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.

BACKGROUND ART 1,5-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. In particular, Diltiazem hydrochloride (chemical name: <BR> <BR> <BR> <BR> (2S,3S)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2-(4- <BR> <BR> <BR> <BR> methOxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride) has been widely used for the treatments for angina pectoris and essential hypertension.

In recent years, various processes have been proposed as to processes for preparing optically active glycidic acid derivatives to be used as intermediates for 1,5- benzothiazepine derivatives. Examples of major methods for preparing glycidic acid derivatives include, for instance, the following: (A) Processes for preparing a glycidic acid derivative by asymmetric hydrolysis method (Japanese Unexamined Patent Publication No. Hei 4-501360, and Japanese Examined Patent Publication Nos. Hei 6-78 and Hei 7-121231); (B) Processes for preparing a glycidic acid derivative by asymmetric transesterification method (Japanese Patent Laid-Open Nos. Hei 4-228095, Hei 5-76389, and Hei 6-78790); (C) Processes for preparing a glycidic acid derivative by chemical, optical resolution method (Japanese Patent Laid-Open No. Sho 60-13776, Japanese Examined Patent Publication No. Hei 4-28268, Japanese Patent Laid- Open No. Hei 2-231480); and (D) Processes for preparing a glycidic acid derivative by asymmetric amidation (International Publication No.

W095/07359).

However, in any of the processes under the items (A) to (D), since a racemic trans-glycidic acid derivative is

used as a starting material, there is a defect that the yield of the desired optical isomer is 50% or less of the racemic form.

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 (2S,3S)-3-(4-acetoxyphenyl)glycidyl alcohol with a mixture of ruthenium dioxide and sodium meta-periodate; and thereafter forming methyl (2R,3S)-3- (4-acetoxyphenyl)glycidate with dimethylsulfuric acid.

However, according to this method, there arise defects that its reaction steps are very complicated, and that the yield is not so high.

In the recent years, various studies have been made on the oxidation reaction using dioxirane compounds [Chemical Reviews, 89, 1187-1201 (1989)1. For instance, there has been reported in "J. Org, Chem., 50, 2847-2853 (1985)" that epoxidation is carried out by adding dimethyldioxirane of no chirality to ethyl trans- cinnamate, and reacting the resulting mixture at 25"C for 22 hours.

However, the dimethyldioxirane has no chirality, so that there arises a defect that a phenyloxirane compound having desired optical activity cannot be obtained.

There has been reported in "J. Am. Chem. Soc., 118, 11311-11312 (1996)" that asymmetric epoxidation of a simple, C2 symmetric compound, trans-stilbene, in which two electron-donating phenyl groups are bonded to its double bond, is carried out by using a chiral dioxirane compound formed by oxidizing a ketone compound represented by the formula: with Oxone [tradename, manufactured by Du Pont; composition: 2KHSO5.KHSO4oK2SO4j.

However, there are no disclosures or suggestions in any of the literatures pertaining to the desired process for preparing an aimed optically active phenyloxirane compound.

In view of the prior art, 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.

These and other objects of the present invention will be apparent from the following description.

DISCLOSURE OF INVENTION The present invention pertains to the following: [1] A process for preparing an optically active phenyloxirane compound represented by the formula (if): wherein ring A is a substituted or unsubstituted benzene ring; R is a group represented by -CO2Rq, or a group convertible to the group represented by -CO2Rq, wherein Rq is an ester residue; and * indicates an asymmetric carbon

atom, comprising treating a styrene derivative (I) represented by the formula (I): wherein 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; [2] The process described in item [1] above, wherein the chiral 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-Alkl-, (ii) -Q-O-Alk2-, (iii ) -Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alk1-, (vi) -Q-NR1-Alk2-,

(vii)-Alk3-NR1-Alk4-, or (viii)-NR1-Alk5-, wherein Q is -CO- group or -S~2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alko, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group, respectively; [3] The process described in item [1] or item [2] above, wherein the chiral ketone compound is an optical isomer of a ketone compound (VI) represented by the formula (VI): wherein each of R" and Rb is hydrogen atom, or a substituent; and Rc and Rd satisfy one of the following (I) to (III): (I) each of Rc and Rd is hydrogen atom, or a substituent; or (II) Rc and Rd are bonded to each other to form a group represented by the formula:

wherein Re, Rf, Rg, and Rh 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)RC and Rd are bonded to each other to form a group represented by the formula: wherein each of Ri, Rj, Rk, and Rm is hydrogen atom or a substituent; and Y is a group represented by the formula: (i) -O-Q-Alkl-, (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-,

(v) -NR -Q-Alk , (vi) -Q-NR1-Alk2-, (vii) -Alk3-NR1-Alk4-, or (viii)-NR1-Alk5-, wherein Q is -CO- group or 502 group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group; [4] The process described in any one of items [1] to [3] above, wherein the reaction of the chiral ketone compound with the oxidizing agent and the reaction of the resulting asymmetric oxidation agent with the styrene derivative (I) are carried out in the same reaction system; (5] A process for preparing an optically active phenyloxirane compound represented by the formula (II): wherein ring A is a substituted or unsubstituted benzene ring; R is a group represented by -CO2Rq, or a group convertible to the group represented by -CO2Rq, wherein Rq is an ester residue; and * indicates an asymmetric carbon atom, comprising treating a styrene derivative (I) represented by the formula (I):

wherein ring A and R are the same as defined above, with a chiral dioxirane compound; [6] The process described in item [5] above, wherein the chiral dioxirane compound is an optical isomer of a dioxirane compound (III) represented by the formula (III): 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-Alkl-, (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alkl-, (vi) -Q-NR1-Alk2-, (vii)-Alk3-NR1-Alk4-, or (viii)-NR1-Alk5- wherein Q is -CO- group or -S02- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group, respectively; [7] The process described in item [5] or item [6] above, wherein the chiral dioxirane compound is an optical isomer of a dioxirane compound (IV) represented by the formula

wherein each of Ra and Rb is hydrogen atom, or a substituent; and Rc and Rd satisfy one of the following (I) to (III): (I) each of Rc and Rd is hydrogen atom, or a substituent; or (II) Rc and Rd are bonded to each other to form a group represented by the formula: wherein Re, Rf, Rg, and Rh 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)RC and Rd are bonded to each other to form a group represented by the formula: wherein each of Ri, Rj, Rk, and Rm is hydrogen atom or a substituent; and Y is a group represented by the formula: (i) -O-Q-Alkl-, (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR -Q-Alk -, (vi) -Q-NR1-Alk2-, (vii)-Alk -NR -Alk4-, or (viii)-NR -Alk5-, wherein Q is -CO- group or -SO2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group; [8] The process described in any one of items [5] to [7] above, comprising the steps of:

reacting an optical isomer of a ketone compound (VI) represented by the formula (VI): wherein each of Ra and Rb is hydrogen atom, or a substituent; and Rc and Rd satisfy one of the following (I) to (III): (I) each of Rc and Rd is hydrogen atom, or a substituent; or (II) Rc and Rd are bonded to each other to form a group represented by the formula: wherein Re, Rf, Rg, and Rh 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)RC and Rd are bonded to each other to form a group represented by the formula: wherein each of Ri, RJ, Rk, and Rm is hydrogen atom or a substituent; and Y is a group represented by the formula: (i) -O-Q-Alk -, (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alk1-, (vi) -Q-NR1-Alk2-, (vii)-Alk3-NR1-Alk4-, or (viii)-NR1-Alk5-, wherein Q is -CO- group or -S~2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group, with an oxidizing agent; and

reacting the styrene derivative (I) with the resulting chiral dioxirane compound (IV); [9] The process described in item t8] above, wherein the reaction of the optical isomer of the ketone compound (VI) with the oxidizing agent and the reaction of the resulting chiral dioxirane compound (IV) with the styrene derivative (I) are carried out in the same reaction system; [10] The process described in any one of items [1] to [9] above, wherein the styrene derivative (I) is a trans isomer, and the optically active phenyloxirane compound (II) is a (2R,3S)-isomer or a (2S,3R)-isomer; [11] The process described in any one of items [1] to [4] above, wherein the styrene derivative (I) is a trans isomer; the chiral ketone compound is a chiral ketone compound (VI-a) represented by the formula (VI-a): wherein each of R" and Rb is hydrogen atom, or a substituent; and Rc and Rd satisfy one of the following (I)

to (III): (I) each of Rc and Rd is hydrogen atom, or a substituent; or (II) Rc and Rd are bonded to each other to form a group represented by the formula: wherein Re, Rf, Rg, and Rh 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)RC and Rd are bonded to each other to form a group represented by the formula:

wherein each of Rt, Rj, Rk, and Rm is hydrogen atom or a substituent; and Y is a group represented by the formula: (i) -O-Q-Alkl-, (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alk1-, (vi) -Q-NR1-Alk2-, (vii)-Alk3-NR1-Alk4-, or (viii)-NR1-Alk5-, wherein Q is -CO- group or -SO2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group; and the optically active phenyloxirane compound (II) is a (2R,3S)-isomer; [12] The process described in any one of items [1] to [4] above, wherein the styrene derivative (I) is a trans isomer, and the chiral ketone compound is a chiral ketone compound (VI-b) represented by the formula (VI-b):

wherein each of Ra and Rb is hydrogen atom, or a substituent; and R' and Rd satisfy one of the following (I) to (III): (I) each of RC and Rd is hydrogen atom, or a substituent; or (II) RC and Rd are bonded to each other to form a group represented by the formula: wherein Re, Rf, Rg, and Rh 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)RC and Rd are bonded to each other to form a group represented by the formula:

wherein each of Ri, Rj, Rk, and Rm is hydrogen atom or a substituent; and Y is a group represented by the formula: (i) -O-Q-Alk , (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alk1-, (vi) -Q-NR -Alkì-, (vii)-Alk -NR -Alk4-, or (viii)-NR -Alk5-, wherein Q is -CO- group or -SO2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group; and the optically active phenyloxirane compound (11) is a (2S,3R)-isomer; [13] The process described in any one of items [5] to [9] above, wherein the styrene derivative (I) is a trans isomer; the chiral dioxirane compound is a chiral dioxirane compound (IV-a) represented by the formula (IV-a):

wherein each of R" and Rb is hydrogen atom, or a substituent; and Ra and Rd satisfy one of the following (I) to (III): (I) each of Ra and Rd is hydrogen atom, or a substituent; or (Il) Ra and Rd are bonded to each other to form a group represented by the formula: wherein Re, Rf, Rg, and Rh 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)RC and Rd are bonded to each other to form a group represented by the formula: wherein each of Ri, Rj, Rk, and Rm is hydrogen atom or a substituent; and Y is a group represented by the formula: (i) -O-Q-Alk1-, (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR -Q-Alk -, (vi) -Q-NR1-Alk2-, (vii )-Alk3-NR1-Alk4-, or (viii)-NR1-Alk5-, wherein Q is -CO- group or -SO2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group; and the optically active phenyloxirane compound (II) is a (2R,3S)-isomer; [14] The process described in any one of items [5] to [9]

above, wherein the styrene derivative (I) is a trans isomer, and the chiral dioxirane compound is a chiral dioxirane compound (IV-b) represented by the formula (IV-b): wherein each of Ra and Rb is hydrogen atom, or a substituent; and Rc and Rd satisfy one of the following (I) to (III): (I) each of Rc and Rd is hydrogen atom, or a substituent; or (II) RC and Rd are bonded to each other to form a group represented by the formula: wherein Re, Rf, Rg, and Rh 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)RC and Rd are bonded to each other to form a group represented by the formula: wherein each of Ri, Rj, Rk, and Rm is hydrogen atom or a substituent; and Y is a group represented by the formula: (i) -O-Q-Alk1 , (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alk1-, (vi) -Q-NR1-Alk2-, (vii)-Alk3-NR1-Alk4-, or (viii)-NR1-Alk5-, wherein Q is -CO- group or 502 group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene

group; and the optically active phenyloxirane compound (11) is a (2S,3R)-isomer; [15] The process described in item [3], [4], [7], [8], [9], [11], [12], [13], or [14] above, wherein Y is represented by -CO-O-CH2- group; Ra, Rb, RC, and Rd satisfy one of the following (a) and (b): (a) each of Ra and Rb is hydrogen atom; and Rc and Rd are bonded to each other to form a group represented by the formula: Rc is hydrogen atom, and Rd is a halogen atom; or Rc is hydrogen atom, and Rd is nitro group; or (b) R" is a halogen atom; Rb is hydrogen atom; and Rc and Rd are bonded to each other to form a group represented by the formula: [16] The process described in item [15] above, wherein each of Ra and Rb is hydrogen atom; and Rc and Rd are bonded

to each other to form a group represented by the formula: [17] The process described in item [5] above, wherein the ketone compound obtained by reducing the chiral dioxirane compound and the optically active phenyloxirane compound (II) are recovered at high purities from a reaction mixture resulting from the treatment of the styrene derivative (I) represented by the formula (I) with the chiral dioxirane compound by a separation process utilizing the solubility differences to organic solvents; [18] The process described in item [1] above, wherein the ketone compound obtained by reducing the asymmetric oxidation agent contained in the reaction mixture and the optically active phenyloxirane compound (II) are recovered at high purities from the reaction mixture by a separation process utilizing the solubility differences to organic solvents; [19] The process described in item [17] or item [18] above, wherein the 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-Alk1 , (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alk1-, (vi) -Q-NR1-Alk2-, (vii )-Alk3-NR1-Alk4-, or (viii)-NRl-Alk5-, wherein Q is -CO- group or -SO2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alkl, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group; [20] The process described in any one of items [17] to [19] above, wherein the ketone compound is an optical isomer of a ketone compound (VI) represented by the formula (VI):

wherein each of Ra and Rb is hydrogen atom, or a substituent; and Rc and Rd satisfy one of the following (I) to (III): (I) each of Rc and Rd is hydrogen atom, or a substituent; or (II) Rc and Rd are bonded to each other to form a group represented by the formula: wherein Re, Rf, Rg, and Rh 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)RC and Rd are bonded to each other to form a group represented by the formula: wherein each of Ri, Rj, Rk, and Rm is hydrogen atom or a substituent; and Y is a group represented by the formula: (i) -O-Q-Alkl-, (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR -Q-Alk -, (vi) -Q-NR1-Alk2-, (vii)-Alk -NR -Alk4-, or (viii)-NR -Alk5-, wherein Q is -CO- group or -S~2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group; [21] The process described in any one of items [1] to [20] above, wherein ring A is phenyl group having one to three substituents selected from the group consisting of lower

alkyl groups, lower alkoxy groups and halogen atoms, and R is a group represented by -CO2Rq, wherein Rq is an ester residue; [22] The process described in item [21] above, wherein ring A is a 4-lower alkylphenyl group or a 4-lower alkoxyphenyl group, and R9 is a lower alkyl group; [23] The process described in item [22] above, wherein ring A is 4-methoxyphenyl group, and Rq is methyl group; [24] A process for preparing a 1,5-benzothiazepine derivative represented by the formula (VII): wherein ring A is a substituted or unsubstituted benzene ring; ring B is a substituted or unsubstituted benzene ring; R2 is hydrogen atom or a substituted alkyl group; R3 is a lower alkanoyl group; and * indicates an asymmetric carbon atom, or pharmaceutically acceptable salts thereof, from an optically active phenyloxirane compound (II) represented by the formula (II):

wherein R is a group represented by -CO2Rq, or a group convertible to the group represented by -CO2Rq, wherein Rq 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; and [25] A process for preparing a nitrocarboxylic acid compound represented by the following formula: wherein ring A is a substituted or unsubstituted benzene ring; ring B is a substituted or unsubstituted benzene ring; and * indicates an asymmetric carbon atom, or salts thereof, from an optically active phenyloxirane compound (11) represented by the formula (II):

wherein R is a group represented by -CO2Rq, or a group convertible to the group represented by -CO2Rq, wherein R9 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.

BEST MODE FOR CARRYING OUT THE INVENTION According to the process of the present invention, a styrene'derivative (I) represented by the formula (I): wherein ring A is a substituted or unsubstituted benzene ring; R is a group represented by -CO2Rq, or a group convertible to the group represented by -CO2Rq, wherein Rq is an ester residue, can be used as a starting material.

In the 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. In addition, the halogen atoms include fluorine atom, chlorine atom, bromine atom, and iodine atom. Among ring A listed above, phenyl group having 1 to 3 substituents selected from the group consisting of lower alkyl groups, lower alkoxy groups and halogen atoms are desirable, 4-lower alkyoxyphenyl groups and 4-lower alkylphenyl groups are more desirable, and 4-methylphenyl group and 4-methoxyphenyl group are particularly desirable.

In the styrene derivative (I) represented by the formula (I), R is a group represented by -CO2Rq, or a group convertible to the group represented by -CO2Rq, wherein R9 is the same as defined above. Examples of the group convertible to the group represented by -CO2Rq include, for instance, a group represented by the formula:

wherein Rr is the same group defined as Rq above; a group represented by the formula: wherein R" and Rt are both hydrogen atoms; or one is hydrogen atom and the other is the same group as defined as Rq above; or Rs and Rt are both the same group as defined as Rq above; or R" and Rt 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.

R9 may be any group as long as it is a well-used ester residue.

Concrete examples of R9 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. 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 4 carbon atoms. Among the R9 listed above, the lower alkyl groups are preferred, and methyl group is particularly preferred.

In addition, examples of the heterocyclic ring formed by bonding R" with Rt together with the adjacent nitrogen atom 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.

Regarding the geometric isomers of the styrene derivative (I) represented by the formula (I), ring A and -R may be bonded to -CH=CH- group in either cis- or trans-configuration.

Among the styrene derivatives (I), it is desired in the formula (I) that ring A is methoxyphenyl group or methylphenyl group, R is methoxycarbonyl group, and ring A

and R are bonded in trans-configuration. Particularly, 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(O-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.

Typical examples of the chiral ketone compound include, for instance, 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-Alkl-, (ii) -Q-O-Alk2-,

(iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alk1-, (vi) -Q-NR1-Alk2-, (vii ) -Alk3-NR1-Alk4-, or (viii)-NR1-Alk5-, wherein Q is -CO- group or -SO2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group, respectively.

In the ketone compound (V), ring Ar is a monocyclic, dicyclic, or tricyclic aromatic ring, which may have a substituent. Examples of 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.

In addition, 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.

Examples of the 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 group, and aralkyl groups having 7 to 10 carbon atoms such as benzyl group and phenetyl group. Among those groups, the electron withdrawing groups are desired, and halogen atoms and nitro group are particularly desired.

On the other hand, in the ketone compound (V), as described above, Y is a group represented by the formula: (i) -O-Q-Alkl-, (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alkl-, (vi) -Q-NR1-Alk2-, (vii )-Alk3-NR1-Alk4-, or (viii)-NR1-Alk5-, wherein Q is -CO- group or -SO2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group, respectively.

Examples of the alkylsulfonyl group in R1 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. In addition, 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.

Concrete examples of the lower alkylene groups in Alk1, Alk2, Alk3, Alk4, and Alk5 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.

Among the 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 (ii) above, wherein Q is carbonyl group. Concretely, Y is preferably -CO-O-CH2-.

Concrete examples of the chiral ketone compound include, for instance, an optical isomer of a ketone compound (VI) represented by the formula (VI):

wherein each of Ra and Rb is hydrogen atom, or a substituent; and RC and Rd satisfy one of the following (I) to (III): (I) each of RC and Rd is hydrogen atom, or a substituent; or (II) RC and Rd are bonded to each other to form a group represented by the formula: wherein Re, Rf, Rg, and Rh 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)RC and Rd are bonded to each other to form a group represented by the formula: wherein each of Ri, Rj, Rk, and Rm is hydrogen atom or a substituent; and Y is a group represented by the formula: (i) -O-Q-Alkl-, (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alk1-, (vi) -Q-NR1-Alk2 (vii)-Alk -NR -Alk4-, or (viii)-NR -Alk5-, wherein Q is -CO- group or -SO2- group; R1 is hydrogen atom, an a lkylsulfonyl group or an arylsulfonyl group; and each of Alkl, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group, respectively.

The substituents in R" to Rm 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 group, and aralkyl groups having 7 to 10 carbon atoms such as benzyl group and phenetyl group. Among those groups, the electron withdrawing groups are desired, and halogen atoms and nitro group are particularly desired.

Incidentally, it is desired that Ra, Rb, RC, and Rd satisfy one of the following (a) and (b): (a) each of Ra and Rb is hydrogen atom; and Rc and Rd are bonded to each other to form a group represented by the formula: R" is hydrogen atom, and Rb is a halogen atom; or RC is hydrogen atom, and Rd is nitro group; or

(b) Ra is a halogen atom; Rb is hydrogen atom; and RC and Rd are bonded to each other to form a group represented by the formula: It is particularly desired that each of Ra and Rb is hydrogen atom; and Rc and Rd are bonded to each other to form a group represented by the formula: The group represented by Y of the ketone compound (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 (VI-a) represented by the formula (VI-a):

wherein Ra, Rb, RC, Rd, and Y are the same as defined above; and a chiral ketone compound (VI-b) represented by the formula (VI-b): wherein Ra, Rb, RC, Rd, and Y are the same as defined above.

The 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.

Examples of the oxidizing agent used in the oxidation reaction 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. Among those oxidizing agents, Oxone, which is an oxidizing agent including potassium peroxomonosulfate, can be favorably used in the present invention. Incidentally, the oxidizing agent, the solvent or the starting compounds may contain metals as impurities. In order not to allow the impurities to be active in the reaction, chelating agents can be used.

Examples of 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.

Examples of 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 dimethylimidazolinone; sulfoxide solvents, such as dimethyl sulfoxide; aliphatic hydrocarbon solvents, which may be halogenated, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, hexane, cyclohexane, and pentane; and aromatic hydrocarbon solvents, which may be halogenated, such as toluene, xylene, chlorobenzene, and dichlorobenzene; water, and mixed solvents thereof. Among those solvents, the ether solvents, the nitrile solvents, the alcohol solvents, water, and mixed solvents thereof can be favorably used.

In particular, 1, 2-dimethoxyethane, 1,4-dioxane, acetonitrile, water, and mixed solvents thereof can be highly favorably used.

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).

Alternatively, 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.

When the asymmetric oxidation agents are reacted with the styrene derivative (I) 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).

Alternatively, 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.

Incidentally, when the chiral ketone compound (VI-a) is used, the asymmetric oxidation agent having the same axial chirality can be prepared. On the other hand, when the chiral ketone compound (VI-b) is 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, <BR> <BR> <BR> <BR> 1,2:4,5-di(O-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.

Typical examples of the chiral dioxirane compound include, for instance, an optical isomer of a dioxirane compound (III) represented by the formula (III): 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-Alkl- ( (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NRl-Q-Alkl- (vi) -Q-NR1-Alk2-, (vii)-Alk3-NR1-Alk4-, or (viii)-NR1-Alk5-, wherein Q is -CO- group or -S~2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group, respectively.

In the dioxirane compound (III), ring Ar is a monocyclic, dicyclic, or tricyclic aromatic ring, which may have a substituent. Examples of 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. In addition, 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.

Examples of the 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 group, and aralkyl groups having 7 to 10 carbon atoms such as benzyl group and phenetyl group. Among those groups, the electron withdrawing groups are desired, and halogen atoms and nitro group are particularly desired.

On the other hand, in the dioxirane compound (III), as described above, Y is a group represented by the formula: (i) -O-Q-Alk1 , (ii) -Q-O-Alk2-, (iii)-Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alk1-, (vi) -Q-NR1-Alk2-, (vii )-Alk3-NR1-Alk4-, or (viii ) -NR1-Alk5-, wherein Q is -CO- group or 502 group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group, respectively.

Examples of the alkylsulfonyl group in R1 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. In addition, 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.

Concrete examples of the lower alkylene groups in Alk1, Alk2, Alk3, Alk4, and Alk5 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.

Among the 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 (ii) above, wherein Q is carbonyl group. Concretely, Y is preferably -CO-O-CH2-.

Concrete examples of the chiral dioxirane compound include, for instance, an optical isomer of a dioxirane compound (IV) represented by the formula (IV): wherein each of R" and Rb is hydrogen atom, or a substituent; and Rc and Rd satisfy one of the following (I) to (III): (I) each of Rc and Rd is hydrogen atom, or a substituent; or (II) Rc and Rd are bonded to each other to form a group represented by the formula:

wherein RB, Rf, Rg, and Rh 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)RC and Rd are bonded to each other to form a group represented by the formula: wherein each of Ri, Rj, Rk, and Rm is hydrogen atom or a substituent; and Y is a group represented by the formula: (i) -O-Q-Alkl-, (ii) -Q-O-Alk2-, (iii) -Alk3-O-Alk4-, (iv) -0-Alk5-, (v) -NR1-Q-Alk1-, (vi) -Q-NR1-Alk2-,

(vii )-Alk3-NR1-Alk4-, or (viii)-NR1-Alk5- wherein Q is -CO- group or -SO2- group; R1 is hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and each of Alk1, Alk2, Alk3, Alk4, and Alk5 is a lower alkylene group, respectively.

The substituents in Ra to Rm 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 group, and aralkyl groups having 7 to 10 carbon atoms such as benzyl group and phenetyl group. Among those groups, the electron withdrawing groups are desired, and halogen atoms and nitro group are particularly desired.

Incidentally, it is desired that Ra, Rb, RC, and Rd satisfy one of the following (a) and (b):

(a) each of Ra and Rb is hydrogen atom; and Rc and Rd are bonded to each other to form a group represented by the formula: Rc is hydrogen atom, and Rd is a halogen atom; or RC is hydrogen atom, and Rd iS nitro group; or (b) R is a halogen atom; Rb is hydrogen atom; and RC and Rd are bonded to each other to form a group represented by the formula: It is particularly desired that each of Ra and Rb is hydrogen atom; and Rc and Rd 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): wherein Ra, Rb, RC, Rd, and Y are the same as defined above; and a chiral dioxirane compound (IV-b) represented by the formula (IV-b): wherein Ra, Rb, RC, Rd, and Y are the same as defined above.

The 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): wherein ring Ar and Y are the same as defined above; and a ketone compound (VI) represented by the formula (VI): wherein R", Rb, RC, Rd, and Y are the same as defined above.

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.

Examples of the oxidizing agent used in the oxidation reaction 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. Among those oxidizing agents, Oxone, which is an oxidizing agent including potassium peroxomonosulfate, can be favorably used in the present invention. Incidentally, the oxidizing agent, the solvent or the starting compounds may contain metals as impurities. In order not to allow the impurities to be active in the reaction, chelating agents can be used.

Examples of 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.

Examples of 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 dimethylimidazolinone; sulfoxide solvents, such as dimethyl sulfoxide; aliphatic hydrocarbon solvents, which may be halogenated, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, hexane, cyclohexane, and pentane; and aromatic hydrocarbon solvents, which may be halogenated, such as toluene, xylene, chlorobenzene, and dichlorobenzene; water, and mixed solvents thereof. Among those solvents, the ether solvents, the nitrile solvents, the alcohol solvents, water, and mixed solvents thereof can be favorably used. In particular, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, water, and mixed solvents thereof can be highly favorably used.

It is desired that 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). Alternatively, 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.

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 (V) or (VI) to the optical isomer of the dioxirane compound (III) or (IV), and the asymmetric oxidation reaction of the styrene derivative (I) with the optical isomer of the dioxirane compound (III) or (IV) may be concurrently carried out in the same reaction system.

Incidentally, when the chiral ketone compound (VI-a) is used, a chiral dioxirane compound (IV-a) can be prepared. On the other hand, when the chiral ketone compound (VI-b) is used, a chiral dioxirane compound (IV-b) can be prepared.

In the process of the present invention, 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.

Examples of 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). Among the 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.

For instance, when the asymmetric oxidation agent formed by the reaction of the optical isomer of the ketone compound (V) or (VI) is used, 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.

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). On the other hand, when the process (b) is employed, 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.

In the process (b), the asymmetric oxidation agent is formed from the optical isomer of the ketone compound (V) or (VI) with an oxidizing agent. After 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. Therefore, when the oxidizing agent is 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).

In particular, when the asymmetric oxidation of the styrene derivative (I) is carried out by adding Oxone, an oxidizing agent, to the mixture of the optical isomer of the ketone compound (V) or (VI) and the styrene derivative (I), 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.

Next, 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.

Meanwhile, in the process of the present invention, 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.

Examples of 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 (VI). Among 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.

It is desired that 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.

For instance, when the optical isomer of the

dioxirane compound (III) or (IV) is 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.

When the process (a) is employed, there is a necessity to use the optical isomer of the dioxirane compound (III) or (IV) in an amount sufficient for asymmetrically oxidizing the styrene derivative (I). On the other hand, when the process (b) is employed, 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.

In the process (b), 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. After 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. Therefore, when the oxidizing agent is 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).

In particular, when the asymmetric oxidation of the styrene derivative (I) is carried out by adding Oxone, an oxidizing agent, to the mixture of the optical isomer of the ketone compound (V) or (VI) and the styrene derivative (I), 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.

The temperature for treating the styrene derivative (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.

Next, 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.

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.

Concretely, the chiral ketone compound can be recovered in a high yield by, for instance, (a-l) 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 (Il) is easily soluble.

Alternatively, the chiral ketone compound can be recovered in a high yield by, for instance, carrying out the above-mentioned step (a-l) or (a-2), dissolving the resulting residue in an organic solvent wherein both of the chiral ketone compound and the optically active phenyloxirane compound (Il) 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.

As the 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. Examples of the organic solvent used in the extraction of the reaction mixture 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.

On the other hand, 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.

As described above, 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.

Examples of the column chromatography include, for instance, conventional silica gel chromatography, and the like.

When the resulting optically active phenyloxirane compound (Il) is purified by crystallization, it is desired that ether solvents, such as diisopropyl ether,

are used as the organic solvents. 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.

In the present invention, when the styrene derivative (I) in which ring A and R are in trans-configuration as shown in the following scheme is used, in the case of a-attack by the asymmetric oxidation agent, the reaction proceeds in the direction of arrow b, to give a (2R,3S)-optically active phenyloxirane compound, and in the case of p-attack by the asymmetric oxidation agent, the reaction proceeds in the direction of arrow a, to give a (2S,3R)-optically active phenyloxirane compound. On the other hand, when the styrene derivative (I) in which ring A and R are in cis-configuration as shown in the following scheme is used, in the case of a-attack by the asymmetric oxidation agent, the reaction proceeds in the direction of arrow d, to give a (2S,3S)-optically active phenyloxirane compound, and in the case of p-attack by the asymmetric oxidation agent, the reaction proceeds in the direction of arrow c, to give a (2R,3R)-optically active phenyloxirane compound. 13-Attack 3R)-Isomer R Mx I ar-fttack b (2R, 3S)- Isomer Cinnamic Acid Derivative Optically Active Glycidic Acid Derivative o c L- 3 P p-Attack(2R, 3R)- Isomer -R C (2R,3R)- Isomer d a-Attack < I a d d (2S,3s)-Isomer (2S, 3S)- Isomer

Among the optically active phenyloxirane compounds mentioned above, 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.

In the present invention, it is desired that the trans-isomer of the styrene derivative (I) is used, and that the asymmetric oxidation agent formed from a chiral ketone compound (VI-a) or (VI-b), for example, the chiral dioxirane compound (IV-a) or (IV-b), is used.

Incidentally, when the trans-isomer of the styrene derivative (I) is used, and the asymmetric oxidation agent formed from the chiral ketone compound (VI-a), for example, the chiral dioxirane compound (IV-a), is used, a (2R,3S)-phenyloxirane compound can be obtained. Also, when the trans-isomer of the styrene derivative (I) is used, and the asymmetric oxidation agent formed from a chiral ketone compound (VI-b), for example, the chiral dioxirane compound (IV-b), is used, a (2S,3R)-phenyloxirane compound can be obtained.

Thus, the optically active phenyloxirane compound

(II) represented by the formula (II): wherein ring A, R and * are the same as defined above, can be prepared in a high yield and at high optical purity.

Next, as the starting material, when the compound in which R is a group represented by -CO2Rq in the optically active phenyloxirane compound (Il) prepared above is used, a 1,5-benzothiazepine derivative represented by the formula (VII): wherein ring A, ring B, and * are the same as defined above; R2 is hydrogen atom or a substituted alkyl group; and R3 is a lower alkanoyl group, can be prepared by a known method.

In the process for preparing a 1,5-benzothiazepine derivative, ring B is a substituted or unsubstituted benzene ring. Concrete examples of 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. Examples of 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. Examples of the phenyl-lower alkyl groups include, for instance, phenylalkyl groups having 7 to 10 carbon atoms, such as benzyl group and phenetyl group. Examples of the 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. In addition, examples of the halogen atoms include, for instance, fluorine atom, chlorine atom, bromine atom, and iodine atom.

R3 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.

R2 is hydrogen atom or a substituted alkyl group.

Concrete examples of the 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.

Examples of the 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. It is particularly desired that R2 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-1,5-benzothiazepin- 4(5H)-one (Diltiazem), (2S,3S)-2-(4-methoxyphenyl)- <BR> <BR> <BR> <BR> 3-acetoxy-5-[2-(dimethylamino)ethyl] -8-chloro- <BR> <BR> <BR> <BR> <BR> 2,3-dihydro-1,5-benzothiazepin-4(5H)-one, <BR> <BR> <BR> <BR> <BR> (2S,3S)-3-acetoxy-5-[3-[4-(2-methoxyphenyl)piperazino]- <BR> <BR> <BR> <BR> <BR> propyl]-2,3-dihydro-2-(4-methoxyphenyl)-8-chloro- 1,5-benzothiazepin-4(5H)-one, (2S,3S)-3-acetoxy-8-benzyl- <BR> <BR> <BR> <BR> 2,3-dihydro-5-[2-(dimethylamino)ethyl]- <BR> <BR> <BR> <BR> <BR> 2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one, (2R,3R)-2-(4-methylphenyl)-3-acetoxy- 5-t2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro- 1, 5-benzothiazepin-4( 5H)-one, and pharmaceutically acceptable salts thereof.

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.

Concretely, 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, Hei 2-17170, Hei 2-286672, Hei 6-279398, Sho 58-99471, Hei 8-269026, Sho 61-118377, Hei 6-228117, Hei 2-78673, Hei 5-43564, and the like.

More concretely, for instance, when a (2R,3S)-isomer is used as the optically active phenyloxirane compound (II) in which R is -CO2Rq, the (2S,3S)-1,5-benzothiazepine derivative represented by the formula:

wherein R4 is hydrogen atom, 2-(dimethylamino)ethyl group, or a group represented by the formula: or a pharmaceutically acceptable salt thereof, can be prepared by: (A-l) reacting the (2R,3S)-isomer with an aminothiophenol derivative (VIII) represented by the formula: wherein ring B and R4 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:

wherein 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: wherein 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: wherein ring A, ring B, R, and R4 are the same as defined above, (B) subjecting the resulting ester compound to intramolecular cyclization, as occasion demands, after the

hydrolysis thereof, to give a 2-(2S,3S)-2-phenyl-3- hydroxy-1,5-benzothiazepine derivative represented by the formula: wherein ring A, and B and R4 are the same as defined above, (C) modifying the nitrogen atom at 5-position of the resulting compound as occasion demands, and acetylating the hydroxyl group substituted on 3-position to give a (2S,3S)-1,5-benzothiazepine derivative, and (D) as occasion demands, converting the product into a pharmaceutically acceptable salt thereof.

On the other hand, when a (2S,3R)-isomer is used as the optically active phenyloxirane compound (II) in which R is -CO2Rq, the (2R,3R)-1,5-benzothiazepine derivative represented by the formula:

wherein ring A, ring B and R4 are the same as defined above, or a pharmaceutically acceptable salt thereof, can be prepared by: (A-l) reacting the (2S,3R)-isomer with the aminothiophenol derivative (VIII) or (A-2) reacting the (2S,3R)-isomer with the nitrothiphenol derivative (IX), followed by the reduction of the nitro group of the resulting product, to give a (2R,3R)-3-(2-aminophenylthio)-3-phenyl-2- hydroxypropionic acid ester compound represented by the formula: wherein ring A, ring B, R and R4 are the same as defined above, (B) subjecting the resulting ester compound to intramolecular cyclization, as occasion demands, after the hydrolysis thereof, to give a (2R,3R)-2-phenyl-3-hydroxy- 1,5-benzothiazepine derivative represented by the formula:

wherein ring A, ring B and R4 are the same defined above, (C) modifying the nitrogen atom at 5-position of the resulting compound as occasion demands, and acetylating the hydroxyl group substituted on 3-position to give a (2R,3R)-1,5-benzothiazepine derivative, and (D) as occasion demands, converting the product into a pharmaceutically acceptable salt thereof.

As one example, the stereochemistry of Diltiazem and an enantiomer thereof can be summarized as follows. For example, as shown in the following scheme, when aminothiophenol represented by the formula: is reacted with the optically active phenyloxirane compound (II) in which R is a group represented by -CO2Rq, the reaction proceeds as follows. In other words, when the (2S,3R)-isomer is reacted with the aminothiophenol to cause cis-opening, or the (2S,3S)-isomer is reacted with the aminothiophenol to cause trans-opening, (2R,3R)-propionic acid derivatives can be obtained. In addition, when the (2R,3S)-isomer is reacted with the aminothiophenol to cause cis-opening, or the (2R,3R)-isomer is reacted with the aminothiophenol to cause trans-opening, (2S,3S)-propionic acid derivatives can be obtained. ci COa-Rq <^> ~ cis-Opening s.s~A/ (2S, 3R)- Isomer a ®) a S n< NH2 CQ.R C02Rq trans-Opening (2R,3R)- Isomer ' ^ trans-Opening (2S,3s) Isomer Optically Active Phenyloxirane Derivative (R= -CO2Rq) Prop ionic Acid Derivative Qcis-Opening cO2Rq A (2R,3S) Isomer "" ~i;NH, NH2 0 nsOpening (2S, 3S)-Isomer (2R,3R)- Isomer

Next, as shown in the following scheme, the (2R,3R)-propionic acid derivative or the (2S,3S)-propionic acid derivative is subjected to intramolecular cyclization, as occasion demands, after hydrolysis thereof, to give a 2-phenyl-3-hydroxy-l,5-benzothiazepine derivative. Thereafter, the nitrogen atom at the 5-position of the resulting 2-phenyl-3-hydroxy-1, 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.

S a >o P > a X or ~ ~ Enantiomer of NH2 2- Diltiazem, etc. H O (2R, 3R) Isomer Propionic Acid Derivative 1,5-Benzothiazepine Derivative NOH :02-Rq N' 3H ----t- Diltiazem, etc. NH2 CO2.Rq H O (2S,3S) Isomer On the other hand, the optically active phenyloxirane compound (II) in which R has a group convertible to a group represented by -CO2Rq, or a salt thereof can be transformed to a 1,5-benzothiazepine derivative by converting the convertible group to a group represented by -CO2Rq, and then reacting in the same manner as above.

Alternatively, it can be transformed to a 1,5-benzothiazepine derivative by converting the convertible group to a group represented by -CO2Rq prior to

the intramolecular cyclization to form 1,5-benzothiazepine structure, and reacting the product thereafter in the same manner as above.

As to processes for converting a group convertible to a group represented by -CO2Rq to a group represented by -CO2Rq, any conventional methods can be employed depending upon the kinds of the convertible groups.

For instance, carboxyl group can be converted to a group represented by -CO2Rq by esterifying the carboxyl group by a conventional method. A group represented by the formula: wherein Rr is the same as defined above, a group represented by the formula: wherein R" and Rt are the same as defined above, and cyano group are first formed into carboxyl group by hydrolysis reaction of the thiol ester, amide, and cyano group, respectively, and the resulting carboxyl group is then converted to a group represented by -CO2Rq in a conventional esterification method.

In addition, thiocarboxyl group can be converted to a group represented by -C02Rq by the removal of hydrogen sulfide followed by esterification in a conventional method.

For example, an optically active phenyloxirane compound (II) in which R is a group represented by the formula: wherein Rr is the same as defined above, a group represented by the formula: wherein Rs and Rt 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 -CO2Rq is prepared, without converting the convertible group to a group represented by -CO2Rq.

Further, the 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: wherein ring A and ring B are the same as defined above; and * indicates asymmetric carbon atom, which is useful for optical resolution agents.

In the process for preparing the nitrocarboxylic acid compound, 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: wherein Hal is a halogen atom.

It is particularly desired that ring A is 4-methoxyphenyl group, and ring B is represented by the above formula, wherein Hal is chlorine atom.

Concretely, the nitrocarboxylic acid compound can be prepared by a process, for instance, comprising reacting the optically active phenyloxirane compound (Il) in which R is -CO2Rq with a nitrothiophenol compound typically exemplified by, for instance, a compound represented by the formula: wherein 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)." In this process, when a (2R,3S)-optically active phenyloxirane compound is used, a (2S,3S)-optically active nitrocarboxylic compound can be prepared. When a (2S,3R)-optically active phenyloxirane compound is used, a (2R,3R)-optically active nitrocarboxylic compound can be prepared.

In the optically active phenyloxirane compound (II), when R is a group convertible to a group represented by -CO2Rq, wherein R9 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 wherein Rq 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. Alternatively, 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 -CO2Rq, wherein Rq is the same as defined above.

Meanwhile, among the ketone compounds (V), the ketone compound in which Y is (i) -O-Q-Alk1- or (v) -NR1-Q-Alkl- can be prepared by the process comprising reacting a compound represented by the formula (X):

wherein Z is -O- or -NR1-; and Ar and R1 are the same as defined above, with a compound represented by the formula (XI): wherein Prot is a protective group for hydroxyl group; and Alk1 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): wherein Ar, Prot, Z, Alk1, and Q are the same as defined above; and subjecting the resulting compound to oxidation reaction.

Among the ketone compounds (V), the ketone compound in which Y is (ii) -Q-O-Alk2- or (vi) -Q-NR1-Alk2- can be

prepared by a process comprising reacting a compound represented by the formula (XIII): wherein Ar and Q are the same as defined above, or a reaction derivative thereof, with a compound represented by the formula (XIV): wherein Z and Alk2 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.

Among the ketone compounds (V), the ketone compound in which Y is (iii) -Alk3-O-Alk4- or (vii) -Alk3-NR1-Alk4- can be prepared by a process comprising reducing a compound represented by the formula (XV):

wherein Ar is the same as defined above, to give a compound represented by the formula (XVI): wherein Ar is the same as defined above; as occasion demands, lengthening the alkyl chain bonded to hydroxyl group of the resulting compound; converting hydroxyl group to amino group; as occasion demands, subjecting the resulting compound to N-alkylsulfonylation or N-arylsulfonylation, to give a compound represented by the formula (XVII): wherein Ar, Alk3 and Z are the same as defined above, subsequently reacting the resulting compound with a compound represented by the formula (XVIII):

wherein L is a leaving group; and Alk4 is the same as defined above; and as occasion demands, when Z is -NH-, subjecting the resulting compound to N-alkylsulfonylation or N-arylsulfonylation.

Among the ketone compounds (V), the ketone compound in which Y is (iv) -0-Alk5- or (viii) -NR1-Alk5- can be prepared by a process comprising reacting the ketone compound represented by the formula (X) with a compound represented by the formula (XIX): wherein L and Alk5 are the same as defined above; and as occasion demands, when Z is -NH-, subjecting the resulting compound to N-alkylsulfonylation or N-arylsulfonylation.

Among the ketone compounds (V), the ketone compound in which Y is -NR1-Alk5- 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.

The 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; N,N'-dicyclohexylcarbodiimide (hereinafter referred to as "DCC"); a combination of DCC and l-hydroxybenzotriazole; active esters formed by using benzotriazol-l-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.

Examples of 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.

The 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. Examples of the solvent 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. Upon the reaction, as occasion demands, for instance, an acid acceptor, such as triethylamine, diisopropylethylamine, or pyridine may be added.

On the other hand, the 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. Examples of the solvent 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.

The 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.

The 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. Examples of the solvent 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.

As to 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.

In the subsequent oxidation reaction, there can be applied conventional processes for the conversion from hydroxymethylene group to carbonyl group, including chromic acid oxidation, ruthenium oxide oxidation, "Swern Oxidation" [Merck Index, 12th Edit., ONR-89], "Dess-Martin Oxidation" [Merck Index, 12th Edit., ONR-22], and the like. For instance, 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 1,1,1-tris(acetyloxy)-1,1-dihydro- 1,2-benziodoxol-3(1H)-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.

The reduction reaction of the compound represented by the formula (XV) can be carried out according to any conventional processes for reducing carboxylic acids. For instance, 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.

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. For instance, 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; reacting the Grignard reagent with an alkylaldehyde or an alkyl ketone; and subsequently treating the resulting compound with water. In addition, the conversion of hydroxyl group to amino group can be also carried out by any conventional processes. For instance, 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.

On the other hand, 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). After the reduction reaction, 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.

Incidentally, the N-alkylsulfonylation or N-arylsulfonylation, an optional step, 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. Examples of the reactive derivative include, for instance, acid halides, such as acid chloride, acid bromide, and acid iodide, and the like.

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.

The 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.

As to the optical resolution process, there may be applicable, for instance, a process for separately crystallizing a diastereomer salt with an optical resolution agent. As to the optical resolution agents, any of generally employed agents for optical resolution can be suitably used. As to 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.

Incidentally, among the styrene derivatives (I) used in the process of the present invention, 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: wherein 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.

As to the lower alkyl acetate, it is desired to use methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, or the like. When 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 desired that the condensation reaction is carried out at 20~ to 60"C.

When 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. When 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.

Preparation Example 1 In a mixture of 7.5 ml of acetonitrile and 5 ml of a 4 x 10-4 M aqueous sodium ethylenediaminetetraacetate (EDTA) solution was dissolved 0.01 mmol of a chiral ketone compound represented by the formula: To the mixture were added 2.5 mmol of Oxone and 7.7 mmol of sodium hydrogencarbonate, and the mixture was stirred at room temperature. The EI-MS (electron ionization mass spectrum) was measured in accordance with passage of time.

As a result, it was confirmed that a peak of 412 (M+) supporting the formation of a chiral dioxirane compound represented by the formula:

gradually increased as compared to the peak of 396 (M+) of the chiral ketone compound.

Next, in 3.8 ml acetonitrile-d3-2.5 ml 4 x 10-4 M aqueous solution of disodium salt of EDTA was dissolved 0.1 mmol of the chiral ketone compound. To the resulting mixture were added 2 mmol of Oxone and 6.2 mmol of sodium hydrogencarbonate, and the mixture was stirred for 24 hours. The supernatant of the reaction mixture was taken out, and the MS (mass spectrometry) and 1H-NMR were then measured therefrom.

First, precise mass spectrometry was taken, and M+ ions (C25H16O6; theoretical value: 412.0947; found value: 412.0950) supporting the formation of the chiral dioxirane compound were detected.

In addition, in 1H-NMR (400 MHz), peaks deduced to be the hydrogen atoms of methylene group of the chiral dioxirane compound were found at 3.85 ppm (d, J=11.8 Hz) and 4.56 ppm (d, J=15.5 Hz).

Incidentally, the peaks deduced to be the hydrogen atoms of methylene group of the chiral ketone compound were found at 4.21 ppm (d, J=15.5 Hz) and 5.49 ppm (d, J=15.4 Hz).

In addition, in 13C-NMR, the quaternary carbon of the dioxirane moiety of the chiral dioxirane compound was found at 95.6 ppm.

Incidentally, the carbonyl carbon of the chiral dioxirane compound was found at 2.305 ppm.

The results were confirmed by the fact that a quaternary carbon was detected by DEPT (Distortionless Enhancement by Polarization Transfer) in 13C-NMR, and a long-range coupling between peaks (at 3.85 ppm and 4.56 ppm) of hydrogen atoms of methylene group was found.

Example 1 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 40 mg (0.1 mmol) of a chiral ketone compound represented by the formula: was then added to the mixture. The resulting mixture was cooled to 0~C on an ice bath. Thereafter, to the above mixture was added a mixture of 6.14 g (10 mmol) of Oxone and 2.6 g (31 mmol) of sodium hydrogencarbonate at

one-hour intervals in six divided portions. After the addition, the mixture was stirred for additional two hours. Thereafter, the resulting reaction mixture was transferred into half-saturated brine, and the mixture was extracted with ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate.

After drying, anhydrous magnesium sulfate was separated by filtration, and the solvents were distilled off from the filtrate. To the resulting residue was added 9 ml of a mixture of ethyl acetate and n-hexane in a volume ratio of 1:8, and the mixture was stirred at room temperature for one hour.

The precipitated white powder was collected by filtration, and evaporated under reduced pressure, to give 32 mg of the chiral ketone compound (recovery: 80% by weight).

On the other hand, the resulting filtrate (yield by HPLC: 91%) was purified by silica gel flash column chromatography (mobile phase: ethyl acetate:n-hexane = 1:8 (volume ratio)), to give 135 mg (isolation yield: 65%) of optically active phenylglycidate represented by the formula:

The 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: was then added to the mixture. The resulting mixture was

stirred at room temperature. Thereafter, to the above mixture was added a mixture of 2.06 g (3.3 mmol) of Oxone and 860 mg (10.3 mmol) of sodium hydrogencarbonate over a period of one hour. After the addition, the mixture was stirred for additional one hour. Thereafter, the resulting reaction mixture was transferred into half-saturated brine, and the mixture was extracted with ether. Thereafter, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate.

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 64tee by HPLC.

Also, the chiral ketone compound could be collected in the same manner as in Example 1 (recovery: 88% by weight).

Example 3 In 7.5 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 5 ml of a 4 x 10-4 M aqueous sodium

ethylenediaminetetraacetate solution, and 46 mg (0.1 mmol) of a chiral ketone compound represented by the formula: was then added to the mixture. The resulting mixture was cooled to 0~C. Thereafter, to the above mixture was added a mixture of 1.84 g (3 mmol) of Oxone and 780 mg (9.3 mmol) of sodium hydrogencarbonate over a period of 7 hours. After the addition, the mixture was stirred for additional 17 hours. Thereafter, the resulting reaction mixture was transferred into half-saturated brine, and the mixture was extracted with ether. Thereafter, the organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate.

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 l. The yield and the optical purity of the resulting phenylglycidate were respectively determined to be 74% and 85%ee by HPLC.

Example 4 In 3.8 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 2.5 ml of a 4 x 10-4 M aqueous disodium ethylenediaminetetraacetate solution, and 4 mg (0.01 mmol) of a chiral ketone compound represented by the formula: was then added to the mixture. The resulting mixture was kept at room temperature. Thereafter, to the above mixture was added a mixture of 1.23 g (2 mmol) of Oxone and 521 mg (6.2 mmol) of sodium hydrogencarbonate. After the addition, the mixture was additionally stirred.

Thereafter, the resulting reaction mixture was washed and dried in the same manner as in Example 1.

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.

Example 5 In 7.5 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 5 ml of a 4 x 10-4 M aqueous disodium ethylenediaminetetraacetate solution, and 4 mg (0.01 mmol) of a chiral ketone compound represented by the formula: was then added to the mixture. The resulting mixture was kept at room temperature. Thereafter, to the above mixture was added a mixture of 1.54 g (2.5 mmol) of Oxone and 650 mg (7.7 mmol) of sodium hydrogencarbonate. After the addition, the resulting mixture was stirred for 4.5 hours. Thereafter, the resulting reaction mixture was washed and dried in the same manner as in Example 1.

The resulting product (yield in HPLC: 92%) was

subjected to the treatments in the same manner as in Example 1, to give 138 mg (isolation yield: 66%) of the same optically active phenylglycidate as in Example 1.

The optical purity of the resulting product was determined to be 74%ee by HPLC.

Also, the chiral ketone compound could be collected in the same manner as in Example 1 (recovery: 80% by weight).

Example 6 In 3.8 ml of l,2-dimethoxyethane was dissolved 192 mg (1.0 mmol) of methyl trans-4-methoxycinnamate at room temperature. Thereafter, to the resulting mixture was added 2.5 ml of a 4 x 10-4 M aqueous disodium ethylenediaminetetraacetate solution, and 4 mg (0.01 mmol) of a chiral ketone compound represented by the formula: was then added to the mixture. The resulting mixture was kept at room temperature. Thereafter, to the above mixture was added a mixture of 1.23 g (2 mmol) of Oxone

and 521 mg (6.2 mmol) of sodium hydrogencarbonate. After the addition, the mixture was stirred for additional 8 hours. Thereafter, the resulting reaction mixture was washed and dried in the same manner as in Example 1.

The resulting product (yield in HPLC: 93%) was subjected to the treatments in the same manner as in Example 1, to give 137 mg (isolation yield: 66%) 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.

Example 7 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 solution, and 50 mg (0.1 mmol) of a chiral ketone compound represented by the formula:

was then added to the mixture. The resulting mixture was kept at room temperature. Thereafter, to the above mixture was added a mixture of 2.06 g (3.3 mmol) of Oxone and 866 mg (10.3 mmol) of sodium hydrogencarbonate over a period of one hour. After the addition, the mixture was stirred for additional 30 minutes. Thereafter, the resulting reaction mixture was transferred into half-saturated brine, and the mixture was extracted with ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate.

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.

Example 8 In 15 ml of 1,2-dimethoxyethane was dissolved at room temperature, 159 mg (1 mmol) of a compound represented by the formula:

Thereafter, to the resulting mixture was added 10 ml of a 4 x 10-4 M aqueous sodium ethylenediaminetetraacetate solution, and 40 mg (0.1 mmol) of the same chiral ketone as one used in Example 1, and then the mixture was cooled to 0~C.

Thereafter, to the above mixture was added a mixture of 3.07 g (5 mmol) of Oxone and 1.3 g (15.5 mmol) of sodium hydrogencarbonate at one-hour intervals in three divided portions.

After the mixture was stirred for additional 18 hours, the resulting reaction mixture was transferred into half-saturated brine. Thereafter, the mixture was extracted with ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate.

After drying, anhydrous magnesium sulfate was separated by filtration, and the solvents were distilled off from the filtrate. To the resulting residue was added 9 ml of a mixture of ethyl acetate and n-hexane in a volume ratio of 1:8, and the mixture was stirred at room temperature for one hour.

The precipitated white powder was collected by filtration, and evaporated under reduced pressure, to give a chiral ketone compound. On the other hand, the resulting filtrate was purified by silica gel flash column

chromatography (mobile phase: ethyl acetate:n-hexane = 1:8 (volume ratio)), to give 90 mg (isolation yield: 51%) of optically active phenyloxirane represented by the formula: The optical purity of the resulting optically active phenyloxirane was determined to be 57tee by HPLC.

Also, the resulting optically active phenyloxirane was found to have the following properties.

1H-NMR (300 MHz, CDCl3): 6 3.40 (1H, d, J=1.8 Hz), 3.82 (3H, S), 4.24 (1H, d, J=1.8 Hz), 6.91 (2H, m), 7.19 (2H, m) The HPLC conditions are as follows: [Column] Chiral OD [Mobile Phase] n-Hexane:ethanol = 9:1 (volume ratio) [Flow Rate] 0.5 ml/min Examples 9 to 15 A cinnamic acid derivative represented by the

formula: wherein RX is a group indicated in Table 1, was used.

In 15 ml of a solvent shown in Table 1 was dissolved 1.0 mmol of the cinnamic acid derivative at room temperature. Thereafter, to the resulting mixture was added 10 ml of a 4 x 10-4 M aqueous disodium ethylenediaminetetraacetate solution, and the same chiral ketone compound as used in Example 1 was subsequently added to the mixture. The resulting mixture was kept at room temperature. Thereafter, to the above mixture was added a mixture of 6.14 g (10 mmol) of Oxone and 2.6 g (31 mmol) of sodium hydrogencarbonate in divided portions.

After the addition, the mixture was additionally stirred.

Thereafter, the resulting reaction mixture was transferred into brine, and the mixture was extracted with ether. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate.

The amount of the chiral ketone compounds, the addition period of time for Oxone and sodium hydrogencarbonate, and the stirring period of time are

collectively shown in Table 1.

From the extract resulting from washing and drying as described above, anhydrous magnesium sulfate was separated by filtration, and the solvents were distilled off from the filtrate. To the resulting residue was added 9 ml of a mixture of ethyl acetate and n-hexane in a volume ratio of 1:8, and the mixture was stirred at room temperature for one hour.

The precipitated white powder was collected by filtration, and evaporated under reduced pressure, to give a chiral ketone compound.

On the other hand, the resulting filtrate was purified by silica gel flash column chromatography (mobile phase: ethyl acetate:n-hexane = 1:8 (volume ratio)), to give an optically active phenylglycidate represented by the formula: wherein Rx is the same as defined above.

The yield and the optical purity of the resulting optically active phenylglycidate are shown in Table 1.

Incidentally, the optical purity was determined by HPLC.

T a b l e 1 0 CO2Rx Amount of Addition Stirring 0 Rx 8 cu Ln c o CO =r C- o o v Ketone ata4 Isolation Optical (mol * (hour) (hour) Yield Purity Q r 0o < =t 2 =t on > 3 a, l O @ n v O 10 > 10 ~> O 2'\ Not 75 Isolated M r ~o r LO L L r( 7 Cr) rl L, O v o L CQ H ,l :r rl cr =1 0 pa) L: O -c O Q) 1 Dimethyoxyethane 2 25 U rl O -CH3 (d Dimethyoxyethane 0 0 0 57 77 X 4D .e . = U g o o o o o v o D sH o z H ." v v r O H v F3 0 H r q) O El X X S [3 z a o r c\l on x ID X Remark *: Yield determined by HPLC analysis was 73%.

It is clear from the results shown in Table 1 that according to the methods of Examples 9 to 15, the optically active phenylglycidate can be produced in high yield and at high optical purity in spite of variety in the ester residue.

Example 16 In 9 ml of 1,2-dimethoxyethane and 4.5 ml of water were suspended 961 mg (5.00 mmol) of methyl trans-4-methoxycinnamate and 79 mg (0.20 mmol) of a chiral ketone compound represented by the formula: To the resulting suspension were added 3.074 g (5.00 mmol) of Oxone and 1.302 g (15.5 mmol) of sodium hydrogencarbonate was added over a period of one hour and 30 minutes, and the mixture was then stirred at 22" to 24"C for two hours and 30 minutes. Thereafter, brine was added to the resulting reaction mixture, and the mixture was extracted with ether. Thereafter, the resulting extract was washed with an aqueous saturated sodium

hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After drying, 546.2 mg out of 31.56 g of the dried extract was used to measure the yield and optical purity of methyl 3-(4-methoxyphenyl) glycidate with HPLC. As a result, it was found that the yield was 88.3%, and the optical purity of (2R,3S)-form was 76.8%ee.

The remaining reaction mixture was concentrated under reduced pressure, and 6.6 mg out of 1.042 g of the resulting residue was used to measure the amount of methyl trans-4-methoxycinnamate with HPLC. As a result, it was found that only 7.3t of the methyl trans- 4-methoxycinnamate remained in the residue.

To the remaining residue was added 17.5 ml of isopropyl ether, and resulting mixture was heated to 45"C to allow the dissolution of the components. With stirring, the solution was cooled to 40"C over a period of 10 minutes. Thereafter, the resulting precipitated crystals were collected by filtration. A portion of the resulting precipitated crystals was taken out therefrom to use as a sample to evaluate its composition with 1H-NMR and HPLC. As a result, it was found that the precipitated crystals contained 73 mg of a chiral ketone compound and 90.7 mg of methyl (2R, 3S)-3-(4-methoxyphenyl) glycidate (optical purity: 98.8%ee).

The filtrate was concentrated under reduced pressure, and 10 ml of isopropyl ether was added again to the residue. The mixture was heated to 40C to 45"C to allow the dissolution of the components. Thereafter, the resulting solution was cooled to 20"C, and subsequently cooled to 11"C over a period of 40 minutes, further cooled to 8.50C over a period of additional one hour and thirty-five minutes. The precipitated crystals were collected by decantation, and the crystals were then washed with ice-cold isopropyl ether, to give 587 mg of methyl (2R, 3S)-3-(4-methoxyphenyl) glycidate (yield: 56.4%, optical purity: 98.5%ee).

The mother liquor was concentrated under reduced pressure, and 265 mg of its residue was subjected to quantitative analysis with 1H-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.

Example 17 In 100 ml of 1,2-dimethoxyethane were dissolved 9.611 g (50 mmol) of methyl trans-p-methoxycinnamate and 1.088 g (2.7 mmol) of a chiral ketone compound represented

by the formula: at room temperature. Thereafter, to the resulting solution was added 50 ml of distilled water at 20"C.

Subsequently, to the resulting mixture was gradually added a mixture of 30.74 g (50 mmol) of Oxone and 13.02 g (155 mmol) of sodium hydrogencarbonate at the same temperature over a period of 1.5 hours. After the addition, the resulting mixture was stirred for additional 5.5 hours at the same temperature, and the resulting reaction mixture was then cooled to 0~ to 5"C.

Thereafter, 500 ml of cold water was added to the mixture, and the resulting mixture was stirred at O" to 5"C for 30 minutes.

The precipitated solid was dissolved in 100 ml of chloroform. After drying, impurities were filtrated off, and the solvents were distilled off from the filtrate under reduced pressure, to give a white solid.

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.

[Conditions for HPLC Analysis] Filler: Chiralcel OD Solvents: n-Hexane:isopropyl alcohol = 10:1 (volume ratio) Flow Rate: 1 ml/min.

Column Temp.: 40"C Detection: Absorption at 220 nm The resulting white solid was subjected to the treatments in the same manner as in Example 1, to give methyl (2R,3S)-3-(p-methoxyphenyl)glycidate and the chiral ketone compound, respectively.

Example 18 In 3 ml of 1,2-dimethoxyethane were dissolved 38 mg (0.2 mmol) of methyl trans-p-methoxycinnamate and 0.8 g (0.002 mmol) of a chiral ketone compound represented by the formula:

Thereafter, to the resulting solution was added 2 ml of a 4.0 x 10-4 M aqueous disodium ethylenediaminetetraacetate (EDTA) solution. To the resulting mixture was added in three portions 612 mg of Oxone and 260 mg of sodium hydrogencarbonate at 30-minute intervals with vigorous stirring at 0~C. The mixture was stirred at the same temperature for 7 hours, and it was confirmed by TLC that no methyl trans-4-methoxycinnamate was remaining. The reaction mixture was extracted with diethyl ether, and the extract was washed with saturated brine. The aqueous layer resulting from the extraction and the washings were combined and extracted again with diethyl ether. The extracts were combined, dried and evaporated, and the residue was purified by silica gel flash column chromatography [solvents: n-hexane:ethyl acetate (4:1)], to give 39 mg of methyl (2R,3S)-3-(p-methoxyphenyl)glycidate.

The product was analyzed by HPLC in the same manner as in Example 17 to find that this product has the optical

purity of 63%ee.

Example 19 In 20 ml of 1,4-dioxane were dissolved 1.922 g (10 mmol) of methyl trans-4-methoxycinnamate and 215 mg (0.5 mmol) of a chiral ketone compound represented by the formula: at room temperature. Thereafter, to the resulting solution was added 10 ml of water. Subsequently, to the resulting mixture was added a mixture of 6.15 g (10 mmol) of Oxone and 2.60 g (31 mmol) of sodium hydrogencarbonate at 20~C at 5-minute intervals over a period of 1.5 hours.

After the addition, the resulting mixture was stirred for additional 30 minutes at the same temperature and for 7 hours at 27"C, and 50 ml of water was added to the resulting mixture. The resulting reaction mixture was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was analyzed by HPLC in the same manner

as in Example 17. As a result, it was deduced that the resulting residue was a mixture of 1.784 g (yield: 85.7%, optical purity: 76.4%ee) of methyl (2R,3S)-3-(p-methoxyphenyl)glycidate, 135.7 mg of methyl trans-4-methoxycinnamate, and 212.1 mg of the chiral ketone compound.

Example 20 In 20 ml of 1,4-dioxane were dissolved 1.922 g (10 mmol) of methyl trans-4-methoxycinnamate and 215 mg (0.5 mmol) of a chiral ketone compound represented by the formula: at room temperature. Thereafter, to the resulting solution was added 10 ml of water and 2.21 g (16 mmol) of potassium carbonate at 20"C. Subsequently, to the resulting mixture was added 6.15 g (10 mmol) of Oxone at the same temperature at 5-minute intervals over a period of 1.5 hours. After the addition, the resulting mixture was stirred for additional 30 minutes at the same

temperature and for 7 hours at 27"C, and 50 ml of water was added to the resulting mixture. The resulting reaction mixture was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was analyzed by HPLC in the same manner as in Example 17. As a result, it was deduced that the resulting residue was a mixture of 1.585 g (yield: 76.1%, optical purity: 78.0eye) of methyl (2R,3S)-3-(p-methoxyphenyl)glycidate, 341.4 mg of methyl trans-4-methoxycinnamate, and 209.7 mg of the chiral ketone compound.

Reference Example 1 rPreparation of Chiral Ketone Compound 1 (1) Optical Resolution of Bianthraquinone Carboxylic Acid In 120 ml of ethanol was dissolved 2.40 g of racemic 1,1' -bis( 2-anthraquinone carboxylic acid) (hereinafter, referred to as "bianthraquinone carboxylic acid"), and resulting mixture was then refluxed with heating. Next, 3.13 g of quinidine represented by the formula:

was gradually added to the resulting solution, and the resulting mixture was then refluxed with heating for 15 minutes. Thereafter, the reaction mixture was allowed to cool to room temperature, and then kept standing overnight. The precipitated quinidine salt of bianthraquinone carboxylic acid was collected by filtration, and the crystals were washed with ethanol, and 114 ml of a 1%aqueous sodium hydroxide was then added to the crystals. The resulting mixture was then heated at 60~C for 30 minutes. After heating the mixture, the mixture was allowed to cool to room temperature, and to the mixture was added 3.5%-hydrochloric acid. The pH of the mixture was adjusted to 2, and the mixture was stirred for 30 minutes.

Next, the 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.

Subsequently, the resulting crystals were condensed under reduced pressure at 60" to 70"C for 16 hours, to give 890 mg of (-)-bianthraquinone carboxylic acid.

The properties of the resulting (-)-bianthraquinone

carboxylic acid are as follows: Decomposition Point (dp): 196.8~ to 220.6~C [a]D25: 25: -225~ (C=0.8, MeOH) IR (nujol) Vmax (cm1): 3490, 1721, 1670, 1584 LC-MS (ESI) m/z: 501 (M-H) 1H-NMR (DMSO-d6): 6 7.80-7.95 (m, 6H), 8.21-8.26 (m, 2H), 8.33 (d, J=8 Hz, 2H), 8.41 (d, J=8 Hz, 2H), 13.0 (brs, 2H) Next, the crystals were analyzed with HPLC under the following conditions. As a result, no contamination of the (+)-form was found.

LiChro CART 250-4 Chira Dec 5 pm MeOH: 1/45 M phosphate buffer (pH 6.5) (50/50) (2) Preparation of Chiral Ketone Compound In 8 ml of a tetrahydrofuran solution containing 331 mg of (-)-bianthraquinone carboxylic acid were added 0.144 ml of oxalyl chloride and one drop of dimethylformamide in argon gas atmosphere, and the mixture was stirred at room temperature for one hour.

The 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:

and 0.551 ml of triethylamine were added dropwise to the mixture over a period of 40 minutes. Thereafter, the 1,3- dihydroxyacetone dimer remaining in the dropping funnel was rinsed off with 20 ml of tetrahydrofuran.

The mixture was stirred for 22 hours at room temperature, and the solvents were then distilled off under reduced pressure. Thereafter, methylene chloride and water were added to the residue, and the resulting mixture was extracted with methylene chloride.

The organic layer was dried over anhydrous sodium sulfate, and the solvents were distilled off. The residue was purified by silica gel flash column chromatography [solvents: ethyl acetate:hexane (1:2 to 2:1)], and the solvents were distilled off from the extract, to give 199 mg (yield: 54%) of a chiral ketone compound represented by the formula:

as amorphous powder.

The properties of the resulting chiral ketone compound are as follows: IR (nujol) Vmnx (cool): 1756, 1737, 1672 LC-MS (APCI, ammonium acetate being added) m/z=574 (M+NH4)+ 1H-NMR (CDCl3): 6 4.20 (d, J=15 Hz, 2H), 5.49 (d, J=15 Hz, 2H), 7.64-7.80 (m, 4H), 7.91-7.96 (m, 2H), 8.01 (d, J=8 Hz, 2H), 8.29-8.33 (m, 2H), 8.58 (d, J=8 Hz, 2H) Reference Example 2 To 35 ml of a methylene chloride solution containing 750 mg of (-)-1,1'-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.

The mixture was stirred for 42 hours at room temperature, and the solvents were then distilled off under reduced pressure. Thereafter, chloroform and an aqueous sodium hydrogencarbonate solution were added to the residue, and the resulting mixture was extracted with chloroform.

The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.

Thereafter, the solvents were distilled off. The residue was purified by silica gel column chromatography [solvent: chloroform], and the solvents were distilled off from the eluent, to give 671 mg (yield: 78%) of a chiral ketone compound represented by the formula: as amorphous powder.

The properties of the resulting chiral ketone compound are as follows: IR (nujol) Vmax (cm1): 1753, 1735, 1239

LC-MS (APCI, ammonium acetate being added) m/z=514 (M+NH4)+ 1H-NMR (COCl3): 6 4.21 (d, J=15 Hz, 2H), 5.59 (d, J=15 Hz, 2H), 7.29 (ddd, J=1.7, 8 Hz, 2H), 7.46 (ddd, J=1.7, 7.9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.67 (d, J=9 Hz, 2H), 7.89 (S, 2H), 8.03 (d, J=8 Hz, 2H), 8.26 (d, J=9 Hz, 2H), 8.59 (S, 2H) Reference Example 3 To 700 ml of an anhydrous acetonitrile solution containing 2.37 g of (R)-(+)-6,6'-dichloro-2,2'-diphen acid prepared according to a method described in "Chem.

Pharm. Bull., 37(8), 2207-2208 (1989)" and 2.05 g of 1,3- dihydroxyacetone dimer was added 16.9 ml of triethylamine.

The resulting mixture was stirred for 15 minutes at room temperature. To the solution was added 15.5 g of 2- chloro-1-methylpyridinium iodide, and the resulting mixture was stirred under nitrogen gas atmosphere for 12 hours at room temperature. Thereafter, the mixture was refluxed with heating for additional one hour. The solvents in the reaction mixture were distilled off under reduced pressure. Methylene chloride and water were added to the residue, and the mixture was then extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvents were then distilled off. The residue was purified by silica gel

flash column chromatography [solvents: ethyl acetate:hexane (2:1) (volume ratio)], and the solvents were distilled off from the eluent, to give 450 mg (yield: 16g) of a chiral ketone compound represented by the formula: as amorphous powder.

The properties of the resulting chiral ketone compound are as follows: 1H-NMR (CDCl3): 6 4.19 (d, J=15 Hz, 2H), 5.50 (d, J=15 Hz, 2H), 7.40-7.73 (m, 6H) 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. The ethyl acetate layer was concentrated, and the residue was then heated and dissolved in 30 ml of 70% water-containing methanol. Thereafter, the solution was stirred and allowed to cool to room temperature, and the resulting mixture was further cooled to 4"C overnight. The precipitated crystals were collected by filtration, and the crystals were washed with ice-cold methanol and dried at 50"C, to isolate 7.58 g of methyl trans-4-methoxycinnamate (yield: 78.9%).

Reference Example 5 The amount 6.81 g (50 mmol) of p-anisaldehyde, 35.2 g (400 mmol) of ethyl acetate, and an ethanol solution of sodium ethoxide being prepared by dissolving 1.61 g (70 mmol) of metallic sodium in 25 ml of ethanol were mixed together. The resulting mixture was stirred at room temperature for 13 hours, and then at 50"C for three hours. The solvents were distilled off from the reaction mixture under reduced pressure. To the residue was added 30 ml of methanol, and the reaction mixture was then reacted at room temperature for five hours. Thereafter, the resulting reaction mixture was distilled off under reduced pressure, and 30 ml of methanol was then added to the residue, and the mixture was reacted at 50"C for 18 hours. To the reaction mixture was added 4.2 g of acetic acid to terminate the reaction. Subsequently, water and ethyl acetate were added to the mixture, and the ethyl acetate layer was collected, 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 7.78 g (81.0%) of methyl trans-4-methoxycinnamate.

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 Reference Example 1 or 2, to give the results shown in Table 2.

T a b l e 2<BR> Condensation Reaction Transesterification Reaction<BR> Ref. Yield<BR> Example Base Reaction Temp. Acid Reaction<BR> No. (eq) Reaction Period (eq) Period (%)<BR> 6 Metallic Sodium (1.1) Room Temp. for None Room Temp. 75.1<BR> 18 hours for 5 days<BR> 7 Ethanol Solution of Room Temp. for Sulfuric Acid Refluxing 79.9<BR> Sodium Ethoxide (1.4) 40 hours, (1.9) for<BR> 50~C for 3 hours 14 hours<BR> 8 t-Butanol Solution Room temp. None Room Temp. 77.0<BR> of Potassium for 3 hours for<BR> t-Butoxide (1.3) 37 hours<BR> 9 t-Butanol Solution Room temp. Sulfuric Acid Refluxing 78.9<BR> of Potassium for 5 hours (1.8) for<BR> t-Butoxide (1.3) 16 hours

Reference Example 10 In 6 ml of tetrahydrofuran was dissolved 160 mg (0.48 mmol) of a chiral dicarboxylic acid compound represented by the formula: reported in Bull. Chem. Soc. Jpn, 57, 1943-1947. To the resulting solution were added 0.105 ml (1.20 mmol) of oxalyl chloride and one drop of dimethylformamide at room temperature under nitrogen gas atmosphere. The mixture was stirred at the same temperature for one hour. The reaction mixture was diluted with 80 ml of tetrahydrofuran, and to the resulting mixture was added dropwise a solution of 65 mg (0.36 mmol) of 1,3-dihydroxyacetone dimer and 0.4 ml (2.88 mmol) of triethylamine in 20 ml of tetrahydrofuran for about 40 minutes. The mixture was stirred at the same temperature overnight. The reaction was evaporated to remove the solvent, and the residue was dissolved in chloroform. The solution was washed with saturated brine, dried and

evaporated to remove the solvent. The resulting crude product was purified by silica gel flash column chromatography [pretreated with n-hexane: triethylamine (100:1); solvent: n-hexane:ethyl acetate (1:1)] to give 41 mg (yield: 22%) of a chiral ketone compound represented by the formula: As described above, it is found that 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.

As an example of 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)]. Contrary to the trans-stilbene used therein, a simple C2 symmetric compound, since the styrene derivative (I), a starting material compound of

the present invention, is a complicated compound having no symmetric element, the asymmetric reaction control is considered to be more difficult than the reaction control of trans-stilbene. Nevertheless, it is found that the optically active phenyloxirane compound can be prepared in an extremely high optical yield.

In addition, 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.

In 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.

In addition, in the process of the present invention, since the asymmetric oxidation agent resulting from a

chiral ketone compound and an oxidizing agent, i.e., a mild oxidizing agent, is used, the optically active phenyloxirane compound having an easily decomposable oxirane ring can be obtained in high yields.

Further, in the present invention, when a chiral ketone compound is used and oxidized with an oxidizing agent in the reaction system to form an asymmetric oxidation agent, and the asymmetric oxidation of the styrene derivative (I) present in the same reaction system is carried out with the asymmetric oxidation agent, 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.

INDUSTRIAL APPLICABILITY According to the present invention, since 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.

The present invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.