EP0988297A2 - Procede de preparation de composes de phenyloxyrane actifs sur le plan optique - Google Patents

Procede de preparation de composes de phenyloxyrane actifs sur le plan optique

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Publication number
EP0988297A2
EP0988297A2 EP98923162A EP98923162A EP0988297A2 EP 0988297 A2 EP0988297 A2 EP 0988297A2 EP 98923162 A EP98923162 A EP 98923162A EP 98923162 A EP98923162 A EP 98923162A EP 0988297 A2 EP0988297 A2 EP 0988297A2
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EP
European Patent Office
Prior art keywords
alk
group
formula
compound
hydrogen atom
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP98923162A
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German (de)
English (en)
Inventor
Tomiki Hashiyama
Naoyuki Harada
Hiroaki Arakawa
Mari Kusama
Yasuhiko Ozaki
Tooru Kuroda
Masahiko Seki
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Tanabe Seiyaku Co Ltd
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Tanabe Seiyaku Co Ltd
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Publication of EP0988297A2 publication Critical patent/EP0988297A2/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to a process for preparing an optically active phenyloxirane compound. More particularly, the present invention relates to a process for preparing an optically active phenyloxirane compound by asymmetric oxidation, and to a process for preparing a 1, 5-benzothiazepine derivative from the resulting optically active phenyloxirane compound prepared by the above process.
  • 5-benzothiazepine derivatives are compounds useful for the treatments for cardiac diseases, such as angina pectoris, cardiac infarction, and arrythmia, and cardiovascular diseases, such as hypertension, cardiovascular infarction, and cerebral infarction.
  • cardiac diseases such as angina pectoris, cardiac infarction, and arrythmia
  • cardiovascular diseases such as hypertension, cardiovascular infarction, and cerebral infarction.
  • Diltiazem hydrochloride chemical name: ( 2S, 3S ) -3-acetoxy-5- [2- ( dimethylamino )ethyl] -2- ( 4- methoxyphenyl )-2, 3-dihydro-l, 5-benzothiazepin-4( 5H )-one hydrochloride
  • 2S, 3S -3-acetoxy-5- [2- ( dimethylamino )ethyl] -2- ( 4- methoxyphenyl )-2, 3-dihydro-l, 5-benzothiazepin
  • Japanese Patent Laid-Open No. Sho 59-196881 discloses a process for preparing methyl ( 2R, 3S )-3-( 4- acetoxyphenyl )glycidate comprising oxidizing trans-3-(4- acetoxyphenyl)cinnamyl alcohol with m-chloroperbenzoic acid in the presence of tetraisopropoxytitanium and diethyl L-tartrate, to give ( 2S, 3S )-3-( 4- acetoxyphenyl )glycidyl alcohol; oxidizing the resulting
  • Oxone (tradename, manufactured by Du Pont; composition: 2KHS0 5 » KHS0 4 » K 2 S0 4 ] .
  • an object of the present invention is to provide a process for preparing an optically active phenyloxirane compound in high yields and at high optical purity by carrying out asymmetric oxidation, i.e. asymmetric epoxidation, of a complicated styrene derivative having no symmetric element using an asymmetric oxidation agent resulting from a chiral ketone compound and an oxidizing agent (e.g., a chiral dioxirane compound), and to provide a process in which the chiral ketone compound, the starting material for the asymmetric oxidation agent, can be reused in the process for preparing the optically active phenyloxirane compound, thereby making it highly productive and economically advantageous.
  • asymmetric oxidation i.e. asymmetric epoxidation
  • ring A is a substituted or unsubstituted benzene ring
  • R is a group represented by -C0 2 R q , or a group convertible to the group represented by -C0 2 R q , wherein R q is an ester residue
  • * indicates an asymmetric carbon atom, comprising treating a styrene derivative ( I ) represented by the formula ( I ) :
  • ring A and R are the same as defined above, with an asymmetric oxidation agent formed from a chiral ketone compound and an oxidizing agent;
  • ring Ar is a monocyclic, dicyclic, or tricyclic aromatic ring, which may have a substituent; and Y is a group represented by the formula: (i) -O-Q-Alk 1 -, (ii) -Q-O-Alk 2 -,
  • R 1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk 1 , Alk 2 , Alk 3 , Alk 4 , and Alk 5 is a lower alkylene group, respectively;
  • each of R a and R b is hydrogen atom, or a substituent; and R c and R d satisfy one of the following (I) to (III): (I) each of R c and R d is hydrogen atom, or a substituent; or
  • R c and R are bonded to each other to form a group represented by the formula: wherein R e , R f , R 9 , and R h satisfy one of the following (a) and ( b ) :
  • each of the groups is hydrogen atom or a substituent
  • R 1 , R J , R k , and R m is hydrogen atom or a substituent
  • Y is a group represented by the formula: (i) -O-Q-Alk 1 -, (ii) -Q-O-Alk 2 -, (iii)-Alk 3 -0-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR ⁇ Q-Alk 1 -, (vi) -Q-NR ⁇ Alk 2 -,
  • ring A is a substituted or unsubstituted benzene ring
  • R is a group represented by -C0 2 R q , or a group convertible to the group represented by -C0 2 R q , wherein R q is an ester residue
  • * indicates an asymmetric carbon atom, comprising treating a styrene derivative ( I ) represented by the formula (I):
  • ring Ar is a monocyclic, dicyclic, or tricyclic aromatic ring, which may have a substituent;
  • Y is a group represented by the formula:
  • R a and R b are hydrogen atom, or a substituent; and R c and R d satisfy one of the following (I) to (III):
  • each of R c and R d is hydrogen atom, or a substituent
  • R e , R f , R g , and R h satisfy one of the following (a) and ( b ) :
  • R 1 , R j , R k , and R m is hydrogen atom or a substituent; and Y is a group represented by the formula:
  • each of R a and R b is hydrogen atom, or a substituent; and R c and R d satisfy one of the following (I) to (III): (I) each of R c and R d is hydrogen atom, or a substituent; or
  • R e , R f , R 9 , and R h satisfy one of the following (a) and (b): (a) two adjacent groups are bonded to each other to form a benzene ring, which may have a substituent, together with two interconnecting carbon atoms, and each of the remaining two groups is hydrogen atom or a substituent; or
  • each of the groups is hydrogen atom or a substituent
  • R 1 , R J , R k , and R m is hydrogen atom or a substituent
  • Y is a group represented by the formula: (i) -O-Q-Alk 1 -, (ii) -Q-O-Alk 2 -,
  • (II) is a (2R,3S) -isomer or a ( 2S, 3R) -isomer;
  • each of R a and R b is hydrogen atom, or a substituent; and R c and R d satisfy one of the following (I) to ( III ) :
  • each of R c and R d is hydrogen atom, or a substituent
  • R e , R f , R g , and R h satisfy one of the following (a) and ( b ) :
  • each of the groups is hydrogen atom or a substituent; or (III)R C and R d are bonded to each other to form a group represented by the formula:
  • R 1 , R J , R k , and R m is hydrogen atom or a substituent
  • Y is a group represented by the formula:
  • R a and R b are hydrogen atom, or a substituent; and R c and R d satisfy one of the following (I) to (III):
  • each of R c and R d is hydrogen atom, or a substituent
  • R e , R f , R 9 , and R h satisfy one of the following (a) and (b ) : (a) two adjacent groups are bonded to each other to form a benzene ring, which may have a substituent, together with two interconnecting carbon atoms, and each of the remaining two groups is hydrogen atom or a substituent; or (b) each of the groups is hydrogen atom or a substituent; or (III)R C and R d are bonded to each other to form a group represented by the formula:
  • R 1 , R J , R k , and R m is hydrogen atom or a substituent
  • Y is a group represented by the formula:
  • R a and R b are hydrogen atom, or a substituent; and R c and R d satisfy one of the following (I) to (III):
  • each of R c and R d is hydrogen atom, or a substituent
  • R e , R f , R g , and R h satisfy one of the following (a) and ( b ) :
  • R 1 , R J , R, and R m is hydrogen atom or a substituent
  • Y is a group represented by the formula: (i) -O-Q-Alk 1 -, (ii) -Q-O-Alk 2 -,
  • R a and R b are hydrogen atom, or a substituent; and R c and R d satisfy one of the following (I) to (III):
  • each of R c and R d is hydrogen atom, or a substituent
  • R e , R , R 9 , and R satisfy one of the following (a) and ( b ) :
  • each of the groups is hydrogen atom or a substituent
  • R 1 , R j , R k , and R m is hydrogen atom or a substituent
  • Y is a group represented by the formula:
  • each of R a and R b is hydrogen atom; and R c and R d are bonded to each other to form a group represented by the formula:
  • R c is hydrogen atom, and R d is a halogen atom;
  • R c is hydrogen atom, and R d is nitro group
  • R a is a halogen atom
  • R b is hydrogen atom
  • R d are bonded to each other to form a group represented by the formula:
  • ketone compound is an optical isomer of a ketone compound (V) represented by the formula (V): wherein ring Ar is a monocyclic, dicyclic, or tricyclic aromatic ring, which may have a substituent; and Y is a group represented by the formula: (i) -O-Q-Alk 1 -, (ii) -Q-O-Alk 2 -,
  • each of R a and R b is hydrogen atom, or a substituent; and R c and R d satisfy one of the following (I) to (III): (I) each of R c and R d is hydrogen atom, or a substituent; or
  • R e , R f , R 9 , and R h satisfy one of the following (a) and ( b ) :
  • R 1 , R J , R , and R m is hydrogen atom or a substituent
  • Y is a group represented by the formula: (i) -O-Q-Alk 1 -, (ii) -Q-O-Alk 2 -,
  • ring A is a substituted or unsubstituted benzene ring
  • ring B is a substituted or unsubstituted benzene ring
  • R 2 is hydrogen atom or a substituted alkyl group
  • R 3 is a lower alkanoyl group
  • * indicates an asymmetric carbon atom, or pharmaceutically acceptable salts thereof, from an optically active phenyloxirane compound (II) represented by the formula (II):
  • R is a group represented by -C0 2 R q , or a group convertible to the group represented by -C0 2 R q , wherein R q is an ester residue; and ring A and * are the same as defined above, wherein as the optically active phenyloxirane compound
  • ring A is a substituted or unsubstituted benzene ring
  • ring B is a substituted or unsubstituted benzene ring
  • * indicates an asymmetric carbon atom, or salts thereof, from an optically active phenyloxirane compound (II) represented by the formula (II):
  • R is a group represented by -C0 2 R q , or a group convertible to the group represented by -C0 2 R q , wherein R q is an ester residue; and ring A and * are the same as defined above, wherein as the optically active phenyloxirane compound (II), the optically active phenyloxirane compound (II) prepared by the process according to any one of items [1] to [23] above is used.
  • ring A is a substituted or unsubstituted benzene ring;
  • R is a group represented by -C0 2 R q , or a group convertible to the group represented by -C0 2 R q , wherein R q is an ester residue, can be used as a starting material.
  • styrene derivative (I) represented by the formula ( I ) ring A is a substituted or unsubstituted benzene ring as described above.
  • Concrete examples of ring A include phenyl group, or phenyl groups having one to three substituents selected from the group consisting of lower alkyl groups, lower alkoxy groups, and halogen atoms.
  • the lower alkyl groups include alkyl groups having 1 to 4 carbon atoms, such as methyl group, ethyl group, propyl group, and t-butyl group.
  • the lower alkoxy groups include alkoxy groups having 1 to 4 carbon atoms, such as methoxy group, ethoxy group, propoxy group, and butoxy group.
  • the halogen atoms include fluorine atom, chlorine atom, bromine atom, and iodine atom.
  • R is a group represented by -C0 2 R q , or a group convertible to the group represented by -C0 2 R q , wherein R q is the same as defined above.
  • R q is the same as defined above.
  • Examples of the group convertible to the group represented by -C0 2 R q include, for instance, a group represented by the formula: wherein R r is the same group defined as R q above; a group represented by the formula:
  • R s and R t are both hydrogen atoms; or one is hydrogen atom and the other is the same group as defined as R q above; or R s and R* are both the same group as defined as R q above; or R ⁇ and R* are bonded to each other to form a heterocyclic ring, which may have a substituent, together with the adjacent nitrogen atom; thiocarboxyl group; carboxyl group; cyano group, and the like.
  • R may be any group as long as it is a well-used ester residue.
  • R q examples include, for instance, lower alkyl groups having 1 to 4 carbon atoms, such as methyl group, ethyl group, propyl group, and butyl group; cycloalkyl groups having 3 to 7 carbon atoms, such as cyclopentyl group and cyclohexyl group; aryl groups, such as phenyl group and naphthyl group, and the like.
  • lower alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, and butyl group
  • cycloalkyl groups having 3 to 7 carbon atoms such as cyclopentyl group and cyclohexyl group
  • aryl groups such as phenyl group and naphthyl group, and the like.
  • Each of those lower alkyl groups, cycloalkyl groups, and aryl groups may have a substituent.
  • Examples of the substituents of the lower alkyl groups and the cycloalkyl groups include substituted or unsubstituted phenyl group, halogen atoms, and lower alkoxy groups having 1 to 4 carbon atoms.
  • Examples of the substituents of the aryl groups include lower alkyl groups having 1 to 4 carbon atoms, halogen atoms, and lower alkoxy groups having 1 to
  • heterocyclic ring formed by bonding R s with R* together with the adjacent nitrogen atom examples include nitrogen-containing heterocyclic rings having
  • 5 to 6 ring members such as pyrrolidine ring, piperidine ring, morpholine ring, and piperazine ring, and these heterocyclic rings may have a substituent selected from the group consisting of lower alkyl groups having 1 to 4 carbon atoms and halogen atoms.
  • ring A is methoxyphenyl group or methylphenyl group
  • R is methoxycarbonyl group
  • ring A and R are bonded in trans-configuration.
  • methyl trans-4-methoxycinnamate can be favorably used.
  • Examples of the chiral ketone compound used in the formation of the asymmetric oxidation agent include, for instance, naturally occurring chiral ketone compounds, such as compounds in which one or more hydroxyl groups in monosaccharides or polysaccharides are converted to oxo groups, and the remaining hydroxyl groups are protected (for instance, 1, 2: 4, 5-di( 0-isopropylidene)-D-erythro- -2,3-hexodiuro-2, 6-pyranose) [Tetrahedron, 47, 2133 (1991)]; and non-naturally occurring chiral ketone compounds, such as ketone compounds having chiral biaryl structure, and the like.
  • naturally occurring chiral ketone compounds such as compounds in which one or more hydroxyl groups in monosaccharides or polysaccharides are converted to oxo groups, and the remaining hydroxyl groups are protected (for instance, 1, 2: 4, 5-di( 0-isopropylidene)-D-
  • Typical examples of the chiral ketone compound include, for instance, an optical isomer of a ketone compound (V) represented by the formula (V):
  • ring Ar is a monocyclic, dicyclic, or tricyclic aromatic ring, which may have a substituent; and Y is a group represented by the formula: (i) -O-Q-Alk 1 -, (ii) -Q-O-Alk 2 -, (iii)-Alk 3 -0-Alk 4 -, (iv) -O-Alk 5 -,
  • ring Ar is a monocyclic, dicyclic, or tricyclic aromatic ring, which may have a substituent.
  • the monocyclic, dicyclic, or tricyclic aromatic ring include, for instance, benzene ring, naphthalene ring, naphthoquinone ring, anthracene ring, anthraquinone ring, phenanthrene ring, and the like.
  • the substituted position of Y bonded to the aromatic ring is not particularly limited as long as axial chirality is caused. It is desired that Y is bonded at the ortho position of the bonds between the two ring Ar's.
  • substituents on the aromatic ring include, for instance, electron withdrawing groups, including halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom, nitro group, methylsulfonyl group, p-toluenesulfonyl group, trifluoromethyl group, cyano group, methoxycarbonyl group, methylsulfoxide group, sulfonylamide group, and the like; and electron donating groups, including lower alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, and butyl group, lower alkoxy groups having 1 to 4 carbon atoms such as methoxy group, ethoxy group, propoxy group, and butoxy group, cycloalkyl groups having 3 to 7 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl
  • Y is a group represented by the formula: (i) -O-Q-Alk 1 -, (ii) -Q-O-Alk 2 -, (iii)-Alk 3 -0-Alk 4 -, (iv) -O-Alk 5 -,
  • alkylsulfonyl group in R 1 examples include, for instance, alkylsulfonyl groups of which the alkyl moiety has 1 to 4 carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, and butylsulfonyl group.
  • examples of the arylsulfonyl group include, for instance, arylsulfonyl groups of which the aryl moiety has 6 to 10 carbon atoms, such as benzenesulfonyl group, p-toluenesulfonyl group, and naphthylsulfonyl group.
  • lower alkylene groups in Alk 1 , Alk 2 , Alk 3 , Alk 4 , and Alk 5 include, for instance, linear or branched, lower alkylene groups having 1 to 4 carbon atoms, such as methylene group, ethylene group, trimethylene group, tetramethylene group, methylmethylene group, methylethylene group, and methyltrimethylene group.
  • groups represented by Y it is desired that Y is a group represented by ( ii ) above, and it is particularly desirable that Y is a group represented by
  • Y is preferably -C0-0-CH 2 - .
  • chiral ketone compound examples include, for instance, an optical isomer of a ketone compound (VI) represented by the formula (VI):
  • R a and R b are hydrogen atom, or a substituent; and R c and R d satisfy one of the following (I) to (III):
  • each of R c and R d is hydrogen atom, or a substituent
  • R e , R f , R 9 , and R h satisfy one of the following (a) and (b):
  • R 1 , R 3 , R k , and R m is hydrogen atom or a substituent
  • Y is a group represented by the formula:
  • R 1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk 1 , Alk 2 , Alk 3 , Alk 4 , and Alk 5 is a lower alkylene group, respectively.
  • the substituents in R a to R m include, for instance, electron withdrawing groups, including halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom, nitro group, methylsulfonyl group, p-toluenesulfonyl group, trifluoromethyl group, cyano group, methoxycarbonyl group, methylsulfoxide group, sulfonylamide group, and the like; and electron donating groups, including lower alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, and butyl group, lower alkoxy groups having 1 to 4 carbon atoms such as methoxy group, ethoxy group, propoxy group, and butoxy group, cycloalkyl groups having 3 to 7 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohex
  • R a , R b , R c , and R d satisfy one of the following (a) and (b):
  • each of R a and R b is hydrogen atom; and R c and R d are bonded to each other to form a group represented by the formula:
  • R a is hydrogen atom, and R b is a halogen atom; or R c is hydrogen atom, and R d is nitro group; or (b) R a is a halogen atom; R b is hydrogen atom; and R° and R d are bonded to each other to form a group represented by the formula:
  • each of R a and R b is hydrogen atom; and R c and R d are bonded to each other to form a group represented by the formula:
  • (VI) may be the same as those listed for the Y of the ketone compound (V).
  • the optical isomers of the ketone compound (VI) include two isomers based on axial chirality, that is, a chiral ketone compound (Vl-a) represented by the formula
  • R a , R b , R c , R d , and Y are the same as defined above.
  • optical isomers of the ketone compound (V) and the optical isomers of the ketone compound (VI) can be converted to the asymmetric oxidation agent by reacting the optical isomers with an oxidizing agent. This reaction can be carried out in the presence or absence of an alkali agent in a suitable solvent.
  • the oxidizing agent used in the oxidation reaction examples include, for instance, peroxo acids, such as m-chloroperbenzoic acid, peracetic acid, peroxonitric acid, peroxocarbonic acid, peroxodisulfuric acid, peroxomonosulfuric acid, peroxoboric acid, and performic acid, and alkali metal salts thereof, peroxides, such as hydrogen peroxide, and the like.
  • peroxo acids such as m-chloroperbenzoic acid, peracetic acid, peroxonitric acid, peroxocarbonic acid, peroxodisulfuric acid, peroxomonosulfuric acid, peroxoboric acid, and performic acid, and alkali metal salts thereof, peroxides, such as hydrogen peroxide, and the like.
  • Oxone which is an oxidizing agent including potassium peroxomonosulfate
  • the oxidizing agent, the solvent or the starting compounds may contain metals as impur
  • chelating agents can be used.
  • the chelating agent include, for instance, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, crown ethers, such as 18-crown-6, and the like.
  • the chelating agent may be directly added to a solution of the styrene derivative ( I ) , or it may be previously dissolved in a solvent to prepare a solution, and then the solution may be added to the solution of the styrene derivative ( I ) .
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate
  • alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, and the like may be used as the alkali agent.
  • solvent used in the oxidation reaction examples include, for instance, organic solvents including ether solvents, such as 1, 2-dimethoxyethane, dimethyl ether, diethyl ether, tetrahydrofuran, 1,4-dioxane, and diglyme; nitrile solvents, such as acetonitrile, propionitrile, and butyronitrile; alcohol solvents, such as methanol, ethanol, propanol, i-propanol, n-butanol, sec-butanol, and t-butanol; ester solvents, such as methyl acetate and ethyl acetate; amide solvents, such as dimethylformamide, diethylformamide, dimethylacetamide, and dimethylimidazolinone; sulfoxide solvents, such as dimethyl sulfoxide; aliphatic hydrocarbon solvents, which may be halogenated, such as dichloromethane, dichloroe
  • the reaction temperature may be a temperature at which the asymmetric oxidation agent can be formed and may be selected depending on the kind of the desired asymmetric oxidation agent. It is desired that the reaction temperature is from -5° to 50°C, preferably from 0° to 40°C.
  • the asymmetric oxidation agent which can be resulted from the oxidation reaction may be once isolated and then subjected to the reaction with the styrene derivative (I).
  • the asymmetric oxidation agent may be reacted with the styrene derivative ( I ) in the same reaction system wherein the asymmetric oxidation agent is formed by the oxidation reaction without isolation.
  • the optical isomers of the ketone compounds (V) and (VI) may be first converted to the asymmetric oxidation agents, and thereafter the resulting asymmetric oxidation agents may be reacted with the styrene derivative ( I ) .
  • the conversion of the optical isomers of the ketone compounds (V) and (VI) to the asymmetric oxidation agents, and the asymmetric oxidation reaction of the styrene derivative ( I ) with the asymmetric oxidation agents may be concurrently carried out in the same reaction system.
  • the asymmetric oxidation agent having the same axial chirality can be prepared.
  • the chiral ketone compound (Vl-b) when used, the asymmetric oxidation agent having the same axial chirality can be prepared.
  • the chiral dioxirane compound which is one of the asymmetric oxidation agents formed from a chiral ketone compound and an oxidizing agent, is a compound having a dioxirane ring ( a three-membered ring consisting of carbon-oxygen-oxygen) and also having chirality.
  • the chirality includes those based on asymmetric carbon atoms, and those based on axial chirality.
  • Examples of the chiral dioxirane compound include, for instance, compounds obtainable by oxidizing naturally occurring chiral ketone compounds, such as compounds in which one or more hydroxyl groups in monosaccharides or polysaccharides are converted to oxo groups, and the remaining hydroxyl groups are protected (for instance, 1,2:4, 5-di(0-isopropylidene)-D-erythro-2, 3-hexodiuro-2, 6- pyranose) [Tetrahedron, 47, 2133 (1991)]; and compounds obtainable by oxidizing non-naturally occurring chiral ketone compounds, such as ketone compounds having chiral biaryl structure, by a process disclosed, for instance, in "Chemical Reviews , 89, 1187 (1989),” thereby to convert the ketone moiety to a dioxirane, and the like.
  • naturally occurring chiral ketone compounds such as compounds in which one or more hydroxyl groups in monosaccharides or polysaccharides
  • chiral dioxirane compound examples include, for instance, an optical isomer of a dioxirane compound (III) represented by the formula (III):
  • ring Ar is a monocyclic, dicyclic, or tricyclic aromatic ring, which may have a substituent; and Y is a group represented by the formula: (i) -O-Q-Alk 1 -, (ii) -Q-O-Alk 2 -,
  • ring Ar is a monocyclic, dicyclic, or tricyclic aromatic ring, which may have a substituent.
  • the monocyclic, dicyclic, or tricyclic aromatic ring include, for instance, benzene ring, naphthalene ring, naphthoquinone ring, anthracene ring, anthraquinone ring, phenanthrene ring, and the like.
  • the substituted position of Y bonded to the aromatic ring is not particularly limited as long as axial chirality is caused. It is desired that Y is bonded at the ortho position of the bonds between the two ring Ar ' s .
  • substituents on the aromatic ring include, for instance, electron withdrawing groups, including halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom, nitro group, methylsulfonyl group, p-toluenesulfonyl group, trifluoromethyl group, cyano group, methoxycarbonyl group, methylsulfoxide group, sulfonylamide group, and the like; and electron donating groups, including lower alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, and butyl group, lower alkoxy groups having 1 to 4 carbon atoms such as methoxy group, ethoxy group, propoxy group, and butoxy group, cycloalkyl groups having 3 to 7 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl
  • alkylsulfonyl group in R 1 examples include, for instance, alkylsulfonyl groups of which the alkyl moiety has 1 to 4 carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, and butylsulfonyl group.
  • examples of the arylsulfonyl group include, for instance, arylsulfonyl groups of which the aryl moiety has 6 to 10 carbon atoms, such as benzenesulfonyl group, p-toluenesulfonyl group, and naphthylsulfonyl group.
  • lower alkylene groups in Alk 1 , Alk 2 , Alk 3 , Alk 4 , and Alk 5 include, for instance, linear or branched, lower alkylene groups having 1 to 4 carbon atoms, such as methylene group, ethylene group, trimethylene group, tetramethylene group, methylmethylene group, methylethylene group, and methyltrimethylene group.
  • Y is a group represented by ( ii ) above, and it is particularly desirable that Y is a group represented by (ii) above, wherein Q is carbonyl group.
  • Y is preferably -C0-0-CH 2 - .
  • chiral dioxirane compound examples include, for instance, an optical isomer of a dioxirane compound (IV) represented by the formula (IV):
  • R a and R b are hydrogen atom, or a substituent; and R c and R d satisfy one of the following (I) to (III):
  • each of R and R d is hydrogen atom, or a substituent
  • R° and R id are bonded to each other to form a group represented by the formula: wherein R e , R f , R 3 , and R h satisfy one of the following (a) and ( b ) :
  • each of the groups is hydrogen atom or a substituent
  • R 1 , R J , R k , and R m is hydrogen atom or a substituent
  • Y is a group represented by the formula:
  • the substituents in R a to R ra include, for instance, electron withdrawing groups, including halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom, nitro group, methylsulfonyl group, p-toluenesulfonyl group, trifluoromethyl group, cyano group, methoxycarbonyl group, methylsulfoxide group, sulfonylamide group, and the like; and electron donating groups, including lower alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, and butyl group, lower alkoxy groups having 1 to 4 carbon atoms such as methoxy group, ethoxy group, propoxy group, and butoxy group, cycloalkyl groups having 3 to 7 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohe
  • R a , R b , R c , and R d satisfy one of the following (a) and (b): (a) each of R a and R b is hydrogen atom; and R c and R d are bonded to each other to form a group represented by the formula:
  • R is hydrogen atom, and R d is a halogen atom; or R c is hydrogen atom, and R d is nitro group; or (b) R a is a halogen atom; R b is hydrogen atom; and R c and R d are bonded to each other to form a group represented by the formula:
  • each of R a and R b is hydrogen atom; and R c and R d are bonded to each other to form a group represented by the formula:
  • the group represented by Y of the dioxirane compound (IV) may be the same as those listed for the Y of the dioxirane compound (III).
  • the optical isomers of the dioxirane compound (IV) include two isomers based on axial chirality, that is, a chiral dioxirane compound (IV-a) represented by the formula (IV-a):
  • optical isomers of the dioxirane compound (III) and the optical isomers of the dioxirane compound (IV) can be easily prepared by oxidizing a corresponding optical isomer of, for instance, a ketone compound (V) represented by the formula (V):
  • This oxidation reaction can be carried out by oxidizing the corresponding optical isomers of the ketone compounds (V) and (VI) in the presence or absence of an alkali agent in a suitable solvent using an oxidizing agent.
  • the oxidizing agent used in the oxidation reaction examples include, for instance, peroxo acids, such as m-chloroperbenzoic acid, peracetic acid, peroxonitric acid, peroxocarbonic acid, peroxodisulfuric acid, peroxomonosulfuric acid, peroxoboric acid, and performic acid, and alkali metal salts thereof, peroxides, such as hydrogen peroxide, and the like.
  • peroxo acids such as m-chloroperbenzoic acid, peracetic acid, peroxonitric acid, peroxocarbonic acid, peroxodisulfuric acid, peroxomonosulfuric acid, peroxoboric acid, and performic acid, and alkali metal salts thereof, peroxides, such as hydrogen peroxide, and the like.
  • Oxone which is an oxidizing agent including potassium peroxomonosulfate
  • the oxidizing agent, the solvent or the starting compounds may contain metals as impur
  • chelating agents can be used.
  • the chelating agent include, for instance, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, crown ethers, such as 18-crown-6, and the like.
  • the chelating agent may be directly added to a solution of the styrene derivative (I), or it may be previously dissolved in a solvent to prepare a solution, and then the solution may be added to the solution of the styrene derivative ( I ) .
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate
  • alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, and the like may be used as the alkali agent.
  • the solvent used in the oxidation reaction include, for instance, organic solvents including ether solvents, such as 1, 2-dimethoxyethane, dimethyl ether, diethyl ether, tetrahydrofuran, 1,4-dioxane, and diglyme; nitrile solvents, such as acetonitrile, propionitrile, and butyronitrile; alcohol solvents, such as methanol, ethanol, propanol, i-propanol, n-butanol, sec-butanol, and t-butanol; ester solvents, such as methyl acetate and ethyl acetate; amide solvents, such as dimethylformamide, diethylformamide, dimethylacetamide, and dimethylimidazol
  • 1,4-dioxane, acetonitrile, water, and mixed solvents thereof can be highly favorably used.
  • the reaction temperature is from -5° to 50°C, preferably from 0° to 40°C.
  • the optical isomer of the dioxirane compound (III) or (IV) which can be resulted from the oxidation reaction may be once isolated and then subjected to the reaction with the styrene derivative (I).
  • the optical isomer of the dioxirane compound (III) or (IV) may be reacted with the styrene derivative ( I ) in the same reaction system wherein the optical isomer is formed by the oxidation reaction without isolation.
  • the optical isomer of the dioxirane compound (III) or (IV) When the optical isomer of the dioxirane compound (III) or (IV) is reacted with the styrene derivative (I) without isolation, the optical isomer of the ketone compound (V) or (VI) may be first converted to the optical isomer of the dioxirane compound (III) or (IV), and thereafter the resulting optical isomer may be reacted with the styrene derivative (I). Alternatively, the conversion of the optical isomer of the ketone compound
  • a chiral dioxirane compound (IV-a) when used, a chiral dioxirane compound (IV-a) can be prepared.
  • a chiral dioxirane compound (IV-b) when used, a chiral dioxirane compound (IV-b) can be prepared.
  • the asymmetric oxidation agent can be reacted with the styrene derivative ( I ) in the presence or absence of an alkali agent in a suitable solvent.
  • solvents and alkali agents include, for instance, any of those solvents and those alkali agents which can be used in the respective formation of the asymmetric oxidation agent from the optical isomer of the ketone compound (V) or (VI).
  • solvents the ether solvents, the nitrile solvents, the alcohol solvents, water, and mixed solvents thereof can be particularly desirably used.
  • Processes for reacting the styrene derivative ( I ) with the asymmetric oxidation agent include, for instance, a process comprising directly adding an asymmetric oxidation agent to a solution of the styrene derivative (I); and a process comprising adding a chiral ketone compound corresponding to the asymmetric oxidation agent and an oxidizing agent to a solution of the styrene derivative ( I ) to form an asymmetric oxidation agent in the same reaction system.
  • the asymmetric oxidation agent formed by the reaction of the optical isomer of the ketone compound (V) or (VI) there can be employed (a) a process comprising adding the asymmetric oxidation agent to a solution of the styrene derivative (I), or (b) a process comprising adding an oxidizing agent to a mixture of the optical isomer of the ketone compound (V) or (VI) and the styrene derivative ( I ) , and reacting the styrene derivative ( I ) with the resulting asymmetric oxidation agent in the same reaction system.
  • the process (a) When the process (a) is employed, there is a necessity to use the asymmetric oxidation agent in an amount sufficient for asymmetrically oxidizing the styrene derivative (I).
  • the optical isomer of the ketone compound (V) or (VI) and the oxidizing agent can be used in amounts sufficient for forming the asymmetric oxidation agent in an amount sufficient for asymmetrically oxidizing the styrene derivative (I) in the reaction mixture.
  • the asymmetric oxidation agent is formed from the optical isomer of the ketone compound (V) or (VI) with an oxidizing agent.
  • the asymmetric oxidation agent asymmetrically oxidizes the styrene derivative ( I )
  • the optical isomer of the original ketone compound (V) or (VI) is regenerated from the asymmetric oxidation agent, so that the regenerated ketone compound (V) or (VI) can be reused.
  • the oxidizing agent when used in an amount of 1 to 10 equivalents of the styrene derivative (I), only the use of the optical isomer of the ketone compound (V) or (VI), the chiral source, in an amount of about 0.001 mol to about 0.1 mol, per one mol of the styrene derivative ( I ) , gives the asymmetric oxidation of the styrene derivative (I) completely, and thereby a desired optically active phenyloxirane compound (II) can be obtained. It is particularly desired that the oxidizing agent is used in an amount of 1.6 to 2.0 equivalents of the styrene derivative ( I ) .
  • Oxone an oxidizing agent
  • Oxone selectively oxidizes the optical isomer of the ketone compound (V) or (VI) as compared to the styrene derivative (I), to give an asymmetric oxidation agent.
  • the asymmetric oxidation agent asymmetrically oxidizes the styrene derivative ( I ) , and thereafter is reduced to the original ketone compound (V) or (VI), which can be repeatedly used. Therefore, only the use of a catalytic amount of the optical isomer of the ketone compound (V) or (VI), the chiral source, makes it possible to asymmetrically oxidize the styrene derivative ( I ) in a high yield, and thereby a desired optically active phenyloxirane compound (II) can be obtained at high optical purity.
  • the temperature for treating the styrene derivative (I) with the asymmetric oxidation agent is not particularly limited, and varies depending on the kinds of the asymmetric oxidation agent and the like. It is desired that the temperature is usually from about -5° to about 50°C, preferably from about 0° to about 40°C.
  • the atmosphere during the reaction is not particularly limited, and it may be usually air or an inert gas, such as nitrogen gas.
  • the unreacted asymmetric oxidation agent contained in the resulting reaction mixture after the reaction of the styrene derivative ( I ) with the asymmetric oxidation agent can be reduced by a process, for instance, comprising washing the reaction mixture with an agent such as brine to remove the oxidizing agent and the like from the reaction mixture, and, as occasion demands, reducing the reaction mixture using a reducing agent, such as hypo (sodium thiosulfate) , sodium hydrogensulfite, sodium metabisulfite, or the like, thereby converting the unreacted asymmetric oxidation agent to the corresponding chiral ketone compound.
  • a reducing agent such as hypo (sodium thiosulfate) , sodium hydrogensulfite, sodium metabisulfite, or the like
  • the chiral dioxirane compound can be reacted with the styrene derivative ( I ) in the presence or absence of an alkali agent in a suitable solvent.
  • solvents and alkali agents include, for instance, any of those solvents and those alkali agents which can be used in the respective preparation of the optical isomers of the dioxirane compounds (III) and (IV) from the optical isomers of the ketone compounds (V) and
  • the solvents the ether solvents, the nitrile solvents, the alcohol solvents, water, and mixed solvents thereof can be particularly desirably used.
  • the amount of the styrene derivative ( I ) is not particularly limited, and is usually about 0.1 g to about 30 g per 100 ml of the solvent.
  • the amount of the chiral dioxirane compound is about one mol to about five mol, preferably about one mol to about two mol, per one mol of the styrene derivative (I).
  • Processes for reacting the styrene derivative ( I ) with the chiral dioxirane compound include, for instance, a process comprising directly adding a chiral dioxirane compound to a solution of the styrene derivative ( I ) ; and a process comprising adding a chiral ketone compound corresponding to the chiral dioxirane compound and an oxidizing agent to a solution of the styrene derivative ( I ) to form a chiral dioxirane compound in the same reaction system.
  • the optical isomer of the dioxirane compound (III) or (IV) when used as a chiral dioxirane compound, there can be employed (a) a process comprising adding the optical isomer of the dioxirane compound (III) or (IV) to a solution of the styrene derivative (I), or (b) a process comprising adding an oxidizing agent to a mixture of the optical isomer of the ketone compound (V) or (VI) and the styrene derivative ( I ) , and reacting the styrene derivative ( I ) with the resulting optical isomer of the dioxirane compound (III) or (IV) in the same reaction system.
  • the optical isomer of the dioxirane compound (III) or (IV) in an amount sufficient for asymmetrically oxidizing the styrene derivative (I).
  • the optical isomer of the ketone compound (V) or (VI) and the oxidizing agent can be used in amounts sufficient for forming the optical isomer of the dioxirane compound (III) or (IV) in an amount sufficient for asymmetrically oxidizing the styrene derivative ( I ) in the reaction mixture.
  • the optical isomer of the dioxirane compound (III) or (IV) is formed from the optical isomer of the ketone compound (V) or (VI) with an oxidizing agent.
  • the optical isomer of the dioxirane compound (III) or (IV) asymmetrically oxidizes the styrene derivative (I)
  • the optical isomer of the original ketone compound (V) or (VI) is regenerated from the optical isomer of the dioxirane compound (III) or (IV), so that the regenerated ketone compound (V) or (VI) can be reused.
  • the oxidizing agent when used in an amount of 1 to 10 equivalents of the styrene derivative ( I ) , only the use of the optical isomer of the ketone compound (V) or (VI), the chiral source, in an amount of about 0.001 mol to about 0.1 mol, per one mol of the styrene derivative ( I ) , gives the asymmetric oxidation of the styrene derivative (I) completely, and thereby a desired optically active phenyloxirane compound (II) can be obtained. It is particularly desired that the oxidizing agent is used in an amount of 1.6 to 2.0 equivalents of the styrene derivative ( I ) .
  • Oxone an oxidizing agent
  • Oxone selectively oxidizes the optical isomer of the ketone compound (V) or (VI) as compared to the styrene derivative (I), to give an optical isomer of the dioxirane compound (III) or (IV).
  • the optical isomer of the dioxirane compound (III) or (IV) asymmetrically oxidizes the styrene derivative ( I ) , and thereafter is reduced to the original ketone compound (V) or (VI), which can be repeatedly used. Therefore, only the use of a catalytic amount of the optical isomer of the ketone compound (V) or (VI), the chiral source, makes it possible to asymmetrically oxidize the styrene derivative (I) in a high yield, and thereby a desired optically active phenyloxirane compound (II) can be obtained at high optical purity.
  • ( I ) with the chiral dioxirane compound is not particularly limited, and it is desired that the temperature is usually from about -5° to about 50°C, preferably from about 0° to about 40 °C.
  • the atmosphere during the reaction is not particularly limited, and it may be usually air or an inert gas, such as nitrogen gas.
  • the unreacted chiral dioxirane compound contained in the resulting reaction mixture after the reaction of the styrene derivative ( I ) with the chiral dioxirane compound can be reduced by a process, for instance, comprising washing the reaction mixture with an agent such as brine to remove the oxidizing agent and the like from the reaction mixture, and, as occasion demands, reducing the reaction mixture using a reducing agent, such as hypo (sodium thiosulfate), sodium hydrogensulfite, sodium metabisulfite, or the like, thereby converting the unreacted chiral dioxirane compound to the corresponding chiral ketone compound .
  • a reducing agent such as hypo (sodium thiosulfate), sodium hydrogensulfite, sodium metabisulfite, or the like
  • the ketone compound formed by reducing the asymmetric oxidation agent such as the chiral dioxirane compound from the reaction mixture containing the resulting chiral ketone compound as described above, and the optically active phenyloxirane compound (II) can be respectively recovered at high purity by a separation process utilizing the solubility differences to organic solvents.
  • the separation process utilizing the solubility differences include extraction methods using organic solvents, crystallizing methods using organic solvents, and the like.
  • the chiral ketone compound can be recovered in a high yield by, for instance, (a-1) adding water to the reaction mixture containing the chiral ketone compound, obtaining the resulting precipitates, and, if required, dissolving the precipitates in an organic solvent, and distilling off the solvent from the solution after the removal of impurities, or (a-2) extracting the reaction mixture containing the chiral ketone compound with an organic solvent, washing and drying the extract, and distilling off the solvent from the extract, and (b) extracting the resulting residue with an organic solvent wherein the chiral ketone compound, including, for instance, the ketone compounds (V) and (VI) is hardly soluble and that the optically active phenyloxirane compound (II) is easily soluble.
  • the chiral ketone compound can be recovered in a high yield by, for instance, carrying out the above-mentioned step (a-1) or (a-2), dissolving the resulting residue in an organic solvent wherein both of the chiral ketone compound and the optically active phenyloxirane compound (II) can be dissolved at a high temperature and under some temperature condition the chiral ketone can only be crystallized, while the optically active phenyloxirane compound (II) remains dissolved, and lowering the temperature of the resulting solution, thereby selectively crystallizing only the chiral ketone compound.
  • the chiral ketone compound can also be recovered in a high yield by extracting the reaction mixture containing the chiral ketone compound with an organic solvent wherein both of the chiral ketone compound and the optically active phenyloxirane compound ( II ) can be dissolved at a high temperature, and under some temperature condition, the chiral ketone can only be crystallized, while the optically active phenyloxirane compound (II) remains dissolved, and lowering the temperature of the extract, thereby selectively crystallizing only the chiral ketone compound .
  • organic solvent to be used to dissolve the precipitates resulting from the addition of water to the above-mentioned reaction mixture for instance, halogenated aliphatic hydrocarbon solvents, such as methylene chloride, chloroform, and carbon tetrachloride; ester solvents, such as ethyl acetate and methyl acetate; aromatic hydrocarbon solvents which may be halogenated, such as chlorobenzene, toluene, xylene, and mesitylene, may be used.
  • organic solvent used in the extraction of the reaction mixture examples include, for instance, aromatic hydrocarbon solvents, such as toluene; ether solvents, such as diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran, and diglyme. Among them, it is desired to use the ether solvents because they can be easily distilled off.
  • the organic solvent used in the extraction of the residue subsequent to the distilling off of the solvent, wherein the chiral ketone compound is hardly soluble and the optically active phenyloxirane compound (II) is easily soluble includes aliphatic hydrocarbon solvents, such as hexane; ester solvents, such as ethyl acetate, and the like. Those solvents can be used alone or in admixture thereof .
  • examples of the organic solvent wherein both of the chiral ketone compound and the optically active phenyloxirane compound (II) can be dissolved at a high temperature, and under some temperature condition, the chiral ketone compound can only be crystallized while the optically active phenyloxirane compound (II) remains dissolved include, for instance, ether solvents, such as diisopropyl ether and t-butyl methyl ether, and the like.
  • the chiral ketone compound can be obtained from the reaction mixture at high purity and in a high yield.
  • the optically active phenyloxirane compound (II) can be obtained at high purity and high optical purity by purifying the extract of the optically active phenyloxirane compound (II) prepared above or the mother liquor after recovering the ketone compound by techniques such as column chromatography and crystallization.
  • column chromatography include, for instance, conventional silica gel chromatography, and the like.
  • optically active phenyloxirane compound (II) When the resulting optically active phenyloxirane compound (II) is purified by crystallization, it is desired that ether solvents, such as diisopropyl ether, are used as the organic solvents.
  • ether solvents such as diisopropyl ether
  • a substantially pure, optically active phenyloxirane compound (II) can be obtained by crystallizing at a temperature lower than the crystallization temperature of the chiral ketone compound.
  • the (2R,3S) -optically active phenyloxirane compound and the ( 2S, 3R) -optically active phenyloxirane compound can be favorably used in the present invention because there is little steric hindrance owing to the fact that ring A and R are in trans-configuration, so that the desired optically active phenyloxirane compound of the present invention can be efficiently obtained.
  • the trans-isomer of the styrene derivative (I) is used, and that the asymmetric oxidation agent formed from a chiral ketone compound (Vl-a) or (Vl-b), for example, the chiral dioxirane compound (IV-a) or (IV-b), is used.
  • the trans-isomer of the styrene derivative (I) is used, and the asymmetric oxidation agent formed from the chiral ketone compound (Vl-a), for example, the chiral dioxirane compound (IV-a), is used, a ( 2R, 3S ) -phenyloxirane compound can be obtained.
  • R 2 is hydrogen atom or a substituted alkyl group
  • R 3 is a lower alkanoyl group
  • ring B is a substituted or unsubstituted benzene ring.
  • ring B include, for instance, unsubstituted benzene ring, and benzene rings having one to three substituents selected from the group consisting of lower alkyl groups, phenyl-lower alkyl groups, lower alkoxy groups, and halogen atoms.
  • the lower alkyl groups include, for instance, alkyl groups having 1 to 4 carbon atoms, such as methyl group, ethyl group, propyl group, and t-butyl group.
  • phenyl-lower alkyl groups include, for instance, phenylalkyl groups having 7 to 10 carbon atoms, such as benzyl group and phenetyl group.
  • lower alkoxy groups include, for instance, alkoxy groups having 1 to 4 carbon atoms, such as methoxy group, ethoxy group, propoxy group, and butoxy group.
  • examples of the halogen atoms include, for instance, fluorine atom, chlorine atom, bromine atom, and iodine atom.
  • R 3 is a lower alkanoyl group, and concrete examples thereof include, for instance, lower alkanoyl groups having 1 to 4 carbon atoms, such as acetyl group, propionyl group, and butyryl group.
  • R 2 is hydrogen atom or a substituted alkyl group.
  • substituted alkyl groups include, for instance, those in which an alkyl moiety is a lower alkyl group having 1 to 4 carbon atoms, such as methyl group, ethyl group, propyl group, and butyl group.
  • substituent on the alkyl group include, for instance, di-lower alkylamino groups, such as dimethylamino group and diethylamino group, and substituted phenylpiperazino groups, such as 4- ( 2-methoxyphenyl )piperazino group.
  • R 2 is 2- (dimethylamino)ethyl group or 3- [4- ( 2-methoxyphenyl )piperazino] propyl group.
  • Concrete examples of the resulting 1, 5-benzothiazepine derivative (VII) or pharmaceutically acceptable salts thereof include, for instance, ( 2S, 3S ) -2- ( 4-methoxyphenyl ) -3-acetoxy-5- [2- ( dimethylamino)ethyl] -2, 3-dihydro-l , 5-benzothiazepin- 4(5H)-one (Diltiazem), ( 2S, 3S ) -2- ( 4-methoxyphenyl )- 3-acetoxy-5-[2- (dimethylamino)ethyl] -8-chloro- 2, 3-dihydro-l, 5-benzothiazepin-4( 5H )-one, ( 2S, 3S )-3-acetoxy-5- [3- [4-(
  • the 1, 5-benzothiazepine derivative (VII) obtainable by the process of the present invention or the pharmaceutically acceptable salts thereof are highly useful compounds in the treatments for cardiac diseases, such as angina pectoris, cardiac infarction, and arrythmia, and cardiovascular diseases, such as hypertension, cardiovascular infarction, and cerebral infarction.
  • cardiac diseases such as angina pectoris, cardiac infarction, and arrythmia
  • cardiovascular diseases such as hypertension, cardiovascular infarction, and cerebral infarction.
  • the 1, 5-benzothiazepine derivative represented by the formula (VII) can be prepared from the optically active phenyloxirane compound (II) according to processes disclosed, for instance, in Japanese Examined Patent Publication Nos. Sho 46-16749 and Sho 63-13994, Japanese Patent Laid-Open Nos. Hei 5-201865 and Hei 2-289558, Japanese Examined Patent Publication No. Hei 2-28594, Chem. Pharm. Bull . 18(10), 2028-2037 (1970), Japanese Patent Laid-Open Nos. Hei 2-17168, Hei 2-229180, Hei 4-234866, Hei 5-222016, Hei 4-221376, Hei 5-202013,
  • R 4 is hydrogen atom, 2- (dimethylamino)ethyl group, or a group represented by the formula:
  • ring B and R 4 are the same as defined above, which includes, for example, 2-aminothiophenol, 2-amino- 5-chlorothiophenol, 2-[ [ 2- ( dimethylamino )ethyl] - amino] thiophenol, a compound represented by the formula:
  • ring B is the same as defined above, and the like and ring A and ring B are the same as defined above, or (A-2) reacting the ( 2R, 3S )-isomer with a nitrothiophenol derivative (IX) represented by the formula:
  • ring B is the same as defined above, which includes, for example, 2-nitrothiophenol, 2-nitro- 5-chlorothiophenol, 2-nitro-5-benzylthiophenol, and the like, followed by the reduction of the nitro group of the resulting product, to give a (2S, 3S )-3-( 2-aminophenylthio)-3-phenyl-2- hydroxypropionic acid ester compound represented by the formula:
  • ring A, ring B and R 4 are the same as defined above, or a pharmaceutically acceptable salt thereof, can be prepared by: (A-1) reacting the ( 2S, 3R) -isomer with the aminothiophenol derivative (VIII) or
  • (2R,3R) -isomer is reacted with the aminothiophenol to cause trans-opening, ( 2S, 3S )-propionic acid derivatives can be obtained.
  • 5-benzothiazepine derivative is subjected to dimethyaminoethylation at the 5-position, and the hydroxyl group substituted on the 3-position is then acetylated, so that a ( 2R, 3R)-1, 5-benzothiazepine derivative or a ( 2S,3S)-1, 5-benzothiazepine derivative can be prepared, respectively.
  • the optically active phenyloxirane compound (II) in which R has a group convertible to a group represented by -C0 2 R q , or a salt thereof can be transformed to a 1, 5-benzothiazepine derivative by converting the convertible group to a group represented by -C0 2 R q , and then reacting in the same manner as above.
  • it can be transformed to a 1, 5-benzothiazepine derivative by converting the convertible group to a group represented by -C0 2 R q prior to the intramolecular cyclization to form 1, 5-benzothiazepine structure, and reacting the product thereafter in the same manner as above.
  • carboxyl group can be converted to a group represented by -C0 2 R by esterifying the carboxyl group by a conventional method.
  • R r is the same as defined above, a group represented by the formula:
  • R r is the same as defined above, a group represented by the formula:
  • R s and R t are the same as defined above, or carboxyl group, or salts thereof can be transformed to a 1, 5-benzothiazepine derivative in the same manner as in the case where the optically active phenyloxirane compound (II) in which R is a group represented by -C0 2 R q is prepared, without converting the convertible group to a group represented by -C0 2 R q .
  • optically active phenyloxirane compound (II) represented by the formula (II) prepared by the process of the present invention can be used as a starting material for a nitrocarboxylic acid compound represented by the formula:
  • ring A and ring B are the same as defined above; and * indicates asymmetric carbon atom, which is useful for optical resolution agents.
  • ring A and ring B may be the same ones as those in the process for preparing the 1 , 5-benzothiazepine derivative. It is desired that ring A is a 4-lower alkoxyphenyl group, and ring B is a substituted benzene ring represented by the formula:
  • Hal is a halogen atom
  • ring A is 4-methoxyphenyl group
  • ring B is represented by the above formula, wherein Hal is chlorine atom.
  • the nitrocarboxylic acid compound can be prepared by a process, for instance, comprising reacting the optically active phenyloxirane compound (II) in which R is -C0 2 R q with a nitrothiophenol compound typically exemplified by, for instance, a compound represented by the formula:
  • Hal is the same as defined above, according to the process disclosed in Japanese Examined Patent Publication No. Sho 61-18549; and subsequently hydrolyzing the resulting product according to the process disclosed in " Chem. Pharm . Bull . , 18(10), 2028-2037 (1970)."
  • the optically active phenyloxirane compound (II) when R is a group convertible to a group represented by -C0 2 R q , wherein R q is the same as defined above, the optically active nitrocarboxylic acid compound can be prepared by firstly converting a compound resulting from the reaction of the optically active phenyloxirane compound (II) with a nitrothiophenol compound to a compound in which R is a group represented by -C0 2 R q , wherein R q is the same as defined above, by a known process generally employed in the conversion to a 1, 5-benzothiazepine derivative; and then hydrolyzing the resulting compound by a known method.
  • the optically active nitrocarboxylic acid compound can be prepared by directly converting a compound resulting from the reaction of the optically active phenyloxirane compound (II) with a nitrothiophenol compound to a compound in which R is carboxyl group using the methods utilized in the conversion to the 1 , 5-benzothiazepine derivative, without converting to a compound in which R is a group represented by -C0 2 R, wherein R q is the same as defined above.
  • the ketone compound in which Y is (i) -O-Q-Alk 1 - or (v) -NR ⁇ Q-Alk 1 - can be prepared by the process comprising reacting a compound represented by the formula (X):
  • Prot is a protective group for hydroxyl group; and Alk 1 and Q are the same as defined above, or a reactive derivative thereof; as occasion demands, when Z is -NH-, subjecting the resulting compound to N-alkylsulfonylation or N-arylsulfonylation; thereafter removing the protective group for hydroxyl group from the resulting compound represented by the formula (XII):
  • the ketone compound in which Y is (ii) -Q-0-Alk 2 - or (vi) -Q-NR ⁇ Alk 2 - can be prepared by a process comprising reacting a compound represented by the formula (XIII):
  • Z and Alk 2 are the same as defined above, or a dimer thereof; and as occasion demands, when Z is -NH-, subjecting the resulting compound to N-alkylsulfonylation or N-arylsulfonylation.
  • the ketone compound in which Y is (iii) -Alk 3 -0-Alk 4 - or (vii) -Alk ⁇ NR ⁇ Alk 4 - can be prepared by a process comprising reducing a compound represented by the formula (XV):
  • L is a leaving group
  • Alk 4 is the same as defined above; and as occasion demands, when Z is -NH-, subjecting the resulting compound to N-alkylsulfonylation or N-arylsulfonylation.
  • the ketone compound in which Y is (iv) -O-Alk 5 - or (viii) -NR X -Alk 5 - can be prepared by a process comprising reacting the ketone compound represented by the formula (X) with a compound represented by the formula (XIX):
  • L and Alk 5 are the same as defined above; and as occasion demands, when Z is -NH-, subjecting the resulting compound to N-alkylsulfonylation or N-arylsulfonylation.
  • the ketone compound in which Y is -NR ⁇ Alk 5 - can be prepared by a process comprising reducing a ketone compound prepared by reacting a compound represented by the formula (X) in which Z is -NH- with a compound represented by the formula (XI) in which Q is carbonyl group or a reactive derivative thereof, that is, a compound represented by the formula (XII) in which Z is -NH- and Q is carbonyl group; as occasion demands, subjecting the resulting compound to N-alkylsulfonylation or N-arylsulfonylation; removing the protective group for hydroxyl group; and thereafter subjecting the resulting product to oxidation reaction.
  • reaction of the compound represented by the formula (X) with the compound represented by the formula (XI) or a reactive derivative thereof and the reaction of the compound represented by the formula (XIII) or a reactive derivative thereof with the compound represented by the formula (XIV) or a dimer thereof can be carried out according to conventional ester formation processes or amide formation processes.
  • the reactive derivatives of the compound represented by the formula (XI) and the compound represented by the formula (XIII) include conventional reactive derivatives of carboxylic acids and sulfonic acids. Examples thereof include, for instance, acid halides, such as acid chloride, acid bromide, and acid iodide; anhydrous mixed acids, such as anhydrous mixed acids containing isobutyl chlorocarbonate, 2, 6-dichlorobenzoic acid chloride, or 2, 4, 6-trichlorobenzoic acid chloride;
  • DCC N, N' -dicyclohexylcarbodiimide
  • DCC N, N' -dicyclohexylcarbodiimide
  • active esters formed by using benzotriazol-1-yl-oxy- tris( dimethylamino )phosphonium hexafluorophosphate, and the like .
  • the protective group for hydroxyl group in the compound represented by the formula (XI) includes conventional protective groups for hydroxyl group.
  • the protective group include, for instance, lower alkanoyl groups, substituted silyl groups, and benzyl group which may have a substituent.
  • the dimer of the compound represented by the formula (XIV) is formed by the addition reaction of an HZ group of one molecule of the compound represented by the formula (XIV) to carbonyl group of another molecule of the compound represented by the formula (XIV).
  • the carbonyl groups and the HZ groups of two molecules can be added to each other to form a ring structure.
  • the dimer can be similarly used even when it is in equilibrium with its monomer .
  • reaction of the compound represented by the formula (X) with the compound represented by the formula (XI), and the reaction of the compound represented by the formula (XIII) with the compound represented by the formula (XIV) or a dimer thereof can be carried out in a suitable solvent in the presence of a condensing agent such as DCC or an N-methylpyridinium halide at ambient temperature or with heating.
  • a condensing agent such as DCC or an N-methylpyridinium halide
  • the solvent examples include, for instance, aliphatic hydrocarbon solvents which may be halogenated, such as hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, and carbon tetrachloride; aromatic hydrocarbon solvents which may be halogenated, such as toluene, xylene, mesitylene, chlorobenzene, and dichlorobenzene; nitrile solvents, such as acetonitrile, propionitrile, and butyronitrile; ether solvents, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and diglyme, and the like.
  • an acid acceptor such as triethylamine, diisopropylethylamine, or pyridine may be added.
  • reaction of the compound represented by the formula (X) with the reactive derivative of the compound represented by the formula (XI), and the reaction of the reactive derivative of the compound represented by the formula (XIII) with the compound represented by the formula (XIV) or a dimer thereof can be carried out in a suitable solvent in the presence or absence of an acid acceptor, including, for instance, an organic base such as triethylamine, trimethylamine, pyridine, or diisopropylethylamine, at ambient temperature or with heating .
  • an organic base such as triethylamine, trimethylamine, pyridine, or diisopropylethylamine
  • the solvent examples include, for instance, aliphatic hydrocarbon solvents which may be halogenated, such as hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, and carbon tetrachloride; aromatic hydrocarbon solvents which may be halogenated, such as toluene, xylene, mesitylene, chlorobenzene, and dichlorobenzene; nitrile solvents, such as acetonitrile, propionitrile, and butyronitrile; ether solvents, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and diglyme, and the like.
  • aliphatic hydrocarbon solvents which may be halogenated, such as hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, and carbon tetrachloride
  • aromatic hydrocarbon solvents which may be halogenated, such
  • reaction of the compound represented by the formula (XVII) with the compound represented by the formula (XVIII), and the reaction of the compound represented by the formula (X) with the compound represented by the formula (XIX) can be carried out according to conventional O-alkylation of an alcohol or N-alkylation of an amine.
  • the leaving group L in the compound represented by the formula (XVIII) and that in the compound represented by the formula (XIX) which can be used herein can be a conventional leaving group, including a halogen atom such as chlorine atom, bromine atom, or iodine atom, or an alkylsulfonyloxy group or an arylsulfonyloxy group, including p-toluenesulfonyloxy group or methanesulfonyloxy group .
  • a halogen atom such as chlorine atom, bromine atom, or iodine atom
  • an alkylsulfonyloxy group or an arylsulfonyloxy group including p-toluenesulfonyloxy group or methanesulfonyloxy group .
  • reaction of the compound represented by the formula (XVII) with the compound represented by the formula (XVIII), and the reaction of the compound represented by the formula (X) with the compound represented by the formula (XIX) can be carried out in a suitable solvent in the presence of an acid acceptor, including, for instance, an organic base such as triethylamine, trimethylamine, pyridine, or diisopropylethylamine at ambient temperature or with heating.
  • an acid acceptor including, for instance, an organic base such as triethylamine, trimethylamine, pyridine, or diisopropylethylamine at ambient temperature or with heating.
  • the solvent examples include, for instance, aliphatic hydrocarbon solvents which may be halogenated, such as hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, and carbon tetrachloride; aromatic hydrocarbon solvents which may be halogenated, such as toluene, xylene, mesitylene, chlorobenzene, and dichlorobenzene; nitrile solvents, such as acetonitrile, propionitrile, and butyronitrile, and the like.
  • aliphatic hydrocarbon solvents which may be halogenated, such as hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, and carbon tetrachloride
  • aromatic hydrocarbon solvents which may be halogenated, such as toluene, xylene, mesitylene, chlorobenzene, and dichlorobenzene
  • nitrile solvents
  • processes for removing the protective group for hydroxyl group from the compound represented by the formula (XII) there can be applied any conventional processes for removing the protective group for hydroxyl group, including hydrolytic processes, catalytic hydrogenation processes, acid treatments with hydrogen fluoride, and the like.
  • Such processes can be carried out by treating the compound represented by the formula (XII) with a base, including, for instance, an alkali metal hydroxide, such as potassium hydroxide or sodium hydroxide, an alkali metal carbonate, such as potassium carbonate or sodium carbonate, an organic acid, such as formic acid or trifluoroacetic acid, and an inorganic acid, such as hydrochloric acid or hydrofluoric acid, in a suitable solvent, including, for instance, an alcohol solvent, such as methanol or ethanol, an ether solvent, such as tetrahydrofuran, 1,4-dioxane, or diglyme, or the like.
  • a base including, for instance, an alkali metal hydroxide, such as potassium hydroxide or sodium hydroxide, an alkali metal carbonate, such as potassium carbonate or sodium carbonate, an organic acid, such as formic acid or trifluoroacetic acid, and an inorganic acid, such as hydrochloric acid or hydrofluoric acid,
  • the oxidation reaction can be carried out by treating the resulting product formed by the removal reaction of the protective group for hydroxyl group with an oxidizing agent including, for instance, chromic acid or a derivative thereof, such as pyridinium chlorochromate, ruthenium oxide, oxalyl dichloride- dimethylsulfoxide, or 1, 1, l-tris( acetyloxy )-l, 1-dihydro- 1, 2-benziodoxol-3( lH)-one in a suitable solvent.
  • an oxidizing agent including, for instance, chromic acid or a derivative thereof, such as pyridinium chlorochromate, ruthenium oxide, oxalyl dichloride- dimethylsulfoxide, or 1, 1, l-tris( acetyloxy )-l, 1-dihydro- 1, 2-benziodoxol-3( lH)-one in a suitable solvent.
  • the solvent includes, for instance, aliphatic hydrocarbon solvents which may be halogenated, such as hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, and carbon tetrachloride; aromatic hydrocarbon solvents which may be halogenated, such as toluene, xylene, mesitylene, chlorobenzene, and dichlorobenzene; nitrile solvents, such as acetonitrile, propionitrile, and butyronitrile, and the like.
  • aliphatic hydrocarbon solvents which may be halogenated, such as hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, and carbon tetrachloride
  • aromatic hydrocarbon solvents which may be halogenated, such as toluene, xylene, mesitylene, chlorobenzene, and dichlorobenzene
  • nitrile solvents such
  • the reduction reaction of the compound represented by the formula (XV) can be carried out according to any conventional processes for reducing carboxylic acids.
  • the reduction reaction can be carried out by treating the compound represented by the formula (XV) with a reducing agent, including, for instance, diborane, lithium aluminum hydride, and the like, in a suitable solvent, including, for instance, an ether solvent, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, or diglyme, or the like.
  • a reducing agent including, for instance, diborane, lithium aluminum hydride, and the like
  • a suitable solvent including, for instance, an ether solvent, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, or diglyme, or the like.
  • the lengthening of the alkyl moiety bonded to hydroxyl group of the compound represented by the formula (XVI) resulting from by the reduction reaction can be carried out according to any conventional processes.
  • the lengthening of the alkyl moiety can be carried out by a process comprising treating the compound represented by the formula (XVI) with a halogenating agent, including, for instance, a thionyl halide such as thionyl chloride or thionyl bromide, or, in the alternative, converting hydroxyl group of the compound represented by the formula (XVI) to a leaving group with a compound, such as a p-toluenesulfonyl halide, such as p-toluenesulfonyl chloride or p-toluenesulfonyl bromide, and thereafter treating the resulting leaving group with the halogenating agent listed above; reacting the resulting halide with magnesium to form a Grignard reagent;
  • the conversion of hydroxyl group to amino group can be also carried out by any conventional processes.
  • such conversion can be carried out by treating the compound represented by the formula (XVI) or the compound which is obtained by lengthening the alkyl moiety of the compound (XVI) with such a halogenating agent as mentioned above, and reacting the resulting product with ammonia.
  • the reduction reaction of the compound represented by the formula (XII) in which Z is -NH- and Q is carbonyl group can be carried out by a similar process to the reduction reaction of the compound represented by the formula (XV).
  • removal of a protective group for hydroxyl group from the product obtained by N-alkylsulfonylation or N-arylsulfonylation, and the subsequent oxidation reaction can be carried out in the same manner as those processes of the removal of the protective group for hydroxyl group of the compound represented by the formula (XIV) and the following oxidation reaction described above.
  • the N-alkylsulfonylation or N-arylsulfonylation can be carried out according to conventional processes of sulfonization of amines.
  • the reaction can be carried out using an alkylsulfonic acid, an arylsulfonic acid, or a reactive derivative thereof.
  • the reactive derivative include, for instance, acid halides, such as acid chloride, acid bromide, and acid iodide, and the like.
  • the alkylsulfonic acid or arylsulfonic acid When the alkylsulfonic acid or arylsulfonic acid is used, it is desired that the N-alkylsulfonylation or N-arylsulfonylation is carried out in the presence of a condensing agent in a suitable solvent. On the other hand, when a reactive derivative is used, it is desired that the N-alkylsulfonylation or N-arylsulfonylation is carried out in the presence or absence of an acid acceptor in a suitable solvent.
  • optical isomers of the ketone compound (V) can be prepared by a process comprising optically resolving the compound represented by the formula ( X ) , the compound represented by the formula (XIII), the compound represented by the formula (XV), the compound represented by the formula ( XVI ) , and the compound represented by the formula (XVII) according to conventional process, and thereafter employing the preparation process described above.
  • optical resolution process there may be applicable, for instance, a process for separately crystallizing a diastereomer salt with an optical resolution agent.
  • optical resolution agents any of generally employed agents for optical resolution can be suitably used.
  • the optical resolution agents it is desired, for instance, to use optically active amines, and it is particularly desired to use quinidine, cinchonidine, quinine, brucine, optical isomers of amino acids, amino acid esters, amino alcohols, and the like.
  • the compound in which R is a lower alkoxycarbonyl group can be prepared at high yields by a process comprising carrying out condensation reaction of a benzaldehyde compound represented by the formula:
  • ring A is a substituted or unsubstituted benzene ring, with a lower alkyl acetate in the presence or absence of a solvent and in the presence of a base; and as occasion demands, subjecting the resulting product to transesterification in the presence or absence of an acid.
  • the lower alkyl acetate it is desired to use methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, or the like.
  • the lower alkyl acetate such as methyl acetate or ethyl acetate, which can also act as a solvent, is used, other solvents are not necessarily used.
  • the bases used in the condensation reaction of the benzaldehyde compound with the lower alkyl acetate include inorganic strong bases.
  • examples thereof include alkali metal alkoxides including, for instance, lithium methoxide, lithium ethoxide, lithium n-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium n-butoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium n-butoxide, potassium tert-butoxide, and the like; metallic alkali metals including, for instance, metallic lithium, metallic sodium, metallic potassium, and the like; alkali metal hydrides including, for instance, lithium hydride, sodium hydride, potassium hydride, and the like; alkali metal hydroxides including, for instance, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.
  • the condensation reaction can be favorably carried out at room temperature or with heating, and it is particularly
  • the ester residue of the resulting condensate does not have a desired ester residue
  • the ester residue can be converted to a desired ester residue by a conventional esterification reaction.
  • the transesterification reaction can be carried out using a lower alkanol corresponding to the desired ester residue.
  • the alcohol used also acts as a solvent, other solvents are not necessarily used.
  • the acids used in the transesterification reaction include inorganic acids including, for instance, sulfuric acid, hydrochloric acid, phosphoric acid, and the like; and organic acids including, for instance, methanesulfonic acid, p-toluenesulfonic acid, and the like. Since the reaction also favorably proceeds even in the absence of the acid, the transesterification reaction can be carried out by directly adding an alcohol to a reaction mixture resulting from the condensation reaction. It is desired that the transesterification reaction is carried at a temperature between room temperature and a reflux temperature of the solvent, and it is particularly desired that the transesterification reaction is carried out at 20° to 80°C.
  • the present invention will be more specifically described by the following examples, without intending to restrict the scope or spirit of the present invention thereto .
  • the precipitated white powder was collected by filtration, and evaporated under reduced pressure, to give
  • optical purity of the resulting optically active phenylglycidate was determined to be 81%ee by HPLC.
  • Example 2 In 15 ml of 1, 2-dimethoxyethane was dissolved 192 mg (1.0 mmol) of methyl trans-4-methoxycinnamate at room temperature. Thereafter, to the resulting mixture was added 10 ml of a 4 x 10 "4 M aqueous disodium ethylenediaminetetraacetate (EDTA) solution, and 55 mg (0.1 mmol) of a chiral, asymmetric ketone compound represented by the formula:
  • the resulting product was subjected to the treatments in the same manner as in Example 1, to give 0.126 g (isolation yield: 61%) of the same optically active phenylglycidate as in Example 1.
  • the optical purity of the resulting optically active phenylglycidate was determined to be 64%ee by HPLC.
  • the chiral ketone compound could be collected in the same manner as in Example 1 (recovery: 88% by weight ) .
  • Example 4 The yield and the optical purity of the resulting phenylglycidate were respectively determined to be 74% and 85%ee by HPLC.
  • Example 4 The yield and the optical purity of the resulting phenylglycidate were respectively determined to be 74% and 85%ee by HPLC.
  • the resulting product was subjected to the treatments in the same manner as in Example 1, to give the same optically active phenylglycidate as in Example 1.
  • the yield and the optical purity of the resulting phenylglycidate were respectively determined to be 70% and 62%ee by HPLC.
  • the optical purity of the resulting product was determined to be 74%ee by HPLC.
  • the chiral ketone compound could be collected in the same manner as in Example 1 (recovery: 80% by weight) .
  • optical purity of the resulting optically active phenylglycidate was determined to be 73%ee by HPLC.
  • the resulting product was subjected to the treatments in the same manner as in Example 1, to give 107 mg (isolation yield: 51%) of the same optically active phenylglycidate as in Example 1.
  • the optical purity of the resulting optically active phenylglycidate was determined to be 73%ee by HPLC.
  • optical purity of the resulting optically active phenyloxirane was determined to be 57%ee by HPLC.
  • HPLC conditions are as follows: [Column] Chiral OD
  • R x is a group indicated in Table 1, was used.
  • the precipitated white powder was collected by filtration, and evaporated under reduced pressure, to give a chiral ketone compound.
  • R x is the same as defined above.
  • the mother liquor was concentrated under reduced pressure, and 265 mg of its residue was subjected to quantitative analysis with 1 H-NMR and HPLC. As a result, it was found that the mother liquor comprises 6 mg of the chiral ketone compound and 181.5 mg of racemic methyl trans-3-( 4-methoxyphenyl) glycidate. This reveals that no decomposition of the product and that no side reactions took place in the separation process.
  • the resulting white solid was analyzed with HPLC under the following conditions. As a result, it was deduced that the resulting white solid was a mixture of 8.298 g of methyl ( 2R, 3S )-3- ( p-methoxyphenyl )glycidate, 0.902 g of methyl ( 2S, 3R) -3- (p-methoxyphenyl )glycidate, 0.323 g of methyl p-methoxycinnamate, and 0.966 g of the chiral ketone compound.
  • reaction mixture was extracted by adding ethyl acetate thereto.
  • the extract was dried, and the solvents were then distilled off.
  • the resulting extract was dissolved in methanol to allow recrystallization. Thereafter, the solvents were distilled off until a point where about 17 ml of solvents remained. Thereafter, the resulting crystals were collected by filtration.
  • reaction mixture was diluted with 102 ml of tetrahydrofuran, and 20 ml of a tetrahydrofuran solution (suspension) containing 89 mg of 1, 3-dihydroxyacetone dimer represented by the formula:
  • bianthracene carboxylic acid To 35 ml of a methylene chloride solution containing 750 mg of ( - )-l, 1 ' -bis( 2-anthracene carboxylic acid) (hereinafter referred to as "bianthracene carboxylic acid”) were added 0.37 ml of oxalyl chloride and several drops of dimethylformamide under argon gas atmosphere. The resulting mixture was stirred for two hours at room temperature.
  • the reaction mixture was diluted with 420 ml of methylene chloride, and to the resulting mixture was added dropwise 80 ml of a methylene chloride solution (suspension) containing 230 mg of 1 , 3-dihydroxyacetone dimer and 1.4 ml of triethylamine over a period of one hour and thirty minutes. Thereafter, the 1,3- dihydroxyacetone dimer remaining in the dropping funnel was rinsed off with 20 ml of methylene chloride.
  • Reference Example 4 The amount 6.81 g (50 mmol) of p-anisaldehyde, 35.2 g (400 mmol) of ethyl acetate, and 12.5 g of a methanol solution of sodium methoxide (28%, 65 mmol) were mixed together, and the resulting mixture was stirred at 60°C for six hours. The solvent was distilled off from the reaction mixture under reduced pressure, and 30 ml of a methanol solution containing 8.8 g (90 mmol) of concentrated sulfuric acid was added to the residue. The resulting mixture was refluxed with heating for eight hours.
  • the solvent was distilled off from the reaction mixture, and 30 ml of methanol was added to the residue, and the resulting mixture was refluxed again with heating for nine hours.
  • the solvents were distilled off from the reaction mixture.
  • To the residue was added 30 ml of methanol, and the mixture was then refluxed with heating for four hours. Thereafter, water and ethyl acetate were added to the mixture, and the ethyl acetate layer was obtained. A portion of the ethyl acetate layer was taken out and analyzed with HPLC. As a result, it could be deduced that the ethyl acetate layer contained 8.01 g (83.4%) of methyl trans-4-methoxycinnamate therein.
  • Reference Examples 6 to 9 The same procedures as in the methods of Reference Example 1 or 2 were carried out except for using a different base in place of the methanol solution of sodium methoxide or the ethanol solution of sodium ethoxide to carry out condensation reaction, followed by transesterification reaction in the same manner as in
  • the optically active phenyloxirane compound represented by the formula (II) can be prepared with high stereoselectivity and in high yields by treating the styrene derivative ( I ) represented by the formula ( I ) with the asymmetric oxidation agent resulting from a chiral ketone compound and an oxidizing agent.
  • asymmetric oxidation by Oxone and a chiral ketone compound there has been known the asymmetric epoxidation of trans-stilbene [J. Am . Chem. Soc , 118, 11311 (1996)].
  • the reaction in general, in the asymmetric reaction, the reaction is very often carried at an extremely low temperature of about -78 °C in order to obtain high stereoselectivity. In the process of the present invention, however, since the asymmetric oxidation can be carried out at high stereoselectivity at a temperature from 0°C to room temperature, the present invention is easily applicable to industrial purposes.
  • the styrene derivative (I) the starting material compound of the present invention, since the electron withdrawing ester moiety is directly bound to a double bond, it has been considered that the asymmetric oxidation with an asymmetric oxidation agent resulting from a chiral ketone compound and an oxidizing agent does not easily proceed. Nevertheless, the asymmetric oxidation reaction can be completed even at low temperatures in a relatively short period of time.
  • the optically active phenyloxirane compound having an easily decomposable oxirane ring can be obtained in high yields.
  • the chiral ketone compound resulting from the asymmetric oxidation agent by the asymmetric reaction is oxidized again by an oxidizing agent existed in the reaction system to be regenerated as an asymmetric oxidation agent. Therefore, the asymmetric oxidation reaction can be carried out by using just a catalytic amount of the chiral ketone compound. Moreover, since the chiral ketone compound is a chemically stable compound, the chiral ketone compound can be recovered for reuse.
  • the optically active phenyloxirane compound can be prepared in high yields, and the chiral catalyst used upon its preparation can be reused, there can be exhibited excellent effects of being capable of preparing the optically active phenyloxirane compound with good productivity and economical advantage.

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Abstract

Cette invention concerne un procédé de préparation d'un composé de phényloxyrane actif sur le plan optique, lequel composé correspond à la formule (II) où l'anneau A représente un anneau de benzène substitué ou non. R représente un groupe -CO2Rq ou un groupe pouvant être transformé en un groupe -CO¿2R?q, étant entendu que Rq représente un résidu d'ester. Le symbole * représente enfin un atome de carbone asymétrique. Ce procédé fait appel à un dérivé de styrène correspondant à la formule (I) où l'anneau A et R sont tels que définis précédemment. Ce procédé consiste à traiter le dérivé de styrène à l'aide d'un agent d'oxydation asymétrique qui se compose d'un composé de cétone chiral et d'un agent oxydant ou, encore, d'un composé de dioxyrane chiral.
EP98923162A 1997-06-11 1998-06-05 Procede de preparation de composes de phenyloxyrane actifs sur le plan optique Withdrawn EP0988297A2 (fr)

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US4552695A (en) * 1983-04-21 1985-11-12 Shionogi & Co., Ltd. Process for production of diltiazem hydrochloride
JPS59196881A (ja) * 1983-04-21 1984-11-08 Shionogi & Co Ltd 新規なエポキシド誘導体
JPS6013776A (ja) * 1983-07-05 1985-01-24 Sawai Seiyaku Kk 光学活性３−（ｐ−アルコキシフエニル）グリシツド酸誘導体の製造法
US4885375A (en) * 1988-05-18 1989-12-05 Marion Laboratories, Inc. Resolution of 3-(4-methoxyphenyl)glycidic acid with in situ conversion to alkyl esters
NL8801311A (nl) * 1988-05-20 1989-12-18 Stamicarbon Fenylglycidaatstereoisomeren, omzettingsprodukten daarvan met 2-nitrothiofenol en de bereiding van diltiazem.
JPH0678B2 (ja) * 1988-09-02 1994-01-05 田辺製薬株式会社 光学活性３―フェニルグリシッド酸エステル類化合物の製法
FI95931C (fi) * 1988-09-02 1996-04-10 Tanabe Seiyaku Co Menetelmä (2R,3S)-3-(4-metoksifenyyli)glysidiinihapon alemman alkyyliesterin valmistamiseksi
IT1249777B (it) * 1990-05-17 1995-03-18 Zambon Spa Processo per la preparazione di intermedi per la sintesi del diltiazem
FR2672600B1 (fr) * 1991-02-08 1994-10-14 Synthelabo Procede de preparation du (-)-(2r,3s)-2,3-epoxy-3-(4-methoxyphenyl) propionate de methyle.
JP2622251B2 (ja) * 1992-09-03 1997-06-18 田辺製薬株式会社 光学活性３−（４−メトキシフェニル）グリシッド酸エステル類化合物の製法
ZA94284B (en) * 1993-01-27 1994-08-17 Shionogi & Co Process for preparing benzothiazepine derivatives

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