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WO2021095091A1 - Dérivé aminoaryle, produit intermédiaire, et procédés de fabrication de ceux-ci - Google Patents

Dérivé aminoaryle, produit intermédiaire, et procédés de fabrication de ceux-ci 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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Japanese (ja)
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英彰 梅本
小川　晃一
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FUJIMOTO CHEMICALS Co Ltd
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FUJIMOTO CHEMICALS Co Ltd
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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 Table
    • 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.

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Abstract

L'invention fournit notamment : un produit intermédiaire destiné à obtenir un dérivé aminoaryle sans isolement en tant que produit intermédiaire à groupe amino protégé, par exemple par réaction avec un réactif électrophile, ou similaire, en tant que réactif de réaction nucléophile ; un dérivé aminoaryle obtenu à l'aide de ce produit intermédiaire ; et procédés de fabrication de ce produit intermédiaire et de ce dérivé aminoaryle.　En outre, l'invention concerne un procédé de fabrication d'un composé (A) qui inclut une étape (1) au cours de laquelle au moins un groupe halogène, un composé aromatique (a1) ou un composé aromatique complexe (a2) possédant au moins un groupe amino, et un agent de silylation, sont mis en réaction en présence d'un réactif métallique organique, dans un cycle aromatique ou un cycle aromatique complexe.
PCT/JP2019/044117 2019-11-11 2019-11-11 Dérivé aminoaryle, produit intermédiaire, et procédés de fabrication de ceux-ci Ceased WO2021095091A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017186358A (ja) * 2014-10-29 2017-10-12 ギリアード サイエンシーズ， インコーポレイテッド フィロウイルス科ウイルス感染症を処置するための方法

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JP2017186358A (ja) * 2014-10-29 2017-10-12 ギリアード サイエンシーズ， インコーポレイテッド フィロウイルス科ウイルス感染症を処置するための方法

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DAVID, S. ET AL. ET AL.: "Synthesis of delta-beta-D- ribofuranosylcytosine (pseudocytidine) and its a- anomer", CARBOHYDRATE RESEARCH, vol. 29, no. 1, 1973, pages 15 - 24, XP055824142, ISSN: 0008-6215 *
DEY, S ET AL.: "2] Ferrocenophanes with Nitrogen in Bridging Positions", ORGANOMETALLICS, vol. 34, no. 12, 2015, pages 3039 - 3046, XP055824150, ISSN: 0276-7333 *
KENYON, P. ET AL.: "Controlled Polymerization in Polar Solvents to Ultrahigh Molecular Weight Polyethylene", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 140, no. 21, 2018, pages 6685 - 6689, XP055824145, ISSN: 0002-7863 *

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