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WO2016133217A1 - Procédé de fabrication d'un composé oxindole optiquement actif et sel de triazolium utilisé en son sein en tant que catalyseur - Google Patents

Procédé de fabrication d'un composé oxindole optiquement actif et sel de triazolium utilisé en son sein en tant que catalyseur Download PDF

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WO2016133217A1
WO2016133217A1 PCT/JP2016/054960 JP2016054960W WO2016133217A1 WO 2016133217 A1 WO2016133217 A1 WO 2016133217A1 JP 2016054960 W JP2016054960 W JP 2016054960W WO 2016133217 A1 WO2016133217 A1 WO 2016133217A1
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貴史 大井
亨介 大松
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Nagoya University NUC
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/50—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/36—Oxygen atoms in position 3, e.g. adrenochrome
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a method for producing an optically active oxindole compound and a triazolium salt used as a catalyst therefor.
  • Optically active oxindole derivatives (especially oxindole derivatives substituted at the 3-position with an amino group) exist as partial structures of biologically active substances such as AG-041R and cartellin C, and are intermediates in the synthesis of pharmaceuticals and agrochemicals. Widely used. In recent years, synthesis of oxindole derivatives having an asymmetric carbon at the ⁇ -position has been desired for the purpose of developing higher-performance pharmaceutical derivatives.
  • an electrophilic stereoselective ⁇ -amination reaction method of a specific oxindole derivative is known.
  • an amination reagent in this ⁇ -amination reaction azodicarboxylic acid esters, nitroso compounds, azide iodinanes and the like have been conventionally used (for example, Non-Patent Documents 1 to 4).
  • the present invention provides an amino group having various substituents at the ⁇ -position of an oxindole compound without undergoing a reaction that reductively cleaves the nitrogen-nitrogen bond, nitrogen-oxygen bond, etc. of the product.
  • the object is to provide a method for stereoselective introduction in only stages.
  • Another object of the present invention is to provide a method for stereoselectively introducing an amino group having various substituents at the ⁇ -position to other substrates in one step with the same reaction mechanism.
  • this invention also aims at providing the catalyst which can be used for the said method.
  • a hydroxylamine compound capable of introducing various substituents onto nitrogen is used as an amino source, and an electrophilic amination reagent is generated by reacting with trihalogenated acetonitrile in the system.
  • an electrophilic amination reagent is generated by reacting with trihalogenated acetonitrile in the system.
  • This method can be used for ⁇ -hydroxylation reactions on carbonyl compounds (especially oxindole compounds) and intramolecular ring-closing ⁇ -amination reactions of carbonyl compounds having amino groups at the ends (especially oxindole compounds having amino groups at the ends). Is also applicable. Based on such knowledge, the present inventors have further studied and completed the present invention. That is, the present invention includes the following configurations.
  • R 1 are the same or different and each represents a halogen atom or an organic group.
  • R 2 represents a hydrogen atom or an organic group.
  • R 3 represents an organic group.
  • R 4 represents an optionally substituted amino group or hydroxyl group.
  • n represents an integer of 0 to 4.
  • X 1 represents a halogen atom or a monovalent anion.
  • R 5 , R 8 , R 9 and R 10 are the same or different and each represents an optionally substituted aryl group.
  • R 6 represents an optionally substituted primary alkyl group.
  • R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group.
  • R 1 , R 2 , R 3 and n are the same as defined above.
  • Item 2 The production method according to Item 1, wherein the reaction step is performed in the presence of a base.
  • R 4 in the general formula (1A) is an optionally substituted amino group
  • the reaction step includes the compound represented by the general formula (4A) and Item 3.
  • R 4 in the general formula (1A) is a hydroxyl group
  • the reaction step includes the compound represented by the general formula (4A) and Item 3.
  • the method according to Item 1 or 2 which is a step of reacting with hydrogen peroxide.
  • R 1 are the same or different and each represents a halogen atom or an organic group.
  • R 11 represents an organic group.
  • R represents an organic group.
  • n represents an integer of 0 to 4.
  • X 1 represents a halogen atom or a monovalent anion.
  • R 5 , R 8 , R 9 and R 10 are the same or different and each represents an optionally substituted aryl group.
  • R 6 represents an optionally substituted primary alkyl group.
  • R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group.
  • R 11 represents an organic group.
  • the manufacturing method provided with the reaction process which makes the hydroxylamine compound represented by these react.
  • Item 6 The production method according to Item 5, wherein the reaction step is performed in the presence of a base.
  • R 1 are the same or different and each represents a halogen atom or an organic group.
  • R 2 represents a hydrogen atom or an organic group.
  • R 12 represents a divalent linking group.
  • n represents an integer of 0 to 4.
  • X 1 represents a halogen atom or a monovalent anion.
  • R 5 , R 8 , R 9 and R 10 are the same or different and each represents an optionally substituted aryl group.
  • R 6 represents an optionally substituted primary alkyl group.
  • R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group.
  • R 1 , R 2 , R 12 and n are the same as defined above.
  • R 13 represents an alkyl group.
  • Item 8 The production method according to Item 7, wherein the intramolecular cyclization reaction step is performed in the presence of a base.
  • X 1 represents a halogen atom or a monovalent anion.
  • R 5 , R 8 , R 9 and R 10 are the same or different and each represents an optionally substituted aryl group.
  • R 6 represents an optionally substituted primary alkyl group.
  • R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group.
  • the carbonyl compound is General formula (4A):
  • R 1 are the same or different and each represents a halogen atom or an organic group.
  • R 2 represents a hydrogen atom or an organic group.
  • R 3 represents an organic group.
  • n represents an integer of 0 to 4.
  • R 1 and n are the same as defined above.
  • R represents an organic group.
  • R 1 , R 2 and n are the same as defined above.
  • R 12 represents a divalent linking group.
  • R 13 represents an alkyl group.
  • Item 11 The asymmetric ⁇ -amination or asymmetric ⁇ -hydroxylation catalyst of the carbonyl compound according to Item 9, which is a compound represented by:
  • R 1 are the same or different and each represents a halogen atom or an organic group.
  • R 2 represents a hydrogen atom or an organic group.
  • R 3 represents an organic group.
  • R 4 represents an optionally substituted amino group or hydroxyl group.
  • n represents an integer of 0 to 4.
  • R 1 and n are the same as defined above.
  • R 11 represents an organic group.
  • R represents an organic group.
  • R 1 , R 2 and n are the same as defined above.
  • R 12 represents a divalent linking group.
  • an electrophilic amination reagent is generated by using a hydroxylamine compound capable of introducing various substituents on nitrogen as an amino source and reacting with a trihalogenated acetonitrile compound in the system.
  • this amination reagent in combination with a chiral 1,2,3-triazolium salt catalyst, ⁇ -amination reaction can be directly performed on carbonyl compounds (especially oxindole compounds). Can be realized with enantioselectivity.
  • This reaction proceeds efficiently under mild conditions, and carbonyl compounds (especially oxindole compounds) having amino groups of various structures at the ⁇ -position can be synthesized stereoselectively in one step.
  • carbonyl compounds especially oxindole compounds
  • the reaction for reductively cleaving the nitrogen-nitrogen bond, nitrogen-oxygen bond, etc. of the product required in the above conventional method is unnecessary, the reaction can be carried out more easily and with high yield. it can.
  • the strategy of generating such highly reactive electrophilic species in the system is an enantioselective ⁇ of a carbonyl compound (especially an oxindole compound) using hydrogen peroxide as an oxygen source using the same type of catalyst. It can also be applied to hydroxylation reactions and intramolecular ring-closing ⁇ -amination reactions of carbonyl compounds having an amino group at the terminal (particularly oxindole compounds having an amino group at the terminal).
  • Example 5-1 The crystal structure of the compound S5 obtained in Example 5-1 is shown. For clarity, the hydrogen atom is omitted.
  • the crystal structure of the compound S6 obtained in Example 5-2 is shown. For clarity, the hydrogen atom is omitted.
  • the crystal structure of the compound S8 obtained in Example 5-3 is shown. For clarity, the hydrogen atom is omitted.
  • optically active compound (1A) In the first embodiment of the present invention, a specific compound (oxindole compound), a hydroxylamine compound or hydrogen peroxide in the presence of a triazolium salt and a trihalogenated acetonitrile compound Can be effectively reacted to obtain an optically active compound.
  • amino groups or hydroxy groups into which various substituents are introduced can be introduced into the ⁇ -position with respect to various substrate compounds (oxindole compounds) with wide substrate selectivity. Therefore, it is possible to obtain various optically active compounds.
  • a specific compound (oxindole compound), a hydroxylamine compound or hydrogen peroxide is usually reacted in a solvent in the presence of a triazolium salt and a trihalogenated acetonitrile compound.
  • oxindole compound a hydroxylamine compound or hydrogen peroxide is usually reacted in a solvent in the presence of a triazolium salt and a trihalogenated acetonitrile compound.
  • Substrate Compound The compound used as a substrate to be subjected to the reaction is not particularly limited.
  • R 1 are the same or different and each represents a halogen atom or an organic group.
  • R 2 represents a hydrogen atom or an organic group.
  • R 3 represents an organic group.
  • n represents an integer of 0 to 4.
  • any of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom can be employed.
  • a chlorine atom, a bromine atom, etc. are preferable.
  • the organic group represented by R 1 is not particularly limited, and is a hydrocarbon group (alkyl group, cycloalkyl group, alkenyl group, aryl group), alkoxy group, alkoxycarbonyl group, aryloxy group. Etc.
  • the alkyl group as the organic group represented by R 1 is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, acyclic aliphatic alkyl group such as sec-butyl group and tert-butyl group (preferably an acyclic aliphatic alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms); benzyl group, methylbenzyl group, Examples thereof include aralkyl groups such as phenethyl group, methylphenethyl group, naphthylmethyl group, and methylnaphthylmethyl group (preferably aralkyl groups having 7 to 20 carbon atoms, particularly 7 to 14 carbon atoms).
  • a linear acyclic aliphatic alkyl group can also be employ
  • These alkyl groups include substituents such as the halogen atoms, cycloalkyl groups described below, alkenyl groups described below, aryl groups described below, alkoxy groups described below, alkoxycarbonyl groups described below, aryloxy groups described below, cyano groups, It can also have about 1 to 3 pieces.
  • the cycloalkyl group as the organic group represented by R 1 is not particularly limited, and examples thereof include a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, and a cyclopentyl group.
  • examples thereof include cycloalkyl groups such as a methyl group, a cyclohexyl group, a cyclohexylmethyl group, and a cyclohexylethyl group having 3 to 10 carbon atoms (preferably a cycloalkyl group having 3 to 8 carbon atoms).
  • cycloalkyl groups include substituents such as the halogen atom, the alkyl group, the alkenyl group described below, the aryl group described below, the alkoxy group described below, the alkoxycarbonyl group described below, the aryloxy group described below, and the cyano group. It can also have about 1 to 3 pieces.
  • the alkenyl group as the organic group represented by R 1 is not particularly limited, and examples thereof include alkenyl groups such as vinyl groups and allyl groups (preferably having 2 to 6 carbon atoms, particularly 2 carbon atoms). -4 alkenyl groups) and the like. These alkenyl groups include the halogen atom, the alkyl group, the cycloalkyl group, the alkenyl group, the aryl group described below, the alkoxy group described below, the alkoxycarbonyl group described below, the aryloxy group described below, and the cyano group. It may have about 1 to 3 substituents such as
  • the aryl group as the organic group represented by R 1 is not particularly limited, and examples thereof include a phenyl group, a tolyl group (o-tolyl group, m-tolyl group, p-tolyl group), Examples include xylyl group (o-xylyl group, m-xylyl group, p-xylyl group), naphthyl group and the like.
  • These aryl groups are the halogen atom, the alkyl group, the cycloalkyl group, the alkenyl group, the aryl group, the alkoxy group described below, the alkoxycarbonyl group described below, the aryloxy group described below, and the cyano group. It may have about 1 to 3 substituents such as
  • the alkoxy group as the organic group represented by R 1 is not particularly limited, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, and an isobutoxy group.
  • acyclic aliphatic alkoxy groups such as sec-butoxy group and tert-butoxy group (preferably an acyclic aliphatic alkoxy group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms).
  • an acyclic linear aliphatic alkoxy group can also be employ
  • These alkoxy groups include the halogen atom, the alkyl group, the cycloalkyl group, the alkenyl group, the aryl group, the alkoxy group, the alkoxycarbonyl group described later, the aryloxy group described below, and the cyano group. It may have about 1 to 3 substituents such as
  • the alkoxycarbonyl group as the organic group represented by R 1 is not particularly limited, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n- Aliphatic alkoxycarbonyl groups such as butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group (preferably an aliphatic alkoxycarbonyl group having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms), etc. Is mentioned.
  • a linear aliphatic alkoxycarbonyl group can also be employ
  • alkoxycarbonyl groups include the halogen atom, the alkyl group, the cycloalkyl group, the alkenyl group, the aryl group, the alkoxy group, the alkoxycarbonyl group, the aryloxy group described below, and cyano. It may have about 1 to 3 substituents such as a group.
  • the aryloxy group as the organic group represented by R 1 is not particularly limited.
  • xylyloxy group o-xylyloxy group, m-xylyloxy group, p-xylyloxy group
  • naphthyloxy group a group having a phenoxy group, a tolyloxy group (o-tolyloxy group, m-tolyloxy group, p-tolyloxy group)
  • xylyloxy group o-xylyloxy group, m-xylyloxy group, p-xylyloxy group
  • aryloxy groups include the halogen atom, the alkyl group, the cycloalkyl group, the alkenyl group, the aryl group, the alkoxy group, the alkoxycarbonyl group, the aryloxy group, the cyano, It may have about 1 to 3 substituents such as a group.
  • R 1 from the viewpoint of yield, stereoselectivity, etc., a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group and the like are preferable, an unsubstituted alkyl group, an unsubstituted group An alkoxy group and the like are more preferable, and an unsubstituted acyclic aliphatic alkyl group and an unsubstituted acyclic aliphatic alkoxy group are more preferable.
  • n is plural (an integer of 2 to 4)
  • the plural R 1 s may be the same or different.
  • n which is the number of R 1 , is an integer of 0 to 4, preferably an integer of 0 to 2, more preferably 0 or 1, from the viewpoints of yield, stereoselectivity, and the like.
  • R 1 is most preferably an unsubstituted acyclic aliphatic alkyl group, and n is most preferably 1.
  • R 1 is an unsubstituted acyclic ring. Most preferably, it is a formula aliphatic alkoxy group, and n is 1.
  • the organic group represented by R 2 is not particularly limited, and any group that can be used as a general protecting group for a nitrogen atom can be employed.
  • methoxycarbonyl group ethoxy Alkoxycarbonyl groups such as carbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group (hereinafter sometimes referred to as “Boc”), benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group; trimethylsilyl group, triethylsilyl group Silyl groups such as tert-butyldimethylsilyl group; acyl groups such as acetyl group, pivaloyl group and benzoyl group; sulfonyl groups such as benzenesulfonyl group and p-toluenesulfonyl group; methoxymethyl group, tetrahydropyranyl group, acetoxymethyl Acetal type protecting
  • the organic group represented by R 3 is not particularly limited, and is a hydrocarbon group (alkyl group, cycloalkyl group, alkenyl group, aryl group), alkoxy group, alkoxycarbonyl group, aryloxy group.
  • a hydrocarbon group is preferable from the viewpoints of yield, stereoselectivity, and the like.
  • an alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, or the like is more preferable.
  • a hydrocarbon group alkyl group, cycloalkyl group, an alkenyl group, an aryl group, or the like.
  • Etc. are more preferable.
  • an alkyl group, an alkenyl group or an aryl group is more preferable, an alkyl group or an alkenyl group is further preferable, and an aralkyl group or an alkenyl group is particularly preferable.
  • an alkyl group, an alkenyl group or an aryl group is more preferable, an alkyl group or an alkenyl group is further preferable, and an aralkyl group or an alkenyl group is particularly preferable.
  • Etc. are more preferable.
  • the organic group represented by R 11 is not particularly limited, and is a hydrocarbon group (alkyl group, cycloalkyl group, alkenyl group, aryl group), alkoxy group, alkoxycarbonyl group, aryloxy group.
  • a hydrocarbon group alkyl group, cycloalkyl group, alkenyl group, aryl group
  • alkoxy group alkoxycarbonyl group, aryloxy group.
  • an aliphatic alkyl group, an aralkyl group, a cycloalkyl group, an aryl group and the like are preferable, an aralkyl group, a cycloalkyl group, an aryl group and the like are more preferable, An aryl group and the like are further preferable, and an unsubstituted cycloalkyl group, an unsubstituted or substituted aryl group, and the like are particularly preferable.
  • hydroxylamine compounds (5) that satisfy these conditions include:
  • Etc. are more preferable.
  • the amount of the hydroxylamine compound (5) or hydrogen peroxide used is not particularly limited, and is usually about 0.5 to 20 moles per mole of the compound (4A) from the viewpoint of yield, stereoselectivity, etc.
  • the amount is preferably about 1 to 10 moles.
  • hydrogen peroxide an excessive amount of hydrogen peroxide water can be used.
  • X 1 represents a halogen atom or a monovalent anion.
  • R 5 , R 8 , R 9 and R 10 are the same or different and each represents an optionally substituted aryl group.
  • R 6 represents an optionally substituted primary alkyl group.
  • R 7 represents an optionally substituted aliphatic alkyl group or an optionally substituted cycloalkyl group.
  • triazolium salt (2) (Hereinafter also referred to as “triazolium salt (2)”).
  • any of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom can be adopted.
  • X 1 is preferably a halogen atom, more preferably a chlorine atom, a bromine atom, or the like, and further preferably a bromine atom, from the viewpoints of yield, stereoselectivity, and the like.
  • aryl group represented by R 5 those described above can be employed.
  • the kind and number of substituents are the same.
  • a substituted aryl group is preferable from the viewpoints of yield, stereoselectivity, and the like, and an aryl group substituted with 1 to 2 halogen atoms, aryl groups, and the like is more preferable.
  • an aryl group substituted with 1 to 2 halogen atoms, aryl groups, and the like is more preferable.
  • the primary alkyl group represented by R 6 is not particularly limited, and examples thereof include acyclic groups such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, and an isobutyl group.
  • Aliphatic primary alkyl group (preferably an acyclic aliphatic primary alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms); benzyl group, methylbenzyl group, phenethyl group, methylphenethyl group, naphthyl
  • An aromatic primary alkyl group such as an aralkyl group such as a methyl group or a methylnaphthylmethyl group (preferably an aromatic primary alkyl group such as an aralkyl group having 7 to 20 carbon atoms, particularly 7 to 14 carbon atoms), etc.
  • a linear acyclic aliphatic primary alkyl group can also be used, and a branched acyclic primary aliphatic alkyl group is also used.
  • You can also These primary alkyl groups include the halogen atom, the cycloalkyl group, the alkenyl group, the aryl group, the alkoxy group, the alkoxycarbonyl group, the aryloxy group, and the cyano group. It may have about 1 to 3 substituents.
  • the aliphatic alkyl group represented by R 7 is not particularly limited, and examples thereof include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec- And acyclic aliphatic alkyl groups such as a butyl group and a tert-butyl group (preferably an acyclic aliphatic alkyl group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms).
  • a linear acyclic aliphatic alkyl group can also be employ
  • These aliphatic alkyl groups have 1 to 3 substituents such as the halogen atom, the alkenyl group, the aryl group, the alkoxy group, the alkoxycarbonyl group, the aryloxy group, and the cyano group. It can also have a degree.
  • the cycloalkyl group represented by R 7 is not particularly limited, and examples thereof include a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, a cyclopentylmethyl group, and cyclohexyl.
  • a cyclic aliphatic alkyl group such as a cyclohexylmethyl group and a cyclohexylethyl group (preferably a cyclic aliphatic alkyl group having 3 to 10 carbon atoms, particularly 3 to 8 carbon atoms).
  • cycloalkyl groups include substituents such as the halogen atom, the alkyl group, the alkenyl group, the aryl group, the alkoxy group, the alkoxycarbonyl group, the aryloxy group, and the cyano group. It can also have about 1 to 3 pieces.
  • R 8 and R 9 As the aryl group represented by R 8 and R 9 , those described above can be adopted. The kind and number of substituents are the same. Among these, from the viewpoints of yield, stereoselectivity, etc., an unsubstituted aryl group or an aryl group substituted with one halogen atom is preferable, and a phenyl group or a chlorophenyl group is more preferable. R 8 and R 9 may be the same or different.
  • aryl group represented by R 10 those described above can be employed.
  • the kind and number of substituents are the same.
  • an aryl group substituted with an unsubstituted aryl group or two alkyl groups preferably a halogenated alkyl group, particularly a perfluoroalkyl group
  • the alkoxy group, etc. are preferable, and a phenyl group, a dimethoxyphenyl group, and a bis (trifluoromethyl) phenyl group are more preferable.
  • triazolium salts (2) may be known or commercially available compounds, and may be synthesized according to the methods described in the previous reports (J. Am. Chem. Soc. 2011, 133, 1307-1309., Etc.). You can also.
  • the amount of triazolium salt (2) to be used is not particularly limited, and from the viewpoint of yield, stereoselectivity, etc., for example, it is usually preferably about 0.01 to 0.2 mol, preferably 0.02 to 0.1 mol, per 1 mol of compound (4A). A molar degree is more preferable.
  • Such a triazolium salt (2) is not limited to the production method of the present invention, and can be used as an asymmetric ⁇ -amination or asymmetric ⁇ -hydroxylation catalyst of a carbonyl compound.
  • Trihalogenated acetonitrile compound used in the present invention has the general formula (3): CX 2 3 CN (3) [Wherein X 2 is the same or different and represents a halogen atom. ] (Hereinafter also referred to as “trihalogenated acetonitrile compound (3)”).
  • the halogen atom represented by X 2 may be the same or different (preferably the same), and any of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom can be adopted. From the viewpoints of yield, stereoselectivity and the like, in this step, a chlorine atom, a bromine atom and the like are preferable, and a chlorine atom is more preferable. That is, CCl 3 CN is most preferable as the trihalogenated acetonitrile compound (3).
  • the amount of the trihalogenated acetonitrile compound (3) used is not particularly limited, and is usually preferably about 0.01 to 5.0 moles per mole of the compound (4A) from the viewpoint of yield, stereoselectivity, etc. About 2.0 mol is more preferable.
  • Examples of the base that can be used in the present invention include alkali metal phosphates such as potassium phosphate and sodium phosphate; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and rubidium carbonate; trimethylamine, triethylamine and the like. Examples include amines. These can be used alone or in combination of two or more. Among these, alkali metal carbonates are preferable and potassium carbonate is more preferable from the viewpoints of yield, stereoselectivity, and the like.
  • the amount of the base used is not particularly limited, and is generally preferably 0.2 to 5 mol, more preferably 0.5 to 2 mol, relative to 1 mol of compound (4A) from the viewpoints of yield, stereoselectivity and the like.
  • the solvent examples include aromatic hydrocarbons such as toluene, xylene, benzene, mesitylene; aliphatic halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane; diethyl ether, dimethoxyethane, diisopropyl ether, tert-butyl.
  • chain ethers such as methyl ether; esters such as ethyl acetate and ethyl propionate; ketones such as acetone and methyl ethyl ketone. These can be used alone or in combination of two or more.
  • aromatic hydrocarbons are preferable for ⁇ -amination and chain ethers are preferable for hydroxylation from the viewpoints of yield, stereoselectivity, and the like.
  • the present invention is preferably carried out under anhydrous conditions and under an inert gas atmosphere (nitrogen gas, argon gas, etc.), and the reaction temperature can be carried out under heating, at room temperature or under cooling. It is about ⁇ 78 ° C. to room temperature (25 ° C.), preferably about ⁇ 50 to 20 ° C., more preferably about ⁇ 25 to 10 ° C.
  • the reaction time can be a time for which the reaction proceeds sufficiently, and is usually about 10 minutes to 72 hours, preferably about 1 to 48 hours.
  • the target compound After completion of the reaction, the target compound can be obtained through normal isolation and purification steps as necessary. If the reaction of the present invention is used, various useful optically active compounds can be obtained.
  • reaction mechanism in the present invention is not particularly limited, and the following reaction formula 1:
  • reaction 2 [Wherein, R 11 and X 2 are the same as defined above. ] Or reaction 2:
  • the amination reagent (6A) when used in place of the trihalogenated acetonitrile compound (3) and the hydroxylamine compound (5), the trihalogenated acetonitrile compound (3) and hydrogen peroxide are used.
  • the amination reagent (6B) is used instead of the above is also included.
  • optically active compound (1A) is a novel compound not described in any literature.
  • optically active compound (1B) In the second embodiment of the present invention, a specific compound and a hydroxylamine compound are effectively reacted in the presence of a triazolium salt and a trihalogenated acetonitrile compound, An optically active compound can be obtained.
  • various optically active compounds can be obtained because amino groups having various substituents introduced therein can be introduced into the ⁇ -position with respect to various substrate compounds. It is also possible.
  • various optically active compounds are obtained by reacting a specific compound with a hydroxylamine compound, usually in a solvent in the presence of a triazolium salt and a trihalogenated acetonitrile compound. Can do.
  • Substrate compound The compound used as a substrate to be subjected to the reaction is not particularly limited, and for example, a general formula (4B):
  • R 1 and n are the same as defined above.
  • R represents an organic group.
  • compound (4B) can be employed.
  • R is an organic group.
  • organic groups include hydrocarbon groups (alkyl groups, cycloalkyl groups, alkenyl groups, aryl groups), alkoxy groups, alkoxycarbonyl groups, aryloxy groups, and the like. Can do. The same applies to preferred types, types and numbers of substituents and the like.
  • the hydroxylamine compound used in the present invention is a hydroxylamine compound represented by the general formula (5) described above. What was demonstrated above is employable about the preferable kind, usage-amount, etc. of each substituent. The same applies to preferred specific examples of the hydroxylamine compound.
  • the triazolium salt used as a catalyst is a triazolium salt represented by the general formula (2) described above. What was demonstrated above is employable about the preferable kind of each substituent, the usage-amount, a synthesis method, etc. The same applies to specific examples of triazolium salts.
  • Trihalogenated acetonitrile compound used in the present invention is a trihalogenated acetonitrile compound represented by the general formula (3) described above. What was demonstrated above is employable about the preferable kind of substituent, usage-amount, etc.
  • reaction conditions of the present invention those described in the first embodiment can be adopted.
  • reaction mechanism in the present invention is not particularly limited, and an amination reagent (6A) is produced according to the above-described reaction formula 1, and this amination reagent (6A) and the catalyst are used as a catalyst. It is considered that the intramolecular ring closure reaction of compound (4B) is promoted by the action with triazolium salt (2). At this time, as a by-product
  • this invention includes the case where the said amination reagent (6A) is used instead of the said trihalogenated acetonitrile compound (3) and a hydroxylamine compound (5).
  • optically active compound (1B) is a novel compound not described in any literature.
  • a specific compound (an oxindole compound having an amino group at the terminal) is formed in the presence of a triazolium salt and a trihalogenated acetonitrile compound.
  • An optically active compound can be obtained by an internal ring-closing reaction.
  • various asymmetric spiro compounds can be obtained with wide substrate selectivity with respect to various substrate compounds.
  • a specific compound (an oxindole compound having an amino group at the terminal) is usually subjected to an intramolecular ring-closing reaction in a solvent in the presence of a triazolium salt and a trihalogenated acetonitrile compound.
  • a specific compound an oxindole compound having an amino group at the terminal
  • a solvent in the presence of a triazolium salt and a trihalogenated acetonitrile compound.
  • Substrate compound used as a substrate to be subjected to the reaction is not particularly limited.
  • R 1 , R 2 and n are the same as defined above.
  • R 12 represents a divalent linking group.
  • R 13 represents an alkyl group.
  • compound (4C) can be employed.
  • R 1 , R 2 and n may be those described above. The same applies to preferred types, types and numbers of substituents, and the like.
  • R 12 is a divalent linking group.
  • a divalent linking group include a single bond; an alkylene group having 1 to 6 carbon atoms such as a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, and a butylene group; a carbonyl group; -; -S-; a linking group combining two or more of these, and the like.
  • R 13 is an alkyl group. As such an alkyl group, what was mentioned above is employable. The same applies to preferred types, types and numbers of substituents, and the like.
  • Etc. can be used.
  • the triazolium salt used as a catalyst is a triazolium salt represented by the general formula (2) described above. What was demonstrated above is employable about the preferable kind of each substituent, the usage-amount, a synthesis method, etc. The same applies to specific examples of triazolium salts.
  • Trihalogenated acetonitrile compound used in the present invention is a trihalogenated acetonitrile compound represented by the general formula (3) described above. What was demonstrated above is employable about the preferable kind of substituent, usage-amount, etc.
  • reaction conditions of the present invention those described in the first embodiment can be adopted.
  • optically active compound in which the ⁇ -position is aminated is a novel compound not described in any literature.
  • the optical rotation was measured with a HORIBA SEPA-500 polarimeter. High resolution mass spectra were performed with Thermo Fisher Scientific Exactive (ESI). Analytical thin layer chromatography (TLC) was performed on Merck pre-coated TLC plates (silica gel 60 GF254, 0.25 mm). Flash column chromatography was performed using CHROMATOREX DIOL MB100-40 / 75 (spherical, 40-75 ⁇ m; Fuji Silysia Chemical), CHROMATOREX NH DM2035 (spherical, 60 ⁇ m; Fuji Silysia Chemical), and silica gel 60 (Merck 1.09385). .9929, 230-400 mesh).
  • Enantiomeric excess is determined by chiral column [ ⁇ 4.6 mm ⁇ 250 mm, DAICEL CHIRALCEL OD-3 (OD3), CHIRALCEL OZ-3 (OZ3), CHIRALPAK AS-H (ASH), CHIRALPAK ID-3 (ID3), CHIRALPAK IE -3 (IE3), and CHIRALPAK IF-3 (IF3)] were determined by HPLC analysis using hexane (Hex), isopropyl alcohol (IPA) and ethanol (EtOH) as eluents.
  • Hex hexane
  • IPA isopropyl alcohol
  • EtOH ethanol
  • Et 3 N represents triethylamine.
  • Hex represents hexane.
  • t-BuOMe represents tert-butyl methyl ether.
  • Bn represents a benzyl group.
  • TBAB represents tetrabutylammonium bromide.
  • THF represents tetrahydrofuran. The same applies hereinafter.
  • the obtained cyclohexanone oxime was suspended in ethanol (20 mL). Next, sodium cyanoborohydride (NaBH 3 CN; 0.75 g, 12 mmol) was added to the mixture, and a 6 N methanol solution of HCl (16 mL) was added dropwise at 0 ° C. After stirring at room temperature for 3 hours, the reaction mixture was poured into water and the whole mixture was neutralized with KOH pellets at 0 ° C. After extraction with ethyl acetate, the organic extract was washed with brine and dried over Na 2 SO 4 .
  • NaBH 3 CN sodium cyanoborohydride
  • N-alkylhydroxylamine compounds were obtained in the same manner.
  • N-cyclohexyl-o-methylhydroxylamine was obtained in the same manner as in Synthesis Example 1-3 except that o-methylhydroxylammonium chloride was used in place of hydroxylammonium chloride.
  • 1 H NMR (400 MHz, CDCl 3 ) ⁇ 5.33 (1H, brs), 3.54 (3H, s), 2.84 (1H, tt, J 10.6, 3.8 Hz), 1.88-1.84 (2H, m), 1.77 -1.73 (2H, m), 1.65-1.60 (1H, m), 1.33-1.05 (5H, m).
  • CDI carbonyldiimidazole.
  • Bz represents a benzoyl group. The same applies hereinafter.
  • N-cyclohexylhydroxylamine (3c; 0.11 g, 1 mmol) obtained in Synthesis Example 1-3 was introduced, and stirring was continued for another 6 hours. Saturated aqueous NH 4 Cl was added to quench the reaction mixture.
  • the obtained oxime compound (1.45 g, 10 mmol) was suspended in ethanol (20 mL). Next, sodium cyanoborohydride (NaBH 3 CN; 0.75 g, 12 mmol) was added to the mixture, and acetic acid (5.7 mL, 100 mmol) was added dropwise. After stirring for 12 hours, the reaction mixture was poured into water and all the mixture was neutralized with saturated aqueous NaHCO 3 solution. The solvent was removed under vacuum and extracted with ethyl acetate. The orange extract was dried over Na 2 SO 4 and the solvent was evaporated.
  • sodium cyanoborohydride NaBH 3 CN; 0.75 g, 12 mmol
  • acetic acid 5.7 mL, 100 mmol
  • Example 1 Asymmetric ⁇ -amination of oxindole compound
  • Example 1-1 Synthesis of compound 4l
  • Example 1-3 The same treatment as in Example 1-1 was performed, except that various hydroxylamine compounds were used and the compounds shown in Table 1 were used as catalysts. The results are shown in Table 1. When 1d ⁇ Br or 1e ⁇ Br was used as the catalyst, almost no optically active compound was obtained, and only a mixture of stereoisomers (racemate) was obtained.
  • Example 1-4 Unless otherwise specified, the above procedure was performed except that various compounds were used as substrate compounds, various hydroxylamine compounds as hydroxylamine compounds, and any triazolium salt obtained in Synthesis Examples 2-1 to 2-6 was used as a catalyst. The same treatment as in Example 1-1 and Example 1-2 was performed. As a result, it was confirmed that an optically active compound having a substituent shown in Table 2 below was obtained. The results are shown in Table 2.
  • Example 1-5 Asymmetric amination using compound S3
  • Example 1-6 Reversibility in amination reagent formation
  • Example 2 Asymmetric ⁇ -hydroxylation of oxindole compound
  • Example 2-1 Synthesis of compound 5a
  • Triazolium salt 1b ⁇ Br (3.76 mg, 0.005 mmol) obtained in Synthesis Example 2-2, oxindole compound 2a (30.9 mg, 0.10 mmol), and diethyl ether (1.0) of K 2 CO 3 (13.8 mg, 0.10 mmol) mL) solution was degassed by alternately evacuating and refilling with argon.
  • the obtained mixture was cooled to ⁇ 10 ° C., 30% H 2 O 2 aqueous solution (50 ⁇ L, 0.50 mmol) and CCl 3 CN (10 ⁇ L, 0.10 mmol) were added to the reaction mixture. Thereafter, stirring was continued for 24 hours at the same temperature.
  • the target optically active ⁇ -hydroxylated oxindole compound 4 was obtained (28.6 mg, 88% yield, 94% enantioselectivity). This result corresponds to entry 1 in Table 2 described later.
  • Example 2-2 Unless otherwise limited, the same treatment as in Example 2-1 was performed except that various compounds were used as the substrate compound. As a result, it was confirmed that an optically active compound having a substituent shown in Table 3 below was obtained. The results are shown in Table 3.
  • 4-MeC 6 H 4 represents a 4-methylphenyl group.
  • 4-MeOC 6 H 4 represents a 4-methoxyphenyl group.
  • 4-FC 6 H 4 represents a 4-fluorophenyl group.
  • 3-MeC 6 H 4 represents a 3-methylphenyl group.
  • 3-MeOC 6 H 4 represents a 3-methoxyphenyl group.
  • 2-Naph represents a 2-naphthyl group.
  • 1-Naph represents a 1-naphthyl group.
  • CH 2 Ph represents a benzyl group.
  • CH 2 (4-F) C 6 H 4 represents a 4-fluorobenzyl group.
  • CH 2 (4-MeO) C 6 H 4 represents a 4-methoxybenzyl group.
  • c-Hex represents a cyclohexyl group.
  • Et represents an ethyl group.
  • n-Bu represents an n-butyl group.
  • Example 1-1 The same treatment as in Example 1-1 was performed except that the triazolium salt 1c ⁇ Br obtained in Synthesis Example 2-3 was used as a catalyst.
  • the triazolium salt 1c ⁇ Br obtained in Synthesis Example 2-3 was used as a catalyst.
  • the oxindole compound it was possible to introduce an amino group at the ⁇ -position, and the product 7 was obtained in 73% yield and 90% enantioselectivity.
  • TFA Trifluoroacetic acid
  • the structure is determined by the direct method (IR92: Altomare, A., Cascarano, G., Giacovazzo, C., Guagliardi, A., Burla, M., Polidori, G. & Camalli, MJ Appl. Cryst., 27, 435 ( 1994).) And the extended Fourier transform method. Non-hydrogen atoms were refined anisotropically. Some hydrogen atoms were determined isotropically, some hydrogen atoms were determined using the rising model, and the remaining hydrogen atoms were included in the solidified position. As a result, the determined structure is shown in FIGS.

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Abstract

La présente invention concerne un procédé permettant d'introduire de manière stéréosélective un groupe amino, présentant divers substituant en position α d'un composé oxindole, en une seule étape en ayant un composé spécifique (un composé carbonyle tel qu'un composé oxindole) et un composé hydroxylamine spécifique ou du peroxyde d'hydrogène qui réagissent l'un avec l'autre en présence d'un sel de triazolium spécifique et d'un composé d'acétonitrile trihalogéné spécifique sans subir une réaction de rupture réductrice d'une liaison azote-azote, d'une liaison azote-oxygène ou similaire du produit. De plus, un groupe amino possédant divers substituants est apte à être introduit de manière stéréosélective en position α d'un autre substrat en une étape unique au moyen d'un mécanisme réactionnel similaire. Il est préférable que cette réaction soit effectuée en présence d'une base.
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CN111704620A (zh) * 2020-07-24 2020-09-25 中国科学院成都有机化学有限公司 高光学纯度的[3,2’]-吡咯烷手性螺环氧化吲哚骨架类化合物、其制备方法及应用

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108003086A (zh) * 2017-11-15 2018-05-08 宁波大学 一种3-胺基-2-吲哚酮类化合物的制备方法
CN108003086B (zh) * 2017-11-15 2020-08-14 宁波大学 一种3-胺基-2-吲哚酮类化合物的制备方法
CN111704620A (zh) * 2020-07-24 2020-09-25 中国科学院成都有机化学有限公司 高光学纯度的[3,2’]-吡咯烷手性螺环氧化吲哚骨架类化合物、其制备方法及应用
CN111704620B (zh) * 2020-07-24 2023-05-23 中国科学院成都有机化学有限公司 [3,2’]-吡咯烷手性螺环氧化吲哚骨架类化合物、其制备方法及应用

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