WO2013061999A1 - 光学活性アルコールの製造方法 - Google Patents
光学活性アルコールの製造方法 Download PDFInfo
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- WO2013061999A1 WO2013061999A1 PCT/JP2012/077464 JP2012077464W WO2013061999A1 WO 2013061999 A1 WO2013061999 A1 WO 2013061999A1 JP 2012077464 W JP2012077464 W JP 2012077464W WO 2013061999 A1 WO2013061999 A1 WO 2013061999A1
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- 0 *NC(C1NCCC1)=O Chemical compound *NC(C1NCCC1)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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- 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
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- the present invention relates to a novel method for producing an optically active alcohol.
- Optically active alcohols are extremely important compounds as synthetic raw materials for pharmaceuticals, agricultural chemicals, liquid crystal materials, fine chemicals, and the like.
- There are various methods for producing an optically active alcohol but the most efficient method is a method using a catalytic asymmetric reduction reaction of an asymmetric ketone. For this reason, a large number of asymmetric reduction catalysts for ketones have been developed.
- the hydrogen transfer-type asymmetric reduction reaction using, for example, Patent Document 1 gives a very high asymmetric yield, and in addition, an organic compound such as 2-propanol or formic acid can be used as a hydrogen source. This is the most industrially advantageous method because it does not require special equipment as in the case of using gas.
- transition metal complexes such as rhodium, ruthenium and iridium using optically active Tsdpen [N- (2-amino-1,2-diphenylethyl) -p-toluenesulfonamide] as a ligand have been used as catalysts.
- Tsdpen N- (2-amino-1,2-diphenylethyl) -p-toluenesulfonamide
- This method also provides an optically active alcohol with a good asymmetric yield when a ketone having a carbonyl group directly bonded to an aromatic ring is used as a raw material, but for example, an aromatic ring such as ⁇ -tetralone and a carbonyl group are methylene.
- Non-Patent Document 1 When a ketone connected via a group is used as a raw material, it has a serious defect that the asymmetric yield of the product is greatly reduced (for example, see Non-Patent Document 1). Therefore, this method is not general, and a method for industrially obtaining an optically active alcohol is required as an urgent problem.
- the present invention overcomes the above problems and provides a method for producing optically active alcohols in a high yield and industrially advantageous method using ketones having various structures as raw materials and using an inexpensive asymmetric catalyst. Is.
- the present invention includes the following.
- a method for producing an optically active alcohol comprising reducing a ketone in the presence of an iridium (III) complex having a chiral proline amide compound as a ligand.
- the ketone is of the formula [I]:
- R 1 and R 2 are different from each other and may be a linear or branched alkyl group which may be substituted, a cycloalkyl group which may be substituted, an aryl group which may be substituted, An optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group; R 1 and R 2 may be linked at an appropriate position to form a ring, The ring may further contain the same or different one or more oxygen, optionally substituted nitrogen, or sulfur. ) [1] The production method according to [1].
- a chiral proline amide compound has the formula [III]:
- R 3 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted cycloalkyl group or a substituted group;
- a chiral proline amide compound is (R) -N- (2-methoxy-3-dibenzofuranyl) -2-pyrrolidinecarboxamide or (S) -N- (2-methoxy-3-dibenzofuranyl) )
- An iridium (III) complex having a chiral proline amide compound as a ligand is represented by (R) or (S) -chloro [(1,2,3,4,5- ⁇ ) -pentamethyl-2, 4-cyclopentadien-1-yl] [N- (2-methoxy-3-dibenzofuranyl) -2-pyrrolidinecarboxamidate- ⁇ N1, ⁇ N2] iridium (III) catalyst, (R) or (S) -chloro [(1,2,3,4,5- ⁇ ) -pentamethyl-2,4-cyclopentadien-1-yl] (N-6-quinolinyl-2-pyrrolidinecarboxamidate- ⁇ N1, ⁇ N2) iridium (III)
- the production method according to any one of claims 1 to 6, which is any one of catalysts.
- An iridium (III) complex having a chiral proline amide compound as a ligand is represented by (R) or (S) -chloro [(1,2,3,4,5- ⁇ ) -pentamethyl-2, 4-cyclopentadien-1-yl] (2-pyrrolidinecarboxamidato- ⁇ N1, ⁇ N2)
- the production method according to any one of [1] to [5] and [9], which is any of iridium (III) catalysts is any one of [1] to [5] and [9], which is any of iridium (III) catalysts .
- a ligand used as a catalyst for an asymmetric reaction is a metal complex having a complicated structure and is very expensive.
- the ligand used in the present invention is a chiral proline amide compound having a simple structure.
- (R) and (S) -proline amide are inexpensive compounds because they have low molecular weight and can be easily produced industrially, and the present invention is an industrially highly useful production method.
- the method for producing an optically active alcohol in the present invention is carried out by reducing a ketone in the presence of an iridium (III) complex having a chiral proline amide compound as a ligand.
- the production method of the present invention can be performed, for example, according to the chemical reaction formula shown below.
- the ketone used as the starting material in the production method of the present invention is not particularly limited as long as it is a compound having a ketone group in the molecule, and can be appropriately selected for the target optically active alcohol.
- the ketone used as a starting material in the production method of the present invention has the formula [I]: (Wherein R 1 and R 2 are different from each other and may be a linear or branched alkyl group which may be substituted, a cycloalkyl group which may be substituted, an aryl group which may be substituted, An optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group; R 1 and R 2 may be linked at an appropriate position to form a ring,
- the ring may be the same or different and may contain one or more oxygen, optionally substituted nitrogen or sulfur, and may be substituted with an optionally substituted alicyclic or heterocyclic ring. May be a condensed ring with an aromatic ring or a heteroaromatic ring which may be The compound shown by these is preferable.
- the “linear or branched alkyl group” in the linear or branched alkyl group which may be substituted represented by R 1 and R 2 is, for example, a linear or branched alkyl group having 1 to 20 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, Examples include octyl group, nonyl group, decyl group, dodecyl group, pentadecyl group, hexadecyl group, octadecyl group and the like.
- Examples of the “cycloalkyl group” in the optionally substituted cycloalkyl group represented by R 1 and R 2 include a cycloalkyl group having 3 to 20 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, and the like. , Cyclopentyl group, cyclohexyl group, cycloheptyl group and the like.
- the “aryl group” in the optionally substituted aryl group represented by R 1 and R 2 includes, for example, an aryl group having 6 to 20 carbon atoms, and specifically includes a phenyl group, a 1-naphthyl group, 2 -Naphtyl group, anthryl group, phenanthryl group, 2-biphenyl group, 3-biphenyl group, 4-biphenyl group, terphenyl group and the like.
- heteroaryl group in the optionally substituted heteroaryl group represented by R 1 and R 2 is, for example, a heteroaryl containing an atom selected from a nitrogen atom, a sulfur atom and an oxygen atom as a hetero atom
- heteroaryl containing an atom selected from a nitrogen atom, a sulfur atom and an oxygen atom as a hetero atom
- Specific examples include furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, phthalazinyl, triazinyl , Indolyl group, isoindolyl group, quinolinyl group, isoquinolinyl group, dibenzofuranyl group and the like.
- Examples of the “aralkyl group” in the optionally substituted aralkyl group represented by R 1 and R 2 include those in which the hydrogen atom of the above-described alkyl group is substituted with an aryl group. An ethyl group, a phenylpropyl group, etc. are mentioned.
- heteroarylalkyl group in the optionally substituted heteroarylalkyl group represented by R 1 and R 2 contains, for example, an atom selected from a nitrogen atom, a sulfur atom and an oxygen atom as a hetero atom
- Heteroaryl group is mentioned, specifically, furanyl group, thienyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, phthalazinyl group, Examples thereof include a triazinyl group, an indolyl group, an isoindolyl group, a quinolinyl group, an isoquinolinyl group, and a dibenzofuranyl group.
- alkenyl group in the optionally substituted alkenyl group represented by R 1 and R 2 includes, for example, an alkenyl group having 2 to 20 carbon atoms, and specifically includes a vinyl group, an allyl group, a butenyl group, A hexenyl group etc. are mentioned.
- alkynyl group in the optionally substituted alkynyl group represented by R 1 and R 2 include alkynyl groups having 2 to 20 carbon atoms, and specific examples include ethynyl group and propynyl group. .
- Examples of the substituent (substituent) of the linear or branched alkyl group, cycloalkyl group, aryl group, heteroaryl group, aralkyl group, heteroarylalkyl group, alkenyl group and alkynyl group include a halogen atom (for example, Fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), linear or branched alkyl group (eg methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl) Group, hexyl group, etc.), aralkyl group (for example, phenylethyl group, phenylpropyl group, naphthylmethyl group, etc.), linear or branched alkoxy group (for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, But
- Halogenated alkyl groups eg trifluoromethyl group, trichloromethyl group etc.
- halogenated alkoxy groups eg fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, trifluoroethoxy group, tetrafluoroethoxy group etc.
- Hydroxyl group, protected hydroxyl group eg, acetyl group, benzoyl group, methoxymethyl group, tetrahydropyranyl group, trimethylsilyl group, tert-butyldimethylsilyl group, carbonic acid ester group etc.
- amino group protected hydroxyl group
- Amino groups (amino group protecting groups such as formyl group, acetyl group, benzoyl group, benzyloxycarbonyl group, phthaloyl group, carbamoyl group, ureido group), arylamino group, heteroarylamino group, mercapto group,
- substituent (A) such a substituent (substituent) may be collectively referred to as a substituent (A).
- the number of substituents in the linear or branched alkyl group, cycloalkyl group, aryl group, heteroaryl group, aralkyl group, heteroarylalkyl group, alkenyl group and alkynyl group may be 1 to 4, for example. it can.
- the linear or branched alkyl group, cycloalkyl group, aryl group, heteroaryl group, aralkyl group, heteroarylalkyl group, alkenyl group and alkynyl group may be the same or different and each may be one or more oxygen, Nitrogen which may be substituted, or sulfur may be included.
- nitrogen substituent include the same substituents as exemplified in the linear or branched alkyl group.
- R 1 and R 2 may be linked at an appropriate position to form a ring.
- R 1 and R 2 in the present invention may form a ring together with adjacent carbon atoms or may not form a ring, but a ring is formed when a ring is formed. More preferable than not.
- the ring may be a monocyclic structure or a polycyclic structure. When the ring has a polycyclic structure, it may be a polycyclic or condensed ring composed of 2 or 3 or more monocyclic rings.
- the ring When the ring has a polycyclic structure, it may be a polycyclic or condensed ring composed of two or more aliphatic rings or heterocyclic rings, or a polycyclic or condensed ring composed of aliphatic rings or heterocyclic rings and aromatic rings or heteroaromatic rings. There may be.
- the rings may further contain the same or different one or more oxygen, optionally substituted nitrogen, or sulfur.
- examples of the nitrogen substituent include the same substituents exemplified in the linear or branched alkyl group.
- the ring is preferably a condensed ring of an optionally substituted alicyclic or heterocyclic ring and an optionally substituted aromatic or heteroaromatic ring.
- the “aliphatic ring” in the alicyclic ring which may be substituted include, for example, a 4- to 10-membered alicyclic ring. Specifically, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, And cyclodecane.
- Examples of the “heterocycle” in the optionally substituted heterocycle include a 4- to 10-membered heterocycle, and specific examples include pyrrolidine, piperidine, and tetrahydrofuran.
- the “aliphatic ring or heterocyclic ring” in the optionally substituted alicyclic ring or heterocyclic ring is preferably 4 to 10 members, more preferably 5 to 8 members.
- Examples of the “aromatic ring” in the optionally substituted aromatic ring include 5- to 12-membered aromatic rings, and specific examples include benzene and naphthalene.
- Examples of the “heteroaromatic ring” in the optionally substituted heteroaromatic ring include 5- to 12-membered aromatic rings, specifically, furan, pyrrole, thiophene, oxazole, imidazole, thiazol, pyridine, Examples include pyridazine, pyrimidine, pyrazine and the like.
- the “aromatic ring or heteroaromatic ring” in the optionally substituted aromatic ring or heteroaromatic ring preferably has 5 to 12 members, and more preferably 6 to 10 members.
- Examples of the substituent in the optionally substituted alicyclic or heterocyclic ring, optionally substituted aromatic ring or heteroaromatic ring are the same as the substituents exemplified in the above linear or branched alkyl group. Can be mentioned.
- the number of substituents in the optionally substituted alicyclic or heterocyclic ring, optionally substituted aromatic ring or heteroaromatic ring may be, for example, 1 to 4, and may be 1 to 2. Is preferred
- Examples of the ring include ⁇ -tetralone, ⁇ -tetralone, indanone, 1-benzosuberone, 2-benzosuberone, 3-chromanone, 4-chromanone, ⁇ -coumaranone, dihydroquinolinone, dihydroisoquinolinone, and thiochromanone. And a compound in which an arbitrary part of these cyclic ketones is substituted with the above-mentioned substituent, and ⁇ -tetralone, ⁇ -tetralone and a compound in which any of these parts are substituted with the above-mentioned substituent are more preferable.
- the ketone used as a starting material in the present invention has (i) a carbonyl group, (ii) may be further substituted with a substituent other than the carbonyl group, and (iii) one identical or different in the ring Or a 5- to 12-membered aromatic ring or heteroaromatic group that may be substituted with a 4- to 10-membered aliphatic ring or aromatic ring that may contain two or more oxygen, optionally substituted nitrogen, or sulfur A compound which is a condensed ring of a ring is preferable.
- the carbonyl group may be contained in any position of the 4- to 10-membered aliphatic ring or aromatic ring, but the 4- to 10-membered aliphatic ring or aromatic ring and the 5- to 12-membered aromatic ring or heteroaromatic ring It may be adjacent to the condensed position with the ring or may not be adjacent.
- substituent other than the carbonyl group include the same substituents as exemplified in the linear or branched alkyl group.
- a 4- to 10-membered alicyclic ring that may contain one or two or more oxygen, optionally substituted nitrogen, or sulfur that are the same or different in the ring, which is a ring constituting the condensed ring
- cyclobutane cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclohexene, pyrrolidine, piperidine, tetrahydrofuran and the like.
- a 5- to 12-membered aromatic ring which may be a ring constituting the fused ring, which may contain the same or different one or two or more oxygen, optionally substituted nitrogen, or sulfur in the ring;
- the heteroaromatic ring include benzene, naphthalene, furan, pyrrole, thiophene, oxazole, imidazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine and the like.
- the nitrogen substituent include the same substituents as exemplified in the linear or branched alkyl group.
- Examples of the condensed ring compound include ⁇ -tetralone, ⁇ -tetralone, indanone, 1-benzosuberone, 2-benzosuberone, 3-chromanone, 4-chromanone, ⁇ -coumaranone, dihydroquinolinone, dihydroisoquinolinone, thiochromanone. And a compound in which any part of these cyclic ketones is substituted with the above substituent, and ⁇ -tetralone, ⁇ -tetralone and a compound in which any of these parts are substituted with the above substituent Is more preferable.
- the reduction is performed by a reaction between a ketone and a hydrogen donating compound.
- the hydrogen-donating compound used in the present invention is not particularly limited, and examples thereof include reducing compounds such as formic acid and 2-propanol; and salts of the reducing compounds such as sodium formate, potassium formate, and ammonium formate.
- formic acid or formate or a mixture thereof is preferable because the reaction can be carried out under acidic conditions throughout.
- the hydrogen donating compound is preferably used in combination with a weak base.
- Weak bases include tertiary amines such as triethylamine, trimethylamine, tributylamine and N-methylmorpholine, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkaline earth carbonates such as calcium carbonate and magnesium carbonate Metal salts and the like are preferable, and triethylamine is more preferable.
- the starting iridium (III) compound is a dimer
- the amount of the base used is usually about 2 to 3 mol, preferably about 2 to 2.2 mol, relative to 1 mol of the dimer.
- solvent examples of the solvent used in the production method of the present invention include acetonitrile, ethyl acetate, isopropyl acetate, N, N-dimethylformamide, tetrahydrofuran, dimethoxyethane, dichloromethane, or alcohols such as methanol, ethanol, 2-propanol, and ethylene glycol. These water-containing solvents are exemplified.
- the amount of the solvent to be used is generally about 2 L to about 200 L, preferably about 5 L to about 100 L, per 1 kg of ketone.
- the formic acid-triethylamine mixture described above can also be used as a hydrogen donating compound and a solvent.
- the amount of formic acid used is usually about 1 to 80 mol, preferably about 1 to about 40 mol, per 1 mol of ketone.
- the amount of triethylamine used is usually about 0.1 mol to about 1 mol, preferably about 0.2 mol to about 0.7 mol, relative to 1 mol of formic acid.
- reaction In the reduction reaction in the production method of the present invention, an iridium (III) complex having a chiral proline amide compound as a ligand is added to and dissolved in a solution of the compound [I], and then a hydrogen donating compound is added and reacted. It can implement suitably by making.
- the reaction temperature is usually ⁇ 70 ° C. or higher, preferably about ⁇ 30 ° C. to about 40 ° C.
- the target optically active alcohol can be obtained by performing known processes such as extraction, concentration, filtration, and washing. If necessary, purification operations such as crystallization, recrystallization, distillation and column chromatography can be added to lead to a purer optically active alcohol.
- the optically active alcohol that is a product obtained by the production method of the present invention is not particularly limited as long as it has a hydroxyl group and has a structure corresponding to the raw material ketone.
- the optically active alcohol which is a product in the production method of the present invention has the formula [II]: (Wherein R 1 and R 2 have the same meaning as in formula [I], and * represents an asymmetric carbon atom.) It is preferable that it is a compound shown by these.
- the definition and examples of R 1 and R 2 are the same as those described in formula [I].
- the optically active alcohol which is a product in the production method of the present invention has an alicyclic ring or a heterocyclic ring which may be substituted, and is a condensed ring with an aromatic ring or a heteroaromatic ring which may be further substituted. Is preferred.
- the optically active alcohol that is a product in the production method of the present invention has (i) a hydroxyl group, (ii) may be further substituted with a substituent other than the hydroxyl group, and (iii) is the same in the ring or Differently 5 to 12 membered aromatic ring or hetero ring optionally substituted with one or more oxygen, optionally substituted nitrogen, or 4 to 10 membered aliphatic ring optionally containing sulfur A compound that is a condensed ring of an aromatic ring is more preferable.
- optically active alcohol examples include ⁇ -tetralol, ⁇ -tetralol, indanol, 1-benzosuberol, 2-benzosuberol, 3-chromanol, 4-chromanol, ⁇ -coumaranol, dihydroquinolino.
- an optically active alcohol can be produced by an industrially advantageous method using an iridium (III) complex having a chiral proline amide compound represented by the formula [III] as a ligand and using various ketones as raw materials. it can.
- the optically active alcohol produced by the production method of the present invention can be used as a raw material for synthesis of pharmaceuticals, agricultural chemicals, liquid crystal materials, fine chemicals and the like.
- the catalyst used in the present invention is not particularly limited as long as it is an iridium (III) complex having a chiral proline amide compound as a ligand.
- iridium (III) compound examples include pentamethylcyclopentadienyl iridium (III) chloride dimer, acetylacetonatoiridium (III), tris (norbornadiene) (acetylacetonato) iridium (III), etc. Methylcyclopentadienyl iridium (III) chloride dimer is preferred.
- Chiral proline amide compounds include those represented by the formula [III]:
- R 3 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted cycloalkyl group or a substituted group; A heteroaryl group that may be present, and an asterisk (*) represents an asymmetric carbon atom.
- proline amide compounds represented by the formula [III] include proline amides and N-substituted amides such as N-alkyl amides, N-cycloalkyl amides, N-aryl amides, N-heteroaryl amides, N- Aralkylamide, N-heteroarylalkylamide and the like can be mentioned. These are examples of the R 3 substituent, but the substituent may further have a substituent (hereinafter sometimes referred to as a substituent).
- Examples of the “alkyl group”, “heteroaryl group”, “aralkyl group” and “heteroarylalkyl group” in N-alkylamide are the same as those exemplified for R 1 and R 2 above.
- Examples of the substituent for the “alkyl group”, “heteroaryl group”, “aralkyl group” and “heteroarylalkyl group” in N-alkylamide include the same substituents as those described above for the substituent (A).
- Chiral proline heteroarylamide compounds include (R) -N- (6-quinolinyl) -2-pyrrolidinecarboxamide, (S) -N- (6-quinolinyl) -2-pyrrolidinecarboxamide, (R) -N -(2-Methoxy-3-dibenzofuranyl) -2-pyrrolidinecarboxamide or (S) -N- (2-methoxy-3-dibenzofuranyl) -2-pyrrolidinecarboxamide is a ligand for an iridium complex catalyst. It is preferable from the viewpoint of reactivity and optical purity of the product when used in the reduction reaction.
- the amount of the iridium (III) complex having a chiral proline amide compound as a ligand is usually about 0.1 to about 10 mol%, preferably about 0.2 to about 5 mol%, relative to the ketone. .
- the base used for the preparation of the catalyst is preferably a weak base, tertiary amines such as triethylamine, trimethylamine, tributylamine, N-methylmorpholine, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, calcium carbonate, More preferred are alkaline earth metal carbonates such as magnesium carbonate, and triethylamine is particularly preferred.
- alkali metal hydroxides such as sodium hydroxide and potassium hydroxide and strong bases such as sodium methoxide for the preparation of the catalyst is preferable because the prepared proline amide complex epitheliates rapidly and the optical purity decreases. Absent.
- the amount of the base used is usually about 2 to 3 mol, preferably about 2 to 2.2 mol, relative to 1 mol of the dimer.
- solvent used for catalyst preparation As the solvent used for the preparation of the catalyst, an organic solvent is preferable.
- the organic solvent include aliphatic hydrocarbons (eg, pentane, hexane, heptane, octane, cyclohexane, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, 1 , 2-dichloroethane, chloroform, carbon tetrachloride, o-dichlorobenzene, etc.), alcohols (eg methanol, ethanol, isopropyl alcohol, t-butyl alcohol, t-amyl alcohol etc.), ethers (eg dimethyl ether, ethyl methyl ether) , Diethyl ether, diisopropyl ether, diglyme, tert-butyl methyl ether, dim
- ethers In the case of using alcohols, ethers, amides, sulfoxides, nitriles, ketones, and esters that are miscible with water, up to about 50% of water may be included.
- methanol water-containing methanol, ethanol, water-containing ethanol, methylene chloride, ethyl acetate or acetonitrile is more preferable.
- the iridium (III) complex having a chiral proline amide compound as a catalyst used in the present invention as a ligand dissolves the chiral proline amide compound in a solvent, and an iridium (III) compound and a base (for example, triethylamine) And preferably stirred at room temperature for usually 10 minutes to 20 hours.
- a base for example, triethylamine
- an iridium (III) complex having a chiral proline amide compound as a ligand may be a complex formed from a chiral proline amide and a trivalent iridium (III) compound. That's fine.
- the catalyst used in the production method of the present invention is represented by the formula [III]:
- R 3 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted cycloalkyl group or a substituted group;
- a complex formed from a chiral proline amide represented by the formula (II) and a trivalent iridium compound is preferable.
- this compound is also referred to as an iridium (III) complex.
- Examples of the iridium (III) complex having a chiral proline amide compound as a ligand include (R) or (S) -chloro [(1,2,3,4,5- ⁇ ) -pentamethyl-2,4 -Cyclopentadien-1-yl] [N- (2-methoxy-3-dibenzofuranyl) -2-pyrrolidinecarboxamidate- ⁇ N1, ⁇ N2] iridium (III) complex, (R) or (S) -chloro [ (1,2,3,4,5- ⁇ ) -pentamethyl-2,4-cyclopentadien-1-yl] (N-6-quinolinyl-2-pyrrolidinecarboxamidate- ⁇ N1, ⁇ N2) iridium (III) complex , (R) or (S) -chloro [(1,2,3,4,5- ⁇ ) -pentamethyl-2,4-cyclopentadien-1-yl] (2-pyrrolidinecarboxamidato- ⁇ N
- the iridium (III) complex having a chiral proline amide compound as a ligand can be used in an asymmetric reduction reaction using the prepared solution as a catalyst, but crystalline iridium (III It is more preferable to use a purified and isolated complex for the asymmetric reduction reaction.
- purified and isolated crystalline iridium (III) complex is used as a catalyst for asymmetric reduction reaction, superior chemical and asymmetric yields are achieved in the product compared to using the catalyst preparation solution as it is. Because it is done.
- the iridium (III) complex undergoes partial epimerization during catalyst preparation or while the preparation liquid is left standing due to the action of the base component coexisting in the catalyst preparation solution, resulting in a decrease in the optical purity of the catalyst. Because it will do. For this reason, when using a catalyst preparation liquid as it is, it is necessary to use it immediately after preparation.
- the iridium (III) complex is purified and isolated from the catalyst preparation solution, the base component and epimer (epimer) that cause epimerization can be removed in the process, so the crystallinity is high in optical purity and good in storage stability. The iridium (III) complex is obtained.
- Purification and isolation methods include isolating the produced iridium (III) complex from a solution once by concentration, etc., and then purifying it by a known recrystallization method or reprecipitation method, or using a solvent with high purification efficiency from the beginning.
- the main product precipitated through the purification process can be filtered, washed, and dried, etc., and chemically and optically pure crystalline iridium (III )
- the complex can be easily obtained.
- the purified and isolated crystalline iridium (III) complex has high stability, the chemical purity and the optical purity are constant over a long period of time, and can be stored for a long period at room temperature. When this complex is used as a catalyst for an asymmetric reduction reaction, a reduction product can be obtained with a high chemical yield and an asymmetric yield.
- NMR Nuclear magnetic resonance spectrum
- Gemini-200 manufactured by Varian
- Measurement was performed at room temperature using TMS (tetramethylsilane) as an internal standard substance and CDCl 3 or CD 3 OD as a measurement solvent. All measured values are expressed in ⁇ (ppm).
- High performance liquid chromatography (HPLC) was measured by LC10A (manufactured by Shimadzu Corporation). The optical purity was determined from the difference in retention time in HPLC. Specific rotation was measured by P-1020 (manufactured by JASCO). Unless otherwise stated, commercially available products and solvents were used for the reaction.
- Example 1 529 mg of 7-methoxy- ⁇ -tetralone was dissolved in 30 ml of methanol, and (S) -chloro [(1,2,3,4,5- ⁇ ) -pentamethyl-2,4-cyclopentadien-1-yl] (2 -Pyrrolidinecarboxamidato- ⁇ N1, ⁇ N2) 57 mg of iridium (III) was added. The solution was cooled to ⁇ 10 ° C., and 7.5 ml of a formic acid / triethylamine (molar ratio 5/2) mixed solution was added dropwise. The reaction was completed when stirring was continued for 2 days at the same temperature. The reaction mixture was concentrated under reduced pressure and extracted with methylene chloride.
- the extract was basified with aqueous sodium carbonate solution, and the layers were separated. The organic layer was washed with water and concentrated to give 480 mg of 7-methoxy-2-tetralol as an oil.
- Example 2 292 mg of ⁇ -tetralone was dissolved in 2 ml of methanol, and (S) -chloro [(1,2,3,4,5- ⁇ ) -pentamethyl-2,4-cyclopentadien-1-yl] (2-pyrrolidinecarboxami Dato- ⁇ N1, ⁇ N2) 38 mg of iridium (III) was added.
- the solution was cooled to ⁇ 10 ° C., and 5.0 ml of a formic acid / triethylamine (molar ratio 5/2) mixed solution was added dropwise. The reaction was completed when stirring was continued for 2 days at the same temperature.
- the reaction mixture was concentrated under reduced pressure and extracted with methylene chloride.
- Example 3 352 mg of 7-methoxy- ⁇ -tetralone is dissolved in 20 ml of methanol, and (S) -chloro [(1,2,3,4,5- ⁇ ) -pentamethyl-2,4-cyclopentadien-1-yl] (2 -Pyrrolidinecarboxamidato- ⁇ N1, ⁇ N2) 38 mg of iridium (III) was added.
- the solution was cooled to ⁇ 10 ° C., and 5.0 ml of a formic acid / triethylamine (molar ratio 5/2) mixed solution was added dropwise. The reaction was completed when stirring was continued for 2 days at the same temperature.
- the reaction mixture was concentrated under reduced pressure and extracted with methylene chloride.
- the extract was basified with aqueous sodium carbonate solution, and the layers were separated. The organic layer was washed with water and concentrated to give 334 mg of 7-methoxy- ⁇ -tetralol as an oil.
- Example 4 296 mg of 4-chromanone is dissolved in 40 ml of methanol and (S) -chloro [(1,2,3,4,5- ⁇ ) -pentamethyl-2,4-cyclopentadien-1-yl] (2-pyrrolidinecarboxamidate - ⁇ N1, ⁇ N2) After adding 38 mg of iridium (III), cooling to ⁇ 20 ° C., dropping 4.0 ml of formic acid / triethylamine (molar ratio 5/2) mixed solution, and stirring at the same temperature for 2 days, the reaction is completed. To do.
- reaction solution was concentrated under reduced pressure, extracted with methylene chloride, basified with an aqueous sodium carbonate solution, then separated, and the organic layer was washed with water and concentrated.
- the resulting oily product was purified by silica gel column chromatography to obtain 260 mg of colorless crystals. Obtained.
- the optical purity was 99.0% ee. This is (R) -4-chromanol.
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Abstract
Description
光学活性アルコールの製造方法には種々のものがあるが、最も効率的な方法は非対称ケトンの触媒的不斉還元反応を用いる方法である。このため、数多くのケトンの不斉還元触媒が開発されてきているが、とりわけ野依らの発明によるRuCl(Tsdpen)(p-cymene)に代表される光学活性ジアミン配位子を有する不斉ルテニウム錯体(例えば特許文献1参照)を用いる水素移動型不斉還元反応は非常に高い不斉収率を与える上に、2-プロパノールや蟻酸といった有機化合物を水素源に利用できるために還元剤として高圧水素ガスを用いる場合のような特殊設備が不要であるなどで工業的に最も有利な方法である。
[1] キラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体の存在下にケトンを還元することを特徴とする光学活性アルコールの製造方法。
[2] ケトンが式[I]:
R1およびR2が適宜の位置で連結して環を形成していてもよく、
該環にはさらに同一または異なって1個若しくは2個以上の酸素、置換されていてもよい窒素、または硫黄を含んでいてもよい。)
で示される化合物である[1]に記載の製造方法。
[4] 光学活性アルコールが式[II]:
で示される化合物である[1]~[4]のいずれかに記載の製造方法。
[7] キラルなプロリンアミド類化合物が、(R)-N-(6-キノリニル)-2-ピロリジンカルボキサミドまたは(S)-N-(6-キノリニル)-2-ピロリジンカルボキサミドである[1]~[6]のいずれかに記載の製造方法。
[8] キラルなプロリンアミド類化合物が、(R)-N-(2-メトキシ-3-ジベンゾフラニル)-2-ピロリジンカルボキサミドまたは(S)-N-(2-メトキシ-3-ジベンゾフラニル)-2-ピロリジンカルボキサミドである[1]~[6]のいずれかに記載の製造方法。
[9] キラルなプロリンアミド類化合物が、(R)-2-ピロリジンカルボキサミドまたは(S)-2-ピロリジンカルボキサミドである[1]~[5]のいずれかに記載の製造方法。
[11] キラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体が、(R)または(S)-クロロ〔(1,2,3,4,5-η)-ペンタメチル-2,4-シクロペンタジエン-1-イル〕(2-ピロリジンカルボキサミダト-κN1,κN2)イリジウム(III)触媒のいずれかである[1]~[5]および[9]のいずれかに記載の製造方法。
[12] キラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体が結晶性である[1]~[11]のいずれかに記載の製造方法。
[13] 還元がケトンと水素供与性化合物の反応により行われる[1]~[12]のいずれかに記載の製造方法。
[14] 水素供与性化合物が蟻酸または蟻酸塩である[13]に記載の製造方法。
さらに詳説すれば、通常、不斉反応の触媒として用いる配位子は、複雑な構造をした金属錯体であり、非常に高価であるという問題がある。しかし、本発明に用いる配位子は単純な構造を有するキラルなプロリンアミド類化合物である。とりわけ(R)および(S)-プロリンアミドは分子量が低く工業的に容易に製造可能なため、安価な化合物であり、本発明は産業上非常に利用価値の高い製造方法である。
本発明の製造方法は、例えば下記に示す化学反応式に従って行うことができる。
本発明の製造方法において出発原料に用いられるケトンは、分子内にケトン基を有する化合物であれば特に制限されず、目的とする光学活性アルコールに対して適宜選ぶことができる。
R1およびR2が適宜の位置で連結して環を形成していてもよく、
該環にはさらに同一または異なって1個若しくは2個以上の酸素、置換されていてもよい窒素、または硫黄を含んでいてもよく、置換されていてもよい脂肪環若しくは複素環と、置換されていてもよい芳香環若しくは複素芳香環との縮合環であってもよい)
で示される化合物が好ましい。
前記の直鎖若しくは分岐状のアルキル基、シクロアルキル基、アリール基、ヘテロアリール基、アラルキル基、ヘテロアリールアルキル基、アルケニル基およびアルキニル基における置換基の数は、例えば1~4とすることができる。
該環は、単環構造でも多環構造でもよい。該環が多環構造の場合、2または3以上の単環からなる多環または縮合環であってもよい。該環が多環構造の場合、2以上の脂肪環若しくは複素環からなる多環または縮合環であってもよく、脂肪環若しくは複素環および芳香環若しくは複素芳香環からなる多環または縮合環であってもよい。
該環は、さらに同一または異なって1個若しくは2個以上の酸素、置換されていてもよい窒素、または硫黄を含んでいてもよい。ここで、前記窒素の置換基としては、例えば前記の直鎖若しくは分岐状のアルキル基において例示した置換基と同じものが挙げられる。
置換されていてもよい脂肪環における“脂肪環”としては、例えば4~10員の脂肪環が挙げられ、具体的にはシクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン、シクロノナン、シクロデカンなどが挙げられる。
置換されていてもよい複素環における“複素環”としては、例えば4~10員の複素環が挙げられ、具体的にはピロリジン、ピペリジン、テトラヒドロフランなどが挙げられる。
置換されていてもよい複素芳香環における“複素芳香環”としては、例えば5~12員の芳香環が挙げられ、具体的にはフラン、ピロール、チオフェン、オキサゾール、イミダゾール、チアゾ-ル、ピリジン、ピリダジン、ピリミジン、ピラジンなどが挙げられる。
置換されていてもよい脂肪環若しくは複素環、置換されていてもよい芳香環または複素芳香環における置換基としては、例えば前記の直鎖若しくは分岐状のアルキル基において例示した置換基と同じものが挙げられる。また、置換されていてもよい脂肪環若しくは複素環、置換されていてもよい芳香環または複素芳香環における置換基の数は、例えば1~4個であればよく、1~2個であることが好ましい
前記縮合環である化合物において、カルボニル基以外の置換基としては、例えば前記の直鎖若しくは分岐状のアルキル基において例示した置換基と同じものが挙げられる。
前記縮合環を構成する環である、環内に同一若しくは異なって1個若しくは2個以上の酸素、置換されていてもよい窒素、または硫黄を含んでいてもよい4~10員の脂肪環としては、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン、シクロノナン、シクロデカン、シクロヘキセン、ピロリジン、ピペリジン、テトラヒドロフランなどが挙げられる。
前記縮合環を構成する環である、環内に同一若しくは異なって1個若しくは2個以上の酸素、置換されていてもよい窒素、または硫黄を含んでいてもよい5~12員の芳香環若しくは複素芳香環としては、ベンゼン、ナフタレン、フラン、ピロール、チオフェン、オキサゾール、イミダゾール、チアゾ-ル、ピリジン、ピリダジン、ピリミジン、ピラジンなどが挙げられる。 前記窒素の置換基としては、例えば前記の直鎖若しくは分岐状のアルキル基において例示した置換基と同じものが挙げられる。
前記縮合環を構成する環である4~10員の脂肪環若しくは芳香環及び5~12員の芳香環若しくは複素芳香環の置換基としては、例えば前記の直鎖若しくは分岐状のアルキル基において例示した置換基と同じものが挙げられる。
本発明の製造方法において、還元はケトンと水素供与性化合物の反応により行われる。本発明に用いる水素供与性化合物としては特に限定されず、例えば蟻酸、2-プロパノールなどの還元性化合物;、例えば蟻酸ナトリウム、蟻酸カリウム、蟻酸アンモニウムなどの前記還元性化合物の塩が挙げられる。高い不斉収率を得るためには終始、酸性条件下で反応が行えるため、蟻酸若しくは蟻酸塩又はこれらの混合物が好ましい。蟻酸ナトリウム、蟻酸カリウムまたは蟻酸アンモニウムを単独で使用する場合には液性が塩基性を示すためにイリジウム(III)錯体の配位子であるキラルなプロリンアミド類化合物の塩基触媒によるラセミ化が懸念され、その結果として不斉収率の低下を引き起こす可能性がある。従って蟻酸ナトリウム、蟻酸カリウムまたは蟻酸アンモニウムなどを水媒体中で水素供与性化合物として用いる場合には、例えば酢酸ナトリウム/酢酸などで酸性に調製された緩衝溶液の共存下で反応を行うのが好ましい。
水素供与性化合物の使用量は、通常化合物[I]1モルに対し約1モル~約40モル、好ましくは約2モル~約20モルである。
塩基の使用量は、原料のイリジウム(III)化合物がダイマーである場合、該ダイマー1モルに対して通常約2~3モル、好ましくは約2~2.2モルである。
本発明の製造方法に用いる溶媒としては、例えばアセトニトリル、酢酸エチル、酢酸イソプロピル、N,N-ジメチルホルムアミド、テトラヒドロフラン、ジメトキシエタン、ジクロロメタン、またはメタノール、エタノール、2-プロパノール、エチレングリコールなどのアルコール類やこれらの含水溶媒などが挙げられる。溶媒の使用量は、ケトン1kgに対し、通常約2L~約200L、好ましくは約5L~約100Lである。
本発明の製造方法における還元反応は、化合物[I]の溶液にキラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体を添加、溶解させた後に、水素供与性化合物を添加、反応させることにより好適に実施できる。
本反応の製造方法において、反応温度は、通常-70℃以上であり、好ましくは約-30℃~約40℃である。
反応後は、公知の抽出、濃縮、ろ過、洗浄などの処理を行うことにより、目的とする光学活性アルコールを得ることができる。必要に応じて、結晶化や再結晶、蒸留、カラムクロマトグラフィーなどの精製操作を加えることでより純粋な光学活性アルコールに導くことができる。
本発明の製造方法による生成物である光学活性アルコールは、ヒドロキシル基を有し、原料であるケトンに対応する構造を有するものであれば特に制限されない。
で示される化合物であることが好ましい。
R1、R2の定義および例示は、式[I]で述べたものと同じものが挙げられる。
本発明の製造方法により製造された光学活性アルコールは、医薬品、農薬、液晶材料、ファインケミカルなどの合成原料として用いることができる。
本発明に用いる触媒は、キラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体であれば特に限定されない。
(イリジウム(III)化合物)
イリジウム(III)化合物としては、例えばペンタメチルシクロペンタジエニルイリジウム(III)クロリドダイマー、アセチルアセトナトイリジウム(III)、トリス(ノルボルナジエン)(アセチルアセトナト)イリジウム(III)などが挙げられ、とりわけペンタメチルシクロペンタジエニルイリジウム(III)クロリドダイマーが好ましい。
キラルなプロリンアミド類化合物としては、式[III]:
で示される化合物が挙げられる。
式[III]で表されるプロリンアミド類化合物としては、プロリンアミドの他、N-置換アミド、例えばN-アルキルアミド、N-シクロアルキルアミド、N-アリールアミド、N-ヘテロアリールアミド、N-アラルキルアミド、N-ヘテロアリールアルキルアミドなどが挙げられる。これらはR3置換基の例示であるが、置換基はさらに置換基(以下、置換分ということもある。)を有していてもよい。
N-アルキルアミドにおける“アルキル基”、“ヘテロアリール基”、“アラルキル基”および“ヘテロアリールアルキル基”の置換基としては、前記した置換基(A)と同様のものが挙げられる。
触媒の調製に用いる塩基としては弱塩基が好ましく、トリエチルアミン、トリメチルアミン、トリブチルアミン、N-メチルモルホリンなどの第3級アミン類、炭酸水素ナトリウム、炭酸水素カリウムなどの炭酸水素アルカリ金属塩、炭酸カルシウム、炭酸マグネシウムなどの炭酸アルカリ土類金属塩などがより好ましく、トリエチルアミンが特に好ましい。水酸化ナトリウム、水酸化カリウムなどのアルカリ金属の水酸化物やナトリウムメトキシドなどの強塩基を触媒の調製に用いることは、調製したプロリンアミド錯体が速やかにエピ化し光学純度が低下するために好ましくない。
塩基の使用量は、原料のイリジウム(III)化合物がダイマーである場合、該ダイマー1モルに対して通常約2~3モル、好ましくは約2~2.2モルである。
触媒の調製に用いる溶媒としては有機溶媒が好ましい。有機溶媒としては、例えば脂肪族炭化水素類(例えばペンタン、ヘキサン、ヘプタン、オクタン、シクロヘキサンなど)、芳香族炭化水素類(例えばベンゼン、トルエン、キシレンなど)、ハロゲン化炭化水素類(例えばジクロロメタン、1,2-ジクロロエタン、クロロホルム、四塩化炭素、o-ジクロロベンゼンなど)、アルコール類(例えばメタノール、エタノール、イソプロピルアルコール、t-ブチルアルコール、t-アミルアルコールなど)、エーテル類(例えばジメチルエーテル、エチルメチルエーテル、ジエチルエーテル、ジイソプロピルエーテル、ジグリム、tert-ブチルメチルエーテル、ジメトキシエタン、エチレングリコールジエチルエーテル、テトラヒドロフラン、1,4-ジオキサンなど)、アミド類(例えばN,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドンなど)、スルホキシド類(例えばジメチルスルホキシドなど)、ニトリル類(例えばアセトニトリル、プロピオニトリル、ベンゾニトリルなど)、ケトン類(例えばアセトン、メチルエチルケトン、メチルイソブチルケトンなど)、エステル化合物(例えば酢酸メチル、酢酸エチルなど)などが挙げられる。水とよく混和するアルコール類、エーテル類、アミド類、スルホキシド類、ニトリル類、ケトン類、エステル類を用いる場合には50%程度までの水を含ませてもよい。中でもメタノール、水含有メタノール、エタノール、水含有エタノール、塩化メチレン、酢酸エチルまたはアセトニトリルがより好ましい。
本発明に用いる触媒であるキラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体は、キラルなプロリンアミド類化合物を溶媒に溶解し、イリジウム(III)化合物および塩基(例えばトリエチルアミンなど)を添加し、好ましくは室温で通常10分~20時間攪拌することにより調製することができる。
本発明の製造方法に用いる触媒としては、キラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体は、キラルなプロリンアミド類と3価イリジウム(III)化合物から形成される錯体であればよい。
本発明の製造方法に用いる触媒としては、式[III]:
で示されるキラルなプロリンアミド類と3価のイリジウム化合物から形成される錯体が好ましい。この化合物を、以下イリジウム(III)錯体ともいう。
精製単離の方法としては、生成したイリジウム(III)錯体を溶液から濃縮等で一旦単離した後に公知の再結晶法や再沈殿法で精製する方法や、はじめから精製効率の高い溶媒のもとで錯体形成を行い、精製過程を経て析出してくる主生成物を濾過、洗浄、乾燥させる方法などを用いることができ、これらの方法により化学的かつ光学的に純粋な結晶性イリジウム(III)錯体を容易に得ることができる。
精製単離された結晶性のイリジウム(III)錯体は安定性が高く、化学純度および光学純度が長期間にわたって一定であり、室温で長期保存が可能である。この錯体を触媒として不斉還元反応に用いれば、高い化学収率および不斉収率で還元生成物が得られる。
核磁気共鳴スペクトル(NMR)は、Gemini-200(Varian製)により計測した。内部標準物質としてTMS(Tetramethylsilane)を用い、測定溶媒としてCDCl3またはCD3ODを用いて、室温下で計測した。測定値はすべてδ(ppm)で示した。
高速液体クロマトグラフィー(HPLC)は、LC10A(島津製作所製)により計測した。HPLCにおける保持時間の差から、光学純度を決定した。
比旋光度は、P-1020(JASCO製)により計測した。
反応に用いた溶媒および試薬は特記ない限り、市販品を使用した。
7-メトキシ-β-テトラロン 529mgをメタノール30mlに溶解し、(S)-クロロ〔(1,2,3,4,5-η)-ペンタメチル-2,4-シクロペンタジエン-1-イル〕(2-ピロリジンカルボキサミダト-κN1,κN2)イリジウム(III)57mgを加えた。溶液を-10℃に冷却し、蟻酸/トリエチルアミン(モル比5/2)混合溶液7.5mlを滴下した。同温で2日間攪拌を続けると反応は終了した。反応液を減圧濃縮し、塩化メチレンで抽出した。抽出物に炭酸ナトリウム水溶液を加えて塩基性とした後に分液し有機層を水洗、濃縮したところ、480mgの7-メトキシ-2-テトラロールが油状物として得られた。
光学活性カラム展開溶媒:(CHIRALPAC AD-H;ダイセル化学工業(株)、展開溶媒:n-ヘキサン/2-プロパノール=95/5)を用いて分析したところ、このものは、(R)-7-メトキシ-2-テトラロールであり、目的物(R体)の光学純度は92.0%eeであった。
比旋光度:[α]D 20 +45.6(C=1.24、CHCl3)
1H-NMR (200 MHz, CDCl3): δ1.70-1.89 (1H, m, one of 3-H2), 1.85 (1H, s, OH), 1.96-2.11 (1H, m, one of 3-H2), 2.66-3.11 (4H, m, 1-H2 and 4-H2), 3.77 (3H, s, OMe), 4.07-4.20 (1H, m, 2-H), 6.61 (1H, d, J = 2.7 Hz, ArH), 6.70 (1H, dd, J = 8.4, 2.7 Hz, ArH), 7.00 (1H, d, J = 8.4 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ26.1 (CH2), 31.7 (CH2), 38.6 (CH2), 55.2 (OMe), 67.2 (2-C), 112.4 (ArCH), 114.0 (ArCH), 127.7 (quaternary ArC), 129.4 (ArCH), 135.4 (quaternary ArC), 157.7 (quaternary ArC).
β-テトラロン 292mgをメタノール2mlに溶解し、(S)-クロロ〔(1,2,3,4,5-η)-ペンタメチル-2,4-シクロペンタジエン-1-イル〕(2-ピロリジンカルボキサミダト-κN1,κN2)イリジウム(III)38mgを加えた。溶液を-10℃に冷却し、蟻酸/トリエチルアミン(モル比5/2)混合溶液5.0mlを滴下した。同温で2日間攪拌を続けると反応は終了した。反応液を減圧濃縮し、塩化メチレンで抽出した。抽出物に炭酸ナトリウム水溶液を加えて塩基性とした後に分液し有機層を水洗、濃縮したところ、268mgの2-テトラロールが油状物として得られた。
このものを光学活性カラム(CHIRALPAC AD-H;ダイセル化学工業(株)、展開溶媒:n-ヘキサン/2-プロパノール=50/1)を用いて分析したところ(R)-2-テトラロールであり、目的物(R体)の光学純度は89.6%eeであった。
比旋光度:[α]D 20 +57.6(C=1.07、CHCl3)
1H-NMR (200 MHz, CDCl3): δ1.71-1.90 (1H, m, one of 3-H2), 1.85 (1H, s, OH), 1.97-2.12 (1H, m, one of 3-H2), 2.68-3.14 (4H, m, 1-H2 and 4-H2), 4.08-4.21 (1H, m, 2-H), 7.05-7.15 (4H, m, ArH).
13C-NMR (50.3 MHz, CDCl3): δ26.9 (CH2), 31.4 (CH2), 38.4 (CH2), 67.2 (2-C), 125.8 (ArCH), 125.9 (ArCH), 128.6 (ArCH), 129.5 (ArCH), 134.2 (quaternary ArC), 135.6 (quaternary ArC).
7-メトキシ-α-テトラロン 352mgをメタノール20mlに溶解し、(S)-クロロ〔(1,2,3,4,5-η)-ペンタメチル-2,4-シクロペンタジエン-1-イル〕(2-ピロリジンカルボキサミダト-κN1,κN2)イリジウム(III)38mgを加えた。溶液を-10℃に冷却し、蟻酸/トリエチルアミン(モル比5/2)混合溶液5.0mlを滴下した。同温で2日間攪拌を続けると反応は終了した。反応液を減圧濃縮し塩化メチレンで抽出した。抽出物に炭酸ナトリウム水溶液を加えて塩基性とした後に分液し有機層を水洗、濃縮したところ、334mgの7-メトキシ-α-テトラロールが油状物として得られた。
このものを光学活性カラム(CHIRALPAC AD-H;ダイセル化学工業(株)、展開溶媒:n-ヘキサン/2-プロパノール=50/1)を用いて分析したところ、(R)-7-メトキシ-α-テトラロールであり、目的物(R体)の光学純度は98.1%eeであった。
比旋光度:[α]D 20 ―46.8(C=1.33、CHCl3)
1H-NMR (200 MHz, CDCl3): δ1.68-2.04 (4H, m, 2-H2 and 3-H2), 1.84 (1H, s, OH), 2.56-2.83 (2H, m, 4-H2), 3.79 (3H, s, OMe), 4.72 (1H, dd, J = 5.5, 4.6 Hz, 1-H), 6.77 (1H, dd, J = 8.2, 2.7 Hz, ArH), 6.98 (1H, d, J = 2.7 Hz, ArH), 7.01 (1H, d, J = 8.2 Hz, ArH).
13C-NMR (50.3 MHz, CDCl3): δ19.2 (CH2), 28.4 (CH2), 32.4 (CH2), 55.3 (OMe), 68.4 (1-C), 112.6 (ArCH), 114.3 (ArCH), 129.1 (quaternary ArC), 129.9 (ArCH), 139.8 (quaternary ArC), 157.9 (quaternary ArC).
4-クロマノン 296mgをメタノール40mlに溶解し(S)-クロロ〔(1,2,3,4,5-η)-ペンタメチル-2,4-シクロペンタジエン-1-イル〕(2-ピロリジンカルボキサミダト-κN1,κN2)イリジウム(III)38mgを加えた後にー20℃に冷却し蟻酸/トリエチルアミン(モル比5/2)混合溶液4.0mlを滴下し同温で2日間攪拌を続けると反応は終了する。反応液を減圧濃縮し塩化メチレンで抽出し炭酸ナトリウム水溶液を加えて塩基性とした後に分液し有機層を水洗、濃縮して得られる油状物をシリカゲルカラムクロマトグラフィーで精製すると260mgの無色結晶が得られた。
このものを光学活性カラム(CHIRALPAC IB;ダイセル化学工業(株)、n-ヘキサン/2-プロパノール=95/5)を用いて分析したところ光学純度は99.0%eeであった。このものは(R)-4-クロマノールである。
(結果)
比旋光度:[α]20 D 72.7(C=0.5、EtOH)
1H-NMR (200 MHz, CDCl3): δ1.93-2.19 (3H, m, 3-H2 and OH), 4.19-4.33 (2H, m, 2-H2), 4.75 (1H, br t, J = 3.9 Hz, 4-H), 6.83 (1H, dd, J = 8.2, 1.3 Hz, 8-H), 6.91 (1H, td, J = 7.5, 1.3 Hz, 6-H), 7.20 (1H, ddd, J = 8.2, 7.5, 1.6 Hz, 7-H), 7.30 (1H, dd, J = 7.5, 1.6 Hz, 5-H).
13C-NMR (50.3 MHz, CDCl3): δ30.8 (3-C), 61.9 (2-C), 63.2 (4-C), 117.1 (ArCH), 120.6 (ArCH), 124.3 (quaternary ArC), 129.6 (overlapped, 2 x ArCH), 154.6 (quaternary ArC).
2-ベンジリデンシクロヘキサノン 373mgをメタノール40mlに溶解し(S)-クロロ〔(1,2,3,4,5-η)-ペンタメチル-2,4-シクロペンタジエン-1-イル〕(2-ピロリジンカルボキサミダト-κN1,κN2)イリジウム(III)38mgを加えた後にー20℃に冷却し蟻酸/トリエチルアミン(モル比5/2)混合溶液4.0mlを滴下し同温で2日間攪拌を続けると反応は終了する。反応液を減圧濃縮し塩化メチレンで抽出し炭酸ナトリウム水溶液を加えて塩基性とした後に分液し有機層を水洗、濃縮して得られる油状物をシリカゲルカラムクロマトグラフィーで精製すると273mgの無色結晶が得られた。
このものを光学活性カラム(CHIRALPAC IB;ダイセル化学工業(株)、n-ヘキサン/2-プロパノール=95/5)を用いて分析したところ光学純度は85.3%eeであった。このものは(E)―(1S)―2-ベンジリデンシクロヘキサノールである。
(結果)
比旋光度:[α]20 D-33.0(C=0.5、CHCl3)
1H-NMR (200 MHz, CDCl3): δ1.38-1.71 (4H, m, 2 x CH2), 1.77-2.19 (4H, m, 3H of 2 x CH2 and OH), 2.65-2.79 (1H, m, one of CH2), 4.23 (1H, ddd, J = 8.1, 4.0, 1.3 Hz, 1-H), 6.52 (1H, br s, benzylic H), 7.16-7.25 (3H, m, ArH) , 7.27-7.39 (2H, m, ArH).
13C-NMR (50.3 MHz, CDCl3): δ23.2 (CH2), 27.0 (CH2), 27.3 (CH2), 36.5 (CH2), 73.7 (1-C), 120.8 (ArCH), 126.2 (ArCH), 128.1 (ArCH), 128.9 (ArCH), 137.7 (quaternary ArC), 144.3 (quaternary ArC).
Claims (14)
- キラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体の存在下にケトンを還元することを特徴とする光学活性アルコールの製造方法。
- ケトンが式[I]:
R1およびR2が適宜の位置で連結して環を形成していてもよく、
該環にはさらに同一または異なって1個若しくは2個以上の酸素、置換されていてもよい窒素、または硫黄を含んでいてもよい。)
で示される化合物である請求項1に記載の製造方法。 - 環が、置換されていてもよい脂肪環若しくは複素環と、置換されていてもよい芳香環若しくは複素芳香環との縮合環である請求項2に記載の製造方法。
- キラルなプロリンアミド類化合物が、(R)-プロリンヘテロアリ-ルアミドまたは(S)-プロリンヘテロアリ-ルアミドである請求項1~5のいずれかに記載の製造方法。
- キラルなプロリンアミド類化合物が、(R)-N-(6-キノリニル)-2-ピロリジンカルボキサミドまたは(S)-N-(6-キノリニル)-2-ピロリジンカルボキサミドである請求項1~6のいずれかに記載の製造方法。
- キラルなプロリンアミド類化合物が、(R)-N-(2-メトキシ-3-ジベンゾフラニル)-2-ピロリジンカルボキサミドまたは(S)-N-(2-メトキシ-3-ジベンゾフラニル)-2-ピロリジンカルボキサミドである請求項1~6のいずれかに記載の製造方法。
- キラルなプロリンアミド類化合物が、(R)-2-ピロリジンカルボキサミドまたは(S)-2-ピロリジンカルボキサミドである請求項1~5のいずれかに記載の製造方法。
- キラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体が、(R)または(S)-クロロ〔(1,2,3,4,5-η)-ペンタメチル-2,4-シクロペンタジエン-1-イル〕〔N-(2-メトキシ-3-ジベンゾフラニル)-2-ピロリジンカルボキサミダト-κN1,κN2〕イリジウム(III)触媒、(R)または(S)-クロロ〔(1,2,3,4,5-η)-ペンタメチル-2,4-シクロペンタジエン-1-イル〕(N-6-キノリニル-2-ピロリジンカルボキサミダト-κN1,κN2)イリジウム(III)触媒のいずれかである請求項1~6のいずれかに記載の製造方法。
- キラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体が、(R)または(S)-クロロ〔(1,2,3,4,5-η)-ペンタメチル-2,4-シクロペンタジエン-1-イル〕(2-ピロリジンカルボキサミダト-κN1,κN2)イリジウム(III)触媒のいずれかである請求項1~5および請求項9のいずれかに記載の製造方法。
- キラルなプロリンアミド類化合物を配位子とするイリジウム(III)錯体が結晶性である請求項1~11のいずれかに記載の製造方法。
- 還元がケトンと水素供与性化合物の反応により行われる請求項1~12のいずれかに記載の製造方法。
- 水素供与性化合物が蟻酸または蟻酸塩である請求項13に記載の製造方法。
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WO2002010101A1 (fr) * | 2000-08-01 | 2002-02-07 | Shionogi & Co., Ltd. | Procede de production d'un alcool en presence d'un complexe de metaux de transition contenant un compose amide en tant que liant |
JP2003176266A (ja) * | 2001-12-13 | 2003-06-24 | Sumitomo Chem Co Ltd | 光学活性なアゼチジンアミド配位遷移金属錯体および用途 |
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Also Published As
Publication number | Publication date |
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JPWO2013061999A1 (ja) | 2015-04-02 |
JP6038800B2 (ja) | 2016-12-07 |
EP2772476B1 (en) | 2017-01-11 |
EP2772476A4 (en) | 2015-06-24 |
US20140296584A1 (en) | 2014-10-02 |
EP2772476A1 (en) | 2014-09-03 |
US9174899B2 (en) | 2015-11-03 |
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