当量）より化合物４（０．７１９ｇ、７０％）を得た。
白色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤ３ＯＤ）δ８．００（ｄｄ、Ｊ＝０．９、２．４Ｈｚ、１Ｈ）、７．５６（ｄｄ、Ｊ＝２．４、８．８Ｈｚ、１Ｈ）、６．５６（ｄｄ、Ｊ＝０．９、８．８Ｈｚ、１Ｈ）、２．００－１．７２（ｍ、８Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤ３ＯＤ）δ１５９．５、１４４．５、１３７．４、１３３．１、１０９．９、８２．５、４１．８、２４．５。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１０Ｈ１５Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：１７９．１１８４、実測値：１７９．１１６９。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLihexane solution Compound 4 (0.719 g, 70%) was obtained from (11.0 ml, 17.63 mmol, 3.05 eq) and cyclopentanone (0.997 g, 11.8 mmol, 2.05 eq).
White crystals;
1 1 H-NMR (400 MHz, CD 3 OD) δ8.00 (dd, J = 0.9, 2.4 Hz, 1H), 7.56 (dd, J = 2.4, 8.8 Hz, 1H), 6 .56 (dd, J = 0.9, 8.8Hz, 1H), 2.00-1.72 (m, 8H).
13 C-NMR (100 MHz, CD 3 OD) δ159.5, 144.5, 137.4, 133.1, 109.9, 82.5, 41.8, 24.5.
HRMS (ASAP): C 10 H 15 N 2 O [M + H] + calculated value: 179.1184, measured value: 179.1169.
　（４）化合物５：（Ｅ）－２－（６－アミノピリジン－３－イル）－４－フェニル－３－ブテン－２－オール
Figure JPOXMLDOC01-appb-C000021
 (4) Compound 5: (E) -2- (6-aminopyridine-3-yl) -4-phenyl-3-butene-2-ol
Figure JPOXMLDOC01-appb-C000021
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、トランス－ベンジリデンアセトン（１．７３２ｇ、１１．８ｍｍｏｌ、２．０５当量）より化合物５（１．１１０ｇ、８０％）を得た。
淡黄色固体；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）δ８．０９（ｄ、Ｊ＝２Ｈｚ、１Ｈ）、７．５１（Ｊ＝２．８、８．８Ｈｚ、１Ｈ）、７．４１（ｄ、Ｊ＝７．６、２Ｈ）、７．２９（ｔ、Ｊ＝７．２Ｈｚ、２Ｈ）、７．１９（ｔ、Ｊ＝７．６Ｈｚ、１Ｈ）、６．５９（ｄ、Ｊ＝１６．４Ｈｚ、１Ｈ）、６．５３（ｄ、Ｊ＝１５．６Ｈｚ、１Ｈ）、６．４７（ｄ、Ｊ＝８．８Ｈｚ、１Ｈ）、５．８４（ｂｒ、２Ｈ）、５．４１（ｂｒ、１Ｈ）、１．６１（ｓ、３Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＤＭＳＯ－ｄ６）δ１５８．４、１４４．６、１３８．２、１３６．９、１３５．０、１３１．１、１２８．６、１２７．２、１２６．３、１２５．３、１０７．３、７１．９、２９．５。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１５Ｈ１７Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：２４１．１３４１、実測値：２４１．１３３６。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLihexane solution Compound 5 (1.110 g, 80%) was obtained from (11.0 ml, 17.63 mmol, 3.05 eq) and trans-benzylideneacetone (1.732 g, 11.8 mmol, 2.05 eq).
Light yellow solid;
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ8.09 (d, J = 2 Hz, 1H), 7.51 (J = 2.8, 8.8 Hz, 1H), 7.41 (d, J = 7.6, 2H), 7.29 (t, J = 7.2Hz, 2H), 7.19 (t, J = 7.6Hz, 1H), 6.59 (d, J = 16.4Hz, 1H) ), 6.53 (d, J = 15.6Hz, 1H), 6.47 (d, J = 8.8Hz, 1H), 5.84 (br, 2H), 5.41 (br, 1H), 1.61 (s, 3H).
13 C-NMR (100 MHz, DMSO-d 6 ) δ158.4, 144.6, 138.2, 136.9, 135.0, 131.1, 128.6, 127.2, 126.3, 125. 3, 107.3, 71.9, 29.5.
HRMS (ASAP): C 15 H 17 N 2 O [M + H] + calculated value: 241.1341, measured value: 241.1336.
　（５）化合物６：（６－アミノピリジン－３－イル）ジフェニルメタノール
Figure JPOXMLDOC01-appb-C000022
 (5) Compound 6: (6-aminopyridine-3-yl) diphenylmethanol
Figure JPOXMLDOC01-appb-C000022
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、ベンゾフェノン（１．０５３ｇ、５．７８ｍｍｏｌ、１．００当量）より化合物６（１．２６１ｇ、７９％）を得た。
白色固体；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ７．８０（ｄｄ、Ｊ＝０．８、２．４Ｈｚ、１Ｈ）、７．３４（ｄｄ、Ｊ＝２．４、８．８Ｈｚ、１Ｈ）、７．３２－７．２２（ｍ、１０Ｈ）、６．３８（ｄｄ、Ｊ＝０．８、８．８Ｈｚ、１Ｈ）、４．４４（ｂｒ、２Ｈ）、３．６６（ｂｒ、１Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１５７．２、１４７．１、１４６．６、１３８．０、１３２．７、１２７．９、１２７．７、１２７．１、１０７．９、８０．３。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１８Ｈ１７Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：２７７．１３４１、実測値：２７７．１３３６。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLi hexane solution Compound 6 (1.261 g, 79%) was obtained from (11.0 ml, 17.63 mmol, 3.05 eq) and benzophenone (1.053 g, 5.78 mmol, 1.00 eq).
White solid;
1 1 H-NMR (400 MHz, CDCl 3 ) δ7.80 (dd, J = 0.8, 2.4 Hz, 1H), 7.34 (dd, J = 2.4, 8.8 Hz, 1H), 7. 32-7.22 (m, 10H), 6.38 (dd, J = 0.8, 8.8Hz, 1H), 4.44 (br, 2H), 3.66 (br, 1H).
13 C-NMR (100 MHz, CDCl 3 ) δ157.2, 147.1, 146.6, 138.0, 132.7, 127.9, 127.7, 127.1, 107.9, 80.3.
HRMS (ASAP): C 18 H 17 N 2 O [M + H] + calculated value: 277.1341, measured value: 277.1336.
　（６）化合物７：（６－アミノピリジン－３－イル）（３，４－ジフルオロフェニル）（フェニル）メタノール
Figure JPOXMLDOC01-appb-C000023
   (6) Compound 7: (6-aminopyridine-3-yl) (3,4-difluorophenyl) (phenyl) methanol
Figure JPOXMLDOC01-appb-C000023
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、３、４－ジフルオロベンゾフェノン（１．２６１ｇ、５．７８ｍｍｏｌ、１．００当量）より化合物７（１．５２１ｇ、８４％）を得た。
淡黄色固体；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ７．６７（ｄ、Ｊ＝２．８Ｈｚ、１Ｈ）、７．３２－７．２０（ｍ、６Ｈ）、７．１６（ｄｄｄ、Ｊ＝２．０、７．６、１１．６Ｈｚ、１Ｈ）、７．０５（ｍ、１Ｈ）、６．９８（ｍ、１Ｈ）、６．３８（ｄ、Ｊ＝８．４Ｈｚ、１Ｈ）、４．４９（ｂｒ、２Ｈ）、４．１４（ｂｒ、１Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１５７．４、１５０．８（ｄｄ、Ｊ＝１２．４、４０．４Ｈｚ）、１４８．３（ｄｄ、Ｊ＝１２．３、４１．２Ｈｚ）、１４７．２、１４５．８、１４３．７（ｔ、Ｊ＝４．２Ｈｚ）、１３７．９、１３２．０、１２８．２、１２７．６、１２７．５、１２３．８（ｄｄ、Ｊ＝４．１、６．５Ｈｚ）、１１７．０（ｄ、Ｊ＝１８．１Ｈｚ）、１１６．５（ｄ、Ｊ＝１６．５Ｈｚ）、１０８．０、７９．８。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１８Ｈ１５Ｎ２ＯＦ２［Ｍ＋Ｈ］＋の計算値：３１３．１１５２、実測値：３１３．１１３３。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLi hexane solution Compound 7 (1.521 g, 84%) was obtained from 3,4-difluorobenzophenone (1.261 g, 5.78 mmol, 1.00 eq) (11.0 ml, 17.63 mmol, 3.05 eq).
Light yellow solid;
1 1 H-NMR (400 MHz, CDCl 3 ) δ7.67 (d, J = 2.8 Hz, 1H), 7.32-7.20 (m, 6H), 7.16 (ddd, J = 2.0, 7.6, 11.6Hz, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.38 (d, J = 8.4Hz, 1H), 4.49 (br, 2H), 4.14 (br, 1H).
13 C-NMR (100 MHz, CDCl 3 ) δ157.4, 150.8 (dd, J = 12.4, 40.4 Hz), 148.3 (dd, J = 12.3, 41.2 Hz), 147. 2, 145.8, 143.7 (t, J = 4.2Hz), 137.9, 132.0, 128.2, 127.6, 127.5, 123.8 (dd, J = 4.1) , 6.5Hz), 117.0 (d, J = 18.1Hz), 116.5 (d, J = 16.5Hz), 108.0, 79.8.
HRMS (ASAP): C 18 H 15 N 2 OF 2 [M + H] + calculated value: 313.1152, measured value: 313.11.133.
　（７）化合物８：１－（６－アミノピリジン－３－イル）－１－（ピリジン－３－イル）エタン－１－オール
Figure JPOXMLDOC01-appb-C000024
 (7) Compound 8: 1- (6-aminopyridine-3-yl) -1- (pyridin-3-yl) ethane-1-ol
Figure JPOXMLDOC01-appb-C000024
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、３－アセチルピリジン（１．４３５ｇ、１１．８ｍｍｏｌ、２．０５当量）より化合物８（０．６９９ｇ、５６％）を得た。
白色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤ３ＯＤ）δ８．６０（ｄｄ、Ｊ＝０．８、２．４Ｈｚ、１Ｈ）、８．３９（ｄｄ、Ｊ＝１．６、４．８Ｈｚ、１Ｈ）、７．９５（ｄｄ、０．８、２．４Ｈｚ、１Ｈ）、７．８７（ｄｄｄ、Ｊ＝１．６、２．６、８．０Ｈｚ、１Ｈ）、７．４７（ｄｄ、Ｊ＝２．４、８．８Ｈｚ、１Ｈ）、７．３８（ｄｄｄ、Ｊ＝０．８、４．８、８．０Ｈｚ、１Ｈ）、６．５４（ｄｄ、Ｊ＝０．９、８．８Ｈｚ、１Ｈ）、１．８９（ｓ、３Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤ３ＯＤ）δ１５９．９、１４８．２、１４７．９、１４６．３、１４５．２、１３８．０、１３５．９、１３３．４、１２４．８、１１０．０、７４．０、３０．４。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１２Ｈ１４Ｎ３Ｏ［Ｍ＋Ｈ］＋の計算値：２１６．１１３７、実測値：２１６．１１１２。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLihexane solution Compound 8 (0.699 g, 56%) was obtained from (11.0 ml, 17.63 mmol, 3.05 eq) and 3-acetylpyridine (1.435 g, 11.8 mmol, 2.05 eq).
White crystals;
1 1 H-NMR (400 MHz, CD 3 OD) δ8.60 (dd, J = 0.8, 2.4 Hz, 1H), 8.39 (dd, J = 1.6, 4.8 Hz, 1H), 7 .95 (dd, 0.8, 2.4Hz, 1H), 7.87 (ddd, J = 1.6, 2.6, 8.0Hz, 1H), 7.47 (dd, J = 2.4) , 8.8Hz, 1H), 7.38 (ddd, J = 0.8, 4.8, 8.0Hz, 1H), 6.54 (dd, J = 0.9, 8.8Hz, 1H), 1.89 (s, 3H).
13 C-NMR (100 MHz, CD 3 OD) δ159.9, 148.2, 147.9, 146.3, 145.2, 138.0, 135.9, 133.4, 124.8, 110.0 , 74.0, 30.4.
HRMS (ASAP): C 12 H 14 N 3 O [M + H] + calculated value: 216.1137, measured value: 216.1112.
　（８）化合物９：１－（６－アミノピリジン－３－イル）－１－（ベンゾ［ｂ］チオフェン－２－イル）エタン－１－オール
Figure JPOXMLDOC01-appb-C000025
 (8) Compound 9: 1- (6-aminopyridine-3-yl) -1- (benzo [b] thiophen-2-yl) ethane-1-ol
Figure JPOXMLDOC01-appb-C000025
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、２－アセチルベンゾ［ｂ］チオフェン（２．０８８ｇ、１１．８ｍｍｏｌ、２．０５当量）より化合物９（１．０３８ｇ、６６％）を得た。
白色固体；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）δ８．０４（ｄｄ、Ｊ＝０．８、２．８Ｈｚ、１Ｈ）、７．８４（ｄｄ、Ｊ＝０．８、８．０Ｈｚ、１Ｈ）、７．７３（ｄｄ、Ｊ＝１．２、７．２Ｈｚ、１Ｈ）、７．４６（ｄｄ、Ｊ＝２．８、８．８Ｈｚ、１Ｈ）、７．３３－７．２４（ｍ、２Ｈ）、７．１９（ｄ、Ｊ＝０．４Ｈｚ、１Ｈ）、６．３８（ｄｄ、Ｊ＝０．４、８．４Ｈｚ、１Ｈ）、６．１３（ｓ、１Ｈ）、５．８３（ｓ、２Ｈ）、１．９０（ｓ、３Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＤＭＳＯ－ｄ６）δ１５８．６、１５６．５、１４４．５、１３９．５、１３８．８、１３４．７、１３１．２、１２４．１、１２３．８、１２３．３、１２２．２、１１８．９、１０７．０、７２．３、３０．９。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１５Ｈ１５Ｎ２ＯＳ［Ｍ＋Ｈ］＋の計算値：２７１．０９０５、実測値：２７１．０８７８。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLihexane solution Compound 9 (1.038 g, 66%) was obtained from (11.0 ml, 17.63 mmol, 3.05 eq), 2-acetylbenzo [b] thiophene (2.088 g, 11.8 mmol, 2.05 eq). It was.
White solid;
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ8.04 (dd, J = 0.8, 2.8 Hz, 1H), 7.84 (dd, J = 0.8, 8.0 Hz, 1H), 7.73 (dd, J = 1.2, 7.2Hz, 1H), 7.46 (dd, J = 2.8, 8.8Hz, 1H), 7.33-7.24 (m, 2H) , 7.19 (d, J = 0.4Hz, 1H), 6.38 (dd, J = 0.4, 8.4Hz, 1H), 6.13 (s, 1H), 5.83 (s, 2H), 1.90 (s, 3H).
13 C-NMR (100 MHz, DMSO-d 6 ) δ158.6, 156.5, 144.5, 139.5, 138.8, 134.7, 131.2, 124.1, 123.8, 123. 3, 122.2, 118.9, 107.0, 72.3, 30.9.
HRMS (ASAP): C15H15N2OS [M + H] + calculated value: 271.0905, measured value: 271.0878.
　（９）化合物１０：１－（６－アミノピリジン－３－イル）－１－（２、５－ジメチルフラン－３－イル）エタン－１－オール
Figure JPOXMLDOC01-appb-C000026
 (9) Compound 10: 1- (6-aminopyridine-3-yl) -1- (2,5-dimethylfuran-3-yl) ethane-1-ol
Figure JPOXMLDOC01-appb-C000026
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、３－アセチル－２、５－ジメチルフラン（１．６３７ｇ、１１．８ｍｍｏｌ、２．０５当量）より化合物１０（１．０４１ｇ、７８％）を得た。
淡褐色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）δ７．９１（ｄｄ、Ｊ＝０．４、２．４Ｈｚ、１Ｈ）、７．３３（ｄｄ、Ｊ＝２．４、８．４Ｈｚ、１Ｈ）、６．３５（０．８、８．４Ｈｚ、１Ｈ）、５．８８（ｓ、１Ｈ）、５．７２（ｂｒ、２Ｈ）、５．１９（ｓ、１Ｈ）、２．１４（ｓ、３Ｈ）、２．０５（ｓ、３Ｈ）、１．６３（ｓ、３Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＤＭＳＯ－ｄ６）δ１５８．３、１４７．５、１４４．５、１４４．４、１３５．１、１３２．５、１２８．０、１０７．３、１０７．１、６９．９、３１．１、１３．２、１３．１。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１３Ｈ１７Ｎ２Ｏ２［Ｍ＋Ｈ］＋の計算値：２３３．１２９０、実測値：２３３．１２５２。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLi hexane solution Compound 10 (1.041 g, 78%) from (11.0 ml, 17.63 mmol, 3.05 eq), 3-acetyl-2,5-dimethylfuran (1.637 g, 11.8 mmol, 2.05 eq). Got
Light brown crystals;
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ7.91 (dd, J = 0.4, 2.4 Hz, 1H), 7.33 (dd, J = 2.4, 8.4 Hz, 1H), 6.35 (0.8, 8.4Hz, 1H), 5.88 (s, 1H), 5.72 (br, 2H), 5.19 (s, 1H), 2.14 (s, 3H) , 2.05 (s, 3H), 1.63 (s, 3H).
13 C-NMR (100 MHz, DMSO-d 6 ) δ158.3, 147.5, 144.5, 144.4, 135.1, 132.5, 128.0, 107.3, 107.1, 69. 9, 31.1, 13.2, 13.1.
HRMS (ASAP): C 13 H 17 N 2 O 2 [M + H] + calculated value: 233.1290, measured value: 233.1252.
　（１０）化合物１１：（２－アミノ－５－メチルピリジン－３－イル）ジフェニルメタノール
Figure JPOXMLDOC01-appb-C000027
 (10) Compound 11: (2-amino-5-methylpyridine-3-yl) diphenylmethanol
Figure JPOXMLDOC01-appb-C000027
　２－アミノ－３－ブロモ－５－メチルピリジン（１．０００ｇ、５．３５ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．５８１ｇ、５．３５ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１０．２ｍｌ、１６．３１ｍｍｏｌ、３．０５当量）、ベンゾフェノン（１．０７２ｇ、５．８８ｍｍｏｌ、１．１０当量）より化合物１１（０．８３８ｇ、５４％）を得た。
淡褐色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤ３ＯＤ）δ７．６８（ｄｄ、Ｊ＝０．８、２．４Ｈｚ、１Ｈ）、７．３４－７．２５（ｍ、６Ｈ）、７．２３－７．１８（ｍ、４Ｈ）、６．５９（ｄｄ、Ｊ＝０．８、２．４Ｈｚ、１Ｈ）、２．０２（ｓ、３Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤ３ＯＤ）δ１５７．２、１４６．７、１４６．４、１４０．５、１２９．０、１２８．９、１２８．４、１２６．９、１２２．１、８２．６、１７．４。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１９Ｈ１９Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：２９１．１４９７、実測値：２９１．１５０６。 2-Amino-3-bromo-5-methylpyridine (1.000 g, 5.35 mmol, 1.00 eq), chlorotrimethylsilane (0.581 g, 5.35 mmol, 1.00 eq), 1.6 M n Compound 11 (0.838 g, 54%) was obtained from a BuLihexane solution (10.2 ml, 16.31 mmol, 3.05 eq) and benzophenone (1.072 g, 5.88 mmol, 1.10 eq).
Light brown crystals;
1 1 H-NMR (400 MHz, CD 3 OD) δ7.68 (dd, J = 0.8, 2.4 Hz, 1H), 7.34-7.25 (m, 6H), 7.23-7.18 (M, 4H), 6.59 (dd, J = 0.8, 2.4Hz, 1H), 2.02 (s, 3H).
13 C-NMR (100 MHz, CD 3 OD) δ157.2, 146.7, 146.4, 140.5, 129.0, 128.9, 128.4, 126.9, 122.1, 82.6 , 17.4.
HRMS (ASAP): C 19 H 19 N 2 O [M + H] + calculated value: 291.1497, measured value: 291.1506.
　（１１）化合物１２：（２－アミノピリジン－４－イル）ジフェニルメタノール
Figure JPOXMLDOC01-appb-C000028
 (11) Compound 12: (2-aminopyridine-4-yl) diphenylmethanol
Figure JPOXMLDOC01-appb-C000028
　２－アミノ－４－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、ベンゾフェノン（１．１５９ｇ、６．３６ｍｍｏｌ、１．１０当量）より化合物１２（１．３４８ｇ、８４％）を得た。
白色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）δ７．８０（ｄ、Ｊ＝５．６Ｈｚ、１Ｈ）、７．３３－７．１９（ｍ、１０Ｈ）、６．４３（ｓ、１Ｈ）、６．３５－６．３１（ｍ、２Ｈ）、５．８３（ｂｒ、２Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＤＭＳＯ－ｄ６）δ１５９．５、１５６．８、１４６．９、１４６．７、１２７．６、１２７．６、１２６．８、１１１．７、１０６．９、７９．９。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１８Ｈ１７Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：２７７．１３４１、実測値：２７７．１３２９。 2-Amino-4-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLihexane solution Compound 12 (1.348 g, 84%) was obtained from (11.0 ml, 17.63 mmol, 3.05 eq) and benzophenone (1.159 g, 6.36 mmol, 1.10 eq).
White crystals;
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ7.80 (d, J = 5.6 Hz, 1H), 7.33-7.19 (m, 10H), 6.43 (s, 1H), 6 .35-6.31 (m, 2H), 5.83 (br, 2H).
13 C-NMR (100 MHz, DMSO-d 6 ) δ159.5, 156.8, 146.9, 146.7, 127.6, 127.6, 126.8, 111.7, 106.9, 79. 9.
HRMS (ASAP): C 18 H 17 N 2 O [M + H] + calculated value: 277.1341, measured value: 277.1329.
　（１２）化合物１３：（５－アミノピリジン－２－イル）ジフェニルメタノール
Figure JPOXMLDOC01-appb-C000029
 (12) Compound 13: (5-aminopyridine-2-yl) diphenylmethanol
Figure JPOXMLDOC01-appb-C000029
　５－アミノ－２－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）、ベンゾフェノン（１．１５９ｇ、６．３６ｍｍｏｌ、１．１０当量）より化合物１３（１．１８６ｇ、７４％）を得た。
淡黄色結晶
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ８．０４（ｄ、Ｊ＝２．４Ｈｚ、１Ｈ）、７．３０－７．２２（ｍ、１０Ｈ）、６．９０（ｄｄ、Ｊ＝２．８、８．４Ｈｚ、１Ｈ）、６．８４（ｄ、Ｊ＝８．４Ｈｚ、１Ｈ）、６．０７（ｓ、１Ｈ）、３．７１（ｂｒ、２Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１５３．３、１４６．７、１４１．３、１３４．９、１２８．１、１２７．８、１２７．１、１２２．９、１２２．０、８０．４。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１８Ｈ１５Ｎ２Ｏ［Ｍ－Ｈ］－の計算値：２７５．１１８４、実測値：２７５．１１８１。 5-Amino-2-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq), 1.6 M n-BuLihexane solution Compound 13 (1.186 g, 74%) was obtained from (11.0 ml, 17.63 mmol, 3.05 eq) and benzophenone (1.159 g, 6.36 mmol, 1.10 eq).
Pale yellow crystals
1 1 H-NMR (400 MHz, CDCl 3 ) δ8.04 (d, J = 2.4 Hz, 1H), 7.30-7.22 (m, 10H), 6.90 (dd, J = 2.8, 8.4Hz, 1H), 6.84 (d, J = 8.4Hz, 1H), 6.07 (s, 1H), 3.71 (br, 2H).
13 C-NMR (100 MHz, CDCl 3 ) δ153.3, 146.7, 141.3, 134.9, 128.1, 127.8, 127.1, 122.9, 122.0, 80.4.
HRMS (ASAP): C 18 H 15 N 2 O [M-H] - Calculated: 275.1184, Found: 275.1181.
　（１３）化合物１４：（４－アミノピリジン－２－イル）ジフェニルメタノール
Figure JPOXMLDOC01-appb-C000030
 (13) Compound 14: (4-aminopyridine-2-yl) diphenylmethanol
Figure JPOXMLDOC01-appb-C000030
　４－アミノ－２－ブロモピリジン（０．３５０ｇ、２．０２ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．２２０ｇ、２．０２ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（３．９ｍｌ、６．１７ｍｍｏｌ、３．０５当量）、ベンゾフェノン（０．４０５ｇ、２．２２ｍｍｏｌ、１．１０当量）より化合物１４（０．２９２ｇ、５２％）を得た。
淡黄色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ８．１７（ｄ、Ｊ＝５．２Ｈｚ、１Ｈ）、７．３２－７．２４（ｍ、１０Ｈ）、６．４３（ｄｄ、Ｊ＝２．４、５．６Ｈｚ、１Ｈ）、６．２４（ｄ、Ｊ＝２．４Ｈｚ、１Ｈ）、４．１１（ｂｒ、２Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１６４．０、１５３．０、１４８．２、１４６．３、１２８．２、１２７．８、１２７．１、１０８．５、１０８．５、８０．７。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１８Ｈ１７Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：２７７．１３４１、実測値：２７７．１３３１。 4-Amino-2-bromopyridine (0.350 g, 2.02 mmol, 1.00 eq), chlorotrimethylsilane (0.220 g, 2.02 mmol, 1.00 eq), 1.6 M n-BuLihexane solution Compound 14 (0.292 g, 52%) was obtained from (3.9 ml, 6.17 mmol, 3.05 eq) and benzophenone (0.405 g, 2.22 mmol, 1.10 eq).
Pale yellow crystals;
1 1 H-NMR (400 MHz, CDCl 3 ) δ8.17 (d, J = 5.2 Hz, 1H), 7.32-7.24 (m, 10H), 6.43 (dd, J = 2.4, 5.6Hz, 1H), 6.24 (d, J = 2.4Hz, 1H), 4.11 (br, 2H).
13 C-NMR (100 MHz, CDCl 3 ) δ164.0, 153.0, 148.2, 146.3, 128.2, 127.8, 127.1, 108.5, 108.5, 80.7.
HRMS (ASAP): C 18 H 17 N 2 O [M + H] + calculated value: 277.1341, measured value: 277.1331.
　（１４）化合物１５：（４－アミノフェニル）ジフェニルメタノール
Figure JPOXMLDOC01-appb-C000031
 (14) Compound 15: (4-aminophenyl) diphenylmethanol
Figure JPOXMLDOC01-appb-C000031
　４－ブロモアニリン（０．７００ｇ、４．０７ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．４４２ｇ、４．０７ｍｍｏｌ、１．００当量）、１．１Ｍのｓ－ＢｕＬｉヘキサン－シクロヘキサン溶液（１１．８ｍｌ、１３．０２ｍｍｏｌ、３．２０当量）、ベンゾフェノン（０．７４１ｇ、４．０７ｍｍｏｌ、１．００当量）より化合物１５（０．７１３ｇ、６４％）を得た。
淡褐色固体；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ７．３２－７．２３（ｍ、１０Ｈ）、７．００（ｍ、２Ｈ）、６．６０（ｍ、２Ｈ）、３．６５（ｂｒ、２Ｈ）、２、７６（ｓ、１Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１４７．３、１４５．５、１３７．３、１２９．２、１２７．９、１２７．８、１２７．１、１１４．５、８１．８。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１９Ｈ１８ＮＯ［Ｍ＋Ｈ］＋の計算値：２７６．１３８８、実測値：２７６．１３９５。 4-Bromoaniline (0.700 g, 4.07 mmol, 1.00 eq), chlorotrimethylsilane (0.442 g, 4.07 mmol, 1.00 eq), 1.1 M s-BuLihexane-cyclohexane solution (11) Compound 15 (0.713 g, 64%) was obtained from .8 ml (13.02 mmol, 3.20 eq) and benzophenone (0.741 g, 4.07 mmol, 1.00 eq).
Light brown solid;
1 1 H-NMR (400 MHz, CDCl 3 ) δ7.32-7.23 (m, 10H), 7.00 (m, 2H), 6.60 (m, 2H), 3.65 (br, 2H), 2,76 (s, 1H).
13 C-NMR (100 MHz, CDCl 3 ) δ147.3, 145.5, 137.3, 129.2, 127.9, 127.8, 127.1, 114.5, 81.8.
HRMS (ASAP): C 19 H 18 NO [M + H] + calculated value: 276.1388, measured value: 276.1395.
　（１５）化合物１６：（６－アミノピリジン－３－イル）（フェニル）ケトン
Figure JPOXMLDOC01-appb-C000032
 (15) Compound 16: (6-aminopyridine-3-yl) (phenyl) ketone
Figure JPOXMLDOC01-appb-C000032
　２－アミノ－５－ブロモピリジン（０．５ｇ、２．８９ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．３１４ｇ、２．８９ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（５．５ｍｌ、８．８２ｍｍｏｌ、３．０５当量）、ベンゾイルクロリド（０．４４７ｇ、３．１８ｍｍｏｌ、１．１０当量）より化合物１６（０．２３１ｇ、４０％）を得た。
淡黄色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ８．５４（ｄ、Ｊ＝２．０Ｈｚ、１Ｈ）、８．０２（ｄｄ、Ｊ＝２．０、８．４Ｈｚ、１Ｈ）、７．７８－７．７２（ｍ、２Ｈ）、７．５８（ｔｔ、Ｊ＝１．６、７．２Ｈｚ、１Ｈ）、７．４８（ｔ、Ｊ＝７．６Ｈｚ、２Ｈ）、６．５５（ｄｄ、Ｊ＝０．８、８．８Ｈｚ、１Ｈ）、４．９６（ｂｒ、２Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１９４．０、１６０．７、１５２．７、１３９．６、１３８．０、１３２．１、１２９．５、１２８．４、１２４．０、１０７．８。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１２Ｈ１１Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：１９９．０８７１、実測値：１９９．０８３６。 2-Amino-5-bromopyridine (0.5 g, 2.89 mmol, 1.00 eq), chlorotrimethylsilane (0.314 g, 2.89 mmol, 1.00 eq), 1.6 M n-BuLihexane solution Compound 16 (0.231 g, 40%) was obtained from (5.5 ml, 8.82 mmol, 3.05 eq) and benzoyl chloride (0.447 g, 3.18 mmol, 1.10 eq).
Pale yellow crystals;
1 1 H-NMR (400 MHz, CDCl 3 ) δ8.54 (d, J = 2.0 Hz, 1H), 8.02 (dd, J = 2.0, 8.4 Hz, 1H), 7.78-7. 72 (m, 2H), 7.58 (tt, J = 1.6, 7.2Hz, 1H), 7.48 (t, J = 7.6Hz, 2H), 6.55 (dd, J = 0) 8.8, 8.8Hz, 1H), 4.96 (br, 2H).
13 C-NMR (100 MHz, CDCl 3 ) δ 194.0, 160.7, 152.7, 139.6, 138.0, 132, 129.5, 128.4, 124.0, 107.8.
HRMS (ASAP): C 12 H 11 N 2 O [M + H] + calculated value: 199.0871, measured value: 199.0836.
　（１６）化合物１７：５－（２－（（トリメチルシリル）オキシ）ブチル）ピリジン－２－アミン
Figure JPOXMLDOC01-appb-C000033
 (16) Compound 17: 5- (2-((trimethylsilyl) oxy) butyl) Pyridine-2-amine
Figure JPOXMLDOC01-appb-C000033
　２－アミノ－５－ブロモピリジン（０．５ｇ、２．８９ｍｍｏｌ、１．００当量）、クロロトリメチルシラン（０．３１４ｇ、２．８９ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（５．５ｍｌ、８．８２ｍｍｏｌ、３．０５当量）、１、２－エポキシブタン（０．２２９ｇ、３．１８ｍｍｏｌ、１．１０当量）より化合物１７（０．０．４５７ｇ、６６％）を得た。
淡褐色オイル；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ７．９１（ｄ、Ｊ＝２．４Ｈｚ、１Ｈ）、７．３３－７．３０（ｍ、１Ｈ）、６．４８（ｄｄ、Ｊ＝０．８、８．４Ｈｚ、１Ｈ）、４．３０（ｂｒ、２Ｈ）、３．６６（ｍ、１Ｈ）、２．６３（ｄｄ、Ｊ＝４．８、１３．６Ｈｚ、１Ｈ）、２．５４（ｄｄ、Ｊ＝７．２、１４．０Ｈｚ、１Ｈ）、１．５８－１．４０（ｍ、２Ｈ）、０．９３（ｔ、Ｊ＝７．２Ｈｚ、３Ｈ）、０．０３（ｓ、９Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１５６．６、１４８．４、１３９．２、１２４．７、１０８．０、７４．９、３９．７、２９．７、１０．０、０．０。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１２Ｈ２３Ｎ２ＯＳｉ［Ｍ＋Ｈ］＋の計算値：２３９．１５８０、実測値：２３９．１５５７。 2-Amino-5-bromopyridine (0.5 g, 2.89 mmol, 1.00 eq), chlorotrimethylsilane (0.314 g, 2.89 mmol, 1.00 eq), 1.6 M n-BuLihexane solution Compound 17 (0.0.457 g, 66%) was obtained from 1,2-epoxybutane (0.229 g, 3.18 mmol, 1.10 eq) (5.5 ml, 8.82 mmol, 3.05 eq). It was.
Light brown oil;
1 1 H-NMR (400 MHz, CDCl 3 ) δ7.91 (d, J = 2.4 Hz, 1H), 7.33-7.30 (m, 1H), 6.48 (dd, J = 0.8, 8.4Hz, 1H), 4.30 (br, 2H), 3.66 (m, 1H), 2.63 (dd, J = 4.8, 13.6Hz, 1H), 2.54 (dd, J = 7.2, 14.0Hz, 1H), 1.58-1.40 (m, 2H), 0.93 (t, J = 7.2Hz, 3H), 0.03 (s, 9H).
13 C-NMR (100 MHz, CDCl 3 ) δ156.6, 148.4, 139.2, 124.7, 108.0, 74.9, 39.7, 29.7, 10.0, 0.0.
HRMS (ASAP): C 12 H 23 N 2 OSI [M + H] + calculated value: 239.1580, measured value: 239.1557.
　〔実施例５〕化合物１８：（６－アミノピリジン－３－イル）ビス（４－メトキシフェニル）メタノールの合成
Figure JPOXMLDOC01-appb-C000034
   [Example 5] Compound 18: Synthesis of (6-aminopyridine-3-yl) bis (4-methoxyphenyl) methanol
Figure JPOXMLDOC01-appb-C000034
　Ａｒ雰囲気下、室温にて２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）を１０ｍｌのＴＨＦに溶解し－１００℃に冷却した。同温度にてクロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）を加えて１時間攪拌した。得られた溶液を、２ｍｌのＴＨＦに懸濁した４、４’－ジメトキシベンゾフェノン（１．４００ｇ、５．７８ｍｍｏｌ、１．００当量）に滴下し、０．５時間攪拌した後に室温まで昇温した。続いて市水、ＮａＣｌを加えて有機層を分液し、さらに水層をＴＨＦで２回抽出した。有機層を混合してＮａ２ＳＯ４で乾燥した後にろ過し、ろ液を減圧濃縮した。濃縮残渣をカラムクロマトグラフィー［Ｓｉｌｉｃａｇｅｌ　６０Ｎ（ｓｐｈｅｒｉｃａｌ、ｎｕｔｒａｌ）、クロロホルム／メタノール］にて精製して化合物１８（１．６３０ｇ、８４％）を得た。
淡褐色固体；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）δ７．５９（ｄｄ、Ｊ＝０．４、２．４Ｈｚ、１Ｈ）、７．１７（ｄｄ、Ｊ＝２．４、８．８Ｈｚ、１Ｈ）、７．１４－７．０９（ｍ、４Ｈ）、６．８７－６．８２（ｍ、４Ｈ）、６．３８（ｄｄ、Ｊ＝０．８、８．８Ｈｚ、１Ｈ）、６．０７（ｓ、１Ｈ）、５．８５（ｂｒ、２Ｈ）、３．７２（ｓ、６Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＤＭＳＯ－ｄ６）δ１５８．３、１５７．８、１４６．８、１４０．２、１３６．９、１３１．６、１２８．７、１１２．８、１０６．８、７８．５、５５．０。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ２０Ｈ２１Ｎ２Ｏ３［Ｍ＋Ｈ］＋の計算値：３３７．１５５２、実測値：３３７．１５３４。 In an Ar atmosphere, 2-amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 equivalent) was dissolved in 10 ml of THF and cooled to -100 ° C. at room temperature. At the same temperature, chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq) and 1.6 M n-BuLihexane solution (11.0 ml, 17.63 mmol, 3.05 eq) were added for 1 hour. Stirred. The obtained solution was added dropwise to 4,4'-dimethoxybenzophenone (1.400 g, 5.78 mmol, 1.00 eq) suspended in 2 ml of THF, stirred for 0.5 hours, and then heated to room temperature. .. Subsequently, city water and NaCl were added to separate the organic layer, and the aqueous layer was further extracted twice with THF. The organic layers were mixed , dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by column chromatography [Silica gel 60N (spherical, nutral), chloroform / methanol] to obtain compound 18 (1.630 g, 84%).
Light brown solid;
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ7.59 (dd, J = 0.4, 2.4 Hz, 1H), 7.17 (dd, J = 2.4, 8.8 Hz, 1H), 7.14-7.09 (m, 4H), 6.87-6.82 (m, 4H), 6.38 (dd, J = 0.8, 8.8Hz, 1H), 6.07 (s) , 1H), 5.85 (br, 2H), 3.72 (s, 6H).
13 C-NMR (100 MHz, DMSO-d 6 ) δ158.3, 157.8, 146.8, 140.2, 136.9, 131.6, 128.7, 112.8, 106.8, 78. 5, 55.0.
HRMS (ASAP): C 20 H 21 N 2 O 3 [M + H] + calculated value: 337.1552, measured value: 337.1534.
　〔実施例６〕クロロｔ－ブチルジメチルシランを用いたハロゲン化ピリジルアミンと求電子剤との反応によるアルコール合成の一般的手順．
　Ａｒ雰囲気下、室温にてハロゲン化ピリジルアミンのＴＨＦ溶液（０．６Ｍ）にクロロｔ－ブチルジメチルシラン（１．００当量）を加えた。続いて溶液を氷冷してｎ－ＢｕＬｉ（１．０５当量）を加えた後に、室温まで昇温して約０．５～２時間攪拌した。反応液を－１００℃に冷却してｎ－ＢｕＬｉ（２．００当量）を加えて０．５時間攪拌し、求電子剤のＴＨＦ溶液を加えた。反応液を０～１０分間攪拌した後に、室温まで昇温して市水、一級塩酸を加えて水層を分液した。水層にＮａＯＨ水溶液（５０％）を加えてｐＨを約１０とした後にＴＨＦで３回の抽出を行い、得られた有機層をＮａ２ＳＯ４で乾燥後、ろ過した。ろ液を減圧濃縮し、残渣をカラムクロマトグラフィー［Ｓｉｌｉｃａｇｅｌ　６０Ｎ（ｓｐｈｅｒｉｃａｌ、ｎｕｔｒａｌ）、クロロホルム／メタノール］にて精製して目的の化合物を得た。 [Example 6] A general procedure for alcohol synthesis by reacting a halogenated pyridylamine with an electrophile using chlorot-butyldimethylsilane.
Chloro-t-butyldimethylsilane (1.00 equivalent) was added to a THF solution (0.6 M) of pyridylamine halide at room temperature under an Ar atmosphere. Subsequently, the solution was ice-cooled, n-BuLi (1.05 eq) was added, the temperature was raised to room temperature, and the mixture was stirred for about 0.5 to 2 hours. The reaction mixture was cooled to −100 ° C., n-BuLi (2.00 equivalents) was added, the mixture was stirred for 0.5 hours, and a THF solution of an electrophile was added. After stirring the reaction solution for 0 to 10 minutes, the temperature was raised to room temperature, and city water and primary hydrochloric acid were added to separate the aqueous layer. After adding an aqueous NaOH solution (50%) to the aqueous layer to adjust the pH to about 10, extraction was performed three times with THF, and the obtained organic layer was dried over Na 2 SO 4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography [Silica gel 60N (spherical, nutral), chloroform / methanol] to obtain the desired compound.
　上記の手順に従い化合物１９、２０を得た。 Compounds 19 and 20 were obtained according to the above procedure.
　（１）化合物１９：（６－アミノピリジン－３－イル）（フェニル）メタノール
Figure JPOXMLDOC01-appb-C000035
 (1) Compound 19: (6-aminopyridine-3-yl) (phenyl) methanol
Figure JPOXMLDOC01-appb-C000035
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロｔ－ブチルジメチルシラン（０．８７１ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１回目：３．８ｍｌ、６．０７ｍｍｏｌ、１．０５当量、２回目：７．２ｍｌ、１１．５６ｍｍｏｌ、２．００当量）、ベンズアルデヒド（０．６７５ｇ、６．３６ｍｍｏｌ、１．１０当量）より化合物１９（０．５７１ｇ、４９％）を得た。
白色結晶；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）δ７．８６（ｄ、Ｊ＝２．４ｚ、１Ｈ）、７．３５－７．１７（ｍ、６Ｈ）、６．３６（ｄ、Ｊ＝８．４Ｈｚ、１Ｈ）、５．７９（ｂｒ、２Ｈ）、５．６６（ｄ、Ｊ＝４．４Ｈｚ、１Ｈ）、５．５４（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＤＭＳＯ－ｄ６）δ１５８．８、１４５．８、１４５．７、１３５．６、１２８．８、１２８．０、１２６．５、１２５．９、１０７．５、７２．１。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１２Ｈ１３Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：２０１．１０２８、実測値：２０１．１００１。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chloro t-butyldimethylsilane (0.871 g, 5.78 mmol, 1.00 eq), 1.6 M n- BuLi hexane solution (1st time: 3.8 ml, 6.07 mmol, 1.05 eq), 2nd time: 7.2 ml, 11.56 mmol, 2.00 eq), benzaldehyde (0.675 g, 6.36 mmol, 1.10) Compound 19 (0.571 g, 49%) was obtained from (equivalent).
White crystals;
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ7.86 (d, J = 2.4z, 1H), 7.35-7.17 (m, 6H), 6.36 (d, J = 8. 4Hz, 1H), 5.79 (br, 2H), 5.66 (d, J = 4.4Hz, 1H), 5.54 (d, J = 4.0Hz, 1H).
13 C-NMR (100 MHz, DMSO-d 6 ) δ158.8, 145.8, 145.7, 135.6, 128.8, 128.0, 126.5, 125.9, 107.5, 72. 1.
HRMS (ASAP): C 12 H 13 N 2 O [M + H] + calculated value: 201.1028, measured value: 201.1001.
　（２）化合物２０：１－（６－アミノピリジン－３－イル）ヘキサン－１－オール
Figure JPOXMLDOC01-appb-C000036
   (2) Compound 20: 1- (6-aminopyridine-3-yl) hexane-1-ol
Figure JPOXMLDOC01-appb-C000036
　２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）、クロロｔ－ブチルジメチルシラン（０．８７１ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１回目：３．８ｍｌ、６．０７ｍｍｏｌ、１．０５当量、２回目：７．２ｍｌ、１１．５６ｍｍｏｌ、２．００当量）、ｎ－ヘキサナール（０．６３７ｇ、６．３６ｍｍｏｌ、１．１０当量）より化合物２０（０．８３７ｇ、７５％）を得た。
白色固体；
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）δ７．７９（ｄ、Ｊ＝２．０Ｈｚ、１Ｈ）、７．３１（ｄｄ、Ｊ＝２．４、８．４Ｈｚ、１Ｈ）、６．４０（ｄ、Ｊ＝８．４Ｈｚ、１Ｈ）、５．７３（ｂｒ、２Ｈ）、４．８６（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）、４．３１（ｄｔ、Ｊ＝４．０、６．８Ｈｚ、１Ｈ）、１．６４－１．５６（ｍ、１Ｈ）、１．５２－１．４３（ｍ、１Ｈ）、１．３２－１．１０（ｍ、６Ｈ）、０．８３（ｔ、Ｊ＝６．８Ｈｚ、３Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＤＭＳＯ－ｄ６）δ１５８．８、１４５．４、１３５．０、１２９．１、１０７．５、７０．２、３８．７、３１．２、２５．０、２２．１、１３．９。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１１Ｈ１９Ｎ２Ｏ［Ｍ＋Ｈ］＋の計算値：１９５．１４９７、実測値：１９５．１４６８。 2-Amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 eq), chloro t-butyldimethylsilane (0.871 g, 5.78 mmol, 1.00 eq), 1.6 M n- BuLi hexane solution (1st time: 3.8 ml, 6.07 mmol, 1.05 eq), 2nd time: 7.2 ml, 11.56 mmol, 2.00 eq), n-hexanal (0.637 g, 6.36 mmol, 1) Compound 20 (0.837 g, 75%) was obtained from (10 equivalents).
White solid;
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ7.79 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 2.4, 8.4 Hz, 1H), 6.40 ( d, J = 8.4Hz, 1H), 5.73 (br, 2H), 4.86 (d, J = 4.0Hz, 1H), 4.31 (dt, J = 4.0, 6.8Hz) , 1H), 1.64-1.56 (m, 1H), 1.52-1.43 (m, 1H), 1.32-1.10 (m, 6H), 0.83 (t, J) = 6.8Hz, 3H).
13 C-NMR (100 MHz, DMSO-d 6 ) δ158.8, 145.4, 135.0, 129.1, 107.5, 70.2, 38.7, 31.2, 25.0, 22. 1, 13.9.
HRMS (ASAP): C 11 H 19 N 2 O [M + H] + calculated value: 195.1497, measured value: 195.1468.
　〔実施例７〕化合物２１：２－アミノニコチン酸メチルの合成
Figure JPOXMLDOC01-appb-C000037
   [Example 7] Synthesis of compound 21: methyl 2-aminonicotinate
Figure JPOXMLDOC01-appb-C000037
　Ａｒ雰囲気下、室温にて２－アミノ－５－ブロモピリジン（０．２００ｇ、１．１６ｍｍｏｌ、１．００当量）を２ｍｌのＴＨＦに溶解し、クロロｔ－ブチルジメチルシラン（０．１７４ｇ、１．１６ｍｍｏｌ、１．００当量）を加えた。続いて溶液を氷冷して１４．６％（ｗ／ｗ）のｎ－ＢｕＬｉヘキサン溶液（０．６０９ｇ、１．３９ｍｍｏｌ、１．２０当量）を加えた後に、室温まで昇温して１．５時間攪拌した。反応液を－７０℃に冷却して１４．６％（ｗ／ｗ）のｎ－ＢｕＬｉヘキサン溶液（１．０１ｇ、２．３１ｍｍｏｌ、２．００当量）を加えて０．５時間攪拌し、続いてクロロギ酸メチル（０．１２０ｇ、１．２７ｍｍｏｌ、１．１０当量）のＴＨＦ溶液を加えて１０分間攪拌した。反応液に市水を加えて室温まで昇温したのち、一級塩酸を加え、化合物２１を含有する溶液を得た。この溶液について、東京化成工業株式会社から購入した化合物２１を標準品として用い、下記のＨＰＬＣ条件で分析を行い、保持時間が一致したことから、化合物２１の生成を確認した。また，化合物２１の含有量をＨＰＬＣ定量により求めた結果、収率４５％であることを確認した。 2-Amino-5-bromopyridine (0.200 g, 1.16 mmol, 1.00 eq) was dissolved in 2 ml of THF under an Ar atmosphere at room temperature, and chloro t-butyldimethylsilane (0.174 g, 1. 16 mmol, 1.00 eq) was added. Subsequently, the solution was ice-cooled, a 14.6% (w / w) n-BuLihexane solution (0.609 g, 1.39 mmol, 1.20 equivalents) was added, and then the temperature was raised to room temperature. The mixture was stirred for 5 hours. The reaction mixture was cooled to −70 ° C., 14.6% (w / w) n-BuLihexane solution (1.01 g, 2.31 mmol, 2.00 eq) was added, and the mixture was stirred for 0.5 hours, followed by A THF solution of methyl chloroformate (0.120 g, 1.27 mmol, 1.10 eq) was added and stirred for 10 minutes. City water was added to the reaction solution to raise the temperature to room temperature, and then primary hydrochloric acid was added to obtain a solution containing compound 21. For this solution, compound 21 purchased from Tokyo Chemical Industry Co., Ltd. was used as a standard product, and analysis was performed under the following HPLC conditions. Since the retention times were the same, the formation of compound 21 was confirmed. Further, as a result of determining the content of compound 21 by HPLC quantification, it was confirmed that the yield was 45%.
　＜ＨＰＬＣ条件＞
カラム        ：ｓｃｈｅｒｚｏ　ＳＳ－Ｃ１８　１００×３ｍｍ
カラム温度    ：４０℃
注入量        ：５μｌ
検出波長      ：２８０ｎｍ
流速          ：０．５ｍｌ／ｍｉｎ
移動相Ａ      ：ｐＨ＝４．７に調整した１００ｍＭギ酸アンモニウム水溶液
移動相Ｂ      ：ＭｅＣＮ／ｍｉｌｌｉＱ水＝７／３
グラジエント  ：Ｂ：５％→１００％（０～２０分）
Ｂ：１００％（２０～２５分）
Ｂ：１００％→５％（２５～２６分）
Ｂ：５％（２６～３０分）
化合物２１の保持時間：６．４分 <HPLC conditions>
Column: scherzo SS-C18 100 x 3 mm
Column temperature: 40 ° C
Injection volume: 5 μl
Detection wavelength: 280 nm
Flow velocity: 0.5 ml / min
Mobile phase A: 100 mM ammonium formate aqueous solution adjusted to pH = 4.7 Mobile phase B: MeCN / milliQ water = 7/3
Gradient: B: 5% → 100% (0 to 20 minutes)
B: 100% (20 to 25 minutes)
B: 100% → 5% (25-26 minutes)
B: 5% (26-30 minutes)
Retention time of compound 21: 6.4 minutes
　〔実施例８〕化合物２２：２－アミノ－５－メチルピリジンの合成
Figure JPOXMLDOC01-appb-C000038
 [Example 8] Synthesis of compound 22: 2-amino-5-methylpyridine
Figure JPOXMLDOC01-appb-C000038
　Ａｒ雰囲気下、室温にて２－アミノ－５－ブロモピリジン（１．０００ｇ、５．７８ｍｍｏｌ、１．００当量）を１０ｍｌのＴＨＦに溶解し－７０℃に冷却した。同温度にてクロロトリメチルシラン（０．６２８ｇ、５．７８ｍｍｏｌ、１．００当量）、１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（１１．０ｍｌ、１７．６３ｍｍｏｌ、３．０５当量）を加え、４５分間攪拌した後に、ヨウ化メチル（０．８２０ｇ、５．７８ｍｍｏｌ、１．００当量）のＴＨＦ溶液を加えた。１０分間攪拌した後に室温まで昇温し、化合物２２を含有する溶液を得た。この溶液について、富士フィルム和光純薬株式会社から購入した化合物２２を標準品として用い、下記のＨＰＬＣ条件で分析を行い、保持時間が一致したことから、化合物２２の生成を確認した。また，化合物２２の含有量をＨＰＬＣ定量により求めた結果、収率８２％であることを確認した。 Under an Ar atmosphere, 2-amino-5-bromopyridine (1.000 g, 5.78 mmol, 1.00 equivalent) was dissolved in 10 ml of THF and cooled to −70 ° C. at room temperature. At the same temperature, chlorotrimethylsilane (0.628 g, 5.78 mmol, 1.00 eq) and 1.6 M n-BuLihexane solution (11.0 ml, 17.63 mmol, 3.05 eq) were added for 45 minutes. After stirring, a THF solution of methyl iodide (0.820 g, 5.78 mmol, 1.00 eq) was added. After stirring for 10 minutes, the temperature was raised to room temperature to obtain a solution containing compound 22. For this solution, compound 22 purchased from Fuji Film Wako Pure Chemical Industries, Ltd. was used as a standard product, and analysis was performed under the following HPLC conditions. Since the retention times were the same, the formation of compound 22 was confirmed. Moreover, as a result of determining the content of compound 22 by HPLC quantification, it was confirmed that the yield was 82%.
　＜ＨＰＬＣ条件＞
カラム        ：ｓｃｈｅｒｚｏ　ＳＳ－Ｃ１８　１００×３ｍｍ
カラム温度    ：４０℃
注入量        ：５μｌ
検出波長      ：２８０ｎｍ
流速          ：０．５ｍｌ／ｍｉｎ
移動相Ａ      ：ｐＨ＝４．７に調整した１００ｍＭギ酸アンモニウム水溶液
移動相Ｂ      ：ＭｅＣＮ／ｍｉｌｌｉＱ水＝７／３
グラジエント  ：Ｂ：５％→１００％（０～１２分）
Ｂ：１００％（１２～１５分）
Ｂ：１００％→５％（１５～１６分）
Ｂ：５％（１６～２０分）
化合物２２の保持時間：４．９分 <HPLC conditions>
Column: scherzo SS-C18 100 x 3 mm
Column temperature: 40 ° C
Injection volume: 5 μl
Detection wavelength: 280 nm
Flow velocity: 0.5 ml / min
Mobile phase A: 100 mM ammonium formate aqueous solution adjusted to pH = 4.7 Mobile phase B: MeCN / milliQ water = 7/3
Gradient: B: 5% → 100% (0-12 minutes)
B: 100% (12 to 15 minutes)
B: 100% → 5% (15-16 minutes)
B: 5% (16 to 20 minutes)
Retention time of compound 22: 4.9 minutes
　〔実施例９〕化合物２３の合成と、誘導体２４：Ｎ－（ｔ－ブチルジメチルシリル）（ピリジン－２－イル）アミンの合成
Figure JPOXMLDOC01-appb-C000039
 [Example 9] Synthesis of compound 23 and synthesis of derivative 24: N- (t-butyldimethylsilyl) (pyridin-2-yl) amine
Figure JPOXMLDOC01-appb-C000039
　Ａｒ雰囲気下、室温にて２－アミノ－５－ブロモピリジン（１．００ｇ、５．７８ｍｍｏｌ、１．００当量）を１０ｍｌのＴＨＦに溶解し、クロロｔ－ブチルジメチルシラン（０．８７１ｇ、５．７８ｍｍｏｌ、１．００当量）を加えた。続いて溶液を氷冷して１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（３．８ｍｌ、６．０７ｍｍｏｌ、１．０５当量）を加えた後に、室温まで昇温して２時間攪拌した。反応液を－７０℃に冷却して１．６Ｍのｎ－ＢｕＬｉヘキサン溶液（７．２ｍｌ、１１．５６ｍｍｏｌ、２．００当量）を加えて１０分間攪拌し、化合物２３の溶液を得た。 In an Ar atmosphere, 2-amino-5-bromopyridine (1.00 g, 5.78 mmol, 1.00 equivalent) was dissolved in 10 ml of THF at room temperature, and chloro t-butyldimethylsilane (0.871 g, 5. 78 mmol, 1.00 eq) was added. Subsequently, the solution was ice-cooled, a 1.6 M n-BuLihexane solution (3.8 ml, 6.07 mmol, 1.05 eq) was added, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. The reaction mixture was cooled to −70 ° C., 1.6 M n-BuLihexane solution (7.2 ml, 11.56 mmol, 2.00 eq) was added, and the mixture was stirred for 10 minutes to obtain a solution of compound 23.
　化合物２３は不安定であり単離や分析が困難であるため、メタノールでクエンチして構造を確認した。同温度にてメタノール（０．４６３ｇ、１４．４５ｍｍｏｌ、２．５０当量）を加えて０．５時間攪拌した後に．反応液を室温下、減圧下で濃縮乾固した。残渣の一部を重クロロホルムに懸濁し、ろ過により不溶物を除いて得られた溶液について１Ｈ－ＮＭＲ、１３Ｃ－ＮＭＲ、ＨＲＭＳを測定し、誘導体２４が得られたことを確認した。なお、１Ｈ－ＮＭＲ、１３Ｃ－ＮＭＲのいずれのスペクトルも、誘導体２４のピーク以外には少量の溶媒ピーク（ＴＨＦ、メタノール）が認められるのみであり、その他の不純物に相当するピーク（例えば、２－アミノピリジン）は認められなかった。 Since compound 23 is unstable and difficult to isolate and analyze, it was quenched with methanol to confirm its structure. After adding methanol (0.463 g, 14.45 mmol, 2.50 eq) at the same temperature and stirring for 0.5 hours. The reaction mixture was concentrated to dryness at room temperature and under reduced pressure. A part of the residue was suspended in deuterated chloroform, and the solution obtained by removing the insoluble matter by filtration was measured by 1 H-NMR, 13 C-NMR, and HRMS, and it was confirmed that the derivative 24 was obtained. In both 1 H-NMR and 13 C-NMR spectra, only a small amount of solvent peaks (THF, methanol) are observed in addition to the peak of the derivative 24, and peaks corresponding to other impurities (for example, for example). 2-Aminopyridine) was not observed.
　本手順により誘導体２４が得られたことから、化合物２３の生成を確認できた。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ８．０５（ｄｄ、Ｊ＝１．６、４．８Ｈｚ、１Ｈ）、７．３６（ｄｄｄ、Ｊ＝１．６、７．４、８．４Ｈｚ、１Ｈ）、６．５７（ｄｄｄ、Ｊ＝０．４、４．８、７．２Ｈｚ、１Ｈ）、６．４６（ｄ、Ｊ＝８．４Ｈｚ、１Ｈ）、４．１２（ｂｒ、１Ｈ）、０．９７（ｓ、９Ｈ）、０．２７（ｓ、６Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１５９．９、１４８．６、１４８．２、１３９．５、１３７．１、１１３．２、１０９．７、１０９．６、２６．４、１７．５、－４．６。
ＨＲＭＳ（ＡＳＡＰ）：Ｃ１１Ｈ２１Ｎ２Ｓｉ［Ｍ＋Ｈ］＋の計算値：２０９．１４７４：実測値２０９．１４７８。 Since the derivative 24 was obtained by this procedure, the formation of compound 23 could be confirmed.
1 1 H-NMR (400 MHz, CDCl 3 ) δ8.05 (dd, J = 1.6, 4.8 Hz, 1H), 7.36 (ddd, J = 1.6, 7.4, 8.4 Hz, 1H) ), 6.57 (ddd, J = 0.4, 4.8, 7.2Hz, 1H), 6.46 (d, J = 8.4Hz, 1H), 4.12 (br, 1H), 0 .97 (s, 9H), 0.27 (s, 6H).
13 C-NMR (100 MHz, CDCl 3 ) δ159.9, 148.6, 148.2, 139.5, 137.1, 113.2, 109.7, 109.6, 26.4, 17.5, -4.6.
HRMS (ASAP): C 11 H 21 N 2 Si [M + H] + calculated value: 209.1474: measured value 209.1478.
　参考データ：２－アミノピリジン（富士フィルム和光純薬株式会社製）
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）δ８．０６（ｄｄｄ、Ｊ＝０．８、２．０、５．２Ｈｚ、１Ｈ）、７．３９（ｄｄｄ、Ｊ＝２．０、７．２、８．４Ｈｚ、１Ｈ）、６．６１（ｄｄｄ、Ｊ＝０．８、５．２、７．２Ｈｚ、１Ｈ）、６．４７（ｄｔ、Ｊ＝０．８、８．４Ｈｚ、１Ｈ）、４．７０（ｂｒ、２Ｈ）。
１３Ｃ－ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ１５８．５、１４７．９、１３７．５、１１３．７、１０８．４。 Reference data: 2-Aminopyridine (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.)
1 1 H-NMR (400 MHz, CDCl 3 ) δ8.06 (ddd, J = 0.8, 2.0, 5.2 Hz, 1H), 7.39 (ddd, J = 2.0, 7.2, 8) .4Hz, 1H), 6.61 (ddd, J = 0.8, 5.2, 7.2Hz, 1H), 6.47 (dt, J = 0.8, 8.4Hz, 1H), 4. 70 (br, 2H).
13 C-NMR (100 MHz, CDCl 3 ) δ158.5, 147.9, 137.5, 113.7, 108.4.

Claims (18)

  1. 　芳香環または複素芳香環上に、１つ以上のハロゲン基と、１つ以上のアミノ基を有する、芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬の存在下で反応させる工程（１）を含む、化合物（Ａ）の製造方法。 An aromatic compound (a1) or a heteroaromatic compound (a2) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring, and a silylating agent (b) are added. , A method for producing a compound (A), which comprises a step (1) of reacting in the presence of an organic metal reagent.
  2. 　前記有機金属試薬が、アルキルリチウム、アリールリチウム、又は、グリニャール試薬を含む、請求項１に記載の製造方法。 The production method according to claim 1, wherein the organometallic reagent contains an alkyllithium, an aryllithium, or a Grignard reagent.
  3. 　前記化合物（Ａ）が、有機リチウム化合物、又は、有機マグネシウム化合物である、請求項１又は２に記載の製造方法。 The production method according to claim 1 or 2, wherein the compound (A) is an organic lithium compound or an organic magnesium compound.
  4. 　前記アミノ基が、１級アミノ基である、請求項１～３のいずれか１項に記載の製造方法。 The production method according to any one of claims 1 to 3, wherein the amino group is a primary amino group.
  5. 　前記シリル化剤（ｂ）が、１価のシリル化剤である、請求項１～４のいずれか１項に記載の製造方法。 The production method according to any one of claims 1 to 4, wherein the silylating agent (b) is a monovalent silylating agent.
  6. 　前記シリル化剤（ｂ）が、２価のシリル化剤であって、
    　前記工程（１）において、前記シリル化剤は、前記アミノ基に対して、０．２５～０．７５等量用いられる、請求項１～４のいずれか１項に記載の製造方法。     The silylating agent (b) is a divalent silylating agent.
    The production method according to any one of claims 1 to 4, wherein the silylating agent is used in an equal amount of 0.25 to 0.75 with respect to the amino group in the step (1).
  7. 　前記シリル化剤（ｂ）が、ｎ価のシリル化剤（ｎは３～９までの整数）であって、
    　前記工程（１）において、前記シリル化剤は、前記アミノ基に対して、[（１／ｎ）－０．１]～[（１／ｎ）＋０．１]等量用いられる、請求項１～４のいずれか１項に記載の製造方法。     The silylating agent (b) is an n-valent silylating agent (n is an integer from 3 to 9).
    In the step (1), the silylating agent is used in equal amounts of [(1 / n) -0.1] to [(1 / n) + 0.1] with respect to the amino group, claim 1. The production method according to any one of 4 to 4.
  8. 　前記工程（１）において、前記シリル化剤は、前記アミノ基に対して、０．７５～１．２５等量用いられる、請求項５に記載の製造方法。 The production method according to claim 5, wherein in the step (1), the silylating agent is used in an amount of 0.75 to 1.25 equal to the amino group.
  9. 　前記芳香族化合物（ａ１）は、ベンゼン、ナフタレン、アントラセン、テトラセン、ピレン、ベンゾピレン、ペリレン、テトラセン、アズレン、及び、トロポンからなる群より選択される骨格を有する、請求項１～８のいずれか１項に記載の製造方法。 The aromatic compound (a1) has a skeleton selected from the group consisting of benzene, naphthalene, anthracene, tetracene, pyrene, benzopyrene, perylene, tetracene, azulene, and tropone, any one of claims 1 to 8. The manufacturing method described in the section.
  10. 　前記芳香族化合物（ａ１）は、ベンゼン環を１～１００個を含む、請求項１～９のいずれか１項に記載の製造方法。 The production method according to any one of claims 1 to 9, wherein the aromatic compound (a1) contains 1 to 100 benzene rings.
  11. 　前記複素環式化合物（ａ２）は、フラン、チオフェン、ピリジン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、ピリダジン、ピリミジン、ピラジン、１，２，３－トリアジン、１，３，５－トリアジン、１，２，４－トリアジン、キノリン、イソキノリン、ベンゾチオフェン、ベンゾフラン、シンノリン、キナゾリン、キノキサリン、フタラジン、ベンゾオキサゾール、１，２－ベンゾイソオキサゾール、ベンゾチアゾール、１，２－ベンゾイソチアゾール、１，２－ベンゾイソチアゾール－３（２Ｈ）－オン、２，１－ベンゾイソチアゾール－３（１Ｈ）－オン、プテリジン、アクリジン、キサンテン、ベンゾ－Ｃ－シンノリン、並びに、Ｎ－Ｈ基が保護された、ピロール、イミダゾール、ピラゾール、１，２，３－トリアゾール、１，２，４－トリアゾール、インドール、イソインドール、ベンゾイミダゾール、インダゾール、ベンゾトリアゾール、及び、プリンからなる群より選択される骨格を有する、請求項１～８のいずれか１項に記載の製造方法。 The heterocyclic compound (a2) includes furan, thiophene, pyridine, oxazole, isoxazole, thiazole, isothiazole, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,3,5-triazine, 1, 2,4-Triazine, quinoline, isothiazole, benzothiophene, benzofuran, cinnoline, quinazoline, quinoxalin, phthalazine, benzoxazole, 1,2-benzoisoxazole, benzothiazole, 1,2-benzoisothiazole, 1,2-benzo Isothiazole-3 (2H) -one, 2,1-benzoisothiazole-3 (1H) -one, pteridine, aclysine, xanthene, benzo-C-cinnoline, and N-H group-protected pyrrole, Claim 1 having a skeleton selected from the group consisting of imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, indole, isothiazole, benzimidazole, indazole, benzotriazole, and purine. The production method according to any one of 8 to 8.
  12. 　前記複素環式化合物（ａ２）は、複素環を１～１００個を含む、請求項１～８、１１のいずれか１項に記載の製造方法。 The production method according to any one of claims 1 to 8 and 11, wherein the heterocyclic compound (a2) contains 1 to 100 heterocycles.
  13. 　請求項１～１２のいずれか１項に記載の製造方法で得られた化合物（Ａ）と、求電子剤とを反応させる工程（２）を含む、
    　化合物（Ｂ）の製造方法。     A step (2) of reacting the compound (A) obtained by the production method according to any one of claims 1 to 12 with an electrophile is included.
    Method for producing compound (B).
  14. 　芳香環または複素芳香環上に、１つ以上のハロゲン基と、１つ以上のアミノ基を有する、芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬の存在下で反応させる工程（１）、並びに、
    　前記工程（１）で得られた化合物（Ａ）と、求電子剤とを反応させる工程（２）を含む、
    　化合物（Ｂ）の製造方法。     An aromatic compound (a1) or a heteroaromatic compound (a2) having one or more halogen groups and one or more amino groups on an aromatic ring or a heteroaromatic ring, and a silylating agent (b) are added. , The step of reacting in the presence of an organic metal reagent (1), and
    The step (2) of reacting the compound (A) obtained in the step (1) with the electrophile is included.
    Method for producing compound (B).
  15. 　前記求電子剤が、ケトン、アルデヒド、エステル、アミド、酸ハライド、ハロゲン、ハロアルカン、ハロギ酸エステル、カルバモイルハライド、エポキシド、イミン、ニトリル、酸無水物、及び、スルホニルハライドからなる群より選択される１つ以上の基を有する、請求項１３又は１４に記載の製造方法。 The electrophile is selected from the group consisting of ketones, aldehydes, esters, amides, acid halides, halogens, haloalkanes, halogiates, carbamoyl halides, epoxides, imines, nitriles, acid anhydrides, and sulfonyl halides. The production method according to claim 13 or 14, which has one or more groups.
  16. 　前記化合物（Ｂ）が、アルコール化合物、シリルエーテル化合物、ケトン化合物、アルデヒド化合物、イミン化合物、アミン化合物、エステル化合物、カーバメート化合物、スルホニル化合物、又は、アルカン化合物である、請求項１３～１５のいずれか１項に記載の製造方法。 Any of claims 13 to 15, wherein the compound (B) is an alcohol compound, a silyl ether compound, a ketone compound, an aldehyde compound, an imine compound, an amine compound, an ester compound, a carbamate compound, a sulfonyl compound, or an alkane compound. The manufacturing method according to item 1.
  17. 　芳香環または複素芳香環上の1か所以上がメタル化され、1つ以上の、窒素原子をメタル化されたＮ－シリルアミノ基［（Ｍ）Ｎ（ＳｉＲ１Ｒ２Ｒ３）。Ｒ１～Ｒ３は、それぞれ独立して置換されていてもよい、炭素数１～１０の鎖状または環状のアルキル基、アルケニル基、アルキニル基、又は、アリール基を表す。Ｍは、金属原子を表す。］を有する化合物（Ａ）。 One or more metallized N-silylamino groups on the aromatic or heteroaromatic ring and one or more metalized nitrogen atoms [(M) N (SiR 1 R 2 R 3 ). R 1 to R 3 represent a chain or cyclic alkyl group having 1 to 10 carbon atoms, an alkenyl group, an alkynyl group, or an aryl group, which may be substituted independently of each other. M represents a metal atom. ] The compound (A) having.
  18. 　１つ以上のハロゲン基と、１つ以上のアミノ基とにより置換されている芳香族化合物（ａ１）または複素芳香族化合物（ａ２）と、シリル化剤（ｂ）とを、有機金属試薬で反応させて得られる、化合物（Ａ）。
          The aromatic compound (a1) or heteroaromatic compound (a2) substituted with one or more halogen groups and one or more amino groups is reacted with the silylating agent (b) with an organometallic reagent. Compound (A) obtained by allowing the compound (A) to be obtained.
PCT/JP2019/044117 2019-11-11 2019-11-11 Aminoaryl derivative, intermediate of same, method for producing said aminoaryl derivative, and method for producing said intermediate WO2021095091A1 (en)

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