WO2012081585A1 - Procédé de fabrication de composé alcool optiquement actif - Google Patents

Procédé de fabrication de composé alcool optiquement actif Download PDF

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WO2012081585A1
WO2012081585A1 PCT/JP2011/078816 JP2011078816W WO2012081585A1 WO 2012081585 A1 WO2012081585 A1 WO 2012081585A1 JP 2011078816 W JP2011078816 W JP 2011078816W WO 2012081585 A1 WO2012081585 A1 WO 2012081585A1
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group
formula
unsubstituted
substituted
optically active
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PCT/JP2011/078816
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Japanese (ja)
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真也 明石
井上　勉
毅 大熊
則義 新井
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国立大学法人北海道大学
日本曹達株式会社
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Priority to JP2012548794A priority Critical patent/JP5616977B2/ja
Publication of WO2012081585A1 publication Critical patent/WO2012081585A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a method for producing an optically active alcohol compound.
  • this invention relates to the manufacturing method of the optically active alcohol compound including hydrogenating the carbonyl compound represented by a formula (I) diastereoselectively and enantioselectively.
  • Optically active alcohol derivatives having a heterocycle are known as pharmaceuticals and intermediates thereof.
  • esreboxetine registered trademark
  • formula (1) which is an antidepressant represented by formula (1)
  • a compound effective for attention deficit hyperactivity disorder represented by formula (2) etc.
  • Patent Document 2 formula (3)
  • Patent Document 3 A compound useful for pain disorder represented by (Patent Document 2), a compound having an aspartic protease inhibitory activity represented by Formula (4) (Patent Document 3), and the like are known.
  • R 2 represents a halogen atom
  • R 3 represents a C1-6 alkyl group, etc.
  • * represents an optically active carbon
  • R 4 represents an aminocarbonyloxy group
  • R 5 represents a C1-6 alkyl group
  • R 6 represents an aminocarbonyl group, etc.
  • * represents an optically active carbon.
  • Patent Document 4 a synthesis method by asymmetric dihydroxylation
  • Patent Documents 1, 5, 6, Patent Documents 2, 3, and 4 a synthesis method by asymmetric dihydroxylation
  • Patent Documents 1, 5, 6, Patent Documents 2, 3, and 4 a synthesis method using an optically active raw material
  • An object of the present invention is to provide a method for producing an optically active alcohol compound, comprising diastereoselectively and enantioselectively hydrogenating a carbonyl compound represented by the following formula (I).
  • the present invention includes the following. [1] comprising hydrogenating a carbonyl compound represented by formula (I) in the presence of a ruthenium compound represented by formula (II) and a base, formula (IIIa), formula (IIIb), A method for producing any of the optically active alcohol compounds represented by formula (IIIc) or formula (IIId).
  • R represents an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted 5- to 8-membered heteroaryl group, or an unsubstituted or substituted vinyl group.
  • Het represents an unsubstituted or substituted 3- to 8-membered heterocycle. * Indicates that the carbon atom is an asymmetric carbon.
  • X and Y each independently represent a hydrogen atom, a hydroxyl group, a tetrahydroboric acid, a halogen atom, a C1-20 alkoxy group, or a C1-20 acyloxy group.
  • Px represents an optically active or racemic phosphine ligand.
  • n represents the number of Px and is 1 or 2.
  • A represents an optically active or racemic diamine ligand. However, both Px and A are not racemic.
  • A is a ligand represented by Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), or Formula (IIe), [1] or [2] The production method according to [2].
  • R 1 CH (NH 2 ) CH 2 (NR 2 R 3 ) (IIa) R 1 CH (NR 2 R 3 ) CH 2 (NH 2 ) (IIb) (H 2 N) HR 4 CB—CHR 4 (NH 2 ) (IIc) R 1 CH (NH 2 ) CR 5 R 5 (NH 2 ) (IId) R 1 CH (NH 2 ) R 1 CH (NH 2 ) (IIe) (In formula (IIa), formula (IIb), formula (IIc), formula (IId) and formula (IIe), R 1 is an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cycloalkyl group, an unsubstituted Or a substituted C7-20 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or
  • R 2 , R 3 and R 5 are each independently a hydrogen atom, an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted A C3-8 cycloalkyl group having a group, or an unsubstituted or substituted C7-20 aralkyl group.
  • R 2 and R 3 may combine to form a ring. However, both R 2 and R 3 are not hydrogen atoms.
  • R 4 represents a hydrogen atom, an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cycloalkyl group, An unsubstituted or substituted C7-20 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted 3- to 8-membered heterocyclic group.
  • B represents an unsubstituted or substituted ethylene group, or an unsubstituted or substituted heterocyclic divalent group. When B is an ethylene group having a plurality of substituents, the plurality of substituents may be bonded to form a ring.
  • optically active alcohol compound of the present invention diastereoselective and enantioselective is possible regardless of whether the carbon atom marked with * in the carbonyl compound represented by the formula (I) is optically active or racemic. Therefore, any one of the optically active alcohol compounds represented by formula (IIIa), formula (IIIb), formula (IIIc) or formula (IIId) can be obtained with high selectivity.
  • the optically active alcohol compound represented by the formula (IIIa), the formula (IIIb), the formula (IIIc) or the formula (IIId) is a compound useful as a pharmaceutical and an intermediate thereof.
  • the method for producing an optically active alcohol compound of the present invention includes hydrogenating a carbonyl compound represented by the above formula (I) in the presence of a ruthenium compound represented by the above formula (II) and a base. It is a waste.
  • R represents an unsubstituted or substituted C6-10 aryl group, an unsubstituted or substituted 5- to 8-membered heteroaryl group, or an unsubstituted or substituted vinyl group. Indicates. Examples of the unsubstituted C6-10 aryl group in R include a phenyl group and a naphthyl group.
  • the “substituent” in the C6-10 aryl group having a substituent is not particularly limited, and examples thereof include a hydroxyl group; a thiol group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a cyano group; Group: formyl group; unsubstituted or substituted amino group such as amino group, methylamino group, benzylamino group, anilino group, dimethylamino group; methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group Group, s-butyl group, t-butyl group, n-pentyl group, n-hexyl group and other alkyl groups, preferably C1-6 alkyl groups; vinyl group, allyl group, 2-methoxyethenyl group and other alkenyl groups Al
  • Examples of the unsubstituted 5- to 8-membered heteroaryl group in R include thienyl, furyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, thiazolyl, isothiazolyl, 1,3,4 -Thiadiazolyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, pyridyl group, pyrimidyl group, pyridazyl group, pyrazyl group, 1,2,4-triazyl group and the like.
  • the “substituent” in the 5- to 8-membered heteroaryl group having a substituent is not particularly limited, and examples thereof include the same as those mentioned as the “substituent” in the aryl group having the substituent. be able to.
  • the “substituent” in the vinyl group having a substituent in R is not particularly limited, and examples thereof include the same as those mentioned as the “substituent” in the aryl group having the substituent.
  • Het represents an unsubstituted or substituted 3- to 8-membered heterocycle.
  • the unsubstituted 3- to 8-membered heterocycle in Het include an epoxy group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholino group, a pyrrolidinyl group, a piperazinyl group, an oxazolinyl group, an imidazolinyl group, an oxazonidinyl group, and 1 , 2-pyranyl group, thiazinyl group, dioxanyl group, thiomorpholino group and the like.
  • the “substituent” in the 3- to 8-membered heterocycle having a substituent is not particularly limited, and examples thereof include the same as those mentioned as the “substituent” in the aryl group having the substituent. it can.
  • * indicates that the carbon atom is an asymmetric carbon, and the carbon atom may be either optically active or racemic.
  • X and Y each independently represent a hydrogen atom, a hydroxyl group, a tetrahydroboric acid, a halogen atom, a C1-20 alkoxy group, or a C1-20 acyloxy group.
  • a halogen atom in X and Y a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc. can be mentioned, for example.
  • Examples of the C1-20 alkoxy group in X and Y include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an s-butoxy group, an i-butoxy group, and a t-butoxy group. Can do.
  • Examples of the C1-20 acyloxy group in X and Y include an acetoxy group, a propionyloxy group, a pivaloyloxy group, a benzoyloxy group, a 2-chlorobenzoyloxy group, and a 4-methylbenzoyloxy group.
  • Px represents an optically active or racemic phosphine ligand.
  • the phosphine ligand is typically monodentate or bidentate.
  • Examples of the monodentate phosphine ligand include trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, tricyclohexylphosphine, tri (p-tolyl) phosphine, diphenylmethylphosphine, dimethylphenylphosphine, diisopropylmethylphosphine, 1- [ 2- (diphenylphosphino) ferrocenyl] ethyl methyl ether, 2- (diphenylphosphino) -2′-methoxy-1,1′-binaphthyl and the like.
  • bidentate phosphine ligand examples include bisdiphenylphosphinomethane, bisdiphenylphosphinoethane, bisdiphenylphosphinopropane, unsubstituted or substituted 2,2′-bis- (diphenylphosphino)- 1,1′-binaphthyl (BINAP) and the like can be mentioned.
  • BINAP having a substituent examples include 2,2′-bis- (di-p-triphosphino) -1,1′-binaphthyl (Tol-BINAP), 2,2′-bis [bis (3,5 -Dimethylphenyl) phosphino] -1,1'-binaphthyl (Xylyl-BINAP) and the like.
  • Px an optically active phosphine ligand is preferable, and a bidentate phosphine ligand having axial asymmetry is more preferable.
  • n represents the number of Px and is 1 or 2.
  • A represents an optically active or racemic diamine ligand.
  • A is preferably an optically active diamine ligand.
  • both Px and A are not racemic.
  • the diamine ligand in A is not particularly limited as long as it can stably form a metal complex, but the above formula (IIa), the above formula (IIb), the above formula (IIc), the above A diamine ligand represented by the formula (IId) or the above formula (IIe) is preferred.
  • R 1 represents an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20.
  • Examples of the unsubstituted C1-20 alkyl group in R 1 include, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, isobutyl group, t-butyl group, Examples thereof include an n-pentyl group and an n-hexyl group.
  • the “substituent” in the C1-20 alkyl group having a substituent in R 1 is not particularly limited, but examples thereof include a hydroxyl group; a thiol group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; Group; nitro group; formyl group; unsubstituted or substituted amino group such as amino group, methylamino group, benzylamino group, anilino group and dimethylamino group; alkenyl group such as vinyl group, allyl group and 2-methoxyethenyl group Alkynyl groups such as ethynyl group, 1-propynyl group, 2-phenylethynyl group, propargyl group; methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, t-butoxy group, etc
  • Alkoxy groups preferably C1-6 alkoxy groups; alkeni such as vinyloxy group and allyloxy group Oxy group; alkynyloxy group such as ethynyloxy group and propargyloxy group; aryloxy group such as phenoxy group and benzyloxy group; heteroaryloxy group such as 2-pyridyloxy; haloalkoxy group such as fluoromethoxy group and dibromomethoxy group Group, preferably C1-6 haloalkoxy group; alkylthiocarbonyl group such as methylthiocarbonyl group, ethylthiocarbonyl group, etc., preferably C1-6 alkylthiocarbonyl group; alkylsulfonyl such as methylsulfonylamino group, t-butylsulfonylamino group An amino group, preferably a C1-6 alkylsulfonylamino group; an arylsulfonylamino group such as
  • alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group, preferably C1-6 alkoxycarbonyl group
  • aryl group such as phenyl group, 1-naphthyl group and 2-naphthyl group, preferably C6-12 Aryl group
  • unsaturated 5-membered ring group such as furanyl group, thiophenyl group, pyrrolyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group; and the like, pyridyl group, pyridazinyl group, pyrazinyl group, etc.
  • Saturated hetero 6-membered ring Groups saturated heterocyclic groups such as tetrahydrofuranyl and piperidinyl groups; N unsubstituted or N-substituted aminocarbonyl groups such as aminocarbonyl groups and dimethylaminocarbonyl groups; alkylthio groups such as methylthio groups, ethylthio groups and t-butylthio groups; Groups, alkenylthio groups such as allylthio groups; alkynylthio groups such as ethynylthio groups and propargylthio groups; arylthio groups such as phenylthio groups and 4-chlorophenylthio groups; heteroarylthio groups such as 2-pyridylthio groups; benzylthio groups and phenethyl groups Aralkylthio group such as thio group; Alkylsulfonyl group such as methylsulfonyl group, eth
  • Examples of the unsubstituted C2-20 alkenyl group for R 1 include a vinyl group, an allyl group, and a 2-methoxyethenyl group.
  • the “substituent” in the C2-20 alkenyl group having a substituent is not particularly limited, but examples thereof include the same as those mentioned as the “substituent” in the C1-20 alkyl group having the substituent. be able to.
  • Examples of the unsubstituted C3-8 cycloalkyl group in R 1 include a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group.
  • the “substituent” in the C3-8 cycloalkyl group having a substituent is not particularly limited.
  • the same “substituent” as the “substituent” in the C1-20 alkyl group having the substituent may be used. Can be mentioned.
  • Examples of the unsubstituted C7-20 aralkyl group in R 1 include a benzyl group and a phenethyl group.
  • the “substituent” in the C7-20 aralkyl group having a substituent is not particularly limited, and examples thereof include the same as those mentioned as the substituent in the C1-20 alkyl group having the substituent. it can.
  • the unsubstituted or substituted C6-10 aryl group of R 1 and the unsubstituted or substituted 3- to 8-membered heterocyclic group are not particularly limited, and examples thereof include unsubstituted or substituted R in R A C6-10 aryl group having a group, an unsubstituted or substituted 5- to 8-membered heteroaryl ring in R, and an unsubstituted or substituted 3- to 8-membered heterocyclic group in Het
  • R 1 is preferably an unsubstituted or substituted C 6-10 aryl group.
  • R 2 , R 3 and R 5 are each independently a hydrogen atom, an unsubstituted or substituted C1-20 alkyl group, an unsubstituted group Or a C2-20 alkenyl group having a substituent, a C3-8 cycloalkyl group having an unsubstituted or substituted group, or a C7-20 aralkyl group having an unsubstituted or substituted group. Note that R 2 and R 3 are not both hydrogen atoms.
  • an unsubstituted or substituted C1-20 alkyl group an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cyclo
  • the alkyl group or the unsubstituted or substituted C7-20 aralkyl group is not particularly limited.
  • R 1 an unsubstituted or substituted C1-20 alkyl group, unsubstituted or substituted
  • the C2-20 alkenyl group having a substituent the C3-8 cycloalkyl group having an unsubstituted or substituted group, or the C7-20 aralkyl group having an unsubstituted or substituted group
  • R 2 , R 3 and R 5 an unsubstituted or substituted C1-20 alkyl group is preferable, and an unsubstituted or substituted C1-6 alkyl group is particularly preferable.
  • R 2 and R 3 may combine to form a ring. Specific examples of the ring formed by combining R 2 and R 3 include, for example, a pyrrolidine ring, a piperidine ring, and a morpholine ring.
  • R 4 represents a hydrogen atom, an unsubstituted or substituted C1-20 alkyl group, an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3 -8 cycloalkyl group, unsubstituted or substituted C7-20 aralkyl group, unsubstituted or substituted C6-10 aryl group, or unsubstituted or substituted 3- to 8-membered heterocyclic group Indicates.
  • a C7-20 aralkyl group having a substituent, an unsubstituted or substituted C6-10 aryl group, or an unsubstituted or substituted 3-8 membered heterocyclic group is not particularly limited.
  • an unsubstituted or substituted C1-20 alkyl group an unsubstituted or substituted C2-20 alkenyl group, an unsubstituted or substituted C3-8 cycloalkyl group, A substituted or substituted C7-20 aralkyl group, an unsubstituted or substituted C6-10 aryl group, or Examples thereof include the same ones as mentioned as specific examples of the substituted or substituted 3- to 8-membered heterocyclic group.
  • R 4 an unsubstituted or substituted C1-20 alkyl group is preferable, and an unsubstituted or substituted C1-6 alkyl group is particularly preferable.
  • B represents an unsubstituted or substituted ethylene group, or an unsubstituted or substituted heterocyclic divalent group.
  • the “substituent” in the ethylene group having a substituent in B is not particularly limited. For example, the same as those mentioned as the “substituent” in the C6-10 aryl group having a substituent in R above Can be mentioned.
  • B is an ethylene group having a plurality of substituents, the plurality of substituents may be bonded to form a ring.
  • Examples of the ring formed by combining a plurality of substituents include hydrocarbon rings such as cyclobutane ring, cyclopentane ring and cyclohexane ring; ether bonds such as tetrahydrofuran ring, 1,3-dioxolane ring and morpholine ring.
  • a saturated ring having a nitrogen atom such as a pyrrolidine ring, a piperidine ring or a piperazine ring; an aromatic ring such as a benzene ring or a pyridine ring;
  • base examples of the base used in the hydrogenation reaction of the present invention include triethylamine, diisopropylethylamine, pyridine, 1,4-diazabicyclo [2.2.2] octane (DABCO), and 1,8-diazabicyclo [5.4.
  • Organic bases such as undec-7-ene (DBU); metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, magnesium methoxide, magnesium ethoxide; organolithium compounds such as n-butyllithium Lithium amides such as lithium diisopropylamide and lithium bistrimethylsilylamide; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; sodium hydride and calcium hydride And metal hydrides thereof.
  • DBU undec-7-ene
  • metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, magnesium methoxide
  • Hydrogenation in the method for producing an optically active alcohol compound of the present invention is not particularly limited by the method.
  • a carbonyl compound represented by formula (I) serving as a reaction substrate, a ruthenium compound represented by formula (II) serving as a catalyst, and a base are charged into a reactor, and then hydrogen gas at a predetermined pressure or a predetermined amount of Hydrogenation can be carried out by supplying a hydrogen donor.
  • the ruthenium compound represented by the formula (II) is prepared according to the method described in Japanese Patent Application Laid-Open No. 2005-068113, Japanese Patent Application Laid-Open No. 2003-104993, and the like. Or may be prepared and used in a hydrogenation reaction system.
  • the amount of the ruthenium compound represented by the formula (II) in the hydrogenation reaction system varies depending on the size of the reaction vessel and the activity of the ruthenium compound, but is preferably 1/50 to the carbonyl compound as the reaction substrate. It is 1 / 2,000,000 times mole, more preferably 1/500 to 1 / 500,000 times mole.
  • the amount of the base used is preferably 2 to 500,000 times mol, more preferably 2 to 5,000 times mol, with respect to the ruthenium compound represented by the formula (II).
  • the hydrogenation reaction can be carried out without solvent or in a solvent.
  • the solvent used in the hydrogenation reaction is not particularly limited as long as it is inert to the hydrogenation reaction and can dissolve the carbonyl compound and the ruthenium compound.
  • Specific examples of the solvent used include aromatic hydrocarbon solvents such as toluene and xylene; aliphatic hydrocarbon solvents such as pentane and hexane; halogen-containing hydrocarbon solvents such as methylene chloride; diethyl ether and tetrahydrofuran (THF) Ether solvents such as methanol, ethanol and benzyl alcohol; organic solvents containing heteroatoms such as acetonitrile, dimethylformamide (DMF), N-methylpyrrolidone and dimethyl sulfoxide (DMSO); it can.
  • aromatic hydrocarbon solvents such as toluene and xylene
  • aliphatic hydrocarbon solvents such as pentane and hexane
  • alcohol solvents are preferable as the solvent.
  • the amount of the solvent used depends on the solubility of the carbonyl compound represented by the formula (I) and is preferably 0.1 to 10,000 with respect to 100 parts by weight of the carbonyl compound represented by the formula (I). Part by weight, more preferably 20 to 1,000 parts by weight.
  • the pressure of the hydrogen gas is preferably 1 to 200 atm, more preferably 3 to 50 atm.
  • a hydrogen donor for example, a hydrogen storage alloy or diimide can be used, and the supply amount of the hydrogen donor is based on the carbonyl compound represented by the formula (I):
  • the equivalent is preferably 1 to 100 times equivalent.
  • the temperature in the hydrogenation reaction is preferably ⁇ 50 ° C. to + 100 ° C., more preferably + 25 ° C. to + 40 ° C.
  • the reaction time depends on the reaction conditions such as the concentration of the reaction substrate, temperature and pressure, the size of the reaction vessel, etc., but is preferably several minutes to several days.
  • the reaction format may be a batch type or a continuous type.
  • the optically active alcohol compounds represented by the formulas (IIIa) to (IIId), which are target products are obtained by isolation and purification by methods such as distillation, recrystallization and silica gel column chromatography. be able to.
  • the structure of the target product can be determined by known analytical means such as 1 H-NMR, optical rotation measurement, liquid chromatography, gas chromatography and the like.
  • the crude product was concentrated and then purified by silica gel column chromatography to obtain 0.283 g (0.96 mmol) of optically active N-benzoyl-morpholin-2-yl-phenyl-methanol in a 96% yield.
  • Example 2 Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine RuCl 2 ⁇ (S) -binap ⁇ ⁇ (R) -dmapen ⁇ is converted to RuCl 2 ⁇ (S)-
  • Example 3 Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine RuCl 2 ⁇ (S) -binap ⁇ ⁇ (R) -dmapen ⁇ is converted to RuCl 2 ⁇ (S)-
  • Example 4 Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine RuCl 2 ⁇ (S) -binap ⁇ ⁇ (R) -dmapen ⁇ is converted to RuCl 2 ⁇ (S)-
  • Example 5 Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine 4.45 g (15 mmol, racemate) of N-benzoyl-morpholin-2-yl-phenyl-methanone
  • the amount of isopropanol was 10.2 ml
  • the amount of potassium t-butoxide was 4.8 ml (0.48 mmol) as a 0.1 M isopropanol solution
  • This enantiomer was analyzed and found to be N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine.
  • Example 8 Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine 4.45 g (15 mmol, racemate) of N-benzoyl-morpholin-2-yl-phenyl-methanone
  • Example 9 Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine RuCl 2 ⁇ (S) -binap ⁇ ⁇ (R) -dmapen ⁇ is converted to RuCl 2 ⁇ (S)-
  • Example 10 Preparation of N-benzoyl- (2S) -2-[(R) -hydroxy-phenyl-methyl] -morpholine RuCl 2 ⁇ (S) -binap ⁇ ⁇ (R) -dmapen ⁇ is converted to RuCl 2 ⁇ (S)-
  • Example 11 Preparation of N-benzoyl- (2R) -2-[(S) -hydroxy-phenyl-methyl] -morpholine RuCl 2 ⁇ (S) -binap ⁇ ⁇ (R) -dmapen ⁇ is converted to RuCl 2 ⁇ (S)-
  • the crude product was concentrated and purified by silica gel column chromatography to obtain 8.77 g (30.0 mmol) of optically active Nt-butoxycarbonyl-piperidin-3-yl-phenyl-methanol in 100% yield. .
  • the enantiomer was analyzed and found to be Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy-phenyl-methyl] -piperidine.
  • Example 13 Preparation of Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy-phenyl-methyl] -piperidine
  • the amount of Nt-butoxycarbonyl-piperidin-3-yl-phenyl-methanone was 11.57 g ( 40 mmol, racemate), the amount of isopropanol to 38.8 ml, the amount of potassium t-butoxide to 1.2 ml (1.2 mmol) as a 1.0 M isopropanol solution, RuCl 2 ⁇ (S) -binap ⁇ ⁇
  • the crude product thus obtained was analyzed by HPLC (same conditions as in Example 12, retention time of diastereomer 12.2 minutes, 14.8 minutes). The production ratio of diastereomer was> 99: 1. .
  • the crude product was concentrated and purified by silica gel column chromatography, and 4.81 g (14.9 mmol) of optically active Nt-butoxycarbonyl-piperidin-3-yl-3-chloro-phenylmethanol was obtained in a yield of 99%. Obtained.
  • the production ratio of diastereomers was> 99: 1.
  • the crude product was concentrated and purified by silica gel column chromatography. 1.12 g (3.8 mmol) of optically active Nt-butoxycarbonyl-piperidin-3-yl-2-thienyl-methanol was obtained in a yield of 95%. Obtained.
  • this enantiomer was found to be Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy- (2-thienyl) -methyl] -piperidine.
  • Example 16 Preparation of Nt-butoxycarbonyl (3S) -3-[(S) -hydroxy- (2-thienyl) -methyl] -piperidine RuCl 2 ⁇ (S) -binap ⁇ ⁇ (R) -dmapen ⁇ is replaced by RuCl 2
  • the obtained crude product was analyzed by HPLC (same conditions as in Example 1, retention time of diastereomer 13.0 minutes, 15.3 minutes). The production ratio of diastereomer was> 99: 1. It was.
  • the crude product was concentrated and purified by silica gel column chromatography. As a result, 0.888 g (4.0 mmol) of optically active 1-phenyl-hexahydro-oxazolo- [3,4-a] pyridin-3-one was 100%. Obtained in yield.
  • the production ratio of diastereomers was> 99: 1.
  • the crude product was concentrated and purified by silica gel column chromatography to obtain 0.834 g (2.85 mmol) of optically active N-benzoyl-piperidin-2-yl-phenyl-methanol in a yield of 95%.
  • the crude product was concentrated and purified by silica gel column chromatography to obtain 1.10 g (39 mmol) of optically active N-benzoyl-piperidin-2-yl-phenyl-methanol in a yield of 98%.
  • the obtained crude product was subjected to gas chromatography ( ⁇ -DEX 120 (30 m ⁇ 0.25 ⁇ m), 120 ° C., 20 minutes, 5 ° C./minute, 150 ° C., 60 minutes, carrier gas: helium (100 kPa), detector. : FID, retention times of 4 isomers 54.1 min, 55.1 min, 56.6 min, 58.3 min) The production ratio of diastereomers was 95: 5.
  • the crude product was concentrated and purified by silica gel column chromatography. As a result, 0.491 mg (2.76 mmol) of optically active phenyl- (tetrahydrofuran-2-yl) -methanol was obtained in a yield of 92%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Furan Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne un procédé destiné à fabriquer un composé alcool optiquement actif représenté par la formule (IIIa), ou similaire, de manière diastéréosélective et énantiosélective qui comporte une hydrogénation d'un composé carbonyle représenté par la formule (I), en présence d'un composé ruthénium représenté par la formule (II), et d'une base. (Dans la formule (I) : R représente un groupe aryle C6-10 possédant un groupe non substitué ou substitué, ou similaire. Het représente un hétérocycle à 3-8 chaînons possédant un groupe non substitué ou substitué.) (Dans la formule (II) : X et Y représentent chacun de manière indépendante un groupe hydroxyle, un tétrahydroborate, ou similaire. Px représente un ligand de phosphine optiquement actif ou racémique. n représente le nombre de Px, et équivaut à 1 ou 2. A représente un ligand de diamine optiquement actif ou racémique. Cependant Px et A ne peuvent pas être tous les deux racémiques.) (Dans la formule (IIIa) : R et Het sont tels que définis dans la formule (I).)
PCT/JP2011/078816 2010-12-15 2011-12-13 Procédé de fabrication de composé alcool optiquement actif WO2012081585A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020505336A (ja) * 2017-02-21 2020-02-20 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ キラルピロリジン−２−イル−メタノール誘導体の製造方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000041997A1 (fr) * 1999-01-18 2000-07-20 Nippon Soda Co., Ltd. Procede de preparation d'amino-alcools optiquement actifs
WO2004007506A1 (fr) * 2002-07-15 2004-01-22 Nippon Soda Co.,Ltd. Composes de ruthenium, ligands diamine, et procede de preparation d'alcools optiquement actifs
JP2008515916A (ja) * 2004-10-07 2008-05-15 ビテ ファーマシューティカルズ， インコーポレイテッド ジアミノアルカンアスパラギン酸プロテアーゼ阻害剤
JP2009515893A (ja) * 2005-11-14 2009-04-16 ビテ ファーマシューティカルズ， インコーポレイテッド アスパラギン酸プロテアーゼ抑制剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000041997A1 (fr) * 1999-01-18 2000-07-20 Nippon Soda Co., Ltd. Procede de preparation d'amino-alcools optiquement actifs
WO2004007506A1 (fr) * 2002-07-15 2004-01-22 Nippon Soda Co.,Ltd. Composes de ruthenium, ligands diamine, et procede de preparation d'alcools optiquement actifs
JP2008515916A (ja) * 2004-10-07 2008-05-15 ビテ ファーマシューティカルズ， インコーポレイテッド ジアミノアルカンアスパラギン酸プロテアーゼ阻害剤
JP2009515893A (ja) * 2005-11-14 2009-04-16 ビテ ファーマシューティカルズ， インコーポレイテッド アスパラギン酸プロテアーゼ抑制剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, no. 20, 2008, pages 5550 - 5553 *
JOURNAL OF ORGANIC CHEMISTRY, vol. 73, no. 22, 2008, pages 9084 - 9093 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020505336A (ja) * 2017-02-21 2020-02-20 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ キラルピロリジン−２−イル−メタノール誘導体の製造方法

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