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WO2009157066A1 - Procédé de production d’un produit de réaction de mannich à catalyseur asymétrique - Google Patents

Procédé de production d’un produit de réaction de mannich à catalyseur asymétrique Download PDF

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Publication number
WO2009157066A1
WO2009157066A1 PCT/JP2008/061563 JP2008061563W WO2009157066A1 WO 2009157066 A1 WO2009157066 A1 WO 2009157066A1 JP 2008061563 W JP2008061563 W JP 2008061563W WO 2009157066 A1 WO2009157066 A1 WO 2009157066A1
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group
general formula
enantiomer
production method
compound represented
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Japanese (ja)
Inventor
雄二郎 林
智之 大西
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Ajinomoto Co Inc
Tokyo University of Science
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Ajinomoto Co Inc
Tokyo University of Science
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/76—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms

Definitions

  • the present invention relates to a method for producing an asymmetric catalytic Mannich reaction product.
  • the Mannich reaction is an important carbon-carbon bond formation reaction in organic chemistry, and ⁇ -aminoaldehyde generated by this reaction can be converted into ⁇ -amino acids, ⁇ -amino alcohols, ⁇ by using oxidation / reduction reactions and the like. , ⁇ -unsaturated amines, 1,3-diamines and other natural products and pharmaceuticals.
  • the asymmetric catalytic Mannich reaction which obtains a large amount of optically active substance from a small amount of asymmetric source, is currently under active research all over the world.
  • an addition reaction between an imine and an aldehyde can be mentioned.
  • Patent Document 1 discloses a method for producing ⁇ -aminoaldehyde that is produced by Mannich reaction and catalyzed by proline.
  • Non-Patent Document 1 reports an asymmetric catalytic Mannich reaction between N-Boc-imine and an aldehyde catalyzed by proline.
  • Non-Patent Document 1 even when acetaldehyde is used as the reactant aldehyde, the asymmetric catalytic Mannich reaction that generates an ⁇ -unsubstituted aldehyde can be performed with high reaction efficiency. It was difficult.
  • Non-Patent Document 2 discloses an asymmetric catalytic Mannich reaction using acetaldehyde and N-Boc-imine.
  • the present invention provides a method for producing an asymmetric catalytic Mannich reaction product, which can obtain a corresponding Mannich reaction product from imine and acetaldehyde with a higher asymmetric yield than conventional ones. Objective.
  • the present inventors conducted intensive research in view of the above problems. As a result, it was found that when a specific asymmetric catalyst and an acid are used and imine and acetaldehyde are reacted, the asymmetric catalytic Mannich reaction proceeds with higher enantioselectivity than in the past.
  • the present invention has been completed. Specifically, the present invention provides the following.
  • R 1 represents an aryl group, a heteroaryl group, an alkyl group, a vinyl group, and an alkynyl group that may have a substituent
  • R 2 represents an alkyl group that may have a substituent
  • Alkenyl, alkynyl, alkylsulfonyl alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, acyl, acylalkyl, acylalkenyl Group, acylalkynyl group, amide group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, aryl group, aryloxy group, heteroaryl group, cycloalkylalkyl group, cycloalkylalkenyll group,
  • the asymmetric catalytic Mannich reaction between imine and acetaldehyde can be performed with higher enantioselectivity and reaction efficiency than before. You can make progress.
  • acetaldehyde used in the invention described in (1) is easily available, the asymmetric catalytic Mannich reaction can be performed at low cost.
  • the inventions described in [2] and [3] limit the types of acids used as catalysts in the asymmetric catalytic Mannich reaction of the present invention. Therefore, according to the inventions described in [2] and [3], the asymmetric catalytic Mannich reaction can proceed with higher enantioselectivity and reaction efficiency.
  • examples of the “inorganic acid” include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.
  • R 2 is an alkoxycarbonyl group, an acyl group, an arylsulfonyl group, or an alkylsulfonyl group.
  • the invention described in [6] limits the type of organic catalyst used as a catalyst in the asymmetric catalytic Mannich reaction of the present invention. Therefore, according to the invention described in [6], the asymmetric catalytic Mannich reaction can be advanced with higher enantioselectivity and reaction efficiency.
  • the invention described in [7] to [10] is a ⁇ -amino acid, ⁇ -amino alcohol, ⁇ , ⁇ -unsaturated amine, or 1,3- It is a manufacturing method of diamine. According to the inventions described in [7] to [10], ⁇ -amino acids, ⁇ -amino alcohols, ⁇ , ⁇ -unsaturated amines, or 1,3-diamines have high enantioselectivity and reaction efficiency. Can be generated.
  • the asymmetric catalytic Mannich reaction between imine and acetaldehyde can be performed with higher enantioselectivity and reaction efficiency than before. Can be advanced.
  • acetaldehyde used in the present invention is easily available, the asymmetric catalytic Mannich reaction can be performed at a low cost.
  • the production method of the present invention performs an asymmetric catalytic Mannich reaction, and an imine represented by the following general formula (1) and acetaldehyde are represented by the following general formula (2) or an asymmetric catalyst thereof: It reacts in the presence of an enantiomer and an acid to obtain a compound represented by the following general formula (3) or an enantiomer thereof.
  • R 1 represents an aryl group, a heteroaryl group, an alkyl group, a vinyl group, and an alkynyl group that may have a substituent
  • R 2 represents an alkyl group that may have a substituent
  • Alkenyl, alkynyl, alkylsulfonyl alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, acyl, acylalkyl, acylalkenyl Group, acylalkynyl group, amide group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, aryl group, aryloxy group, heteroaryl group, cycloalkylalkyl group, cycloalkylalkenyll group,
  • an imine represented by the general formula (1) is used as an electrophilic reagent.
  • R 1 is an optionally substituted aryl group, heteroaryl group, alkyl group, vinyl group, and alkynyl group
  • R 2 is a substituent group.
  • alkyl group May have an alkyl group, an alkenyl group, an alkynyl group, an alkylsulfonyl group, an alkoxyalkyl group, an alkoxyalkenyl group, an alkoxyalkynyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkenyl group, an alkoxycarbonylalkynyl group , Acyl group, acylalkyl group, acylalkenyl group, acylalkynyl group, amide group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, aryl group, aryloxy group, heteroaryl group, cycloalkyl A Kill group, cycloalkylalkenyl group, cycloalkylalkynyl group, heterocycloalkylalkyl group, heterocycloal
  • R 1 is preferably an aryl group or a heteroaryl group
  • R 2 is preferably an alkoxycarbonyl group, an acyl group, an arylsulfonyl group, or an alkylsulfonyl group.
  • R 2 is more preferably a tert-butoxycarbonyl group, a benzoyl group, or a p-toluenesulfonyl group.
  • alkyl group used alone or as part of another group may be linear or branched unless otherwise specified.
  • it is C1-C20, More preferably, it is C1-C6.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl. Group, n-pentyl group and the like.
  • This alkyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include an alkoxy group, a carbonyl group, an alkoxycarbonyl group, an alkylthio group, an acyl group, an aryloxy group, an arylthio group, a halogen atom, an amino group, a nitro group, a cyano group, a thiol group, and a hydroxyl group.
  • an “alkenyl group” used alone or as part of another group may be linear or branched unless otherwise specified. Although there is no restriction
  • Examples of the alkenyl group include a vinyl group, 1-propenyl group, allyl group, isopropenyl, 1-butenyl group, isobutenyl group and the like.
  • the alkenyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include the groups described above as substituents for the alkyl group.
  • an “alkynyl group” used alone or as part of another group may be linear or branched unless otherwise specified.
  • it is C2-C20, More preferably, it is C2-C6.
  • alkynyl groups include ethynyl group, 1-propynyl group, 2-propynyl group, isopropynyl group, 1-butynyl group, isobutynyl group and the like.
  • the alkynyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include the groups described above as substituents for the alkyl group.
  • an “alkylsulfonyl group” used alone or as part of another group represents a monovalent group in which a sulfonyl group is bonded to the alkyl group, and includes a methylsulfonyl group, ethyl Sulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, n-hexyl Examples thereof include a sulfonyl group and an n-heptylsulfonyl group.
  • the alkylsulfonyl group may be unsubstituted or one or more hydrogen atoms may be substituted with other substituents.
  • substituents include the groups described above as substituents for the alkyl group.
  • the “alkoxy group” refers to a monovalent group in which an oxygen atom is bonded to the alkyl group, and includes a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group.
  • alkylthio group means a monovalent group in which a sulfur atom is bonded to the alkyl group, and includes a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group.
  • an “acyl group” used alone or as a part of another group is a group obtained by removing a hydroxyl group from a carboxylic acid unless otherwise specified.
  • acyl group is C1-C20, More preferably, it is C1-C6.
  • Examples of acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, benzoyl, naphthoyl, furoyl and the like.
  • the acyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • Substituents include alkyl groups, alkoxy groups, alkoxyalkyl groups, alkoxycarbonyl groups, alkoxycarbonylalkyl groups, alkylthio groups, aryloxy groups, arylthio groups, halogen atoms, amino groups, nitro groups, cyano groups, thiol groups, hydroxyl groups Etc.
  • an “amide group” means a group in which one hydrogen atom of an amino group is substituted with the acyl group, and includes a formylamide group, an acetamide group, a propionamide group, a butyramide group, an isobutyl group. Examples include amide group, barrel amide group, isovaleramide group, pivaloylamide group, benzamide group, naphthamide group, and fullamide group.
  • a “cycloalkyl group” used alone or as part of another group represents a non-aromatic saturated cyclic hydrocarbon group unless otherwise specified.
  • a cycloalkyl group Preferably it is C3-C10, More preferably, it is C3-C6.
  • the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.
  • the cycloalkyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an acyl group, an acylalkyl group, an alkylthio group, an aryloxy group, an arylthio group, a halogen atom, an amino group, a nitro group, A cyano group, a thiol group, a hydroxyl group, etc. are mentioned.
  • a “heterocycloalkyl group” used alone or as part of another group, unless otherwise indicated, has one or more carbon atoms on the ring of the cycloalkyl group substituted with a heteroatom. Indicates a group.
  • the hetero atom include an oxygen atom, a nitrogen atom, and a sulfur atom.
  • heterocycloalkyl groups include tetrahydrofuryl group, morpholinyl group, piperazinyl group, piperidyl group, pyrrolidinyl group and the like.
  • the heterocycloalkyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include the groups described above as substituents for the cycloalkyl group.
  • a “cycloalkenyl group” used alone or as part of another group indicates a non-aromatic unsaturated cyclic hydrocarbon group unless otherwise specified. There may be one unsaturated bond on the ring, or two or more. Although there is no restriction
  • the cycloalkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and the like.
  • This cycloalkenyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include the groups described above as substituents for the cycloalkyl group.
  • a “heterocycloalkenyl group” used alone or as part of another group, unless otherwise indicated, has one or more carbon atoms on the ring of the cycloalkenyl group substituted with a heteroatom. Indicates a group.
  • the hetero atom include an oxygen atom, a nitrogen atom, and a sulfur atom.
  • the heterocycloalkenyl group include a dihydrofuryl group, an imidazolyl group, a pyrrolinyl group, and a pyrazolinyl group.
  • the heterocycloalkenyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include the groups described above as substituents for the cycloalkyl group.
  • an “aryl group” used alone or as a part of another group is an aromatic hydrocarbon group unless otherwise specified, and two or more rings may be condensed.
  • aryl group Preferably it is C5-C14, More preferably, it is C6-C10.
  • the aryl group include a phenyl group, an indenyl group, a naphthyl group, a phenanthryl group, and an anthryl group.
  • the aryl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include alkyl group, alkoxy group, alkoxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, acyl group, acylalkyl group, alkylthio group, alkylenedioxy group, aryloxy group, arylthio group, halogen atom, amino Group, nitro group, cyano group, thiol group, hydroxyl group and the like.
  • an “aryloxy group” used alone or as part of another group represents a monovalent group in which an oxygen atom is bonded to the aryl group, and includes a phenoxy group and an indenoxy group. , Naphthoxy group, phenanthroxy group, anthoxy group and the like.
  • the aryloxy group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include the groups described above as substituents for the aryl group.
  • an “arylthio group” used alone or as a part of another group represents a monovalent group in which a sulfur atom is bonded to the aryl group, and includes a phenylthio group, an indenylthio group, A naphthylthio group, a phenanthrylthio group, an anthrylthio group, and the like can be given.
  • the arylthio group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include the groups described above as substituents for the aryl group.
  • a “heteroaryl group” used alone or as part of another group is a group in which one or more carbon atoms on the ring of the aryl group are substituted with a heteroatom unless otherwise specified. Indicates. Examples of the hetero atom include an oxygen atom, a nitrogen atom, and a sulfur atom.
  • heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, triazinyl, tetrazolyl, oxazolyl, indolizinyl, indolyl, isoindolyl, Indazolyl group, purinyl group, quinolidinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, oxadiazolyl group, thiazolyl group, thiadiazolyl group, benzimidazolyl group, furyl group, thienyl group and the like can be mentioned.
  • the heteroaryl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include the groups described above as substituents for the aryl group.
  • an “arylsulfonyl group” used alone or as part of another group represents a monovalent group in which a sulfonyl group is bonded to the aryl group, and includes a phenylsulfonyl group, p -Toluenesulfonyl group, indenylsulfonyl group, naphthylsulfonyl group, phenanthrylsulfonyl group, anthrylsulfonyl group and the like.
  • the arylsulfonyl group may be unsubstituted or one or more hydrogen atoms may be substituted with a substituent.
  • substituents include the groups described above as substituents for the aryl group.
  • acetaldehyde In the method for producing the asymmetric catalyst Mannich reaction product of the present invention, acetaldehyde is used as a nucleophile. Since acetaldehyde is easily available, a product can be obtained at low cost even when an asymmetric catalytic Mannich reaction is performed on an industrial scale.
  • Acetaldehyde is highly reactive both as a nucleophile and as an electrophile and is generally not suitable as a nucleophile for the asymmetric catalytic Mannich reaction.
  • a certain catalyst is used as the asymmetric catalyst. Therefore, even if acetaldehyde is used, only a desired reaction product can be produced with high enantioselectivity and reaction efficiency.
  • Asymmetric catalyst represented by general formula (2) In the method for producing the asymmetric catalyst Mannich reaction product of the present invention, a catalyst represented by the general formula (2) is used as the catalyst.
  • R 3 and R 4 are each independently an aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, heterocycloalkenyl group which may have a substituent.
  • R 3 and R 4 may have is not particularly limited, and may be an electron withdrawing group or an electron donating group.
  • the electron donating group which is a substituent that R 3 and R 4 may have is not particularly limited, but is an alkyl group, an alkoxy group, an alkylthio group, an aryloxy group, an arylthio group, a dialkyl. Mention may be made of amino groups, alkylamino groups, amino groups, diarylamino groups, arylamino groups and alkylarylamino groups.
  • the electron withdrawing group which is a substituent which R 3 and R 4 may have is not particularly limited, but is an acyl group, a nitro group, a cyano group, a carboxyl group, a thiocarboxyl. Groups, sulfo groups, alkoxycarbonyl groups, halogenated alkyl groups, and carbamoyl groups.
  • R 5 represents a hydrogen atom, a silyl group, or an alkyl group.
  • silyl group refers to a group represented by H 3 Si— or a group in which one or more hydrogen atoms of this group are substituted with an alkyl group, an aryl group, or the like.
  • silyl groups include trimethylsilyl (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBS) group, triisopropylsilyl (TIPS) group, t-butyldiphenylsilyl (TBDPS) group, and the like. It is done.
  • R 6 represents a hydroxyl-protecting group
  • n represents 0 or 1.
  • hydroxyl-protecting group commonly used protecting groups such as an alkyl group, an acetyl group, and a silyl group can be used.
  • the substitution position of the OR 6 group may be either the 3-position or the 4-position.
  • R 3 and R 4 are aryl groups which may have a substituent and R 6 is a silyl group or an alkyl group are preferable.
  • R 3 and R 4 are more preferably an aryl group which may be substituted with an electron withdrawing group.
  • such a compound is represented by the following chemical formula (2-1) in which R 2 and R 3 are 3,5-bis (trifluoromethyl) phenyl groups, R 4 is TMS, and n is 0.
  • the asymmetric catalyst represented by the general formula (2) can be produced using proline or a derivative thereof (3-hydroxyproline, 4-hydroxyproline, etc.) as a starting material ((a) H. Gotoh, R., et al. Masui, H. Ogino, M. Shoji, Y. Hayashi, Angew. Chem. Int. Ed. 2006, 45, p. 6853, (b) Y. Hayashi, T. Okano, S. Arakeke, D. Hazelard, Angew. Chem. Int. Ed. 2007, 46, p. 4922, (c) H. Gotoh, Y. Hayashi, Org. Lett. 2007, 9, p. 2859, etc.).
  • an acid is used as a catalyst.
  • an acid used as a catalyst for example, the benzoic acid, acetic acid, phenol, and inorganic acid which may have a substituent can be mentioned.
  • inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.
  • the production method of the present invention comprises imine represented by the general formula (1), acetaldehyde, an asymmetric catalyst represented by the general formula (2) or an enantiomer thereof, and an acid.
  • the reaction is carried out in the presence to obtain a compound represented by the above general formula (3) or an enantiomer thereof.
  • the amount of acetaldehyde used is preferably 1 equivalent to 30 equivalents, more preferably 1 equivalent to 10 equivalents, relative to the imine represented by the general formula (1).
  • the amount of the asymmetric catalyst used is preferably 0.01 equivalents or more and 1 equivalents or less, more preferably 0.05 equivalents or more and 0.3 equivalents or less with respect to the imine represented by the general formula (1).
  • the amount of the acid used is preferably 0.01 equivalents or more and 2 equivalents or less, and 0.05 equivalents or more and 0.3 equivalents or less with respect to the imine represented by the general formula (1). More preferred.
  • solvent for performing the above reaction examples include, but are not limited to, tetrahydrofuran (THF), 1,4-dioxane, toluene, dichloromethane, chloroform, acetonitrile, methanol, and ethanol.
  • the reaction temperature is preferably ⁇ 20 ° C. or higher and 50 ° C. or lower, and more preferably ⁇ 5 ° C. or higher and 30 ° C. or lower. If the reaction temperature is too high, side reactions are liable to occur and the yield may be reduced. On the other hand, when the reaction temperature is too low, the reaction rate decreases.
  • the reaction time depends on the conditions of imine, acetaldehyde, asymmetric catalyst, etc. used, but is usually 12 to 72 hours.
  • the compound represented by the general formula (3) obtained by the production method of the present invention or the enantiomer thereof can be isolated and purified by a conventionally known method such as extraction, silica gel chromatography, and crystallization. Further, when the compound represented by the general formula (3) or its enantiomer is an unstable compound, it may be isolated and purified after performing oxidation or reduction using a conventionally known method, if necessary. .
  • a compound represented by the general formula (4) or an enantiomer thereof can be synthesized by oxidizing the compound represented by the general formula (3) or the enantiomer thereof.
  • R 1 and R 2 are the same as described above.
  • the compound represented by the general formula (7) or its enantiomer can be synthesized by reacting the compound represented by the general formula (3) with the Wittig reagent represented by the general formula (6).
  • R 1 and R 2 are the same as above, and R 7 and R 8 each independently represent a hydrogen atom or a monovalent organic group.
  • a compound represented by the general formula (8) or an enantiomer thereof can be synthesized by reductive amination of the compound represented by the general formula (3) or the enantiomer thereof.
  • R 1 and R 2 are the same as described above, and R 9 and R 10 each independently represent a hydrogen atom or a monovalent organic group.
  • a method of oxidizing / reducing the compound represented by the general formula (3) or its enantiomer, a method of converting to a compound represented by the general formula (7) by Wittig reaction, and a method of reductive amination include Conventionally known methods can be used (for example, J. Barluenga, B. Olano, S. Fastero, J. Org. Chem. 1985, 50, p. 4052; P. V. Ramachandran, T. E. Burghardt). Chem. Eurr. J. 2005, 11, p.4387; J. W. Yang, C. Chandler, M. Standler, D. Kampen, B. List, Nature, 2008, 452, p.453; , A. F. et al. J. Org. 1, p.3849;. Sato, S.et al, Tetrahedron, 2004,60, see p.7899).
  • Mannich adduct refers to ⁇ -aminoaldehyde, which is an asymmetric catalytic Mannich reaction product, and ⁇ -aminoalcohol obtained by reducing this as necessary.
  • reaction was carried out by adding 0.3 mmol of N-benzylidenebenzamide, 1.5 mmol of acetaldehyde, 0.03 mmol of the above catalyst 1 or 2, and 0.03 mmol of acid at 4 ° C. in the presence of tetrahydrofuran 0. By reacting in 6 mL for 48 hours. Entry 1 was carried out under the same conditions as described above except that the reaction was carried out in 2 mL of acetonitrile in the presence of 20 mol% proline for 3 hours. The results are shown in Table 1.
  • reaction solution was stirred for 72 hours, and then tetrahydrofuran (0.6 mL) and LiAlH 4 (22.7 mg, 0.6 mmol) were added.
  • the mixture was further stirred at ⁇ 50 ° C. for 1 hour, and the reaction was stopped by adding a phosphate buffer having a pH of 7.0.
  • the Mannich reaction product can be produced with higher enantioselectivity than in the past.

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Abstract

Cette invention concerne un procédé de production d'un produit de réaction de Mannich à catalyseur asymétrique, dans lequel à partir d'une imine et d'un acétaldéhyde, un produit de réaction de Mannich correspondant peut être obtenu avec un rendement asymétrique supérieur à celui de l'art antérieur. Le procédé de production d'un produit de réaction de Mannich à catalyseur asymétrique se caractérise en ce qu'une imine donnée réagit avec un acétaldéhyde en présence d'un catalyseur asymétrique donné ou de son énantiomère et d'un acide pour obtenir ainsi un composé donné ou son énantiomère.
PCT/JP2008/061563 2008-06-25 2008-06-25 Procédé de production d’un produit de réaction de mannich à catalyseur asymétrique Ceased WO2009157066A1 (fr)

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