WO2015137417A1 - Intermédiaire synthétique de production de 3-haloaryne et procédé de synthèse dudit intermédiaire synthétique - Google Patents

Intermédiaire synthétique de production de 3-haloaryne et procédé de synthèse dudit intermédiaire synthétique Download PDF

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WO2015137417A1
WO2015137417A1 PCT/JP2015/057210 JP2015057210W WO2015137417A1 WO 2015137417 A1 WO2015137417 A1 WO 2015137417A1 JP 2015057210 W JP2015057210 W JP 2015057210W WO 2015137417 A1 WO2015137417 A1 WO 2015137417A1
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group
compound
synthesis
nmr
alignment
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英斗 吉岡
豪人 宮部
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学校法人兵庫医科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/361—Preparation of halogenated hydrocarbons by reactions involving a decrease in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/06—Six-membered rings
    • C07D327/08—[b,e]-condensed with two six-membered carbocyclic rings
    • 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
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te

Definitions

  • the present invention relates to a synthetic intermediate for producing 3-haloalignment and a synthesis method thereof.
  • Align (1,2-benzyne or o-benzyne, also simply called benzyne) is a general term for highly reactive chemical species having a triple bond on an aromatic ring. Since Align is rich in reactivity, it is used in many fields such as synthesis of biologically active substances such as polycyclic heterocycles and functional molecules (Non-patent Document 1, Patent Documents 1 and 2). As a method for producing alignment, a method requiring severe reaction conditions such as high temperature and strong basicity has been known. In 1983, as a method for generating alignment under mild conditions, a method using an adjacent trimethylsilyl group and trifluoromethanesulfonic acid ester group on an aromatic ring was reported (Non-patent Document 2).
  • Non-patent Document 3 6-trimethylsilyl-2-halophenyltrifluoromethanesulfonate
  • Non-Patent Document 4 6-bromo-4-trimethylsilyl-1H-indole-5
  • iltrifluoromethanesulfonate Non-Patent Document 4
  • this precursor is a compound different from the present invention, and its synthesis method is also different.
  • the following documents are each incorporated herein by reference. P. M. Tadross and B. M. Stoltz, Chem. Rev., 2012, 112, 3550-3577. H. Kobayashi, et al., Chem.
  • a halogen-substituted carbon 6-membered ring aromatic compound generates an alignment due to elimination of a halogen atom with the generation of an anion at a position adjacent to the halogen atom.
  • a heterocyclic 6-membered aromatic compound can generate a precursor without going through a halogen-lithium exchange reaction because the anion on the aromatic ring is more stable and more easily generated.
  • an aromatic compound having a trialkylsilyl group, and an —OSO 2 R 1 group and an —X group at positions adjacent to the trialkylsilyl group.
  • an aromatic compound in which the ring to which the trialkylsilyl group, —OSO 2 R 1 group and —X group are directly bonded is a carbon 6-membered ring is preferably provided.
  • a method for producing alignment which comprises reacting the aromatic compound with fluoride ions.
  • an aromatic compound having a —H (hydrogen) group and a trialkylsilyloxy group and a —X group at both adjacent positions adjacent to the —H group is converted to lithium amide or
  • a method (synthetic method) for synthesizing an aromatic compound (alignment intermediate) which comprises a step of reacting with an art complex type double salt of magnesium amide or zinc amide and a lithium salt.
  • the aromatic compound (alignment intermediate) is the aromatic compound in which the ring to which the —OSO 2 R 1 group and the —X group are directly bonded is a carbon six-membered ring. .
  • R 1 is C m F 2m + 1 (m is an integer) or an aryl or heteroaryl group which may be substituted with alkyl.
  • X is F, Cl or Br.
  • the aromatic moiety contains benzene, naphthalene, indole, benzimidazole, quinoline, isoquinoline or benzofuran.
  • the aromatic moiety contains benzene, naphthalene, indole, quinoline, isoquinoline or benzofuran.
  • the present invention provides an align-generating intermediate compound that is easily synthesized with a small number of steps. With this compound, the synthesis reaction via alignment can be performed more easily. In addition, the introduction of a halogen at a specific position makes the alignment reaction generated from this synthetic intermediate compound also regioselective.
  • halogen or “halo” means fluorine, chlorine, bromine or iodine, unless otherwise specified.
  • cyano means a —CN group.
  • tertiary amino means a group in which hydrogen is substituted with a substituent R other than hydrogen in the —NH 2 group. Preferably, R is an optionally substituted alkyl group.
  • nitro means a —NO 2 group.
  • sulfonyl refers to the divalent group —S ( ⁇ O) 2 —.
  • carbonyl refers to a — (C ⁇ O) — group that is a divalent group.
  • alkyl alkenyl, alkynyl or “cycloalkyl” mean not only monovalent groups, but in some cases divalent or higher groups. For example, when a divalent group is meant, it is used interchangeably with “alkylene”, “alkenylene”, “alkynylene” or “cycloalkylene”, respectively.
  • the prefix “C xy alkyl”, “C xy alkenyl”, “C xy alkynyl” or “C xy cycloalkyl” is prefixed with each of x to y carbon atoms.
  • a group of the specific chain length shown below is representative of “C xy alkyl”, “C xy alkenyl”, “C xy alkynyl” or “C xy cycloalkyl” It is an example. Moreover, about arbitrary bivalent or more groups, when substituting in the position which can form a monocycle or a multicycle, unless it specifically limits, the group more than bivalence may form ring structure.
  • C 1-6 alkyl or “C 1-6 alkylene” means a branched or straight-chain saturated hydrocarbon group having from 1 to 6 carbon atoms, for example, C 1-3 alkyl , C 1-4 alkyl, C 1-6 alkyl, C 2-6 alkyl, C 3-6 alkyl, and the like.
  • Representative C 1-6 alkyl includes, for example, methyl, ethyl, propyl (eg, propan-1-yl, propan-2-yl [or iso-propyl]), butyl (eg, 2-methylpropane-2) -Yl [or tert-butyl], butan-1-yl, butan-2-yl), pentyl (eg, pentan-1-yl, pentan-2-yl, pentane-3-yl), 2-methylbutane-1 -Yl, 3-methylbutan-1-yl, hexyl (eg, hexane-1-yl) and the like.
  • C 2-6 alkenyl or “C 2-6 alkenylene” refers to a linear or branched non-aromatic having 2 to 6 carbon atoms and at least one carbon-carbon double bond. And includes, for example, C 2-3 alkenyl, C 2-4 alkenyl, C 2-6 alkenyl, C 3-6 alkenyl, C 4-6 alkenyl and the like.
  • Representative C 2-6 alkenyl groups include, for example, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl- 1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, and 5-hexenyl Etc.
  • C 2-6 alkynyl or “C 2-6 alkynylene” refers to a linear or branched non-aromatic having 2 to 6 carbon atoms and at least one carbon-carbon triple bond. And includes, for example, C 2-3 alkynyl, C 2-4 alkynyl, C 2-6 alkynyl, C 3-6 alkynyl, C 4-6 alkynyl and the like.
  • Representative C 2-6 alkynyl groups include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2- Examples include pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl and the like.
  • C 3-6 cycloalkyl means a saturated monocyclic carbocycle having from 3 to 6 carbon atoms.
  • Representative C 3-6 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • alkoxy or “alkyloxy” means a —O—R group where R is alkyl as previously described. Also, when the term “Roxy” is used, it means a —O—R group that is a monovalent or divalent group.
  • C 1-6 alkoxy means a C 1-6 alkyl-O— group, for example, C 1-3 alkoxy, C 1-4 alkoxy, C 1-6 alkoxy, C 2-6. Including alkoxy, C 3-6 alkoxy and the like.
  • Representative C 1-6 alkoxy includes, for example, methoxy, ethoxy, propoxy (eg, 1-prop-oxy, 2-prop-oxy [or iso-propoxy]), butoxy (eg, 1-butoxy, 2-butoxy, 2-methyl-2-propoxy- [or tert-butoxy]), penta-oxy (1-penta-oxy, 2-penta-oxy), hexa-oxy (1-hexa-oxy, 3- Hexa-oxy) and the like.
  • propoxy eg, 1-prop-oxy, 2-prop-oxy [or iso-propoxy]
  • butoxy eg, 1-butoxy, 2-butoxy, 2-methyl-2-propoxy- [or tert-butoxy]
  • penta-oxy (1-penta-oxy, 2-penta-oxy
  • hexa-oxy (1-hexa-oxy, 3- Hexa-oxy
  • heterocyclic group means a single atom containing one or more heteroatoms selected from atoms other than carbon (heteroatoms) such as nitrogen, oxygen, sulfur, SO and S ( ⁇ O) 2 in the ring. It means a ring, bicyclic or polycyclic saturated or unsaturated non-aromatic group or aromatic group (heteroaryl group).
  • the heterocyclic group includes, for example, a non-aromatic cyclic amino group, and is preferably an aprotic group.
  • the heterocyclic group in the present invention is preferably a 5- to 7-membered ring, more preferably a 5-membered ring or a 6-membered ring.
  • heterocyclic groups include, for example, morpholino, oxazinyl, dihydrooxazinyl, piperazinyl, thiomorpholino, piperidino, pyrrolidinyl, homomorpholino, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, triazinyl, pyridinyl, pyrimidinyl, pyridazinyl, Examples include pyrazinyl, oxazolyl, isoxazolyl, thienyl or furyl.
  • aryl means a monocyclic, bicyclic or polycyclic carbocyclic aromatic ring. Representative aryl includes phenyl, naphthalenyl, and the like.
  • heteroaryl means a monocyclic, bicyclic or polycyclic heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, SO and S ( ⁇ O) 2 .
  • Representative heteroaryls include pyridyl, pyrimidinyl, indolyl, thiazolyl, benzofuranyl, dihydrobenzofuranyl, imidazolyl, pyrazolyl, quinolyl, isoquinolyl, benzothiophenyl, and the like.
  • saturated or unsaturated means whether the group in question is a saturated group that does not contain a double or triple bond, or is an unsaturated group that contains at least one double or triple bond. Means either.
  • optionally substituted means that the group in question is either unsubstituted or substituted by one or more specific substituents. For example, the number of substitutions is 1, 2, 3, 4, or 5, but preferably, 1, 2, or 3, more preferably 1 or 2, and even more preferably 1 is used. When a target group is substituted with a plurality of substituents, the substituents may be the same or different.
  • intermediate is produced by reaction from starting materials or previous reactants in the manufacturing process or chemical reaction (organic synthesis) and further reacted. It refers to what gives the final product and is limited by its use. That is, in this case, the final product is synthesized via an intermediate.
  • an intermediate that gives a final product in one step or one reaction, or substantially one step or one reaction is called a “precursor”.
  • the intermediate includes a precursor). Even if used substantially as a precursor, the final product may be obtained after multiple steps to modify other moieties.
  • Halogen atoms have also been used in alignment methods via Grignard reactions and halogen-metal exchange reactions. For these reasons, it has been difficult to efficiently generate alignments having halogen atoms by conventional methods.
  • the alignment precursor compound containing a halogen atom has hardly been reported, and the compounds reported so far and their synthesis methods are different from the compounds of the present invention and their synthesis methods.
  • a method for synthesizing an align precursor having a chlorine atom (the same applies to a bromine atom)
  • a method of synthesizing via halogen-lithium exchange has been reported as shown in the following formula (1) (Non-patent Document 3).
  • Non-patent Document 6 A method for synthesizing an align precursor by generating an anion on an aromatic ring has also been reported (Non-patent Document 6).
  • a synthesis method (Non-patent Document 7) has also been reported, these are all different from the present invention.
  • the synthesis of the above-mentioned known alignment precursors is generally high in cost, and the generation efficiency is superior to the present invention.
  • the halogen atom in the raw material is removed during the reaction, and the introduction cost of the halogen atom is higher than in the present invention.
  • the introduction and removal of the groups is necessary and the reagent costs are high because an excess amount is used.
  • the method of this invention is excellent in the production
  • a trialkylsilyl group and an —OSO 2 R 1 group [where R 1 is C m F 2m + 1 (m is an integer) or alkyl are substituted on both adjacent positions adjacent to the trialkylsilyl group.
  • An aromatic or heteroaryl group [X is F, Cl or Br], wherein the trialkylsilyl group, —OSO 2 R 1 group And the ring to which the —X group is directly bonded is an aromatic compound having a six-membered carbon ring.
  • Another embodiment of the present invention has a —H (hydrogen) group, a trialkylsilyloxy group at a position adjacent to the —H group, and a —X group [X is F, Cl, or Br].
  • —OSO 2 R 1 group [R 1 is C m F 2m + 1 (m is an integer) or an aryl or heteroaryl group optionally substituted with alkyl] and —X group [X Is F, Cl or Br].
  • Another embodiment of the present invention is the method of the above embodiment, wherein the ring to which the trialkylsilyl group, —OSO 2 R 1 group and —X group are directly bonded is a carbon 6-membered ring.
  • the aromatic compound of the present invention can easily generate alignment (3-halo alignment) under mild conditions by reacting with fluoride ions. Alignments produced from the present aromatic compounds react regioselectively with various nucleophiles to give various substituted aromatic compounds. Furthermore, when a diene or the like is added, a polycyclic aromatic compound can also be obtained.
  • the aromatic compound of the present invention utilizes the characteristic substituent arrangement (an arrangement having an -OSO 2 R 1 group and an -X group at positions adjacent to the trialkylsilyl group), Unlike general align-forming intermediate compounds, it can be synthesized more easily with fewer steps. Furthermore, since the number of reagents used is small compared to the conventional method, it can be economical. Furthermore, since the number of steps and the number of reagents used are small, the processing and purification of the product can be made simpler, giving an overall good yield. By these things, the aligning precursor which has various substituents can be supplied on the industrially realizable level.
  • a halogen-substituted heterocycle alignment precursor (Non-patent Document 7), which could be synthesized by a conventional method, has a halogen-substituted lane precursor compound having a carbon six-membered ring that is less likely to generate anions than a heterocycle.
  • this aromatic compound has high storage stability, and can be stored for a long period of time, for example, about -30 ° C. to room temperature for about 1 to 2 years or more.
  • the aromatic compound is preferably stored under conditions free from moisture, but can be stored in normal air.
  • the align-generating intermediate compound of the above aspect is described as follows: “—H (hydrogen) group, trialkylsilyloxy group, —X group [X is F, Cl, or Br] adjacent to the —H group”
  • —H (hydrogen) group, trialkylsilyloxy group, —X group [X is F, Cl, or Br] adjacent to the —H group can be synthesized by a method including a step of treating with a specific strong base.
  • Specific strong bases include lithium amide, or an art complex type double salt of magnesium amide or zinc amide and a lithium salt.
  • an “aromatic compound having a trialkylsilyl group, a hydroxyl group and an —X group [X is F, Cl, or Br] at both positions adjacent to the trialkylsilyl group” (The desired phenolic compound) can be synthesized.
  • This compound may be converted to a haloalkyl sulfonate esterifying reagent or (alkyl-substituted) aryl or heteroaryl sulfonate esterifying reagent (including but not limited to C m F 2m + 1 SO 2 F (eg, trifluoromethanesulfonyl fluoride) , Heptafluoropropylsulfonyl fluoride, perfluorobutanesulfonyl fluoride), Tf 2 O (trifluoromethanesulfonic anhydride), TsCl (p-toluenesulfonyl chloride), benzenesulfonyl chloride, N, N′-sulfonyldiimidazole, etc. ) And converting to the corresponding sulfonic acid ester according to a conventional method, the target aligning intermediate compound can be synthesized.
  • the target aligning intermediate compound can be synthesized.
  • the starting material has an “-H (hydrogen) group, a trialkylsilyloxy group at a position adjacent to the —H group, and an —X group [X is F, Cl or Br].
  • the “group compound” (starting silyl ether compound) is not limited thereto, but includes a corresponding “—H (hydrogen) group, a hydroxyl group at a position adjacent to the —H group, and —X
  • the aromatic compound having the group [X is F, Cl or Br] (starting phenol compound) is added to a silyl etherification reagent (HMDS (bis (trimethylsilyl) amine (also known as 1,1,1,3)).
  • HMDS silyl etherification reagent
  • silyl etherification according to a conventional method.
  • the silyl ether compound as a starting material is not limited to this, and can be synthesized by various routes by performing a substituent introduction reaction on an aromatic ring.
  • reaction conditions can be set with reference to known documents such as Non-Patent Document 5, for example.
  • the reaction conditions are not limited thereto, but a solvent: an aprotic solvent (for example, Tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether and mixed solvents thereof), temperature: -80 ° C to 0 ° C.
  • the reaction is more preferable under moisture-free conditions, for example, in an Ar atmosphere.
  • the invention of the above embodiment is not limited to this, but can be illustrated as follows (the aromatic compound portion is exemplified using phenyl).
  • the align-forming intermediate compound of the present invention is the compound of (4) in the figure, and the method of synthesizing the align-generating intermediate compound of the present invention is a reaction from the starting material silyl ether (2) to the phenol compound (3). It is the method characterized by this.
  • An example of a method for synthesizing silyl ether (2) is silyl etherification of a corresponding phenol compound such as the starting phenol compound (1).
  • a strong base is used to make the ortho position of the chlorine atom (the 2nd position in the figure) an anion, and the introduction of the silyl group into the 2nd position by the rearrangement reaction and Regeneration of the secondary phenolic hydroxyl group is achieved at once.
  • the introduction of a silyl group is achieved by a rearrangement reaction from a silyl ether group at the meta position (position 1 in the figure) in order to suppress the formation of alignment due to the elimination of halogen atoms.
  • a silyl ether group and a halogen atom are utilized, and an anion is generated selectively and a silyl group is introduced without using a halogen-lithium exchange reaction. Yes.
  • Still another embodiment of the present invention is an alignment synthetic intermediate or synthesis precursor (synthetic intermediate or synthesis precursor for producing alignment) comprising the aromatic compound of the above embodiment.
  • a method for producing an align (3-haloalign) which comprises reacting the compound of the above embodiment with a fluoride ion.
  • Still another embodiment of the present invention is the alignment obtained by reacting the compound of the above embodiment with fluoride ion or the obtained align (3-haloalign), or the reaction of the fluoride ion to the compound of the above embodiment. Or a reaction mixture or product containing the resulting alignment (3-haloalignment).
  • the align-forming intermediate compound of the present invention can easily generate aligns (for example, benzyne, naphtholine, pyridyne, etc.) under mild conditions by reacting with fluoride ions.
  • the produced alignment reacts regioselectively with various nucleophiles to give various substituted aromatic compounds and polysubstituted aromatic compounds.
  • Align can be used in many ways, including the synthesis of biologically active substances and functional molecules.
  • the alignment generating intermediate compound of the present invention can be synthesized more easily with a smaller number of steps, and therefore alignment can be generated more efficiently. Moreover, it can also synthesize
  • Alignment can be easily generated under mild conditions.
  • Fluoride ion sources include TBAF (tetra-n-butylammonium fluoride), TBAHF 2 , CsF, KF, TBAT (tetra-n-butylammonium difluorotriphenyl silicate), TBAH 2 F 3 , HF • pyridine HF and triethylamine can be exemplified, and preferably TBAF, TBAHF 2 , CsF, KF, TBAT, TBAH 2 F 3 , more preferably TBAF, TBAHF 2 , and CsF can be used.
  • the alignment reaction itself using fluoride ions is a reaction well known to those skilled in the art, and those skilled in the art can appropriately change the reaction conditions according to conventional methods (for example, Non-Patent Document 1 or 5, or Patent Document 1).
  • the reaction conditions are not particularly limited as long as fluoride ions act, and examples of such conditions include, but are not limited to, solvent: polar aprotic Solvent (for example, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylformamide (reagent and solvent) or a mixed solvent thereof; alcohol solvent is not preferred), temperature: 0 to 100 ° C., more preferably The condition is 20 to 80 ° C.
  • the reaction is more preferable under moisture-free conditions, for example, in an Ar atmosphere.
  • generated by this invention it can be made to react with various sphere nucleating agents in a reaction system as it is, and the target compound which has a desired chemical structure can be obtained. Since the generation of align according to the present invention is performed under relatively mild conditions, other substituents present in the compound are not easily affected, and the present invention can be used in the vicinity of the final step of the synthesis step.
  • the invention of the above embodiment (generation of alignment and subsequent reaction) is not limited to this, but can be illustrated as follows (the aromatic compound portion is exemplified using phenyl, Illustrative representative end products X, Y, Z).
  • the aromatic compound is an aromatic compound in which the trialkylsilyl group, —OSO 2 R 1 group, and —X group are bonded to optionally substituted aryl or heteroaryl.
  • skeleton Form example, a monocyclic ring, a condensed ring, etc.
  • the aromatic compound is an optionally substituted benzene, pyridine, pyrimidine, naphthalene, indole, benzimidazole, quinoline, isoquinoline, benzofuran or benzothiophene or an optionally substituted benzene.
  • Pyridine, pyrimidine, naphthalene, indole, quinoline, isoquinoline, benzofuran or benzothiophene which is an aromatic compound in which the trialkylsilyl group, —OSO 2 R 1 group and —X group are bonded.
  • the aromatic moiety is more preferably benzene, pyridine, naphthale, quinoline, pyrimidine, isoquinoline, and even more preferably benzene, pyridine, naphthalene. In the compound having these portions, the effects of the present invention can be more reliably exhibited.
  • the aromatic moiety preferably comprises a benzene ring and is benzene, naphthalene, indole, benzimidazole, quinoline, isoquinoline, benzofuran or benzothiophene or benzene, naphthalene, indole, quinoline, isoquinoline, benzofuran or benzothiophene. More preferably, benzene, naphthalene, indole, benzofuran, and benzothiophene are even more preferable, and benzene and naphthalene are even more preferable.
  • the ring to which the trialkylsilyl group, —OSO 2 R 1 group and —X group are directly bonded is preferably a six-membered ring, More preferably, it is a six-membered ring.
  • a carbon 6-membered ring alignment precursor can be synthesized more easily than a conventional method compared to a hetero 6-membered ring alignment precursor.
  • the aromatic part (parent ring) of the aromatic compound may be substituted with any substituent according to the structure of the target compound. Since the method for synthesizing an align-generating intermediate compound of the present invention and the method for generating an align from the align-generating intermediate compound are highly specific reactions that proceed under mild conditions, there are few restrictions on substituents. If the functional group is difficult to be deprotonated and hardly rearranged, the reaction can be advantageously advanced.
  • substituents R include, but are not limited to, halogen, nitro, cyano, tertiary amino (disubstituted amino), alkyl, haloalkyl, alkene, haloalkene, alkyne. , Haloalkyne, alkoxy, ester (eg, RC (O) O— or ROC (O) —, where R is defined herein), sulfonate ester (eg, ROS ( ⁇ O) 2 where R is defined herein) O- and the like), aryl, aryloxy, arylalkyl, arylalkoxy, heterocyclic group and the like.
  • ester eg, RC (O) O— or ROC (O) —, where R is defined herein
  • sulfonate ester eg, ROS ( ⁇ O) 2 where R is defined herein
  • substituents R may be further substituted with one or more substituents R.
  • the substituent R is preferably halogen, alkyl, haloalkyl, alkoxy, alkene, alkyne, aryl, aryloxy, more preferably halogen, alkyl, haloalkyl, alkoxy. Two or more substituents R may be taken together to form a ring structure.
  • substituent for the aromatic moiety of the align-forming intermediate compound of the present invention any number of 1 to 3, 1 or 2, or 1 substituents is preferably used.
  • a certain aspect of the present invention is the aromatic compound (synthetic intermediate) or method according to any one of the above aspects, wherein X is chloro or fluoro.
  • the aligning intermediate compound of the present invention can be synthesized in a higher yield. From the viewpoint of yield and reaction selectivity of alignment, it is advantageous that X is fluoro.
  • X is converted to other substituents such as alkyl, aryl, alkoxy, formyl, alkylcarbonyl and the like. From the standpoint of ease of conversion, it is advantageous that X is chloro.
  • One embodiment of the present invention is the aromatic compound (synthetic intermediate) or method according to any one of the above embodiments, wherein R 1 is C m F 2m + 1 (m is an integer).
  • R 1 is C m F 2m + 1 (m is an integer).
  • One embodiment of the present invention is the aromatic compound (synthetic intermediate) or method of any of the above embodiments, wherein R 1 is aryl optionally substituted with alkyl.
  • the aromatic compound (synthetic intermediate) or method according to any one of the above embodiments, wherein aryl is benzene or heteroaryl is imidazole.
  • the -OSO 2 R 1 group in which R 1 is toluenyl, that is, a toluenesulfonic acid group is widely used in the field of synthetic organic chemistry, and the present invention can be more easily carried out.
  • the aromatic compound (synthesis intermediate) according to any one of the above embodiments, wherein the alkylsilyl group is a tri-lower alkylsilyl group, particularly a trimethylsilyl group, a triethylsilyl group, or a tert-butyldimethylsilyl group. Or a method.
  • the reaction can be carried out more reliably and efficiently, but from the viewpoint of reaction efficiency, a trimethylsilyl group or a triethylsilyl group is preferable, and a trimethylsilyl group is more preferable.
  • lithium amide or an art complex-type double salt of magnesium amide or zinc amide and a lithium salt is magnesium bistetramethylpiperidide.2 lithium salt (Mg (TMP) 2 .2LiX), Lithium alkylamide, zinc bistetramethylpiperidide dilithium salt (Zn (TMP) 2 ⁇ 2LiX), chloro or bromomagnesium tetramethylpiperidide lithium salt ((TMP) MgX ⁇ LiX), or chloro or bromo Zinc tetramethylpiperidide lithium salt ((TMP) ZnX.LiX) is the method according to any of the above embodiments (X is Cl or Br).
  • Mg (TMP) 2 .2LiX Lithium alkylamide
  • Zn (TMP) 2 ⁇ 2LiX zinc bistetramethylpiperidide dilithium salt
  • chloro or bromomagnesium tetramethylpiperidide lithium salt (TMP) MgX ⁇ LiX
  • lithium alkylamide examples include, but are not limited to, lithium diisopropylamide (LiN (i-Pr) 2 ; LDA) and lithium tetramethylpiperidide (Li (TMP)).
  • the alignment produced from the aromatic compound of the present invention reacts with various nucleophiles in a regioselective manner (for example, the meta position relative to the substituent X on the aromatic) to produce a polysubstituted aromatic Give compound.
  • a regioselective manner for example, the meta position relative to the substituent X on the aromatic
  • Many reactions are known as reactions using align and nucleophile, and a desired nucleophile and reaction can be used depending on the structure of the target compound. Examples of the reaction include synthesis of polycyclic aromatic rings by Diels-Alder type addition reaction using dienes (eg, cyclopentadiene, cyclohexadiene, anthracene, etc.), and various polycyclic rings by known methods. Synthetic heterocycles (for example, derivatives of isoquinoline, xanthene, coumarin, indoline, chromene, dihydrobenzofuran, benzofuran).
  • compounds having F, Cl or Br on the aromatic ring are produced by the alignment of the present invention. It can also be synthesized utilizing the structure of the intermediate compound.
  • the synthetic intermediate (tetrahydrobenzodiazepine compound) of a benzodiazepine compound can also be simply synthesize
  • the substituent X on the aromatic ring is converted to a carbon atom, by various known coupling reactions.
  • a nitrogen atom, an oxygen atom, etc. a compound having a desired structure can be synthesized by an unprecedented strategy.
  • alignment can be easily generated under mild conditions by reacting with fluoride ions according to a known method such as the method described in Non-Patent Document 5. .
  • the generated alignment reacts with various nucleophiles in a regioselective manner to give a polysubstituted aromatic compound.
  • many reactions are known for the reaction using align and nucleophile, and a desired nucleophile and reaction may be used depending on the structure of the target compound. it can. Examples of typical alignment generating reactions and generated alignment reactions are shown below, but the present invention is not limited thereto, and alignment is generated according to a known method such as Non-Patent Document 5, This can be used.
  • the conventional align precursor compound is indicated by 1a
  • the align precursor compound of the present invention is indicated by 1b.
  • the conventional alignment precursor compound 1a produces a dimer 2a in which a rearrangement produced as a side reaction reacts with the desired 3-chloroalignment.
  • the generated alignment reacts with acetonitrile as a solvent without generating the dimer 2b via the side reaction even under the same experimental conditions, 3 and 4 occurred.
  • the alignment precursor compound of the present invention has higher reaction selectivity and yield when producing alignment, compared with the alignment precursor compound having a conventional structure.
  • Alignment produced according to the present invention can react regioselectively with various nucleophiles to give various substituted aromatic compounds and polycyclic aromatic compounds. Therefore, the present invention can be used in various fields such as synthesis of functional molecules such as biologically active substances, pharmaceuticals, pharmaceutical intermediates, and electronic device materials (insulating films).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention a pour but de fournir : un précurseur aryne qui peut être synthétisé facilement en moins d'étapes ; un procédé de synthèse dudit précurseur aryne. Pour atteindre ce but, l'invention porte sur un composé aromatique qui possède : un groupe trialkylsilyle ; un groupe -OSO2R1 [R1 est un groupe hétéroaryle ou un groupe aryle qui peut être substitué par CmF2m+1 (m est un nombre entier) ou par un groupe alkyle] dans les deux positions qui sont adjacentes au groupe trialkylsilyle ; un groupe -X [X est F, Cl, ou Br].
PCT/JP2015/057210 2014-03-13 2015-03-11 Intermédiaire synthétique de production de 3-haloaryne et procédé de synthèse dudit intermédiaire synthétique WO2015137417A1 (fr)

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Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
ADAM E. GOETZ ET AL.: "Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model", NATURE CHEMISTRY, vol. 5, no. 1, 2013, pages 54 - 60, XP055224468, ISSN: 1755-4330 *
CATHERINE HALL ET AL.: "Tandem thia-Fries rearrangement - cyclisation of 2- (trimethylsilyl)phenyl trifluoromethanesulfonate benzyne precursors", CHEMICAL COMMUNICATIONS, vol. 49, no. 69, 2013, pages 7602 - 7604, XP055224479, ISSN: 1359-7345 *
HIROTO YOSHIDA ET AL.: "Synchronous Ar-F and Ar- Sn Bond Formation through Fluorostannylation of Arynes", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 52, 2013, pages 8629 - 8632, XP055224475 *
JAMES D. KIRKHAM ET AL.: "An alkynylboronate cycloaddition strategy to functionalised benzyne derivatives", CHEMICAL COMMUNICATIONS, vol. 46, no. 28, 2010, pages 5154 - 5156, XP055224463, ISSN: 1359-7345 *
MAITE DIAZ ET AL.: "Synthesis of Ellipticine by Hetaryne Cycloadditions - Control of Regioselectivity", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2001, pages 4543 - 4549, XP055224470 *
PAMELA M. TADROSS ET AL.: "Regioselective Reactions of Highly Substituted Arynes", ORGANIC LETTERS, vol. 12, no. 6, 2010, pages 1224 - 1227, XP055224477, ISSN: 1523-7060 *
SARAH M. BRONNER ET AL.: "Efficient Synthesis of 2-(Trimethylsilyl)phenyl Trifluoromethanesulfonate: A Versatile Precursor to o-Benzyne", JOURNAL OF ORGANIC CHEMISTRY, vol. 74, no. 22, 2009, pages 8842 - 8843, XP055224464, ISSN: 0022-3263 *
SARAH M. BRONNER ET AL.: "Overturning Indolyne Regioselectivities and Synthesis of Indolactam V", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 133, no. 11, 2011, pages 3832 - 3835, XP055224469, ISSN: 0002-7863 *
TAKASHI IKAWA ET AL.: "Synthesis of Fluorinated Aromatic Compounds by One-Pot Benzyne Generation and Nucleophilic Fluorination", AUSTRALIAN JOURNAL OF CHEMISTRY, vol. 67, 24 December 2013 (2013-12-24), pages 475 - 480 *
YOSHIO HIMESHIMA ET AL.: "FLUORIDE-INDUCED 1,2- ELIMINATION OF O-TRIMETHYLSILYLPHENYL TRIFLATE TO BENZYNE UNDER MILD CONDITIONS", CHEMISTRY LETTERS, 1983, pages 1211 - 1214, XP055224472 *

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