WO2001040162A1 - Procede de production de benzhydrols optiquement actifs - Google Patents

Procede de production de benzhydrols optiquement actifs Download PDF

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Publication number
WO2001040162A1
WO2001040162A1 PCT/JP2000/008392 JP0008392W WO0140162A1 WO 2001040162 A1 WO2001040162 A1 WO 2001040162A1 JP 0008392 W JP0008392 W JP 0008392W WO 0140162 A1 WO0140162 A1 WO 0140162A1
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group
optically active
general formula
phosphine
salt
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PCT/JP2000/008392
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English (en)
Japanese (ja)
Inventor
Toru Yamano
Satoru Oi
Masayuki Yamashita
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Takeda Chemical Industries, Ltd.
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Priority to AU16480/01A priority Critical patent/AU1648001A/en
Publication of WO2001040162A1 publication Critical patent/WO2001040162A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • 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

Definitions

  • the present invention relates to a method for producing optically active benzhydrols useful as raw materials for the synthesis of pharmaceuticals and the like.
  • Methods for producing optically active alcohols include asymmetric reduction of carbonyl compounds using baker's yeast, optical resolution of racemic alcohols using enzymes, and high-performance liquid mouth chromatography ( Methods of optically resolving racemic alcohols using HPLC) and methods of asymmetric reduction of carbonyl compounds using an asymmetric hydrogenation catalyst are known.
  • a method of obtaining a racemic alcohol by asymmetric reduction of a carbonyl compound using baker's yeast can produce an alcohol with relatively high optical purity, but the absolute configuration of the alcohol is limited.
  • disadvantages such as complicated operation.
  • the method of optically resolving racemic alcohols using enzymes is not efficient because the theoretical yield is 50% at the maximum.
  • HPLC high performance liquid chromatography
  • Japanese Patent Application Laid-Open No. 11-189600 discloses a ruthenium complex, in particular, a compound that provides hydrogen or hydrogen to a carbonyl compound by using a ruthenium complex in which at least one of a phosphine ligand and an amine ligand is an optically active group as a catalyst.
  • a method for producing an alcohol compound by reduction in the presence of is described. However, there is no description that the method is applied to benzophenones to produce optically active benzohydrols.
  • JP-A-9-235255 discloses that a benzophenone derivative or a salt thereof is used as an asymmetric hydrogenation catalyst. There is described a process for producing an optically active form of a benzhydrol derivative or a salt thereof, which is characterized by hydrogenation in the presence. In this method, an optically active ruthenium-phosphine complex and an optically active amine ligand are added to a reaction system, and hydrogenation is performed under high hydrogen pressure and high temperature.
  • JP-A-11-189558 describes a method for producing optically active alcohols by asymmetric hydrogenation by reacting with a transition metal catalyst, an optically active nitrogen-containing compound and hydrogen in the presence of a base.
  • a transition metal catalyst an optically active nitrogen-containing compound
  • hydrogen in the presence of a base.
  • the present inventors have conducted intensive studies on the asymmetric reduction method as a method for producing optically active benzhydrols, and found that a ruthenium-phosphine-amine complex derived from a ruthenium complex, a phosphine, and an amine was simply prepared in advance. Separation, preferably by purification, allows the efficiency to be improved unexpectedly, even under mild conditions of low hydrogen pressure and room temperature (eg, 10 to 50), without being greatly affected by the type of raw material. For the first time, they have found that optically active benzhydrols can be obtained with high yield and high yield, and based on this finding, have completed the present invention.
  • R 1 and R 2 are the same or different and each represent a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group which may have a substituent, a ring A and a ring B Represents a benzene ring which may further have a substituent] or a salt thereof represented by the general formula (III)
  • R 3 , R 4 and R 5 are the same or different and each represents a hydrocarbon group which may have a substituent, and R 3 and R 4 are bonded to each other to have a substituent. Or a cyclic hydrocarbon which may be formed) or the general formula (IV)
  • W a is a divalent hydrocarbon group
  • R 3, R 4, R 6 and R 7 are the same or different connexion, it indicates a hydrocarbon group which may have a substituent
  • R 3 R 4 may be bonded to each other to form a cyclic hydrocarbon which may have a substituent
  • R 6 and R 7 may be bonded to each other to form a cyclic hydrocarbon which may have a substituent.
  • R 8 and R 9 are the same or different and each represent a hydrogen atom or a hydrocarbon group which may have a substituent] or a general formula (VI)
  • Z represents a divalent hydrocarbon residue
  • R 8 and R 9 represent the same or different and represent a hydrogen atom or a hydrocarbon group which may have a substituent.
  • the substituents that ring A and ring B may further have are a halogen atom, an optionally substituted hydroxy group, an optionally substituted alkyl group and an optionally substituted
  • the production method according to the above 1) which is 1 to 4 selected from an optionally substituted amino group, an optionally substituted acyl group, and an optionally esterified carboxyl group;
  • X and Y are the same or different and represent a hydrogen atom, a halogen atom or a hydroxyl group, m and ⁇ are the same or different and are an integer of 0 to 4, and other symbols are the same as those described in 1) above.
  • the production method according to the above 1) which is a complex represented by the following meaning:
  • X and Y are the same or different and represent a hydrogen atom, a halogen atom or a carboxyl group, m and ⁇ are the same or different and are an integer of 0 to 4, and other symbols are as defined in the above 1).
  • the production method according to the above 1), wherein the complex is represented by:
  • X and Y are the same or different and represent a hydrogen atom, a halogen atom or a hydroxyl group, m and ⁇ are the same or different and are an integer of 0 to 4, and other symbols are the same as those described in 1) above.
  • the production method according to the above 1) which is a complex represented by the following meaning:
  • X and Y are the same or different and represent a hydrogen atom, a halogen atom or a carbonyl group, m and ⁇ are the same or different and are an integer of 0 to 4, and the other symbols are the same as those described in 1) above.
  • the production method according to the above 1) which is a complex represented by the following meaning:
  • X and Y are hydrogen atoms, halogen atoms or carbohydrates
  • XylBINAP is 2,2'-bis [bis (3,5-dimethylphenyl) phosphino] -1,1'-binaphthyl
  • DAIPEN is triisopropyl-2,2-bis (p-methoxyphenyl)
  • xylBINAP and DAIPEN each represent an optically active group].
  • BINAP is 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl
  • DPEN is 1, 2-diphenylethylenediamine, and at least one of BINAP and DPEN represents an optically active group
  • M represents an alkali metal or an alkaline earth metal
  • Y 1 represents a hydroxy group, an alkoxy group or an alkylthio group
  • Q represents 1 or 2].
  • xylBINAP is 2,2'-bis [bis (3,5-dimethylphenyl) phosphino]-1,1'-binaphthyl
  • DAIPEN is triisopropyl-2,2-bis (p-methoxyphenyl)
  • N-acylation is performed to produce an optically active form of 2- [N- (2,3-dimethoxy-hydroxybenzyl) -14-chlorophenyl]]-rubumoyl-2,2-dimethylethyl acetate.
  • examples of the hydrocarbon group in the “hydrocarbon group which may have a substituent” include an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, and an aryl group.
  • examples of the acyl group in the ⁇ acyl group optionally having a group '' include an alkanoyl group, a cycloalkanoyl group, an alkenyl group, a cycloalkenyl group, an arylcarbonyl group, an alkoxycarbonyl group, an arylalkyloxycarbonyl group, and an aryl group And a carbonyl group.
  • the alkyl group include an alkyl group having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and 1-ethylpropyl. , Hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, and the like. Of these, an alkyl group having 1 to 6 carbon atoms is preferable, and neopentyl is particularly preferable.
  • cycloalkyl group examples include a cycloalkyl group having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo
  • alkenyl group examples include an alkenyl group having 2 to 10 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-11-propenyl, 1-butenyl, 2- Butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4_pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3_hexenyl, 5_hexenyl, Examples include 1-heptenyl and 1-octenyl.
  • cycloalkenyl group examples include a cycloalkenyl group having 3 to 10 carbon atoms, for example, 2-cyclopentene-1-yl, 3-cyclopentene-1-yl, 2-cyclohexene-1-yl , 3-cyclohexene-1-yl and the like.
  • aryl groups include aryl groups having 6 to 14 carbon atoms, such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenyl, tolyl (o_, m—, P-), xylyl, mesityl, Cumenyl and the like. Of these, phenyl and naphthyl are preferred.
  • alkanoyl groups include alkanoyl groups having 1 to 18 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanyl, octanoyl, palmitoyl, and stearoyl. No. Of these, acetyl, vivaloyl and the like are preferable.
  • cycloalkanol group examples include a cycloalkanol group having 4 to 11 carbon atoms, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl and the like.
  • alkenoyl group examples include an alkenoyl group having 3 to 18 carbon atoms, such as acryloyl, crotonyl, and oleoyl.
  • cycloalkenoyl group examples include a cycloalkenoyl group having 4 to 11 carbon atoms, such as 2-cyclohexenecarbonyl.
  • arylcarbonyl group examples include an arylcarbonyl group having 7 to 14 carbon atoms, such as benzoyl.
  • alkoxycarbonyl group examples include an alkoxycarbonyl group having 2 to 5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and tert-butoxycarbonyl.
  • aralkyloxycarbonyl group examples include an aralkyloxycarbonyl group having 8 to 10 carbon atoms, such as benzyloxycarbonyl.
  • aryloxycarbonyl group examples include an aryloxycarbonyl group having 7 to 15 carbon atoms, such as phenoxycarbonyl and p-tolyloxycarbonyl.
  • substituent of the “hydrocarbon group” and the “acyl group” in the “hydrocarbon group optionally having a substituent” and the “acyl group optionally having a substituent” include, for example, a halogen atom ( E.g., fluorine, chlorine, bromine, iodine, etc.), 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), an alkoxy group having 1 to 6 carbon atoms, hydroxy, Examples thereof include nitro and an amino group which may be substituted.
  • the number of substituents is, for example, 1 to 3, preferably 1 or 2.
  • optionally substituted amino group examples include, for example, an amino group which may be mono- or di-substituted by a hydrocarbon group or an acyl group.
  • examples of the hydrocarbon group or the acyl group include the same groups as described above.
  • Substituted amino groups include, for example, methylamino, dimethylamino, ethyl Amino, getylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dibutylamino, pentylamino, neopentylamino, diarylamino, cyclohexylamino, acetylamino, pentionylamino, benzoylamino, benzoylamino, methylbenzoylamino Examples include phenylamino, tert-butoxycarbonylamino, benzyloxycarbonylamino and the like.
  • R 1 and R 2 are preferably a hydrogen atom, an alkyl group, an aryl group, an alkanol group, an alkoxycarbonyl group or an aralkyloxycarbonyl group.
  • R 1 and R 2 are more preferably a hydrogen atom, an alkanol group having 1 to 6 carbon atoms (preferably acetyl, bivaloyl, etc.), an alkoxycarbonyl group having 2 to 5 carbon atoms (preferably tert-butoxycarbonyl) ) And an aralkyloxycarbonyl group having 8 to 10 carbon atoms (preferably benzyloxycarbonyl).
  • examples of the substituent which the ring A and the ring B may further have include, for example, a halogen atom, an optionally substituted hydroxy group, an optionally substituted alkyl Groups, an amino group which may be substituted, a diasyl group which may have a substituent, a carboxyl group which may be esterified, and the like.
  • the number of substituents is, for example, 1 to 4, preferably 1 to 3.
  • halogen atom examples include fluorine, chlorine, bromine, and iodine. Of these, chlorine and bromine are preferred, and chlorine is particularly preferred.
  • optionally substituted hydroxy group examples include a hydroxy group, an optionally substituted alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group, an aryloxy group and the like.
  • the “optionally substituted hydroxy group” also includes “a siloxy group optionally substituted with 1 to 3 hydrocarbon groups”.
  • alkoxy group examples include an alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, Neo pentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • An alkoxy group having 1 to 4 carbon atoms is preferred, and methoxy is particularly preferred.
  • alkenyloxy group examples include an alkenyloxy group having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, and 2-cycloalkenyl. Hexenyl methoxy and the like.
  • aralkyloxy group examples include an aralkyloxy group having 7 to 10 carbon atoms, such as benzyloxy and phenethyloxy.
  • acyloxy group examples include an alkoxy group having 2 to 13 carbon atoms, and more preferably an alkanoyloxy group having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isoptyryloxy, etc.) and the like.
  • alkanoyloxy group having 2 to 4 carbon atoms
  • aryloxy group examples include an aryloxy group having 6 to 14 carbon atoms, such as phenoxy and naphthyloxy.
  • alkoxy group, alkenyloxy group, aralkyloxy group, acyloxy group and aryloxy group may have one or two substituents at substitutable positions.
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • an alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), Hydroxy, nitro, amino and the like.
  • hydrocarbon group in the “siloxy group optionally substituted with 1 to 3 hydrocarbon groups” examples include, for example, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an aryl group, an aralkyl group, and an alkynyl group. And the like.
  • the number of carbon atoms in these hydrocarbon groups is preferably 1 to 14.
  • alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group and aryl group examples include those exemplified as R 1 and R 2 respectively.
  • aralkyl group examples include aralkyl groups having 7 to 15 carbon atoms, such as benzyl, phenether, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, and naphthyl. Methyl, ⁇ -naphthylethyl, / 3-naphthylmethyl, 3-naphthylethyl and the like.
  • alkynyl group examples include an alkynyl group having 2 to 10 carbon atoms, such as an ethynyl group and a 2-propynyl group.
  • the hydrocarbon group is preferably an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 14 carbon atoms.
  • Suitable examples of the “siloxy group optionally substituted with 1 to 3 hydrocarbon groups” include, for example, a group selected from an alkyl group having 1 to 4 carbon atoms and an aryl group having 6 to 14 carbon atoms. And a siloxy group substituted by 1 to 3 (eg, trimethylsiloxy, triethylsiloxy, tert-butyldimethylsiloxy, triisopropylsiloxy, tert-butyldiphenylsiloxy, etc.). In particular, tert-butyldimethylsiloxy is preferred.
  • alkyl group in the “optionally substituted alkyl group” examples include those exemplified as R 1 and R 2 . Of these, an alkyl group having 1 to 6 carbon atoms is preferable, and methyl is particularly preferable.
  • substituent in the “optionally substituted alkyl group” examples include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) and 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) And the like.
  • halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • 1 to 3 halogen atoms eg, fluorine, chlorine, bromine, iodine
  • alkoxy group having 1 to 6 carbon atoms which may be substituted, hydroxy, nitro and an amino group which may be substituted.
  • the number of substituents is, for example, 1 to 3, preferably 1 or 2.
  • Examples of the “optionally substituted amino group” and the “optionally substituted amino group” as a substituent which ring A and ring B may further have include, for example, a hydrocarbon group or an acyl group And an amino group which may be mono- or di-substituted.
  • examples of the hydrocarbon group and the acyl group include those exemplified as R 1 and R 2 . Of these, an alkanoyl group having 2 to 18 carbon atoms, an arylcarbonyl group having 7 to 14 carbon atoms, and the like are preferable.
  • substituted amino group examples include methylamino, dimethylamino, ethylamino, acetylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dibutylamino, pentylamino, neopentylamino, diarylamino, cyclohexylamino, cyclohexylamino.
  • Pionylamino benzoylamino, phenylamino, N-methyl-N-phenylamino, tert-butoxycarbonylamino, benzyloxycarbonylamino and the like.
  • acyl group those exemplified as R 1 and R 2 can be mentioned. Of these, an alkanoyl group having 2 to 18 carbon atoms, an arylpropyl group having 7 to 14 carbon atoms, and the like are preferable.
  • Examples of the “carboxyl group which may be esterified” include a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an aralkyloxycarbonyl group having 8 to 10 carbon atoms, and an aryloxycarbonyl group having 7 to 15 carbon atoms. Groups and the like.
  • Examples of the “C 2 to C 5 alkoxycarbonyl group”, “C 8 to C 10 aralkyloxycarbonyl group” and “C 7 to C 15 aryloxy carbonyl group” include R 1 and R 1 , respectively. 2 are exemplified.
  • the substituent which ring A and ring B may further have is preferably a halogen atom, an optionally substituted hydroxy group, an optionally substituted alkyl group having 1 to 4 carbon atoms and a substituted From 1 to 4 amino groups which may be substituted.
  • a halogen atom preferably a chlorine atom
  • an alkoxy group having 1 to 4 carbon atoms preferably methoxy
  • a siloxy group substituted with 1 to 3 alkyl groups having 1 to 4 carbon atoms preferably tert.
  • Amino group optionally substituted by an alkoxycarbonyl group having 2 to 5 carbon atoms or an aralkyloxycarbonyl group having 8 to 10 carbon atoms (preferably tert-butoxycarbonylamino, benzylo).
  • An alkyl group having 1 to 4 carbon atoms (preferably benzyloxycarbonylaminomethyl and the like) which may be substituted with; an alkoxycarbonyl group having 2 to 5 carbon atoms or 8 to 1 carbon atoms;
  • An amino group which may be substituted by an aralkyloxycarbonyl group (preferably tert-butoxy) Niruamino, benzyl O alkoxycarbonyl ⁇ Mino) and the like are preferable.
  • the substituent on ring A is preferably a halogen atom (preferably a chlorine atom); an alkoxy group having 1 to 4 carbon atoms (preferably methoxy); an alkoxycarbonyl group having 2 to 5 carbon atoms or 8 to 10 carbon atoms.
  • An amino group optionally substituted with an aralkyloxycarbonyl group preferably tert-butoxycarbonylamino, benzyloxycarbonylamino, etc.
  • 4 alkyl groups preferably tert-butoxycarbonylaminomethyl, benzyloxycarbonylaminomethyl, etc.
  • An amino group preferably tert-butoxycarbonylamino, benzyloxycarbonylamino, etc.).
  • Ring A has, as a substituent, two alkoxy groups each having 1 to 4 carbon atoms (preferably methoxy), an alkoxyl group having 2 to 5 carbon atoms, or an aryl group having 8 to 10 carbon atoms.
  • An alkyl group having 1 to 4 carbon atoms which may be substituted by an amino group (preferably teri-butoxycarbonylamino, benzyloxycarbonylamino, etc.) which may be substituted by a carbonyloxy group ( And preferably one tert-butoxycarbonylaminomethyl, benzyloxycarbonylaminomethyl).
  • the substituent on ring B is preferably an octylogen atom (preferably a chlorine atom); a siloxy group substituted with 1 to 3 carbon atoms of an alkyl group having 1 to 4 carbon atoms (preferably tert-butyldimethylsiloxane), and the like. It is.
  • Ring B is a siloxy group (preferably tert-butyl) having 1 or 2 halogen atoms (preferably chlorine atoms) or 1 to 3 carbon atoms, which is substituted with an alkyl group having 1 to 4 carbon atoms. It is preferable to have one dimethyloxy group. Further, the substitution position on the B ring of these substituents is preferably para-position with respect to the group represented by Formula 1 NRR 2 (the symbols have the same meanings as described above).
  • Ring A and ring B preferably do not have the same type of substituent at the same substitution position, that is, they do not preferably have a symmetrical relationship.
  • the compound represented by the general formula (I) or a salt thereof is a known compound described in JP-A-9-235255 and the like, and is a method known per se, for example, JP-A-6-239843 (European Patent Publication No. 567026) And JP-A-8-299899, "DA Walsh, Synthesis 1980, p. 677” or the like, or a method analogous thereto.
  • Examples of the salt of the compound represented by the general formula (I) include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid. Is mentioned.
  • Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt.
  • the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. And salts thereof.
  • salts with inorganic acids include salts with hydrochloric acid, sulfuric acid, nitric acid, bromic acid, iodic acid, borofluoric acid, perchloric acid, phosphoric acid, and the like.
  • Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, P — Salts with toluenesulfonic acid and the like.
  • Suitable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ordinine and the like.
  • salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid and the like.
  • the salt of the compound represented by the general formula (I) is preferably an inorganic salt such as a hydrochloride, a sulfate, a nitrate, a bromate, an iodate, a borofluoride, a perchlorate; Organic acid salts such as methanesulfonate, benzenesulfonate and P-toluenesulfonate.
  • an inorganic salt such as a hydrochloride, a sulfate, a nitrate, a bromate, an iodate, a borofluoride, a perchlorate
  • Organic acid salts such as methanesulfonate, benzenesulfonate and P-toluenesulfonate.
  • the “optically active ruthenium-phosphine-amine complex” used in the production method of the present invention is a phosphine represented by the general formula ( ⁇ ) or the general formula (IV) or a salt thereof, a general formula (V) or An amine represented by the general formula (VI) or a salt thereof and a ruthenium complex can be prepared by a method known per se, for example, J. Am. Chem. So, 120, 13529 (1998); Angew. Chem. Int. Ed., 37 , 1703 (1998); can be produced by reacting according to the method described in JP-A-1189600 or a method analogous thereto.
  • phosphine, amine and ruthenium complex are added to the reaction system.
  • the timing and order of addition are not particularly limited, and they may be added simultaneously to the reaction system, or may be added separately with a time lag.
  • the optically active ruthenium-phosphine-amine complex thus obtained is isolated by known means, for example, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography, etc., and preferably after purification. Used in the production method of the present invention. That is, the ruthenium-phosphine-amine complex is a reaction for producing an optically active form of the compound represented by the general formula (II) or a salt thereof from the compound represented by the general formula (I) or a salt thereof. Is produced outside the reaction system, applied after isolation.
  • the ruthenium-phosphine-amine complex isolated here may be a single compound.
  • the compound may be represented by any one of the general formulas (VII), (VIII), (IX) and (X). Or a salt thereof, wherein m or n are not necessarily the same.
  • the hydrogen group include those exemplified as the hydrocarbon group in the “siloxy group optionally substituted with one to three hydrocarbon groups”.
  • substituents in the “optionally substituted hydrocarbon group” represented by R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 include, for example, a “halogen atom”, “ “Nitro group”, “cyano group”, “optionally substituted acyl group”, “optionally substituted amino group”, “optionally substituted hydroxy group”, “optionally substituted thiol” Group “,” carboxyl group which may be esterified "and the like.
  • the number of substituents is, for example, 1 to 5, preferably 1 to 3.
  • halogen atom examples include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.
  • acyl group in the “optionally substituted acyl group” examples include those exemplified as R 1 and R 2 .
  • the acyl group may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include 1 to 3 halogen atoms (eg, fluorine, chlorine, iodine, etc.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • Examples of the thiol group which may be substituted include a thiol group, an alkylthio, a cycloalkylthio, an aralkylthio, an acylthio, an arylthio and the like.
  • Preferred examples of the alkylthio group include an alkylthio group having 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, and neopentyne. Luthio, hexylthio, heptylthio, nonylthio and the like.
  • cycloalkylthio group examples include a cycloalkylthio group having 3 to 10 carbon atoms, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
  • aralkylthio group examples include an aralkylthio group having 7 to 10 carbon atoms, such as benzylthio and phenethylthio.
  • acylthio group examples include an acylthio group having 2 to 13 carbon atoms, more preferably an alkanolthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.). .
  • arylthio groups include arylthio groups having 6 to 14 carbon atoms, such as phenylthio and naphthylthio.
  • examples of the cyclic hydrocarbon include a benzene ring and a cycloalkane having 3 to 10 carbon atoms (eg, , Cyclobutane, cyclopentane, cyclohexane, etc.), and cycloalgen having 3 to 10 carbon atoms (eg, cyclobutene, cyclopentene, cyclohexene, etc.).
  • substituents in the “cyclic hydrocarbon which may have a substituent” include the substituents in the “hydrocarbon group which may have a substituent” represented by R 3 and the like. What was done.
  • the number of substituents is, for example, 1 to 5, preferably Is one to three.
  • the “optionally substituted cyclic hydrocarbon” formed by R 6 and R 7 bonded to each other includes the “substituted cyclic hydrocarbon” formed by R 3 and R 4 bonded to each other. Cyclic hydrocarbons which may be substituted ".
  • the “divalent hydrocarbon group” represented by Z and W includes, for example, “a divalent acyclic hydrocarbon group” and “a divalent cyclic hydrocarbon group”.
  • divalent acyclic hydrocarbon group examples include alkylene having 1 to 8 carbon atoms, alkenylene having 2 to 8 carbon atoms, alkynylene having 2 to 8 carbon atoms, and the like.
  • alkylene having 1 to 8 carbon atoms examples include —CH 2 —, _ (CH 2 ) 2 —,-(CH 2 ) 3 —, one (CH 2 ) 4 —, one (CH 2 ) 5 —, one (CH 2 ) 6 _, one (CH 2 ) 7 _, _ (CH 2 ) 8 —, one CH (CH 3 ) —, _C (CH 3 ) 2 _, one (CH (CH 3 )) 2 —, _ (CH 2 ) 2 C (CH 3 ) 2 _, _ (CH 2 ) 3 C (CH 3 ) 2 — and the like.
  • alkynylene having 2 to 8 carbon atoms for example, _C ⁇ C one, -CH 2 -C ⁇ C one, - CH 2 - C ⁇ C- CH 2 - CH ", and the like.
  • divalent cyclic hydrocarbon group examples include cycloalkanes having 5 to 8 carbon atoms, cycloalkenes having 5 to 8 carbon atoms, and aromatic hydrocarbons having 6 to 14 carbon atoms (eg, benzene, naphthalene, indene, anthracene). ), A ring-assembled hydrocarbon having 12 to 20 carbon atoms (eg, biphenyl, cyclohexylbenzene, 1, -binaphthyl, 1,2'-binaphthyl, etc.) obtained by removing any two hydrogen atoms And other divalent groups.
  • cycloalkanes, cycloalkylenes having 5 to 8 carbon atoms, aromatic hydrocarbons having 6 to 14 carbon atoms and ring-assembled hydrocarbons having 12 to 20 carbon atoms include alkyl groups having 1 to 4 carbon atoms (eg, methyl , Ethyl, propyl, isopropyl, etc.).
  • divalent cyclic hydrocarbon group examples include 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,2-cycloheptylene, 1,3-cycloheptylene, 1,4-cycloheptylene, 3-cyclohexene-1,4-yylene, 3-cyclohexene-1 1,2-Yylene, 2,5-cyclohexadiene 1,4-phenylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,4— Naphthylene, 6-naphthylene, 2,6-naphthylene, 2,7-naphthylene, 1,5-indenylene, 2,5-indenylene, 1, -binaphthyl 2,2'-diyl.
  • Z and W are preferably alkylene having 1 to 8 carbon atoms (preferably ethylene), phenylene, 1,1′-binaphthyl-2,2′-diyl and the like.
  • the phosphine represented by the general formula (III) include, for example, trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, tricyclohexylphosphine, tri (P-tolyl) phosphine, and diphenylmethylphosphine. And tertiary phosphines such as dimethylphenylphosphine.
  • the phosphine is an optically active phosphine in which R 3 , R 4 and R 5 are all three different groups, or an optically active phosphine in which at least one of R 3 , R 4 and R 5 is an optically active group Is preferred.
  • phosphine represented by the general formula (IV) include, for example, bis (diphenylphosphino) ethane; bis (diphenylphosphino) propane; bis (diphenylphosphino) propane; bis (diphenylphosphino) butane; Bis (dimethylphosphino) ethane; bis (dimethylphosphino) propane; 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (hereinafter abbreviated as BINAP); on the naphthyl ring of BINAP BINAP derivatives having a substituent such as an alkyl group or a aryl group (2,2'-bis (diphenylphosphino) -6,6'-dimethyl-1,1'-binaphthyl); the naphthyl ring of BINAP is partially BINAP derivatives hydrogenated to, for example, 8 BINAP (2,2
  • Tricyclohexyl-1,2-bis (diphenylphosphino) ethane CYCPH0S
  • DIPAMP 1,2-bis [(0-methoxyphenyl) phenylphosphino] ethane
  • SKEWPH0S 1,2-bis [(0-methoxyphenyl) phenylphosphino] pentane
  • the phosphine is preferably an optically active phosphine, and among them, an optically active phosphine such as BINAP, H8 BINAP, Tol-BINAP, Xyl-BINAP, BI CHEP, CHIRAPHOS, CYCPHOS, DIPAMP, PROPHOS, SKEWPHOS is preferred.
  • BINAP, Xyto BINAP, etc. are preferred.
  • Examples of the amine represented by the general formula (V) include, for example, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, cyclopentylamine, cyclohexylamine, benzylamine, dimethylamine, methylamine, dipropylamine, dihexylamine, dicyclopentylamine.
  • Min dicyclohexylamine, dibenzylamine, diphenylamine, phenylethylamine, piperidine, piperazine, phenylethylamine, naphthylethylamine, cyclohexylethylamine, cycloheptylethylamine And the like.
  • the amine is preferably an optically active amine, and among them, optically active amines such as phenylethylamine, naphthylethylamine, cyclohexylethylamine, cycloheptylethylamine and the like are preferable.
  • Examples of the amine represented by the general formula (VI) include methylenediamine, ethylenediamine, 1,2-diaminopropane, 1,3-diaminopropane, 1,4-diaminobutane, 2,3-diaminobutane, and 1,2-cyclopentane Diamine, 1,2-cyclohexyl Sandiamine, N-methylethylenediamine, ', ⁇ '-dimethylethylenediamine, 0-phenylenediamine, ⁇ -phenylenediamine, 1,2-diphenylethylenediamine, 1,2-cyclohexane Xanthamine, 1,2-cycloheptandiamine, 2,3-dimethylbutanediamine, trimethyl-2,2-diphenylethylenediamine, tributyl-1,2-diphenylethylenediamine, Triisopropyl-1,2-diphenyl ethylenediamine, trimethyl-2,2-bis ( ⁇ -methoxyphenyl) ethylenedi
  • Said amine is preferably an optically active amine, among which 1,2-diphenylethylenediamine, 1,2-cyclohexanediamine, 1,2-cycloheptanediamine, 2,3-dimethylbutanediamine, 1-methyl-2,2-diphenylethylenediamine, triisobutyl-2,2-diphenylethylenediamine, triisopropyl-1,2,2-diphenylethylenediamine, trimethyl-2,2-bis ( ⁇ -Methoxyphenyl) Ethylenediamine, triisobutyl-2,2-bis ( ⁇ -methoxyphenyl) ethylenediamine, triisopropyl-2,2-bis ( ⁇ -methoxyphenyl) ethylenediamine, 1-benzyl-2 , 2-Bis ( ⁇ -methoxyphenyl) ethylenediamine, trimethyl-2,2-dinaphthylethylenediamine, triisobutyl-2,2-dinaphthylethylenediamine, toluen
  • an optically active amine such as a propanediamine derivative, a butanediamine derivative, a phenylenediamine derivative, or a cyclohexanediamine derivative can be used.
  • ruthenium complex examples include inorganic ruthenium compounds such as ruthenium (III) chloride hydrate, ruthenium (III) bromide hydrate, and ruthenium (III) iodide hydrate; [ruthenium dichloride (norbornadiene) Polynuclear], [ruthenium dichloride (cyclooctane) polynuclear], bis (methylaryl) ruthenium (Si Ruthenium compounds coordinated by a gen such as chlorobenzene (ruthenium dichloride (benzene) binuclear), [ruthenium dichloride (p-cymene) binuclear], [ruthenium dichloride (trimethylbenzene)] Ruthenium complexes coordinated with aromatic compounds such as binuclear] and [ruthenium dichloride (hexamethylbenzene) binuclear]; ruthenium complexes coordinated with phosphines such as diclolotris (triphenylphosphin
  • Preferred examples of the optically active ruthenium-phosphine-amine complex used in the production method of the present invention include the following.
  • X and Y are the same or different and each represent a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine, iodine) or a carboxyl group. It is preferably a halogen atom (preferably chlorine).
  • a halogen atom eg, fluorine, chlorine, bromine, iodine
  • m and n are the same or different and each represents an integer of 0 to 4, and it is particularly preferable that both m and n are 1.
  • a complex represented by the general formula (X) is preferable.
  • Preferred examples of the complex represented by the general formula (X) include, for example,
  • the usage amount of the optically active ruthenium-phosphine-amine complex varies depending on the reaction vessel, the type of reaction, and the like.
  • the amount is 10 to 1100,000 moles, preferably 1/50 to 1 / 10,000 moles.
  • Examples of the base used in the production method of the present invention include compounds represented by the following general formula (XIII)
  • examples of the alkali metal represented by M include lithium, sodium, potassium, rubidium, and cesium. Of these, sodium and potassium are preferred, and potassium is particularly preferred.
  • Examples of the alkaline earth metal represented by M include magnesium, calcium, stonium, and zolium. Of these, calcium is preferred.
  • M is preferably an alkali metal.
  • Examples of the alkoxy group represented by Y 1 include the alkoxy groups having 1 to 4 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, among those exemplified as the substituent on ring A and ring B.
  • Xy sec-butoxy, tert-butoxy and the like. Of these, methoxy, isopropoxy and tert-butoxy are preferred.
  • alkylthio group represented by Y 1 examples include, among the alkylthio groups exemplified as the substituent in the ⁇ hydrocarbon group which may have a substituent '' represented by R 3 and the like, Examples thereof include an alkylthio group having 1 to 4 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, and tert-butylthio. Of these, methylthio is preferred.
  • Q represents 1 or 2, but is preferably 1.
  • the base represented by the general formula (XI II) include alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, and cesium hydroxide; methoxylithium, sodium methoxide, methoxypotassium, ethoxylithium, and ethoxylithium.
  • Alkoxyalkali metals such as sodium, ethoxypotassium, propoxylithium, propoxysodium, propoxylithium, isopropoxylithium, isopropoxysodium, isopropoxypotassium, tert-butoxypotassium; alkylthioalkali metal such as methylthionadium
  • the base is preferably an alkali metal hydroxide or an alkoxy alkali metal, among which sodium hydroxide, potassium hydroxide, potassium isopropoxy, tert-butoxy potassium and the like are preferable. Particularly preferred are hydroxylating lime and tert-butoxycalime.
  • the amount of the base to be used is, for example, 0.5 to 100 equivalents, preferably 2 to 40 equivalents, relative to the optically active ruthenium-phosphine-amine complex.
  • ruthenium-phosphine-amine complex when a complex represented by the general formulas (VII) to (XII) and at least one of X and Y is a hydrogen atom is used as the ruthenium-phosphine-amine complex, for example, instead of the above-described base, Metal hydrides such as sodium borohydride and lithium aluminum hydride; and organic metal compounds such as methylmagnesium bromide, butylmagnesium bromide, propylmagnesium bromide, methyllithium, ethyllithium and propyllithium can also be used.
  • Metal hydrides such as sodium borohydride and lithium aluminum hydride
  • organic metal compounds such as methylmagnesium bromide, butylmagnesium bromide, propylmagnesium bromide, methyllithium, ethyllithium and propyllithium can also be used.
  • hydrogenation of the compound represented by the general formula (I) or a salt thereof is usually performed in an appropriate solvent.
  • a solvent is not particularly limited as long as it does not adversely affect the reaction and solubilizes the raw material compound and the catalyst.
  • aromatic hydrocarbons such as toluene and xylene
  • aliphatic hydrocarbons such as heptane and hexane.
  • Hydrocarbons such as methylene chloride Hydrogen; ethers such as getyl ether and tetrahydrofuran; alcohols such as methanol, ethanol, 2-propanol, butanol, and benzyl alcohol; nitriles such as acetonitrile; DMF (dimethylformamide) and DMS0 (dimethyl sulfoxide). Used. These solvents may be used in a mixture at an appropriate ratio.
  • the solvent is preferably an alcohol, especially 2-propanol.
  • the above-mentioned solvent is preferably used for the reaction after drying and degassing.
  • the amount of the solvent to be used is appropriately determined depending on the solubility of the compound (I) and the like. For example, when an alcohol (preferably 2-propanol) is used as a solvent, the reaction can be carried out in a solvent more than 100 times the weight of the compound (I) from a state close to no solvent. ) Is preferably used 2 to 50 times by weight.
  • Hydrogenation can be carried out by either a batch or continuous reaction.
  • the hydrogenation is carried out in the presence of hydrogen, and the hydrogen pressure is, for example, 1 to 200 atm, preferably 1 to 10 atm.
  • the reaction temperature is preferably -30 ° C to 100, more preferably 10 to 50 ° C, particularly preferably 20 to 50.
  • the reaction time is preferably 0.5 to 48 hours, more preferably 2 to 24 hours.
  • optically active compound of the compound represented by the general formula ( ⁇ ) or a salt thereof” obtained by the production method of the present invention can be obtained by a known means, for example, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography Can be isolated and purified.
  • Examples of the salts of the compounds represented by the general formulas ( ⁇ ) and (III) to (VI) include those exemplified as the salts of the compounds represented by the general formula (I).
  • An optically active form of a salt of the compound represented by the general formula (II), that is, an optically active benzhydrol is useful as a raw material for synthesizing a medicine (eg, a squalene synthase inhibitor, a triglyceride lowering agent, etc.).
  • a medicine eg, a squalene synthase inhibitor, a triglyceride lowering agent, etc.
  • optically active ruthenium-phosphine-amine complexes used in the examples are: i. Am.
  • the chemical yield is the isolation yield or the yield obtained by high performance liquid chromatography.
  • the optical purity (asymmetric yield) of the optically active substance was evaluated based on the enantiomeric excess e.e.). The enantiomeric excess was determined by the following equation.
  • Enantiomeric excess ee) 100 X [(R)-(S)] / [(R) + (S)] or 100 X [(S)-(R)] / [(R) + (S)]
  • the numerical value in parentheses indicates “the production ratio of each optical isomer in the mixture of optical isomers”.
  • room temperature means 15 to 25.
  • the resulting mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 5 hours.
  • the reaction solution was quantified by HPLC, the enantiomeric excess was 99.33 ⁇ 4e.e. And the yield was 93.6%.
  • the resulting mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 5 hours.
  • the reaction mixture was quantified by HPLC, the enantiomeric excess was 99.6% e.e. and the yield was 95.8%.
  • the obtained solution was added to the above glass autoclave, and argon gas was further blown therein.
  • the resulting mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 5 hours.
  • the reaction mixture was quantified by HPLC, the enantiomeric excess was 99.0 e.e. and the yield was 80.7%.
  • the resulting mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 24 hours.
  • the reaction solution was quantified by HPLC, the enantiomeric excess was 99.6 e.e. and the yield was 95.5%.
  • the resulting mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 24 hours.
  • the reaction mixture was quantified by HPLC, the enantiomeric excess was 98.8 ee and the yield was quantitative.
  • the resulting mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 24 hours.
  • the reaction mixture was quantified by HPLC, the enantiomeric excess was 99.5% e.e. and the yield was 81.3%.
  • the obtained solution was added to the above glass autoclave, and argon gas was further blown therein.
  • the mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 5 hours.
  • the reaction solution was quantified by HPLC, the enantiomeric excess was 99.2% ee and the yield was 84.9%.
  • the resulting mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 7 hours.
  • the reaction mixture was quantified by HPLC, the enantiomeric excess was 93.e.e. and the yield was quantitative.
  • the obtained solution was added to the above-mentioned glass autoclave, and argon gas was further blown therein.
  • the resulting mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 5 hours.
  • the reaction mixture was quantified by HPLC, the enantiomeric excess was 98.7 e.e. and the yield was 97.
  • the obtained solution was added to the above-mentioned glass autoclave, and argon gas was further blown therein.
  • the resulting mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 5 hours.
  • the reaction mixture was quantified by HPLC, the enantiomeric excess was 86.7 e.e. and the yield was 93.
  • the resulting mixed solution was stirred at a hydrogen pressure of 7 atm and room temperature for 5 hours.
  • the reaction solution was quantified by HPLC, the enantiomeric excess was 94.9 e.e. and the yield was 88.7.
  • Example 10 To a solution of the compound obtained in Example 10 (2.0 g) and sodium bicarbonate (0.86 g) in ethyl acetate (20 ml) was added a solution of dimethylmalonic acid monoethyl ester (1.3 g) in ethyl acetate (20 ml). The mixture was added dropwise and stirred for 3 hours under ice cooling. Water (30 ml) was added to the solution, which was washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off.
  • N-[(3R, 5S) -tri (2,2-dimethylpropyl-1-hydroxy) -7-chloro- 5- (2,3-dimethoxyphenyl) -1-2-oxo-1,2,3,5-tetrahydro-4,1-benzobenzoazepine_3-acetyl] piperidine-14-ethyl ester was.
  • the compound obtained in 5) was dissolved in a mixed solution of 1N aqueous sodium hydroxide solution, methanol, and tetrahydrofuran, and stirred at room temperature for 1 hour.
  • 1N Hydrochloric acid and ethyl acetate were added, and the organic layer was washed with water, and dried over anhydrous magnesium sulfate.
  • the solvent was removed and the residue was recrystallized from hexane-getyl ether to give N-[(3R, 5S) -1- (2,2-dimethylpropyl-1-hydroxy) as colorless crystals with a melting point of 135-140.
  • Acetic anhydride and dimethylaminopyridine were added to a pyridine solution of the compound obtained in 6), and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction solution, washed with 1N hydrochloric acid and water, dried, and the solvent was distilled off.
  • optically active benzhydrols obtained by the production method of the present invention are useful as raw materials for synthesizing pharmaceuticals (eg, squalene synthase inhibitors, triglyceride lowering agents, etc.).
  • pharmaceuticals eg, squalene synthase inhibitors, triglyceride lowering agents, etc.
  • optically active ruthenium-phosphine-amine complex isolated in advance, the reaction conditions (hydrogen pressure, reaction Under such conditions as temperature, optically active benzohydrols can be obtained efficiently and with high selectivity.

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Abstract

L'invention se rapporte à un procédé de production de composés optiquement actifs représentés par la formule (II) (dans laquelle R1 et R2 sont chacun hydrogène ou analogue), qui se caractérise en ce qu'il consiste à hydrogéner un composé de formule (I) en présence à la fois d'une base et d'un complexe ruthénium-phosphine-amine optiquement actif préparé par isolement à partir d'une phosphine représentée, par exemple, par la formule générale (III): PR?3R4R5 (où R3, R4 et R5¿ sont chacun hydrocarbyle éventuellement substitué ou analogue), d'une amine représentée par la formule générale (IV): NHR?8R9 (où R8 et R9¿ sont chacun hydrogène ou analogue) et d'un complexe de ruthénium.
PCT/JP2000/008392 1999-11-30 2000-11-29 Procede de production de benzhydrols optiquement actifs WO2001040162A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH029849A (ja) * 1988-03-23 1990-01-12 Sankyo Co Ltd ４―アミノ―３―ヒドロキシカルボン酸類の立体選択的合成法
WO1997010224A1 (fr) * 1995-09-13 1997-03-20 Takeda Chemical Industries, Ltd. Composes de benzoxazepine, leur production et leur utilisation en tant qu'agent d'abaissement des niveaux de lipides
JPH09235255A (ja) * 1995-12-28 1997-09-09 Takasago Internatl Corp ベンズヒドロール誘導体の製造方法
JPH11189600A (ja) * 1997-12-26 1999-07-13 Japan Science & Technology Corp ルテニウム錯体とこれを触媒とするアルコール化合物 の製造方法
JPH11189558A (ja) * 1997-12-26 1999-07-13 Japan Science & Technology Corp 光学活性アルコール類の製造方法

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Publication number Priority date Publication date Assignee Title
JPH029849A (ja) * 1988-03-23 1990-01-12 Sankyo Co Ltd ４―アミノ―３―ヒドロキシカルボン酸類の立体選択的合成法
WO1997010224A1 (fr) * 1995-09-13 1997-03-20 Takeda Chemical Industries, Ltd. Composes de benzoxazepine, leur production et leur utilisation en tant qu'agent d'abaissement des niveaux de lipides
JPH09235255A (ja) * 1995-12-28 1997-09-09 Takasago Internatl Corp ベンズヒドロール誘導体の製造方法
JPH11189600A (ja) * 1997-12-26 1999-07-13 Japan Science & Technology Corp ルテニウム錯体とこれを触媒とするアルコール化合物 の製造方法
JPH11189558A (ja) * 1997-12-26 1999-07-13 Japan Science & Technology Corp 光学活性アルコール類の製造方法

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