CN1266430A

CN1266430A - Process for preparing optically active phenyloxirane compounds

Info

Publication number: CN1266430A
Application number: CN98808123A
Authority: CN
Inventors: 桥山富树; 原田直之; 荒川博章; 草间真理; 尾崎泰彦; 黑田彻; 关雅彦
Original assignee: Tanabe Seiyaku Co Ltd
Current assignee: Tanabe Pharma Corp
Priority date: 1997-06-11
Filing date: 1998-06-05
Publication date: 2000-09-13
Also published as: EP0988297A2; WO1998056762A3; IL133095A0; KR20010013668A; AU7551998A; CA2293404A1; WO1998056762A2

Abstract

A process for preparing an optically active phenyloxirane compound represented by formula (II), wherein ring A is a substitued or unsubstituted benzene ring; R is a group represented by -CO2R<q>, or a group convertible to the group represented by -CO2R<q>, wherein R<q> 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, or a chiral dioxirane compound.

Description

The method for preparing optically active phenyloxirane compounds

Technical field

The present invention relates to the method for preparing optically active phenyloxirane compounds.More specifically, the present invention relates to the method that optically active phenyloxirane compounds are prepared by asymmetric oxidation, and the method that 1,5- benzothiazepine  derivatives are prepared with the optically active phenyloxirane compounds prepared by above method.

Background technology

1,5- benzothiazepine  derivatives are to be used to treat heart disease, the compound of such as angina pectoris, miocardial infarction and cardiac arrhythmia, and angiocardiopathy, such as hypertension, cardiovascular infraction and cerebral infarction.Especially, diltiazem hydrochloride  (chemical names：(2S, 3S) -3- acetoxyl groups -5- [2- (dimethylamino) ethyl] -2- (4- methoxyphenyls) -2,3- dihydro -1,5- benzothiazepine  -4 (5H) -one hydrochloride) it is widely used in treatment angina pectoris and essential hypertension.

In recent years, it has been suggested that the various methods for preparing optically active glycidol acid derivative as 1,5- benzothiazepine  derivatives intermediates.The example of glycidol acid derivative main method is prepared including as follows：

(A) method (the flat 4-501360 of Unexamined Japanese Patent Application No., and the flat 6-78 peace 7-121231 of Japanese Examined Patent application number) of glycidol acid derivative is prepared by asymmetric hydrolysis method；

(B) method (the flat 4-228095 of Japanese Patent Laid-Open Publication, flat 5-76389 peace 6-78790) of glycidol acid derivative is prepared by asymmetric transesterification method；

(C) method (the clear 60-13776 of Japanese Patent Laid-Open Publication, the flat 4-28268 of Japanese Examined Patent application number, the flat 2-231480 of Japanese Patent Laid-Open Publication) of glycidol acid derivative is prepared by chemistry, method for optical resolution；With

(D) method (International Patent Publication No. W WO95/07359) of glycidol acid derivative is prepared by asymmetric amidation；

But, in any method under (A)-(D) items, because with racemic trans-glycidic acid, as raw material, therefore the yield of the optical isomer required for having the drawback that is 50% or less of racemic modification.

The method that the clear 59-196881 of Japanese Patent Laid-Open Publication discloses preparation (2R, 3S) -3- (4- acetoxyl groups phenyl) glycidic acid methyl esters, this method includes：In the presence of tetraisopropoxy titanium and L-TARTARIC ACID diethylester, aoxidize trans- 3- (4- acetoxyl groups phenyl) cinnamyl alcohol with metachloroperbenzoic acid and obtain (2S, 3S) -3- (4- acetoxyl groups phenyl) glycidic alcohol；The mixture of obtained (2S, 3S) -3- (4- acetoxyl groups phenyl) glycidic alcohol ruthenic oxides and sodium metaperiodate is aoxidized；Then (2R, 3S) -3- (4- acetoxyl groups phenyl) glycidic acid methyl esters is formed with dimethyl suflfate.But, this method has the drawback that：Reactions steps are excessively complicated and yield is not high.

In recent years, to about having made various researchs [Chemical Reviews, 89,1187-1201 (1989)] with the oxidation reaction of the ring of dioxa third (dioxirane) compound.For example, by the way that achiral ring of dimethyl dioxa third is added in trans cinnamic acid ethyl ester reported in " J.Org.Chem.; 50,2847-2853 (1985) ", then obtained mixture is reacted 22 hours at 25 DEG C and carries out epoxidised reaction.

But, the ring of dimethyl dioxa third is without chirality, and therefore, it has the disadvantage：It can not obtain with required optically active phenyloxirane compounds.

By using the chiral cycle compound of dioxa third reported in " J.Am.Chem.Soc., 118,11311-11312 (1996) ", it is by using Oxone [trade name, Du Pont productions；Composition：2KHSO₅·KHSO₄·K₂SO₄] oxidation following formula represent assimilation compound formed：

Carry out the asymmetric epoxidation reaction that sample C2 symmetrical compounds are trans- 1,2- talan (phenyl that two of which is powered is combined with its double bond).

But, it there is no any document about required preparation target for the method for optically active phenyloxirane compounds to disclose or propose.

In view of prior art, target of the present invention is to provide the method prepared in high yield with the optical activity phenyloxirane compounds of high-optical-purity, this method by using by chiral ketone compound and oxidant (such as, the chiral cycle compound of dioxa third) the asymmetric oxidation agent for preparing carries out asymmetric oxidation, that is the complicated styrene derivative without symmetrical factor of asymmetric Epoxidation, and the method that the chiral ketone compound for the raw material for being used as asymmetric oxidation agent during optical activity phenyloxirane compounds are prepared is reused is provided, therefore yield can be made to increase and have the advantages that economically.

These and other target of the present invention will be illustrated in illustrating below.

Disclosure of the invention

The present invention relates to herein below：[1] method for preparing optically active phenyl ethylene oxide that lower formula (II) is represented：

Its middle ring A is substituted or unsubstituted phenyl ring；R is-CO₂R^qGroup, or-CO can be converted into₂R^qGroup, wherein R^qIt is ester residue；^*Asymmetric carbon atom is represented, this method includes the styrene derivative (I) for representing formula (I)：

Wherein A and R are defined as above, and are handled with the asymmetric oxidation agent formed by chiral ketone compound and oxidant；[2] method described in [1] more than item, wherein the chiral ketone compound are the optical isomers of the assimilation compound (V) represented by formula (V)：

Its middle ring Ar is the monocyclic, bicyclic or tricyclic aromatic rings can with substituent；Y is the group that following formula is represented：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵- wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；And Alk¹、Alk²、Alk³、Alk⁴And Alk⁵It is each low-grade alkylidene respectively；[3] method described in [1] more than or [2] item, wherein the chiral ketone compound are the optical isomers of the assimilation compound (VI) represented by formula (VI)：

Wherein R^aAnd R^bIndividually hydrogen atom or substituent；And R^cAnd R^dMeet one of following (I)-(III)：(I)R^cAnd R^dIndividually hydrogen atom or substituent；Or (II) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

Wherein R^e、R^f、R^gAnd R^hMeet one of following (a) and (b)：(a) two adjacent groups are bonded to each other the phenyl ring for being formed together with the carbon atoms of two interconnections and can having substituent, and remaining two group is individually hydrogen or substituent；Or (b) these groups are individually hydrogen atom or substituent；Or (III) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

Wherein Rⁱ、R^j、R^kAnd R^mIndividually hydrogen atom or substituent；It is the group that following formula is represented with Y：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵It is each low-grade alkylidene respectively；[4] method any one of [1] more than-[3], wherein in same reaction system carries out the reaction of the chiral ketone compound and the oxidant and obtains asymmetric oxidation agent and the reaction of styrene derivative (I)；[5] method for preparing optically active phenyloxirane compounds that lower formula (II) is represented：Its middle ring A is substituted or unsubstituted phenyl ring；R is-CO₂R^qGroup, or-CO can be converted into₂R^qGroup, wherein R^qIt is ester residue；^*Asymmetric carbon atom is represented, this method includes the styrene derivative (I) for representing formula (I)：

Its middle ring A and R are defined as above, and are handled with the chiral cycle compound of dioxa third；[6] method described in [5] more than item, wherein the cycle compound of chiral dioxa third is the optical isomer of the cycle compound of dioxa third (III) represented by formula (III)：

Its middle ring Ar is the monocyclic, bicyclic or tricyclic aromatic rings can with substituent；Y is the group that following formula is represented：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵- wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；And Alk¹、Alk²、Alk³、Alk⁴And Alk⁵It is each low-grade alkylidene respectively.[7] method described in [5] more than or [6] item, the wherein chiral cycle compound of dioxa third are the optical isomers of the cycle compound of dioxa third (IV) represented by formula (IV)：Wherein R^aAnd R^bIndividually hydrogen atom or substituent；And R^cAnd R^dMeet one of following (I)-(III)：(I)R^cAnd R^dIndividually hydrogen atom or substituent；Or (II) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：Wherein R^e、R^f、R^gAnd R^hMeet one of following (a) and (b)：(a) two adjacent groups are bonded to each other the phenyl ring for being formed together with the carbon atoms of two interconnections and can having substituent, and remaining two group is individually hydrogen or substituent；Or (b) these groups are individually hydrogen atom or substituent；Or (III) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

Wherein Rⁱ、R^j、R^kAnd R^mIndividually hydrogen atom or substituent；It is the group that following formula is represented with Y：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵Individually low-grade alkylidene；[8] method any one of [5] more than-[7], it comprises the following steps：

Make the optical isomer of assimilation compound (VI) and the oxidant reaction represented by lower formula (VI)：Wherein R^aAnd R^bIndividually hydrogen atom or substituent；And R^cAnd R^dMeet one of following (I)-(III)：(I)R^cAnd R^dIndividually hydrogen atom or substituent；Or (II) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

Wherein Rⁱ、R^j、R^kAnd R^mIndividually hydrogen atom or substituent；It is the group that following formula is represented with Y：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵Individually low-grade alkylidene；

React styrene derivative (I) and the cycle compound of chiral dioxa third (IV) of generation；[9] method described in [8] more than item, wherein carrying out the assimilation compound (VI) of the optical isomer and the reaction of the oxidant and the reaction of the obtained cycle compound of chiral dioxa third (IV) and styrene derivative (I) in same reaction system；[10] method any one of [1] more than-[9], wherein the styrene derivative (I) is transisomer, optically active phenyloxirane compounds (II) are (2R, 3S)-isomers or (2S, 3R)-isomers；[11] method any one of [1] more than-[4], wherein the styrene derivative (I) is transisomer；The chiral ketone compound is the chiral ketone compound (VI-a) represented by formula (VI-a)：

Wherein R^aAnd R^bIndividually hydrogen atom or substituent；And R^cAnd R^dMeet one of following (I)-(III)：(I)R^cAnd R^dIndividually hydrogen atom or substituent；Or (II) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：Wherein R^e、R^f、R^gAnd R^hMeet one of following (a) and (b)：(a) two adjacent groups are bonded to each other the phenyl ring for being formed together with the carbon atoms of two interconnections and can having substituent, and remaining two group is individually hydrogen or substituent；Or (b) these groups are individually hydrogen atom or substituent；Or (III) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

Wherein Rⁱ、R^j、R^kAnd R^mIndividually hydrogen atom or substituent；It is the group that following formula is represented with Y：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵Individually low-grade alkylidene；And optically active phenyloxirane compounds (II) are (2R, 3S)-isomers；[12] method any one of [1] more than-[4], wherein the styrene derivative (I) is transisomer；The chiral ketone compound is the chiral ketone compound (VI-b) represented by formula (VI-b)：

Wherein Rⁱ、R^j、R^kAnd R^mIndividually hydrogen atom or substituent；It is the group that following formula is represented with Y：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵Individually low-grade alkylidene；And optically active phenyloxirane compounds (II) are (2S, 3R)-isomers；[13] method any one of [5] more than-[9], wherein the styrene derivative (I) is transisomer；The chiral cycle compound of dioxa third is the cycle compound of chiral dioxa third (IV-a) represented by formula (IV-a)：

Wherein Rⁱ、R^j、R^kAnd R^mIndividually hydrogen atom or substituent；It is the group that following formula is represented with Y：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵Individually low-grade alkylidene；And optically active phenyloxirane compounds (II) are (2R, 3S)-isomers；[14] method any one of [5] more than-[9], wherein the styrene derivative (I) is transisomer；The chiral cycle compound of dioxa third is the cycle compound of chiral dioxa third (IV-b) represented by formula (IV-b)：

Wherein Rⁱ、R^j、R^kAnd R^mIndividually hydrogen atom or substituent；It is the group that following formula is represented with Y：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵Individually low-grade alkylidene；And optically active phenyloxirane compounds (II) are (2S, 3R)-isomers；[15] method described in [3] more than, [4], [7], [8], [9], [11], [12], [13] or [14] item, wherein Y representatives-CO-O-CH₂- group；R^a、R^b、R^cAnd R^dMeet one of following (a) and (b)：(a)R^aAnd R^bIndividually hydrogen atom；R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

R^cIt is hydrogen atom, R^dIt is halogen atom；Or R^cIt is hydrogen atom, R^dIt is nitro；Or (b) R^aIt is halogen atom；R^bIt is hydrogen atom；R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

[16] method described in [15] more than item, wherein R^aAnd R^bIndividually hydrogen atom；R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

[17] method described in [5] more than item, wherein can by using the difference to organic solvent solubility separation process, in the reaction mixture obtained from the styrene derivative (I) represented with chiral cycle compound of dioxa third processing formula (I), isolated high-purity by reducing the assimilation compound and optically active phenyloxirane compounds (II) that the chiral cycle compound of dioxa third is obtained；[18] method described in [1] more than item, wherein can be by using the separation process to organic solvent dissolubility difference, from reaction mixture, the assimilation compound and optically active phenyloxirane compounds (II) that asymmetric oxidation agent contained by reducing in the reaction mixture of isolated high-purity is obtained；[19] method described in [17] more than or [18] item, wherein the assimilation compound are the assimilation compounds (V) for the optical isomer that lower formula (V) is represented：

Its middle ring Ar is the monocyclic, bicyclic or tricyclic aromatic rings can with substituent；Y is the group that following formula is represented：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵Individually low-grade alkylidene；[20] method any one of [17] more than-[19], wherein the assimilation compound are the assimilation compounds (VI) of the optical isomer represented by lower formula (VI)：

Wherein R^e、R^f、R^gAnd R^hMeet one of following (a) and (b)：(a) two adjacent groups are bonded to each other the phenyl ring for being formed together with the carbon atoms of two interconnections and can having substituent, and remaining two group is individually hydrogen or substituent；Or (b) these groups are individually hydrogen atom or substituent；Or (III) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：Wherein Rⁱ、R^j、R^kAnd R^mIndividually hydrogen atom or substituent；It is the group that following formula is represented with Y：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵Individually low-grade alkylidene；[21] method any one of [1] more than-[20], its middle ring A is the phenyl ring with the 1-3 substituents selected from low alkyl group, lower alkoxy and halogen atom, R representatives-CO₂R^qGroup, wherein R^qIt is ester residue；[22] method described in [21] more than item, its middle ring A is 4- lower alkyl phenyls or 4- lower alkoxyphenyls, R^qIt is low alkyl group；[23] method described in [22] more than item, its middle ring A is 4- methoxyphenyls, R^qIt is methyl；[24] method for preparing 1, the 5- benzothiazepine  derivatives or its pharmaceutically acceptable salt of formula (VII) representative,

Its middle ring A is substituted or unsubstituted phenyl ring；Ring B is substituted or unsubstituted phenyl ring；R²It is hydrogen atom or substituted alkyl；R³It is lower alkanol；^*Asymmetric carbon atom is represented, this method uses optically active phenyloxirane compounds (II) that formula (II) is represented：

Wherein R representatives-CO₂R^qGroup, or-CO can be converted into₂R^qGroup, wherein R^qIt is ester residue；Ring A and^*It is defined as above, wherein the method for any one of [1]-[23] more than can be used to prepare for optically active phenyloxirane compounds (II)；[25] method for preparing the nitrocarboxylic acid compound or its salt of following formula representative,

Its middle ring A is substituted or unsubstituted phenyl ring；Ring B is substituted or unsubstituted phenyl ring；^*Asymmetric carbon atom is represented, this method uses optically active phenyloxirane compounds (II) that formula (II) is represented：Wherein R representatives-CO₂R^qGroup, or-CO can be converted into₂R^qGroup, wherein R^qIt is ester residue；Ring A and^*It is defined as above, wherein the method for any one of [1]-[23] more than can be used to prepare for optically active phenyloxirane compounds (II).Preferred embodiment of the present invention

According to the inventive method, the styrene derivative (I) that can be represented with lower formula (I) is used as raw material：

Its middle ring A is substituted or unsubstituted phenyl ring；R representatives-CO₂R^qGroup, or-CO can be converted into₂R^qGroup, wherein R^qIt is ester residue.

In the styrene derivative (I) that formula (I) is represented, ring A is substituted or unsubstituted phenyl ring as described above.Ring A instantiation includes phenyl or the phenyl with the 1-3 substituents for being selected from low alkyl group, lower alkoxy and halogen atom.The low alkyl group includes the alkyl with 1-4 carbon atom, such as methyl, ethyl, propyl group and the tert-butyl group.The lower alkoxy includes the alkoxy with 1-4 carbon atom, such as methoxyl group, ethyoxyl, propoxyl group and butoxy.In addition, halogen atom includes fluorine atom, chlorine atom, bromine atoms and iodine atom.In above listed ring A, the preferably phenyl with the substituent of 1-3 selected from low alkyl group, lower alkoxy and halogen atom, more preferably 4- lower alkoxyphenyls and 4- lower alkyl phenyls, particularly preferred 4- aminomethyl phenyls and 4- methoxyphenyls.

In the styrene derivative (I) that formula (I) is represented, R representatives-CO₂R^qGroup, or-CO can be converted into₂R^qGroup, wherein R^qIt is defined as above.- CO can be converted into₂R^qThe example of group include, the group that such as following formula is represented：

Wherein R^rDefinition and above R^qIt is identical；The group that following formula is represented：Wherein R^sAnd R^tAll it is hydrogen atom；Or one is hydrogen atom, another definition and above R^qIt is identical；Or R^sAnd R^tAll with above R^qDefine identical；Or R^sAnd R^tThat combine the heterocycle for being formed together with adjacent nitrogen-atoms and can having substituent；Thiocarboxyl group；Carboxyl；Cyano group etc..

R^qIt is any commonly employed ester residue.

R^qInstantiation include, e.g., the low alkyl group with 1-4 carbon atom, such as methyl, ethyl, propyl group and butyl；Cycloalkyl with 3-7 carbon atom, such as pentamethylene base and cyclohexyl；Aryl, such as phenyl and naphthyl.These low alkyl groups, cycloalkyl and aryl can each have substituent.The example of the low alkyl group and the substituent of cycloalkyl includes substituted or unsubstituted phenyl, halogen atom and the lower alkoxy with 1-4 carbon atom.The example of the aryl substituent includes low alkyl group, halogen atom and the lower alkoxy with 1-4 carbon atom with 1-4 carbon atom.In above listed R^qIn, preferably low alkyl group, particularly preferred methyl.

In addition, R^sAnd R^tInclude the 5-6 circle heterocycles containing nitrogen-atoms, such as pyrrolidine ring, piperidine ring, morpholine ring and piperazine ring, and these heterocycles with reference to the example of the heterocycle formed together with adjacent nitrogen-atoms and there can be the substituent selected from 1-4 carbon atom lower alkyl and halogen.

The geometric isomer of the styrene derivative (I) represented on formula (I), ring A and-R can be combined into cis- or trans- formula configuration with-CH=CH- groups.

In styrene derivative (I), it is desirable in formula (I) middle ring A be methoxyphenyl or aminomethyl phenyl, R is methoxycarbonyl, and ring A and R are combined with anti-configuration.Particularly suitable for the trans- 4- p-Methoxymethylcinnamates of use.

The example of asymmetric oxidation dosage form chiral ketone compound used in includes; such as, naturally occurring chiral ketone compound, such as one or more hydroxyls wherein in monose or polysaccharide can be converted into oxo base; and the protected compound of remaining hydroxyl is (such as; the red moss -2 of (O- the isopropylidenes)-D- of 1,2: 4,5- bis-; the own allophanamides of 3- (hexodiuro) -2; 6- pyranoses) [Tetrahedron, 47,2133 (1991)]；With non-naturally occurring chiral ketone compound, such as there is the assimilation compound of chiral double heteroaryl structures.

The representative instance of chiral ketone compound includes, e.g., the optical isomer for the assimilation compound (V) that lower formula (V) is represented：

Its middle ring Ar is the monocyclic, bicyclic or tricyclic aromatic rings can with substituent；Y is the group that following formula is represented：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；And Alk¹、Alk²、Alk³、Alk⁴And Alk⁵It is each low-grade alkylidene respectively.

In the assimilation compound (V), ring Ar is the monocyclic, bicyclic or tricyclic aromatic rings can with substituent.The example of the monocyclic, bicyclic or tricyclic aromatic rings includes, e.g., phenyl ring, naphthalene nucleus, naphthoquinones ring, anthracene nucleus, anthraquinone ring, phenanthrene ring etc..As long as in addition, axial chirality can be caused, being not particularly limited the Y combined with the aromatic rings the position of substitution.It is required that Y is combined on the ortho position of the key between two Ar rings.

The example of substituent on aromatic rings includes; such as; electron withdraw group, including halogen atom such as fluorine atom, chlorine atom, bromine atoms and iodine atom, nitro, mesyl, p-toluenesulfonyl, trifluoromethyl, cyano group, methoxycarbonyl, dimethyl sulfoxide base, sulfoamido etc.；And electron-donating group, including the low alkyl group with 1-4 carbon atom such as methyl, ethyl, propyl group and butyl, the lower alkoxy with 1-4 carbon atom such as methoxyl group, ethyoxyl, propoxyl group and butoxy, the cycloalkyl with 3-7 carbon atom, such as cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl and aralkyl such as benzyl and ethoxyphenyl with 7-10 carbon atom.In these groups, preferably electron withdraw group, particularly preferred halogen atom and nitro.

On the other hand, in above-described assimilation compound (V), Y is the group that following formula is represented：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴- (iv) -O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；And Alk¹、Alk²、Alk³、Alk⁴And Alk⁵It is each low-grade alkylidene respectively.

R¹The example of middle alkyl sulphonyl includes, e.g., and moieties have the alkyl sulphonyl of 1-4 carbon atom, such as mesyl, ethylsulfonyl, the third sulfonyl and fourth sulfonyl.In addition, the example of the arylsulfonyl includes, e.g., aryl moiety has the aryl sulfonyl of 6-10 carbon atom, such as benzenesulfonyl, p-toluenesulfonyl and naphthalene sulfonyl base.

Alk¹、Alk²、Alk³、Alk⁴And Alk⁵In the instantiation of low-grade alkylidene include, e.g., the straight or branched-chain lower alkylidene with 1-4 carbon atom, such as methylene, ethylidene, 1,3- propylidene, Isosorbide-5-Nitrae-butylidene, methylmethylene, methyl ethylidene and methyl propylene.

In the group that Y is represented, preferably Y is the group that the above (ii) is represented, and particularly preferred Y is the group that the above (ii) is represented, and wherein Q is carbonyl.Specifically, Y preferably-CO-O-CH₂-。

The instantiation of the chiral ketone compound includes, e.g., the optical isomer for the assimilation compound (VI) that lower formula (VI) is represented：Wherein R^aAnd R^bIndividually hydrogen atom or substituent；And R^cAnd R^dMeet one of following (I)-(III)：(I)R^cAnd R^dIndividually hydrogen atom or substituent；Or (II) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：Wherein R^e、R^f、R^gAnd R^hMeet one of following (a) and (b)：(a) two adjacent groups are bonded to each other the phenyl ring for being formed together with the carbon atoms of two interconnections and can having substituent, and remaining two group is individually hydrogen or substituent；Or (b) these groups are individually hydrogen atom or substituent；Or (III) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：Wherein Rⁱ、R^j、R^kAnd R^mIndividually hydrogen atom or substituent；It is the group that following formula is represented with Y：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk², (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵It is each low-grade alkylidene respectively.

R^a-R^mIn substituent include, e.g., electron withdraw group, including halogen atom such as fluorine atom, chlorine atom, bromine atoms and iodine atom, nitro, mesyl, p-toluenesulfonyl, trifluoromethyl, cyano group, methoxycarbonyl, dimethyl sulfoxide base, sulfoamido etc.；And electron-donating group, including the low alkyl group with 1-4 carbon atom such as methyl, ethyl, propyl group and butyl, the lower alkoxy with 1-4 carbon atom such as methoxyl group, ethyoxyl, propoxyl group and butoxy, the cycloalkyl with 3-7 carbon atom, such as cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl and aralkyl such as benzyl and ethoxyphenyl with 7-10 carbon atom.In these groups, preferably electron withdraw group, particularly preferred halogen atom and nitro.

Furthermore, it desired to R^a、R^b、R^cAnd R^dMeet one of following (a) and (b)：(a)R^aAnd R^bIndividually hydrogen atom；R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

R^aIt is hydrogen atom, R^bIt is halogen atom；Or R^cIt is hydrogen atom, R^dIt is nitro；Or (b) R^aIt is halogen atom；R^bIt is hydrogen atom；R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

Specially require R^aAnd R^bIndividually hydrogen atom；R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

The group that the Y of assimilation compound (VI) is represented can be identical as the group listed by Y with assimilation compound (V).

The optical isomer of the assimilation compound (VI) includes the chiral ketone compound (VI-a) that two isomers based on axial chirality, i.e. following formula (VI-a) are represented：

Wherein R^a、R^b、R^c、R^dIt is defined as above with Y；The chiral ketone compound (VI-b) represented with following formula (VI-b)：

Wherein R^a、R^b、R^c、R^dIt is defined as above with Y.

The optical isomer of its optical isomer and assimilation compound (VI) can be converted into asymmetric oxidation agent by making the optical isomer of assimilation compound (V) with oxidant reaction.In appropriate solvent, the reaction is carried out under the existence or non-existence of alkali.

The example of oxidant used includes in the oxidation reaction, e.g., peroxy acid such as metachloroperbenzoic acid, peracetic acid, pernitric acid, percarbonic acid, peroxy-disulfuric acid, permonosulphuric acid, perboric acid and performic acid and its alkali metal salt, peroxide such as hydrogen peroxide etc..In these oxidants, present invention preferably uses Oxone, that is, the oxidant of permonosulphuric acid potassium is included.In addition, the oxidant, solvent or starting compound can contain metal impurities.To make the impurity not active in the reaction, chelating agent can be used.The example of the chelating agent includes, e.g., ethylenediamine tetra-acetic acid, disodium ethylene diamine tetraacetate, crown ether, such as 18- crown ethers -6.The chelating agent can be directly added into the solution of the styrene derivative (I), or solution can be made in its first dissolving in a solvent, then the solution is added in the solution of the styrene derivative (I).

The carbonate such as sodium carbonate and potassium carbonate of alkali metal can be used；The bicarbonate of alkali metal such as sodium acid carbonate and saleratus etc. are used as alkaline reagent.

The example of solvent for use includes in the oxidation reaction, e.g., and organic solvent includes ether solvents, such as 1,2- dimethoxy-ethanes, dimethyl ether, ether, tetrahydrofuran, the dioxane of Isosorbide-5-Nitrae-and diethylene glycol dimethyl ether；Nitrile solvent, such as acetonitrile, propionitrile and butyronitrile；Alcoholic solvent, such as methanol, ethanol, propyl alcohol, isopropanol, n-butanol, sec-butyl alcohol and the tert-butyl alcohol；Ester solvent, such as methyl acetate and ethyl acetate；Amide solvent, such as dimethylformamide, diethylformamide, dimethyl acetamide and dimethyl-imidazolinone；Sulfoxide solvent, such as dimethyl sulfoxide；Can be by the aliphatic solvent of halogenation, such as dichloromethane, ethlyene dichloride, chloroform, carbon tetrachloride, hexane, hexamethylene and pentane；Can be by the aromatic hydrocarbon solvent of halogenation, such as toluene, dimethylbenzene, chlorobenzene and dichloro-benzenes；Water and its mixed solvent.In these solvents, ether solvents, nitrile solvent, alcoholic solvent, water and its mixed solvent are preferably used.Particularly preferably use 1,2- dimethoxy-ethanes, the dioxane of Isosorbide-5-Nitrae-, acetonitrile, water and its mixed solvent.

The reaction temperature can be the temperature that can be formed under asymmetric oxidation agent, can select the temperature according to the species of required asymmetric oxidation agent.It is required that the reaction temperature is -5 DEG C to 50 DEG C, preferably 0 ° -40 DEG C.

The asymmetric oxidation agent obtained from the oxidation reaction can disposably be isolated, then be reacted again with the styrene derivative (I).In addition, the asymmetric oxidation agent can be made to be reacted with styrene derivative (I) in same reaction system, wherein not separating the asymmetric oxidation agent formed in oxidation reaction.

When carrying out the asymmetric oxidation agent and the reaction of styrene derivative (I) without isolation, the optical isomer of assimilation compound (V) and (VI) can be converted into asymmetric oxidation agent first, asymmetric oxidation agent and styrene derivative (I) that generation is then made again are reacted.In addition, the optical isomer that can carry out assimilation compound (V) and (VI) simultaneously in same reaction system is converted into asymmetric oxidation agent and styrene derivative (I) and the asymmetric oxidation reaction of the asymmetric oxidation agent.

In addition, when using chiral ketone compound (VI-a), can prepare with the chiral asymmetric oxidation agent of same axial.On the other hand, when using chiral ketone compound (VI-b), it can prepare with the chiral asymmetric oxidation agent of same axial.

The chiral cycle compound of dioxa third, i.e., the asymmetric oxidation agent one of formed by chiral ketone compound and oxidant, it is with the third ring of dioxa ring (three-membered ring being made up of carbon-oxygen-oxygen) and also has the compound of chirality.The chirality includes the chirality based on asymmetric carbon atom and axial chirality.

The example of the chiral cycle compound of dioxa third includes; such as; oxo base, and the protected assimilation compound (e.g., 1 of remaining hydroxyl can be converted into by aoxidizing one or more hydroxyls in natural chiral assimilation compound such as wherein monose or polysaccharide; 2: 4; own allophanamide -2, the 6- pyranose of 5- bis- (O- isopropylidenes) the red moss -2,3- of-D-) [Tetrahedron; 47,2133 (1991)] and the compound that results in；With pass through disclosed method, such as, method disclosed in " Chemical Reviews; 89; 1187 (1989) ", by aoxidizing non-naturally occurring chiral ketone compound, then the ketone is partially converted into ring of dioxa third etc. by the compound for such as having the assimilation compound of chiral double heteroaryl structures and resulting in.

The representative instance of the chiral cycle compound of dioxa third includes, e.g., (III) optical isomer for the cycle compound of dioxa third that lower formula (III) is represented：Its middle ring Ar is the monocyclic, bicyclic or tricyclic aromatic rings can with substituent；It is the group that following formula is represented with Y：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴-, or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；And Alk¹、Alk²、Alk³、Alk⁴And Alk⁵It is each low-grade alkylidene respectively.

In the cycle compound of dioxa third (III), ring Ar is the monocyclic, bicyclic or tricyclic aromatic rings can with substituent.The example of the monocyclic, bicyclic or tricyclic aromatic rings includes, e.g., phenyl ring, naphthalene nucleus, naphthoquinones ring, anthracene nucleus, anthraquinone ring, phenanthrene ring etc..As long as in addition, axial chirality can be caused, being not particularly limited the Y combined with the aromatic rings the position of substitution.It is required that Y is combined on the ortho position of the key between two Ar rings.

On the other hand, in the above-described cycle compound of dioxa third (III), Y is the group that following formula is represented：(i) -O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；And Alk¹、Alk²、Alk³、Alk⁴And Alk⁵It is each low-grade alkylidene respectively.

In the group that Y is represented, preferably Y is the group that the above (ii) is represented, and more preferably Y is the group that the above (ii) is represented, and wherein Q is carbonyl.Specifically, Y is preferably-CO-O-CH₂-。

The instantiation of the chiral cycle compound of dioxa third includes, e.g., the optical isomer for the cycle compound of dioxa third (IV) that lower formula (IV) is represented：Wherein R^aAnd R^bIndividually hydrogen atom or substituent；And R^cAnd R^dMeet one of following (I)-(III)：(I)R^cAnd R^dIndividually hydrogen atom or substituent；Or (II) R^cAnd R^dIt is bonded to each other to form the group of following formula representative：

Wherein Rⁱ、R^j、R^kAnd R^mIndividually hydrogen atom or substituent；It is the group that following formula is represented with Y：(i)-O-Q-Alk¹-, (ii)-Q-O-Alk²-, (iii)-Alk³-O-Alk⁴-, (iv)-O-Alk⁵-, (v)-NR¹-Q-Alk¹-, (vi)-Q-NR¹-Alk²-, (vii)-Alk³-NR¹-Alk⁴- or (viii)-NR¹-Alk⁵-, wherein Q is-CO- or-SO₂- group；R¹It is hydrogen atom, alkyl sulphonyl or aryl sulfonyl；Alk¹、Alk²、Alk³、Alk⁴And Alk⁵It is each low-grade alkylidene respectively.

The group that the Y of the cycle compound of dioxa third (IV) is represented can be identical with the group listed by the Y as the cycle compound of dioxa third (III).

The optical isomer of the cycle compound of dioxa third (IV) includes the cycle compound of chiral dioxa third (IV-a) that two isomers based on axial chirality, i.e. following formula (IV-a) are represented：

Wherein R^a、R^b、R^c、R^dAnd be defined as above with Y；The cycle compound of chiral dioxa third (IV-b) represented with following formula (IV-b)：Wherein R^a、R^b、R^c、R^dIt is defined as above with Y.

The optical isomer of the cycle compound of dioxa third (III) and the optical isomer of the cycle compound of dioxa third (IV) can for example be easy to the optical isomer by aoxidizing the assimilation compound (V) that corresponding lower formula (V) is represented：

Its middle ring Ar and Y are defined as above；And prepared by the optical isomer of the assimilation compound (VI) of lower formula (VI) representative：

Wherein R^a、R^b、R^c、R^dIt is defined as above with Y.The oxidation reaction in appropriate solvent, can be carried out in base reagent presence or absence of under with the optical isomer of oxidizing corresponding assimilation compound (V) and (VI).

The example of oxidant used includes in the oxidation reaction, e.g., peroxy acid such as metachloroperbenzoic acid, peracetic acid, pernitric acid, percarbonic acid, peroxy-disulfuric acid, permonosulphuric acid, perboric acid and performic acid and its alkali metal salt, peroxide such as hydrogen peroxide etc..In these oxidants, present invention preferably uses Oxone, that is, the oxidant of permonosulphuric acid potassium is included.In addition, the oxidant, solvent or starting compound can contain metal impurities.To make the impurity not active in the reaction, chelating agent can be used.The example of the chelating agent includes, e.g., ethylenediamine tetra-acetic acid, disodium ethylene diamine tetraacetate, crown ether, such as 18- crown ethers -6.In the solution that the chelating agent can be directly added into the styrene derivative (I), or solution can be made in its first dissolving in a solvent, then the solution is added in styrene derivative (I) solution.

The example of solvent used includes in the oxidation reaction, e.g., and organic solvent includes ether solvents, such as 1,2- dimethoxy-ethanes, dimethyl ether, ether, tetrahydrofuran, the dioxane of Isosorbide-5-Nitrae-and diethylene glycol dimethyl ether；Nitrile solvent, such as acetonitrile, propionitrile and butyronitrile；Alcoholic solvent, such as methanol, ethanol, propyl alcohol, isopropanol, n-butanol, sec-butyl alcohol and the tert-butyl alcohol；Ester solvent, such as methyl acetate and ethyl acetate；Amide solvent, such as dimethylformamide, diethylformamide, dimethyl acetamide and dimethyl-imidazolinone；Sulfoxide solvent, such as dimethyl sulfoxide；Can be by the aliphatic solvent of halogenation, such as dichloromethane, ethlyene dichloride, chloroform, carbon tetrachloride, hexane, hexamethylene and pentane；Can be by the aromatic hydrocarbon solvent of halogenation, such as toluene, dimethylbenzene, chlorobenzene and dichloro-benzenes；Water and its mixed solvent.In these solvents, ether solvents, nitrile solvent, alcoholic solvent, water and its mixed solvent are preferably used.Particularly preferably use 1,2- dimethoxy-ethanes, the dioxane of Isosorbide-5-Nitrae-, acetonitrile, water and its mixed solvent.

It is required that the reaction temperature is -5 DEG C to 50 DEG C, preferably 0-40 DEG C.

The cycle compound of dioxa third (III) obtained from the oxidation reaction or (IV) optical isomer first separation can be gone out, then be reacted again with styrene derivative (I).In addition, react in same reaction system the cycle compound of dioxa third (III) or (IV) optical isomer and styrene derivative (I), wherein not separating the optical isomer formed in oxidation reaction.

When carrying out the reaction of optical isomer and styrene derivative (I) of the cycle compound of dioxa third (III) or (IV) without isolation, the optical isomer of assimilation compound (V) or (VI) can be converted into the cycle compound of dioxa third (III) or the optical isomer of (IV) first, optical isomer and styrene derivative (I) that generation is then made again react.In addition, the optical isomer that can carry out ketone (V) or (VI) simultaneously in same reaction system is converted into the asymmetric oxidation reaction of the cycle compound of dioxa third (III) or the optical isomer and styrene derivative (I) and the cycle compound of dioxa third (III) or the optical isomer of (IV) of (IV).

In addition, when using chiral ketone compound (VI-a), the chiral cycle compound of dioxa third (IV-a) can be prepared.On the other hand, when using chiral ketone compound (VI-b), the chiral cycle compound of dioxa third (IV-b) can be prepared.

In the methods of the invention, in appropriate solvent, the asymmetric oxidation agent can be made to be reacted with styrene derivative (I) in base reagent presence or absence of under.

The example of solvent and base reagent includes, e.g., any those solvents and base reagent that can be used for forming asymmetric oxidation agent by the optical isomer of assimilation compound (V) or (VI) respectively.In these solvents, particularly preferably using ether solvents, nitrile solvent, alcoholic solvent, water and its mixed solvent.

The method for making styrene derivative (I) be reacted with the asymmetric oxidation agent includes, e.g., including asymmetric oxidation agent is directly added into the method in the solution of the styrene derivative (I)；It is included in same reaction system, chiral ketone compound and oxidant corresponding to the asymmetric oxidation agent is added to the method that asymmetric oxidation agent is formed in styrene derivative (I) solution.

For example, when the asymmetric oxidation agent that the reaction of the optical isomer using assimilation compound (V) or (VI) is formed, (a) can be used to include adding the asymmetric oxidation agent method in the solution of the styrene derivative (I), or (b) will be added in the mixed liquor of assimilation compound (V) or the optical isomer and styrene derivative (I) of (VI) including oxidant, and the method for asymmetric oxidation agent reaction for making in same reaction system the styrene derivative (I) and obtaining.

When with method (a), it is necessary to the asymmetric oxidation styrene derivative (I) is carried out with enough asymmetric oxidation agent.On the other hand, when with method (b), the asymmetric oxidation agent can be formed with the optical isomer and oxidant of enough assimilation compound (V) or (VI), the latter is in the reactive mixture with the sufficient amount progress asymmetric oxidation styrene derivative (I).

In method (b), the asymmetric oxidation agent is formed with assimilation compound (V) or (VI) optical isomer and oxidant.After the asymmetric oxidation agent asymmetric oxidation styrene derivative (I), the original assimilation compound (V) of recycling or (VI) optical isomer from the asymmetric oxidation agent, the assimilation compound (V) of so reusable regeneration or (VI).Therefore, when the amount of the styrene derivative (I) with 1-10 equivalents uses oxidant, the optical isomer of about 0.1 mole of chiral source of about 0.001- is used only in every 1 mole of styrene derivative (I) the assimilation compound (V) or (VI) can asymmetric oxidation styrene derivative (I), therefore can obtain required optically active phenyloxirane compounds (II) completely.The amount for especially requiring oxidant used is the 1.6-2.0 equivalents of styrene derivative (I).

In detail, when carrying out asymmetric oxidation styrene derivative (I) in the optical isomer of the assimilation compound (V) or (VI) and the mixed liquor of the styrene derivative (I) by the way that oxidant Oxone is added to, compared with the styrene derivative (I), the Oxone selective oxidations assimilation compound (V) or (VI) optical isomer generation asymmetric oxidation agent.The asymmetric oxidation agent asymmetric oxidation styrene derivative (I), is then reduced into original assimilation compound (V) or (VI), the latter is reusable.Therefore, using only the assimilation compound (V) or the optical isomer of (VI) of catalytic amount, that is chiral source, can be to carry out asymmetric oxidation styrene derivative (I) in high yield, therefore required optically active phenyloxirane compounds (II) of high-optical-purity can be obtained.

The temperature for handling styrene derivative (I) with the asymmetric oxidation agent is not particularly limited, and it changes according to species of the asymmetric oxidation agent etc..It is required that the reaction temperature ordinarily be about -5 DEG C to 50 DEG C, about 40 DEG C of preferably from about 0-.

The gas medium of the reaction is not particularly limited, and generally can be air or inert gas such as nitrogen.

In addition, contained unreacted asymmetric oxidation agent is reduced in reaction mixture obtained by after being reacted styrene derivative (I) and asymmetric oxidation agent as following methods, for example, including with reagent such as salt water washing reaction mixture, oxidant in removing reaction mixture etc., and sometimes on request, the reaction mixture is reduced with reducing agent such as hypo (sodium thiosulfate), sodium hydrogensulfite, sodium metabisulfite etc., the unreacted asymmetric oxidation agent is so converted into corresponding chiral ketone compound.

Meanwhile, in the methods of the invention, in appropriate solvent, in base reagent presence or absence of under the chiral cycle compound of dioxa third can be made to be reacted with styrene derivative (I).

The example of solvent and base reagent includes, such as, any those solvents and base reagent that can be used for preparing the cycle compound of dioxa third (III) and the optical isomer of (IV) by the optical isomer of assimilation compound (V) and (VI) respectively.In these solvents, particularly preferably using ether solvents, nitrile solvent, alcoholic solvent, water and its mixed solvent.

The consumption of styrene derivative (I) is not particularly limited, generally per 100ml solvents about 0.1- about 30g.

The consumption requirement of the chiral cycle compound of dioxa third is every about 5 moles of 1 mole of styrene derivative (I) about 1-, about 2 moles of preferably from about 1-.

Include styrene derivative (I) and the method for chiral cycle compound of dioxa third reaction, e.g., including the method chiral cycle compound of dioxa third being directly added into the solution of the styrene derivative (I)；Be included in same reaction system, chiral ketone compound and oxidant corresponding to the chiral cycle compound of dioxa third are added to the method that the chiral cycle compound of dioxa third is formed in styrene derivative (I) solution.

For example, when using the optical isomer of the cycle compound of dioxa third (III) or (IV) as chiral the third cycle compound of dioxa, the method that (a) can be used to include adding the optical isomer of the cycle compound of dioxa third (III) or (IV) in the solution of the styrene derivative (I), or (b) includes being added to oxidant in the mixed liquor of assimilation compound (V) or the optical isomer and styrene derivative (I) of (VI), and the cycle compound of dioxa third (III) or the method for the optical siomerism precursor reactant of (IV) for making the styrene derivative (I) in same reaction system and obtaining.

When with method (a), it is necessary to the asymmetric oxidation styrene derivative (I) is carried out with the optical isomer of the enough cycle compound of dioxa third (III) or (IV).On the other hand, when with method (b), the optical isomer of the cycle compound of dioxa third (III) or (IV) can be formed with the optical isomer and oxidant of enough assimilation compound (V) or (VI), the latter is in the reactive mixture with the sufficient amount progress asymmetric oxidation styrene derivative (I).

In method (b), the cycle compound of dioxa third (III) or the optical isomer of (IV) are formed with assimilation compound (V) or (VI) optical isomer and oxidant.After the cycle compound of dioxa third (III) or (IV) optical isomer the asymmetric oxidation styrene derivative (I), regenerate the original assimilation compound (V) or the optical isomer of (VI) from the cycle compound of dioxa third (III) or (IV) optical isomer, the assimilation compound (V) of so reusable regeneration or (VI).Therefore, when the amount of the styrene derivative (I) with 1-10 equivalents uses oxidant, about 0.1 mole of about 0.001- is used only in every 1 mole of styrene derivative (I) can asymmetric oxidation styrene derivative (I), therefore can obtain required optically active phenyloxirane compounds (II) completely as the assimilation compound (V) of chiral source or the optical isomer of (VI).The amount for especially requiring oxidant used is the 1.6-2.0 equivalents of styrene derivative (I).

In detail, when carrying out asymmetric oxidation styrene derivative (I) in the mixed liquor of optical isomer and styrene derivative (I) by the way that oxidant Oxone to be added to assimilation compound (V) or (VI), compared with the styrene derivative (I), the optical isomer of the Oxone selective oxidations assimilation compound (V) or (VI) the optical isomer generation cycle compound of dioxa third (III) or (IV).The optical isomer asymmetric oxidation styrene derivative (I) of the cycle compound of dioxa third (III) or (IV), then original assimilation compound (V) or (VI) is reduced into, the latter is reusable.Therefore, using only the assimilation compound (V) or the optical isomer of (VI) of catalytic amount, that is chiral source, can be to carry out asymmetric oxidation styrene derivative (I) in high yield, therefore required optically active phenyloxirane compounds (II) of high-optical-purity can be obtained.

It is not particularly limited with the temperature of the chiral cycle compound of the dioxa third processing styrene derivative (I), it is desirable to which the reaction temperature ordinarily be about -5 DEG C to 50 DEG C, about 40 DEG C of preferably from about 0-.

In addition, styrene derivative (I) can be reduced with unreacted chiral cycle compound of dioxa third contained in the reacted reaction mixture of the chiral cycle compound of dioxa third by following methods, for example, including with reagent such as salt water washing reaction mixture, oxidant in removing reaction mixture etc., and sometimes on request, the reaction mixture is reduced with reducing agent such as hypo (sodium thiosulfate), sodium hydrogensulfite, sodium metabisulfite etc., the unreacted chiral cycle compound of dioxa third is so converted into corresponding chiral ketone compound.

By reducing the asymmetric oxidation agent from the reaction mixture containing obtained above-described chiral ketone compound, the assimilation compound as formed by the chiral cycle compound of dioxa third, and optically active phenyloxirane compounds (II) can be separated with high-purity respectively by using the separation method of its difference to organic solvent solubility.

The method extracted using the other separation method of poor solubility including the use of organic solvent, the method crystallized using organic solvent etc..

Specifically, it can be passed through with separating the chiral ketone compound in high yield, such as, (a-1) add water in the reaction mixture containing the chiral ketone compound and precipitated, if desired, by precipitation dissolving in organic solvent, then solvent is boiled off from solution after removing impurity, or (a-2) extracts the reaction mixture containing the chiral ketone compound with organic solvent, extract solution is washed, dry, then solvent is evaporated off from the extract solution, and (b) extracts resulting residue with organic solvent, the wherein chiral ketone compound, including being almost undissolved and optically active phenyloxirane compounds (II) are readily soluble such as assimilation compound (V) and (VI).

In addition, it can be passed through with separating the chiral ketone compound in high yield, such as, carry out procedure described above (a-1) or (a-2), by the dissolving of obtained residue in organic solvent, wherein at high temperature, the chiral ketone compound and optically active phenyloxirane compounds (II) can dissolve, but under a certain temperature conditionss, only the crystallizable and optically active phenyloxirane compounds of the chiral ketone (II) still dissolve, and the temperature i.e. alternative for reducing obtained solution only crystallizes out the chiral ketone compound.

It can also be carried out with reclaiming the chiral ketone compound in high yield by using organic solvent reaction mixture of the extraction containing the chiral ketone compound, wherein at high temperature, the chiral ketone compound and optically active phenyloxirane compounds (II) all can dissolve, but under a certain temperature conditionss, only the crystallizable and optically active phenyloxirane compounds of the chiral ketone (II) still dissolve, and the temperature for reducing the extract solution is that alternative only crystallizes out the chiral ketone compound.

As for dissolving from the organic solvent for adding water to the precipitation obtained in above-mentioned reaction mixture, it can use such as halogenated aliphatic hydrocarbon solvent, such as dichloromethane, chloroform and carbon tetrachloride；Ester solvent, such as ethyl acetate and methyl acetate；Can be by the aromatic hydrocarbon solvent of halogenation, such as chlorine benzene,toluene,xylene and 1,3,5- trimethylbenzenes.The example of organic solvent for extracting the reaction mixture includes, e.g., aromatic hydrocarbon solvent, such as toluene；Ether solvents, such as ether, Di Iso Propyl Ether, t-butyl methyl ether, the dioxane of Isosorbide-5-Nitrae-, tetrahydrofuran and diethylene glycol dimethyl ether；Ether solvents are wherein preferably used, because it is easy to be evaporated off.

The organic solvent of residue after solvent is evaporated off for extracting, wherein the chiral ketone compound indissoluble and optically active phenyloxirane compounds (II) are readily soluble, including aliphatic solvent, such as hexane；Ester solvent, such as ethyl acetate.These solvents can be used alone or be used in mixed way.

On the other hand, wherein at high temperature, the chiral ketone compound and optically active phenyloxirane compounds (II) can dissolve, but under a certain temperature conditionss, the example of the only organic solvent that the crystallizable and optically active phenyloxirane compounds of chiral ketone compound (II) still dissolve includes, such as, ether solvents, such as Di Iso Propyl Ether and t-butyl methyl ether.

As described above, high-purity and chiral ketone compound in high yield can be obtained from the reaction mixture.

Obtaining the process of optically active phenyloxirane compounds (II) of high-purity and high-optical-purity by application technology such as column chromatography and crystallization, can purify the extract solution of optically active phenyloxirane compounds (II) made above or reclaim the mother liquor after assimilation compound to carry out.

The example of column chromatography includes, e.g., conventional silica gel column chromatography etc..

As optically active phenyloxirane compounds (II) as obtained by crystallization purifying, it is desirable to use ether solvents, such as Di Iso Propyl Ether is used as organic solvent.Basic sterling, optically active phenyloxirane compounds (II) can be obtained by being crystallized at a temperature of less than chiral ketone compound crystallization temperature.

In the present invention, when with styrene derivative (I), when wherein A rings and R are the trans-configurations as shown in following scheme, in the case of asymmetric oxidation agent α-attack, the reaction is obtained (2R, 3S)-optically active phenyloxirane compounds by arrow b directions, in the case of asymmetric oxidation agent β-attack, the reaction is obtained (2S, 3R)-optically active phenyloxirane compounds by arrow a directions.On the other hand, when with styrene derivative (I), when its middle ring A and R are the cis-configurations as shown in following scheme, in the case of asymmetric oxidation agent α-attack, the reaction is obtained (2S, 3S)-optically active phenyloxirane compounds by arrow d directions, in the case of asymmetric oxidation agent β-attack, the reaction is obtained (2R, 3R)-optically active phenyloxirane compounds by arrow c directions.

In above-mentioned optically active phenyloxirane compounds, present invention preferably uses (2R, 3S)-optically active phenyloxirane compounds and (2S, 3R)-optically active phenyloxirane compounds, reason is due to that ring A and R are trans-configurations and there's almost no steric hindrance, therefore can be to obtain optically active phenyloxirane compounds of the presently claimed invention in high yield.

In the present invention, it is required that using the transisomer of the styrene derivative (I), and it is required that use the asymmetric oxidation agent formed by chiral ketone compound (VI-a) or (VI-b), such as chiral cycle compound of dioxa third (IV-a) or (IV-b).In addition, when the transisomer using the styrene derivative (I), and use the asymmetric oxidation agent formed by chiral ketone compound (VI-a), during such as chiral cycle compound of dioxa third (IV-a), (2R, 3S)-phenyloxirane compounds can be obtained.And when the transisomer for using the styrene derivative (I), and use the asymmetric oxidation agent formed by chiral ketone compound (VI-b), during such as chirality cycle compound (IV-b) of dioxa third, (2S, 3R)-phenyloxirane compounds can be obtained.

Therefore, it can prepare in high yield and high-optical-purity lower formula (II) represent optically active phenyloxirane compounds (II)：Its middle ring A, R and^*It is defined as above.

R representatives-the CO in optical activity phenyloxirane compounds (II) made above is used in addition, working as₂R^qWhen the compound of group is as raw material, 1, the 5- benzothiazepine  derivatives that lower formula (VII) is represented can be prepared with known method：

Its middle ring A, ring B and^*It is defined as above；R²It is hydrogen atom or substituted alkyl；R³It is lower alkanol.

In the method for preparing 1,5- benzothiazepine  derivatives, ring B is substituted or unsubstituted phenyl ring.Ring B specific example includes, e.g., unsubstituted phenyl ring and the phenyl ring with the 1-3 substituents for being selected from low alkyl group, phenyl-lower alkyl group, lower alkoxy and halogen atom.The example of low alkyl group includes, e.g., the alkyl with 1-4 carbon atom, such as methyl, ethyl, propyl group and the tert-butyl group.The example of phenyl-lower alkyl group includes, e.g., the phenylalkyl with 7-10 carbon atom, such as benzyl and ethoxyphenyl.The example of the lower alkoxy includes, e.g., the alkoxy with 1-4 carbon atom, such as methoxyl group, ethyoxyl, propoxyl group and butoxy.In addition, the example of halogen atom includes such as fluorine atom, chlorine atom, bromine atoms and iodine atom.

R³It is lower alkanol, its specific example includes, e.g., the lower alkanol with 1-4 carbon atom, such as acetyl group, propiono and bytyry.

R²It is hydrogen atom or substituted alkyl.The instantiation of the substitution alkyl includes, e.g., and wherein moieties are the groups of the low alkyl group with 1-4 carbon atom, such as methyl, ethyl, propyl group and butyl.

The example of substituent on the alkyl includes, e.g., two-low-grade alkyl amino, such as dimethylamino and lignocaine, and the Phenylpiperazinyl replaced, such as 4- (2- methoxyphenyls) piperazinyl.It is preferred that R²It is 2- (dimethylamino) ethyls or 3- [4- (2- methoxyphenyls) piperazinyl] propyl group.

Resulting 1, the instantiation of 5- benzothiazepine  derivatives (VII) or its pharmaceutically acceptable salt includes, such as, (2S, 3S) -2- (4- methoxyphenyls) -3- acetoxyl groups -5- [2- (dimethylamino) ethyl] -2, 3- dihydros -1, 5- benzothiazepines  -4 (5H) -one (your sulphur ), (2S, 3S) -2- (4- methoxyphenyls) -3- acetoxyl groups -5- [2- (dimethylamino) ethyl] -8- chloro- 2, 3- dihydros -1, 5- benzothiazepines  -4 (5H) -one, (2S, 3S) -3- acetoxyl groups -5- [3- [4- (2- methoxyphenyls) piperazinyl]-propyl group] -2, 3- dihydros -2- (4- methoxyphenyls) -8- chloro- 1, 5- benzothiazepines  -4 (5H) -one, (2S, 3S) -3- acetoxyl groups -8- benzyls -2, 3- dihydros -5- [2- (dimethylamino) ethyl] -2- (4- methoxyphenyls) -1, 5- benzothiazepines  -4 (5H) -one, (2R, 3R) -2- (4- aminomethyl phenyls) -3- acetoxyl groups -5- [2- (dimethylamino) ethyl] -8- methyl -2, 3- dihydros -1, 5- benzothiazepines  -4 (5H) -one and its pharmaceutically acceptable salt.

1 obtained by the inventive method, 5- benzothiazepine  derivatives (VII) or its pharmaceutically acceptable salt are to be used to treat heart disease, such as angina pectoris, miocardial infarction and cardiac arrhythmia, and angiocardiopathy, the highly useful compound of such as hypertension, cardiovascular infraction and cerebral infarction.

Specifically, can be according to disclosed method, such as, Japanese Examined Patent application number clear 46-16749 and clear 63-13994, the flat 5-201865 peace 2-289558 of Japanese Patent Laid-Open Publication, the flat 2-28594 of Japanese Examined Patent publication No., Chem.Pharm.Bull. 18 (10), 2028-2037 (1970), the flat 2-17168 of Japanese Patent Laid-Open Publication, flat 2-229180, flat 4-234866, flat 5-222016, flat 4-221376, flat 5-202013, flat 2-17170, flat 2-286672, flat 6-279398, clear 58-99471, flat 8-269026, clear 61-118377, flat 6-228117, flat 2-78673, method in flat 5-43564 etc., formula (VII) is represented 1 is prepared with optically active phenyloxirane compounds (II), 5- benzothiazepine  derivatives.

More particularly, e.g., (wherein R is-CO when with (2R, 3S)-isomers as optically active phenyloxirane compounds (II)₂R^q), (2S, 3S) -1,5- benzothiazepine  derivatives or its pharmaceutically acceptable salt that following formula is represented：Wherein R⁴It is the group that hydrogen atom, 2- (dimethylamino) ethyls or following formula are represented, can be prepared by following reaction：

(A-1) (2R, 3S)-isomers is made to be reacted with the aminothiophenol derivative (VIII) that following formula is represented：Its middle ring B and R⁴It is defined as above, it includes, e.g., compound that 2- aminothiophenols, 2- amino -5- chlorothio-phenols, 2- [[2- (dimethylamino) ethyl]-amino] benzenethiol, following formula are represented etc.：

Its middle ring B is defined as above, and ring A and ring B are defined as above, or (A-2) makes (2R, 3S)-isomers be reacted with the nitro thiophenol derivative (IX) that following formula is represented：

Its middle ring B is defined as above, it includes, such as, 2- nitro thiophenols, 2- nitro -5- chlorothio-phenols, 2- nitro -5- benzyl benzenethiols etc., then (2S, 3S) -3- (2- aminobenzene-thios) -3- phenyl -2 hydroxy propanoic acid ester compounds that following formula is represented are generated by reducing the nitro of obtained product：Its middle ring A, ring B, R and R⁴It is defined as above, obtained ester compounds are carried out intramolecular cyclisation by (B), it is sometimes desirable to which it is carried out after hydrolyzing, 2- (2S, 3S) -2- phenyl -3- hydroxyl -1,5- benzothiazepine  derivatives that generation following formula is represented：

Its middle ring A, ring B and R⁴It is defined as above; (C) nitrogen-atoms is modified on the 5- positions for obtaining compound on demand sometimes; then the hydroxyl that acetylation is substituted on 3- positions obtains (2S; 3S) -1; 5- benzothiazepine  derivatives, and (D) change into its pharmaceutically acceptable salt sometimes for by the product of generation.

On the other hand, (wherein R is-CO when with (2S, 3R)-isomers as optically active phenyloxirane compounds (II)₂R^q), (2R, 3R) -1,5- benzothiazepine  derivatives or its pharmaceutically acceptable salt that following formula is represented：

Its middle ring A, ring B and R⁴It is defined as above, can be prepared by following reaction：(A-1) (2S is made, 3R)-isomers is reacted with aminothiophenol derivative (VIII) or (A-2) makes (2S, 3R)-isomers reacts with nitro thiophenol derivative (IX), then (2R, 3R) -3- (2- aminobenzene-thios) -3- phenyl -2 hydroxy propanoic acid ester compounds that following formula is represented are generated by reducing the nitro of obtained product：Its middle ring A, ring B, R and R⁴It is defined as above, obtained ester compounds are carried out intramolecular cyclisation by (B), it is sometimes desirable to which it is carried out after hydrolyzing, (2R, 3R) -2- phenyl -3- hydroxyl -1,5- benzothiazepine  derivatives that generation following formula is represented：

Its middle ring A, ring B and R⁴It is defined as above; (C) nitrogen-atoms is modified on the 5- positions for obtaining compound on demand sometimes; then the hydroxyl that acetylation is substituted on 3- positions obtains (2R; 3R) -1; 5- benzothiazepine  derivatives, and (D) change into its pharmaceutically acceptable salt sometimes for by the product of generation.

For example, the spatial chemistry of ground that sulphur  and its enantiomer can be summarized below.Such as, as shown in following scheme, the aminothiophenol represented when following formula：

(wherein R is-CO with optically active phenyloxirane compounds (II)₂R^qGroup) reaction when, the reaction is performed as follows.In other words, when (2S, 3R)-isomers and aminothiophenol reaction cause cis open loop or (2S, 3S)-isomers to cause trans open loop with aminothiophenol reaction, (2R, 3R)-propanoic derivatives can be obtained.In addition, when (2R, 3S)-isomers and aminothiophenol reaction cause cis open loop or (2R, 3R)-isomers to cause trans open loop with aminothiophenol reaction, (2S, 3S)-propanoic derivatives can be obtained.

In addition, as shown in following scheme, (2R can will be somebody's turn to do, 3R)-propanoic derivatives or (2S, 3S)-propanoic derivatives carry out intramolecular cyclisation, it is sometimes desirable to which it is carried out after hydrolyzing, generate 2- phenyl -3- hydroxyl -1,5- benzothiazepine  derivatives.Then; by obtained 2- phenyl -3- hydroxyls -1; nitrogen-atoms on 5- benzothiazepine  derivative 5- positions carries out dimethylaminoethyl reaction on 5- positions; then the acetylating hydroxyl groups being substituted on 3- positions are prepared into (2R respectively; 3R) -1; 5- benzothiazepine  derivatives or (2S, 3S) -1,5- benzothiazepine  derivatives.

On the other hand, can have wherein R can change into-CO₂R^qGroup optical activity phenyloxirane compounds (II) or its salt change into 1,5- benzothiazepine  derivatives, it by transformable group by changing into-CO₂R^qThe group of representative, is then reacted by above identical method and carried out.In addition ,-CO can be changed into by by transformable group before molecule inner ring condensation formation 1,5- benzothiazepine  structures₂R^qThe group of representative, then reacts the product by above identical method, it is converted into 1,5- benzothiazepine  derivatives.

For-CO can be converted into₂R^qThe group of the group of representative changes into-CO₂R^qIt is different according to the conversion radical species for the method for the group of representative, any commonly employed method can be used.

, can be by converting carboxylate groups into-CO by esterifying carboxyl group for example, using common method₂R^qThe group of representative.Respectively by the hydrolysis of mercaptan ester, acid amides and cyano group, the group that represent first following formula：Wherein R^rIt is defined as above, and the group that following formula is represented：

Wherein R^sAnd R^tBe defined as above and cyano group formation carboxyl, then with conventional esterification process by obtained converting carboxylate groups into-CO₂R^qThe group of representative.

In addition, by removing hydrogen sulfide, being then esterified by conventional method, thiocarboxyl group being changed into-CO₂R^qThe group of representative.

For example, by the same procedure for preparing optically active phenyloxirane compounds (II), (wherein R is-CO₂R^qThe group of representative), can be by optically active phenyloxirane compounds (II) or its salt, wherein R is the group that following formula is represented：

Wherein R^rThe group for being defined as above and being represented for following formula：

Wherein R^sAnd R^tIt is defined as above or carboxyl, changes into 1,5- benzothiazepine  derivatives, without the transformable group is changed into-CO₂R^qThe group of representative.

In addition, optically active phenyloxirane compounds (II) that the formula (II) that can be prepared with the inventive method is represented prepare the nitrocarboxylic acid compound as optical resolution agent of following formula representative as raw material：

Its middle ring A and ring B are defined as above；^*Represent asymmetric carbon atom.

In the method for preparing the nitrocarboxylic acid compound, ring A and ring B can be identical with ring B with the ring A in preparation 1,5- benzothiazepine  derivative methods.It is required that ring A is 4- lower alkoxyphenyls, ring B is the substituted benzene ring that following formula is represented：Wherein Hal is halogen atom.

Particularly preferred ring A is 4- methoxyphenyls, and ring B is the group that above formula is represented, and wherein Hal is chlorine atom.

Specifically, the nitrocarboxylic acid compound can be prepared by following methods, e.g., this method includes：Method according to the clear 61-18549 of Japanese Examined Patent publication No., it is-CO to make wherein R₂R^qOptically active phenyloxirane compounds (II) and the nitro thiophenol compound reaction of the compound that is represented by such as following formula as representative instance：

Wherein Hal is defined as above；Then obtained product is hydrolyzed by the method described in " Chem.Pharm.Bull., 18 (10), 2028-2037 (1970) ".

In the method, when with (2R, 3S)-optically active phenyloxirane compounds, (2S, 3S)-optically active nitrocarboxylic acid compound can be prepared.When with (2S, 3R)-optically active phenyloxirane compounds, (2R, 3R)-optically active nitrocarboxylic acid compound can be prepared.

In optically active phenyloxirane compounds (II), when R is can to change into-CO₂R^qDuring the group of the group of representative, wherein R^qIt is defined as above, the process for preparing optically active nitrocarboxylic acid compound can be first by being converted into 1, the known method commonly used in 5- benzothiazepine  derivatives, it is-CO that optically active phenyloxirane compounds (II) and nitro thiophenol compound are reacted to obtained compound to change into wherein R₂R^qThe compound of the group of representative, wherein R^qIt is defined as above；Then the compound for hydrolyzing generation by known method is carried out.In addition, can be by using being converted into 1, method used in 5- benzothiazepine  derivatives, optically active phenyloxirane compounds (II) and nitro thiophenol compound are directly reacted to obtained compound and change into the compound that wherein R is carboxyl, and it is-CO not translate into wherein R₂R^qThe compound of the group of representative, wherein R^qIt is defined as above preparing optically active nitrocarboxylic acid compound.

Meanwhile, in the assimilation compound (V), it is (i)-O-Q-Alk that can prepare wherein Y by following methods¹- or (v)-NR¹-Q-Alk¹- assimilation compound, this method includes the compound for representing lower formula (X)：

Wherein Z is-O- or-NR¹-；With Ar and R¹It is defined as above, the compound represented with following formula (XI) or its activity derivatives reaction：Wherein Prot is the protection group of hydroxyl；Alk¹It is defined as above with Q；Sometimes on request, when Z is-NH-, obtained compound carries out to N- is alkylsulfonylated or the aryl sulfonylating reactions of N-；Then hydroxyl protecting group is removed in the compound represented from obtained following formula (XII)：

Wherein Ar, Prot, Z, Alk¹It is defined as above with Q；And obtained compound is subjected to oxidation reaction.

In the assimilation compound (V), it is (ii)-Q-O-Alk that can prepare wherein Y by following methods²- or (vi)-Q-NR¹-Alk²- assimilation compound, this method include make following formula (XIII) represent compound or its reactive derivative：

Wherein Ar and Q are defined as above, and the compound represented with following formula (XIV) or its dimer react：

Wherein Z and Alk²It is defined as above；Sometimes on request, when Z is-NH-, obtained compound carries out to N- is alkylsulfonylated or the aryl sulfonylating reactions of N-.

In the assimilation compound (V), it is (iii)-Alk that can prepare wherein Y by following methods³-O-Alk⁴- or (vii)-Alk³-NR¹-Alk⁴- assimilation compound, this method include by following formula (XV) represent compound reduce：Wherein Ar is defined as above, the compound that generation following formula (XVI) is represented：Wherein Ar is defined as above；Sometimes on request, the chain length for the alkyl that extension is combined with the hydroxyl of resulting compound；Hydroxyl is changed into amino；Sometimes on request, obtained compound is subjected to the compound that N- is alkylsulfonylated or the aryl sulfonylating reaction generation following formulas (XVII) of N- represent：

Wherein Ar, Alk³It is defined as above with Z, obtained compound is reacted with the compound that following formula (XVIII) is represented：

Wherein L is leaving group；Alk⁴It is defined as above；And sometimes on request, when Z is-NH-, obtained compound carries out to N- is alkylsulfonylated or the aryl sulfonylating reactions of N-.

In the assimilation compound (V), it is (iv)-O-Alk that can prepare wherein Y by following methods⁵- or (viii)-NR¹-Alk⁵- assimilation compound, the compound that assimilation compound and the following formula (XIX) that this method includes representing formula (X) are represented reacts：

Wherein L and Alk⁵It is defined as above；Sometimes on request, when Z is-NH-, obtained compound carries out to N- is alkylsulfonylated or the aryl sulfonylating reactions of N-.

In the assimilation compound (V), it is-NR that can prepare wherein Y by following methods¹-Alk⁵- assimilation compound, this method includes assimilation compound prepared by the compound (wherein Q is carbonyl) that will be represented by compound (wherein Z is-NH-) and the formula (XI) for representing formula (X) or its activity derivatives reaction and reduced, will wherein Z be-NH- and Q be carbonyl the compound reduction that represents of formula (XII)；Sometimes on request, obtained compound carries out to N- is alkylsulfonylated or the aryl sulfonylating reactions of N-；Remove hydroxyl protecting group；Then obtained product is subjected to oxidation reaction.

According to conventional ester forming method or acid amides forming method, compound and the compound of formula (XI) representative or the reaction of its reactive derivative that line (X) is represented can be entered, and enter compound or its reactive derivative and the compound of formula (XIV) representative or the reaction of its dimer of line (XIII) representative.

The reactive derivative for the compound that the compound and formula (XIII) that formula (XI) is represented are represented includes the reactive derivative for the carboxylic acid and sulfonic acid commonly used.The example includes, e.g., carboxylic acid halides such as acyl chlorides, acylbromide and acyl iodides；Anhydrous nitration mixture is as contained isobutyl chlorocarbonate, 2,6- dichlorobenzoyl chlorides or 2, the anhydrous nitration mixture of 4,6- trichloro-benzoyl chlorides；N, N '-dicyclohexyl carbodiimide (hereinafter referred to as " DCC ")；DCC and I-hydroxybenzotriazole mixture；By using BTA -1- bases-epoxide-three (active ester of dimethylamino) Phosphonium hexafluorophosphate formation etc..

The protection group of hydroxyl includes conventional hydroxyl protecting group in the compound that formula (XI) is represented.The example of the protection group includes, e.g., lower alkanol, the silicyl of substitution and the benzyl can with substituent.

The addition reaction of the carbonyl for the compound that the HZ groups of compound that the dimer for the compound that formula (XIV) is represented can be represented by the formula (XIV) of 1 molecule are represented with the formula (XIV) of another molecule is formed.Can addition forms ring structure each other by the carbonyl of two molecules and HZ groups.Even when the dimer and monomer are in balance, the dimer can be equally applied.

Can be in appropriate solvent, in the presence of condensing agent such as DCC or halogenation N- picolines, enter the reaction of compound and the compound of formula (XI) representative that line (X) is represented under room temperature or heating, and enter compound and the compound of formula (XIV) representative or the reaction of its dimer of line (XIII) representative.The example of the solvent includes, such as can be by the aliphatic solvent of halogenation, such as hexane, hexamethylene, dichloromethane, ethlyene dichloride, chloroform and carbon tetrachloride；Can be by the aromatic hydrocarbon solvent of halogenation, such as toluene, dimethylbenzene, 1,3,5- trimethylbenzenes, chlorobenzene and dichloro-benzenes；Nitrile solvent, such as acetonitrile, propionitrile and butyronitrile；Ether solvents, such as ether, tetrahydrofuran, the dioxane of Isosorbide-5-Nitrae-and diethylene glycol dimethyl ether.Sometimes on request, acid acceptor, such as triethylamine, diisopropylethylamine or pyridine can be added in the reaction.

On the other hand, can be in appropriate solvent, in acid acceptor, including such as organic base such as triethylamine, trimethylamine, pyridine or diisopropylethylamine presence or absence of under, enter compound and the reaction of the reactive derivative of the compound of formula (XI) representative that line (X) is represented under room temperature or heating, and enter reactive derivative and the compound of formula (XIV) representative or the reaction of its dimer of the compound of line (XIII) representative.The example of the solvent includes, such as can be by the aliphatic solvent of halogenation, such as hexane, hexamethylene, dichloromethane, ethlyene dichloride, chloroform and carbon tetrachloride；Can be by the aromatic hydrocarbon solvent of halogenation, such as toluene, dimethylbenzene, 1,3,5- trimethylbenzenes, chlorobenzene and dichloro-benzenes；Nitrile solvent, such as acetonitrile, propionitrile and butyronitrile；Ether solvents, such as ether, tetrahydrofuran, the dioxane of Isosorbide-5-Nitrae-and diethylene glycol dimethyl ether.

Can be according to the O- of conventional alcohol alkylations or the N- alkylations of amine, enter the reaction of compound and the compound of formula (XVIII) representative that line (XVII) is represented, and enter the reaction of the compound and the compound of formula (XIX) representative of line (X) representative.

Leaving group L can be conventional leaving group in the compound that the compound and formula (XIX) that formula (XVIII) used herein is represented are represented, including halogen atom such as chlorine atom, bromine atoms or iodine atom, or alkylsulfonyloxy or aryl-sulfonyl oxygen, including tolysulfonyl epoxide or mesyloxy.

Can be in appropriate solvent, in acid acceptor, in the presence of such as organic base such as triethylamine, trimethylamine, pyridine or diisopropylethylamine, enter the reaction of compound and the compound of formula (XVIII) representative that line (XVII) is represented under room temperature or heating, and enter the reaction of the compound and the compound of formula (XIX) representative of line (X) representative.The example of the solvent includes, such as can be by the aliphatic solvent of halogenation, such as hexane, hexamethylene, dichloromethane, ethlyene dichloride, chloroform and carbon tetrachloride；Can be by the aromatic hydrocarbon solvent of halogenation, such as toluene, dimethylbenzene, 1,3,5- trimethylbenzenes, chlorobenzene and dichloro-benzenes；Nitrile solvent, such as acetonitrile, propionitrile and butyronitrile.

For the method for hydroxyl protecting group is removed in the compound represented from formula (XII), can using any commonly employed removing hydroxyl protecting group method, including method for hydrolysis, catalytic hydrogenation, with hydrogen fluoride acid treatment method etc..The process can be by appropriate solvent, including such as, alcoholic solvent such as methanol or ethanol, ether solvents such as tetrahydrofuran, 1,4- dioxanes and diethylene glycol dimethyl ether etc., the compound alkali that formula (XII) is represented, including such as, the hydroxide such as potassium hydroxide or sodium hydroxide of alkali metal, the carbonate such as potassium carbonate or sodium carbonate of alkali metal, organic acid, such as formic acid or trifluoroacetic acid and inorganic acid such as hydrochloric acid or hydrofluoric acid treatment are carried out.

, can be using the conventional method that carbonyl is converted into by hydroxy methylene, including chromic acid oxidation, ruthenium oxide oxidation, " Swern oxidations " [Merck index in subsequent oxidation reaction, 12nd edition, ONR-89], " Dess-Martin oxidations " [Merck index, the 12nd edition, ONR-22] etc..For example; can be by appropriate solvent; the product oxidant obtained in hydroxyl protecting group reaction will be removed; including such as; chromic acid or derivatives thereof such as Pyridinium chlorochromate, ruthenium-oxide, the chloro- dimethyl sulfoxide of oxalyl two or 1,1,1- tri- (acetoxyl group) -1; the processing of 1- dihydros -1,2-benziodoxol-3 (1H) -one carries out the oxidation reaction.The solvent includes, such as can be by the aliphatic solvent of halogenation, such as hexane, hexamethylene, dichloromethane, ethlyene dichloride, chloroform and carbon tetrachloride；Can be by the aromatic hydrocarbon solvent of halogenation, such as toluene, dimethylbenzene, 1,3,5- trimethylbenzenes, chlorobenzene and dichloro-benzenes；Nitrile solvent, such as acetonitrile, propionitrile and butyronitrile.

According to the method for any commonly employed reduction carboxylic acid, the reduction reaction of the compound of line (XV) representative can be entered.For example, can be by appropriate solvent, including such as, ether solvents such as ether, tetrahydrofuran, 1,4- dioxanes or diethylene glycol dimethyl ether etc., the compound reducing agent that formula (XV) is represented, including such as diborane, lithium aluminium hydride reduction processing carry out the reduction reaction.

According to any commonly employed method, the length for the moieties being combined with the hydroxyl of formula (XVI) representation compound that reduction reaction is obtained can be extended.For example, the length of the moieties can be extended by following methods, this method is included formula (XVI) representation compound halogenating agent, including such as, thionyl halide such as thionyl chloride or thionyl bromide processing, or, with compound, such as tolysulfonyl halogen such as paratoluensulfonyl chloride or tolysulfonyl bromine, the hydroxyl of formula (XVI) representation compound is converted into leaving group, then handled obtained leaving group with above-mentioned halogenating agent；Make obtained halide and reactive magnesium formation RMgBr；Make the RMgBr and alkyl aldehydes or alkyl reactive ketone；Then by obtained compound water process.In addition, also hydroxyl can be converted into amino by any commonly employed method.For example, by the way that the compound obtained by formula (XVI) representation compound or the moieties of extension compound (XVI) is handled with above-mentioned halogenating agent, then making obtained product carry out the conversion with ammonia reaction.

On the other hand, by the similar approach with the reduction reaction of formula (XV) representation compound, can carry out wherein Z be-NH- and Q be carbonyl formula (XII) representation compound reduction reaction.After reduction reaction; the hydroxyl protecting group of the compound represented by removing formula (XIV) described above and the same procedure of oxidation reaction then; by N- is alkylsulfonylated or the aryl sulfonylating obtained products of N- remove hydroxyl protecting group, oxidation reaction is then carried out.

In addition, can optionally carry out that N- is alkylsulfonylated or N- is aryl sulfonylating according to the common method of the sulfonylation of amine.The reaction is carried out with alkyl sulfonic acid, aryl sulfonic acid or its reactive derivative.The example of the reactive derivative includes, e.g., carboxylic acid halides such as acyl chlorides, acylbromide and acyl iodides etc..

When with alkyl sulfonic acid or aryl sulfonic acid, it is desirable in the presence of condensing agent, carry out that the N- is alkylsulfonylated or the aryl sulfonylating reactions of N- in appropriate solvent.On the other hand, when using reactive derivative, it is desirable in acid acceptor presence or absence of under, carry out that the N- is alkylsulfonylated or the aryl sulfonylating reactions of N- in appropriate solvent.

The optical isomer of the assimilation compound (V) can be prepared by following methods, this method includes：The compound light that the compound and formula (XVII) that compound, the formula (XVI) that compound, the formula (XV) that compound, the formula (XIII) for being represented formula (X) according to conventional method are represented are represented are represented are represented is split, and then prepared by the above-described preparation method of application.

For the method for optical resolution, the method that such as can be respectively crystallized using diastereoisomeric salt and optical resolution agent.For the optical resolution agent, any commonly employed optical resolution agent is suitable for using.For the optical resolution agent, it is desirable to using such as optically active amine, particularly preferably using chinidine, cinchonidine, quinine, brucine, the optical isomer of amino acid, amino-acid ester, amino alcohol etc..

In addition, in styrene derivative (I) used in the methods of the invention, the compound that wherein R is elementary alkoxy carbonyl can be prepared in high yield by following methods, this method is included in the presence or absence of a solvent, in the presence of a base, the benzaldehyde compound for representing following formula：Its middle ring A is substituted or unsubstituted phenyl ring, and condensation reaction is carried out with Lower alkyl acetates；Sometimes on request, under the existence or non-existence of acid, obtained product is subjected to transesterification.

For Lower alkyl acetates, it is desirable to use methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate etc..When the Lower alkyl acetates such as methyl acetate or ethyl acetate used also act as solvent, it is not necessary to use other solvents.

The benzaldehyde compound includes inorganic strong alkali with alkali used in the Lower alkyl acetates condensation reaction.The example includes the alkoxide of alkali metal, and it includes such as lithium methoxide, lithium ethoxide, n-butanol lithium, tert-butyl alcohol lithium, sodium methoxide, caustic alcohol, n-butanol sodium, sodium tert-butoxide, potassium methoxide, potassium ethoxide, n-butanol potassium, potassium tert-butoxide；The alkali metal of metal, it includes such as lithium metal, metallic sodium, metallic potassium；The hydride of alkali metal, it includes such as lithium hydride, sodium hydride, hydrofining；The hydroxide of alkali metal, it includes such as lithium hydroxide, sodium hydroxide, potassium hydroxide.

The condensation reaction is carried out preferably under room temperature or heating, is carried out particularly preferably at 20-60 DEG C.

When the ester residue of resulting condensation product does not have required ester residue, the ester residue can be converted into required ester residue by conventional transesterification.

The transesterification is carried out with the low-level chain triacontanol corresponding to required ester residue.When alcohol used also acts as solvent, it is not necessary to use other solvents.

Acid used includes inorganic acid in transesterification, and it includes such as sulfuric acid, hydrochloric acid, phosphoric acid；Organic acid, it includes such as methanesulfonic acid, p-methyl benzenesulfonic acid.Because the reaction is further preferably even carried out in the presence of anacidity, therefore can carry out the transesterification by alcohol being added directly into the reaction mixture obtained by condensation reaction.It is required that the transesterification is carried out between the temperature of room temperature to solvent refluxing, the transesterification is particularly preferably carried out at 20-80 DEG C.

The present invention will be clarified in more detail by the following example, but do not limit the scope of the invention or spirit.Prepare embodiment 1

In 7.5ml acetonitriles and 5ml4 × 10^-4The chiral ketone compound that 0.01mmol following formulas are represented is dissolved in the mixed liquor of M disodium ethylene diamine tetraacetates (EDTA) aqueous solution：

2.5mmol Oxone and 7.7mmol sodium acid carbonates are added into the mixed liquor, the mixed liquor is stirred at room temperature.Temporally passage determines EI-MS (electronic and ionic mass spectrum).As a result 412 (M are estimated⁺) peak is the cycle compound of chiral dioxa third that the following formula to be formed is represented,

And relative to 396 (M of chiral ketone compound⁺) peak gradually increases.

Then, in 3.8ml acetonitriles-d₃-2.5ml4×10^-4The 0.1mmol chiral ketone compounds are dissolved in MEDTA disodium saline solutions.2mmolOxone and 6.2mmol sodium acid carbonates are added into the obtained mixed liquor, then the mixed liquor is stirred 24 hours.Take out the supernatant of the reaction mixture, then determine MS (mass spectrum) and¹H-NMR。

First, accurate mass spectrum is obtained, the M of the chiral cycle compound of dioxa third of this to be formed is measured⁺Ion (C₂₅H₁₆O₆；Theoretical value：412.0947；Measured value：412.0950).

In addition,¹In H-NMR (400MHz), find the peak of hydrogen atom of the methylene for the chiral cycle compound of dioxa third inferred in 3.85ppm (d, J=11.8Hz) and 4.56ppm (d, J=15.5Hz).

Additionally, it was found that the peak of the hydrogen atom of the methylene for the chiral ketone compound inferred is in 4.21ppm (d, J=15.5Hz) and 5.49ppm (d, J=15.4Hz).

In addition,¹³In C-NMR, find the quaternary carbon of the loop section of dioxa third of the chiral cycle compound of dioxa third in 95.6ppm.

It moreover has been found that the carbonyl carbon of the chiral cycle compound of dioxa third is in 2.305ppm.

By¹³The fact that DEPT (the undistorted enhancing of polarization transfer agent) detects the long-range coupling of (3.85ppm and 4.56ppm) between quaternary carbon and discovery methylene hydrogen atom peak in C-NMR confirms the result.Embodiment 1

At room temperature, the trans- 4- p-Methoxymethylcinnamates of 192mg (1.0mmol) are dissolved in 15ml1,2- dimethoxy-ethanes.Then 10ml4 × 10 are added into the mixed liquor^-4M disodium ethylene diamine tetraacetates (EDTA) aqueous solution, then the chiral ketone compound that addition 40mg (0.1mmol) following formula is represented into the mixed liquor：

The obtained mixed liquor is cooled to 0 DEG C under ice bath.Then press and added 6.14g (10mmol) Oxone and 2.6g (31mmol) sodium bicarbonate mixture into the mixed liquor in six times at interval of 1 hour.After adding, then by the mixed liquor stir 2 hours.Then the obtained reaction mixture is transferred in half saturated salt solution, then by the mixed liquor extracted by ether.Organic layer is washed with saturated brine, then dried through anhydrous magnesium sulfate.

After drying, anhydrous magnesium sulfate is separated by filtration, then solvent is evaporated off from filtrate.9ml ethyl acetate and n-hexane mixed liquor that volume ratio is 1: 8 are added into obtained residue, at room temperature stirs the mixed liquor 1 hour.

The white powder of precipitation is collected by filtration, reduction vaporization obtains the 32mg chiral ketone compound (rate of recovery：80% (weight)).

On the other hand, by obtained filtrate (HPLC yields：91%) through silica gel flash column chromatography (mobile phase：Ethyl acetate: n-hexane=1: 8 (volume ratios)) obtain 135mg (separation yields：65%) optically active phenyl glycidyl acid esters that following formula is represented：

Optical purity through the HPLC optically active phenyl glycidyl acid esters for determining to obtain is 81%.Embodiment 2

At room temperature, the trans- 4- p-Methoxymethylcinnamates of 192mg (1.0mmol) are dissolved in 15ml1,2- dimethoxy-ethanes.Then 10ml4 × 10 are added into the mixed liquor^-4M disodium ethylene diamine tetraacetates (EDTA) aqueous solution, then chiral, the unsymmetrical ketone compound that addition 55mg (0.1mmol) following formula is represented into the mixed liquor：

The obtained mixed liquor is stirred at room temperature.Then the mixture of 2.06g (3.3mmol) Oxone and 860mg (10.3mmol) sodium acid carbonate was added into the mixed liquor with 1 hour.After adding, then by the mixed liquor stir 1 hour.Then the obtained reaction mixture is transferred in half saturated salt solution, then by the mixed liquor extracted by ether.Then, organic layer is washed with saturated brine, then dried through anhydrous magnesium sulfate.

0.126g (separation yields are obtained by the product that the processing of identical method is obtained in embodiment 1：61%) optically active phenyl glycidyl acid esters in the same manner as in Example 1.

Optical purity through the HPLC optical activity phenyl glycidyl acid esters for determining to obtain is 64%ee.

Also the chiral ketone compound (rate of recovery is collected by the identical method of embodiment 1：88% (weight)).Embodiment 3

At room temperature, the trans- 4- p-Methoxymethylcinnamates of 192mg (1.0mmol) are dissolved in 7.5ml1,2- dimethoxy-ethanes.Then, 5ml4 × 10 are added into the mixed liquor^-4M disodium ethylene diamine tetra-acetic acid aqueous solutions, then the chiral ketone compound that addition 46mg (0.1mmol) following formula is represented into the mixed liquor：The obtained mixed liquor is cooled to 0 DEG C.Then the mixture of 1.84g (3mmol) Oxone and 780mg (9.3mmol) sodium acid carbonate was added into the mixed liquor with 7 hours.After adding, then by the mixed liquor stir 17 hours.Then, the obtained reaction mixture is transferred in half saturated salt solution, then by the mixed liquor extracted by ether.Organic layer is washed with saturated brine, then dried through anhydrous magnesium sulfate.

Optically active phenyl glycidyl acid esters in the same manner as in Example 1 is obtained by the product that the processing of identical method is obtained in embodiment 1.Yield and optical purity through the HPLC phenyl glycidyl acid esters for determining to obtain are respectively 74% and 85%ee.Embodiment 4

At room temperature, the trans- 4- p-Methoxymethylcinnamates of 192mg (1.0mmol) are dissolved in 3.8ml1,2- dimethoxy-ethanes.Then 2.5ml4 × 10 are added into the mixed liquor^-4M disodium ethylene diamine tetra-acetic acid aqueous solutions, then the chiral ketone compound that addition 4mg (0.01mmol) following formula is represented into the mixed liquor：The obtained mixed liquor is placed at room temperature.Then the mixture of 1.23g (2mmol) Oxone and 521mg (6.2mmol) sodium acid carbonate is added into the mixed liquor.After adding, the mixed liquor is stirred for.Then identical method in embodiment 1 is pressed, the obtained reaction mixture is washed and dried.

Optically active phenyl glycidyl acid esters in the same manner as in Example 1 is obtained by the product that the processing of identical method is obtained in embodiment 1.Yield and optical purity through the HPLC phenyl glycidyl acid esters for determining to obtain are respectively 70% and 62%ee.Embodiment 5

At room temperature, the trans- 4- p-Methoxymethylcinnamates of 192mg (1.0mmol) are dissolved in 7.5ml1,2- dimethoxy-ethanes.Then 5ml4 × 10 are added into the mixed liquor^-4M disodium ethylene diamine tetra-acetic acid aqueous solutions, then the chiral ketone compound that addition 4mg (0.01mmol) following formula is represented into the mixed liquor：

The obtained mixed liquor is placed at room temperature.Then the mixture of 1.54g (2.5mmol) Oxone and 650mg (7.7mmol) sodium acid carbonate is added into the mixed liquor.After adding, then by the mixed liquor stir 4.5 hours.Then identical method in embodiment 1 is pressed, obtained reaction mixture is washed and dried.

By product (the HPLC yields that the processing of identical method is obtained in embodiment 1：92%) 138mg (separation yields are obtained：66%) optically active phenyl glycidyl acid esters in the same manner as in Example 1.

Optical purity through the HPLC products for determining to obtain is 74%ee.

Also the chiral ketone compound (rate of recovery is collected by the identical method of embodiment 1：80% (weight)).Embodiment 6

At room temperature, the trans- 4- p-Methoxymethylcinnamates of 192mg (1.0mmol) are dissolved in 3.8ml1,2- dimethoxy-ethanes.Then 2.5ml4 × 10 are added into the mixed liquor^-4M disodium ethylene diamine tetra-acetic acid aqueous solutions, then the chiral ketone compound that addition 4mg (0.01mmol) following formula is represented into the mixed liquor：

Obtained mixed liquor is placed at room temperature.Then the mixture of 1.23g (2mmol) Oxone and 521mg (6.2mmol) sodium acid carbonate is added into the mixed liquor.After adding, then by the mixed liquor stir 8 hours.Then, by identical method in embodiment 1, the obtained reaction mixture is washed and dried.

By product (the HPLC yields that the processing of identical method is obtained in embodiment 1：93%) 137mg (separation yields are obtained：66%) optically active phenyl glycidyl acid esters in the same manner as in Example 1.

Optical purity through the HPLC optical activity phenyl glycidyl acid esters for determining to obtain is 73%ee.Embodiment 7

At room temperature, the trans- 4- p-Methoxymethylcinnamates of 192mg (1.0mmol) are dissolved in 15ml1,2- dimethoxy-ethanes.Then, 10ml4 × 10 are added into the mixed liquor^-4M disodium ethylene diamine tetra-acetic acid aqueous solutions, then the chiral ketone compound that addition 50mg (0.1mmol) following formula is represented into the mixed liquor：

The obtained mixed liquor is placed at room temperature.Then, the mixture of 2.06g (3.3mmol) Oxone and 866mg (10.3mmol) sodium acid carbonate was added into the mixed liquor with 1 hour.After adding, then by the mixed liquor stir 30 minutes.Then, the obtained reaction mixture is transferred in half saturated salt solution, then by the mixed liquor extracted by ether.Organic layer is washed with saturated brine, then dried through anhydrous magnesium sulfate..

107mg (separation yields are obtained by the product that the processing of identical method is obtained in embodiment 1：51%) optically active phenyl glycidyl acid esters in the same manner as in Example 1.

Optical purity through the HPLC optical activity phenyl glycidyl acid esters for determining to obtain is 73%ee.Embodiment 8

At room temperature, compound 159mg (1mmol) following formula represented：

It is dissolved in 15ml1,2- dimethoxy-ethanes.Then 10ml4 × 10 are added into the mixed liquor^-4M disodium ethylene diamine tetra-acetic acid aqueous solutions, then 40mg (0.1mmol) and identical chiral ketone used in embodiment 1 are added into the mixed liquor, the mixed liquor is then cooled to 0 DEG C.

Then the mixture for adding 3.07g (5mmol) Oxone and 1.3g (15.5mmol) sodium acid carbonate into the mixed liquor in three times at interval of 1 hour is pressed.

The mixed liquor was stirred for after 18 hours, the obtained reaction mixture is transferred in half saturated salt solution.Then by the mixed liquor extracted by ether.Organic layer is washed with saturated brine, then dried through anhydrous magnesium sulfate.

After drying, anhydrous magnesium sulfate is separated by filtration, then solvent is evaporated off from filtrate.9ml ethyl acetate and n-hexane mixed liquor that volume ratio is 1: 8 are added into obtained residue, at room temperature stirs the mixture 1 hour.

The white powder of precipitation is collected by filtration, reduction vaporization obtains chiral ketone compound.On the other hand, by obtained filtrate through silica gel rapid column chromatography (mobile phase：Ethyl acetate: n-hexane=1: 8 (volume ratios)) purifying obtain 90mg (separation yields：51%) optically active phenyl ethylene oxide that following formula is represented：

Optical purity through the HPLC optically active phenyl ethylene oxides for determining to obtain is 57%ee.

It has also been found that obtained optically active phenyl ethylene oxide has the following properties that.¹H-NMR (300MHz, CDCl₃)：δ 3.40 (1H, d, J=1.8Hz), 3.82 (3H, s), 4.24 (1H, d, J=1.8Hz), 6.91 (2H, m), 7.19 (2H, m).

HPLC conditions are as follows：[post] chirality OD posts [mobile phase] n-hexane: ethanol=9: 1 (volume ratio) [flow velocity] 0.5ml/min embodiments 9-15

The cinnamic acid derivative represented using following formula：

Wherein R^XIt is the group represented in table 1.

At room temperature, 1.0mmol cinnamic acid derivatives are dissolved in the solvent shown in 15ml tables 1.Then 10m14 × 10 are added into the mixed liquor^-4M disodium ethylene diamine tetra-acetic acid aqueous solutions, then added and identical chiral ketone compound used in embodiment 1 into the mixed liquor.Obtained mixed liquor is placed at room temperature.Then the mixture of 6.14g (10mmol) Oxone and 2.6g (31mmol) sodium acid carbonate is added into the mixed liquor by several times.After adding, the mixed liquor is stirred for.Then the obtained reaction mixture is transferred in salt solution, by the mixed liquor extracted by ether.Organic layer is washed with saturated brine, then dried through anhydrous magnesium sulfate.

Amount, Oxone and sodium acid carbonate addition time and the time of stirring of the chiral ketone compound provide in the lump in table 1.

Extract solution is washed, dried as described above, be separated by filtration anhydrous magnesium sulfate, then solvent is evaporated off from filtrate.It is 1: 8 9ml ethyl acetate and the mixed liquor of n-hexane that volume ratio is added into obtained residue, at room temperature stirs the mixed liquor 1 hour.

The white powder of precipitation is collected by filtration, reduction vaporization obtains chiral ketone compound.

On the other hand, by obtained filtrate through silica gel rapid column chromatography (mobile phase：Ethyl acetate: n-hexane=1: 8 (volume ratios)) purify the optically active phenyl glycidyl acid esters for obtaining following formula representative：Wherein R^XIt is defined as above.

The yield and optical purity of obtained optically active phenyl glycidyl acid esters are provided in table 1.In addition optical purity is determined through HPLC.

The Example No. R of table 1^XChiral assimilation solvent adds time mixing time

The amount separation yield optical purity of compound

(mole %) (hour) (hour) (%) (%ee) 9-CH₃- the CH of 10 acetonitrile 2 1.5 59 7210₃10 tert-butyl alcohols 2 24 do not isolate 7511 10 acetonitriles 21 74 7112 - C (the CH of 10 acetonitrile 21 64 7013₃)₃- the CH of 10 acetonitrile 2 1/3 34 7814₃1 dimethoxy-ethane 2 25 53^* 7415 -CH₃The remarks of 10 dimethoxy-ethane 1 3/4 57 77^*：It is 73% that the yield determined is analyzed through HPLC.

Result shown in table 1 will become apparent from：, can be so that optically active phenyl glycidyl acid esters be prepared with high-optical-purity in high yield according to embodiment 9-15 method although ester residue changes.Embodiment 16

The chiral ketone compound that the trans- 4- p-Methoxymethylcinnamates of 961mg (5.00mmol) and 79mg (0.20mmol) following formula are represented is miscible in 9ml 1,2- dimethoxy-ethanes and 4.5ml water.3.074g (5.00mmol) Oxone and 1.302g (15.5mmol) sodium acid carbonate is added into gained suspension with 1.5 hours, then at 22-24 DEG C, then by the mixed liquor stir 2.5 hours.Then salt solution is added into obtained reaction mixture, then by the mixed liquor extracted by ether.Then, obtained extract solution is washed with saturated sodium bicarbonate aqueous solution and saturated brine, then dried through anhydrous magnesium sulfate.After drying, yield and optical purity that 546.2mg is used to determine 3- (4- methoxyphenyls) glycidic acid methyl esters through HPLC are taken out from the dried extracts of 31.56g.It is 88.3% to measure yield, and the optical purity of (2R, 3S)-type is 76.8%ee.

Be concentrated under reduced pressure remaining reaction mixture, and the amount that 6.6mg is used to determine trans- 4- p-Methoxymethylcinnamates through HPLC is taken out from the residue that 1.042g is obtained.Measure remaining trans- 4- p-Methoxymethylcinnamates in residue and only have 7.3%.

17.5ml isopropyl ethers are added into the remaining residue, then obtained mixed liquor is heated to 45 DEG C so that the composition dissolves.Under stirring, the solution is cooled to 40 DEG C with 10 minutes.Then, the crystallization of the precipitation of generation is collected by filtration.Part is taken out from the precipitated crystal to pass through as sample¹H-NMR and HPLC determine its composition.The crystallization for measuring the precipitation contains 73mg chiral ketones compound and 90.7mg (2R, 3S) -3- (4- methoxyphenyls) glycidic acid methyl esters (optical purity：98.8%ee).

The filtrate, then the addition 10ml isopropyl ethers into the residue are concentrated under decompression.Mixed liquor is heated to 40-45 DEG C so that the composition dissolves.Then the solution is cooled to 20 DEG C, is then cooled to 11 DEG C with 40 minutes, then 8.5 DEG C are cooled to 1 hour 35 minutes.Decantation collects the crystallization of precipitation, and then the crystallization is washed with ice-cold isopropyl ether and obtains 587mg (2R, 3S) -3- (4- methoxyphenyls) glycidic acid methyl esters (yield：56.4%, optical purity：98.5%ee).

Be concentrated under reduced pressure mother liquor, and by 265mg, the residue is carried out¹H-NMR and HPLC quantitative analyses.Measure trans- 3- (4- methoxyphenyls) glycidic acid methyl esters containing 6mg chiral ketones compound and 181.5mg racemizations in the mother liquor.As a result the decomposition and side reaction for not occurring product in separation process are shown in.Embodiment 17

At room temperature, chiral ketone compound 9.611g (50mmol) trans- methyl p-methoxy cinnamate and 1.088g (2.7mmol) following formula represented is dissolved in 100ml1,2- dimethoxy-ethanes：

Then at 20 DEG C, 50ml distilled water is added into the solution.Again at the same temperature, with the mixture for being gradually added into 30.74g (50mmol) Oxone and 13.02g (155mmol) sodium acid carbonate for 1.5 hours into the mixed liquor.After adding, the mixed liquor is stirred 5.5 hours again at the same temperature, the reaction mixture is then cooled to 0-5 DEG C.500ml cold water is added into the mixed liquor, again stirs the mixed liquor 30 minutes at 0-5 DEG C.

The solid of precipitation is dissolved in 100ml chloroforms.After drying, impurity is filtered off, then decompression boils off solvent and obtains white solid from filtrate.

Under the following conditions, obtained white solid is analyzed through HPLC.As a result release：The white solid is 8.298g (2R, 3S) -3- (p-methoxyphenyl) glycidic acids methyl esters, 0.902g (2S, 3R) -3- (p-methoxyphenyl) glycidic acids methyl esters, the mixture of the 0.323g methyl p-methoxy cinnamates and 0.966g chiral ketone compound.[HPLC analysis conditions]

Filler：Chiralcel OD

Solvent：N-hexane: isopropanol=10: 1 (volume ratio)

Flow velocity：1ml/min

Column temperature：40℃

Detection：Absorbed at 220nm

Obtained white solid is handled by the identical method of embodiment 1 and respectively obtains (2R, 3S) -3- (p-methoxyphenyl) glycidic acid methyl esters and the chiral ketone compound.Embodiment 18

The chiral ketone compound that 38mg (0.2mmol) trans- methyl p-methoxy cinnamate and 0.8g (0.002mmol) following formula are represented is dissolved in 3ml1,2- dimethoxy-ethanes：

Then 2ml 4 × 10 is added into the solution^-4M disodium ethylene diamine tetraacetates (EDTA) aqueous solution.0 DEG C, be stirred vigorously under, with 30 minutes intervals in three times into the mixed liquor add 612mg Oxone and 260mg sodium acid carbonates.The mixed liquor is stirred 7 hours again at the same temperature, then determines to remain without trans- 4- p-Methoxymethylcinnamates through TLC.Washed by the reaction mixture extracted by ether, then by the extract solution with saturated brine.Merge the water layer obtained in extracting and washing lotion, then use extracted by ether.Merge extract solution, drying and evaporation, residue is through silica gel rapid column chromatography [solvent：N-hexane: ethyl acetate (4: 1)] purifying obtain 39mg (2R, 3S) -3- (p-methoxyphenyl) glycidic acid methyl esters.

The product is analyzed by the identical method of embodiment 17 through HPLC to find：The optical purity of the product is 63%ee.Embodiment 19

At room temperature, the chiral ketone compound trans- 4- p-Methoxymethylcinnamates of 1.922g (10mmol) and 215mg (0.5mmol) following formula represented is dissolved in the dioxane of 20ml Isosorbide-5-Nitraes-：Then 10ml water is added into the solution.Again at 20 DEG C, interval added the mixture of 6.15g (10mmol) Oxone and 2.60g (31mmol) sodium acid carbonate for 5 minutes with 1.5 hours into the mixed liquor.After adding, the mixed liquor is stirred 30 minutes again at the same temperature, stirred 7 hours at 27 DEG C, 50ml water is added into the mixed liquor.Dry, concentrate through anhydrous magnesium sulfate by obtained reaction mixture chloroform recovery, then by the extract solution.By the identical method of embodiment 17, obtained residue is analyzed through HPLC.As a result release：The residue is 1.784g (yields：85.7%, optical purity：The mixture of (2R, 3S) -3- (p-methoxyphenyl) glycidic acids methyl esters 76.4%ee), the trans- 4- p-Methoxymethylcinnamates of the 135.7mg and 212.1mg chiral ketone compound.Embodiment 20

At room temperature, the chiral ketone compound trans- 4- p-Methoxymethylcinnamates of 1.922g (10mmol) and 215mg (0.5mmol) following formula represented is dissolved in the dioxane of 20ml Isosorbide-5-Nitraes-：

Then at 20 DEG C, 10ml water and 2.21g (16mmol) potassium carbonate are added into the solution.Again at the same temperature, it is spaced 5 minutes and added 6.15g (10mmol) Oxone into the mixed liquor with 1.5 hours.After adding, the mixed liquor is stirred 30 minutes again at the same temperature, stirred 7 hours at 27 DEG C, 50ml water is added into the mixed liquor.By obtained reaction mixture chloroform recovery, the extract solution is dried through anhydrous magnesium sulfate, concentrated.By the identical method of embodiment 17, obtained residue is analyzed through HPLC.As a result release：The residue is 1.585g (yields：76.1%, optical purity：The mixture of (2R, 3S) -3- (p-methoxyphenyl) glycidic acids methyl esters 78.0%ee), the trans- 4- p-Methoxymethylcinnamates of the 341.4mg and 209.7mg chiral ketone compound.The optical resolution of reference implementation example 1 [preparing chiral ketone compound] (1) dianthracene quinone carboxylic acid

2.40g racemic 1,1 '-bis- (2- anthraquinone carboxylic acids) (being referred to as dianthracene quinone carboxylic acid later) is dissolved in 120ml ethanol, then the mixed liquor is heated to reflux.Add the chinidine of 3.13g following formulas representative gradually into the obtained solution again,

Then obtained mixed liquor is heated to reflux 15 minutes.Then reaction mixture is cooled to room temperature, stood overnight.The chinidine salt of the dianthracene quinone carboxylic acid of precipitation is collected by filtration, the crystallization is washed with ethanol, 114ml 1%- sodium hydrate aqueous solutions are then added into the crystallization.Heated 30 minutes at 60 DEG C, then by obtained mixed liquor.After heating, the mixed liquor is cooled to room temperature, 3.5%- hydrochloric acid is added into the mixed liquor.The pH of mixed liquor is adjusted to 2, then the mixed liquor is stirred 30 minutes.

Then, the reaction mixture is added into ethyl acetate to extract.Dry extraction liquid, is then evaporated off solvent.Obtained extract is dissolved in methanol and recrystallized.Redistillation solvent to remaining solvent is about 17ml.Obtained crystal is collected by filtration.

Again at 60-70 DEG C, obtained crystallization decompression condensation is obtained into 890mg (-)-dianthracene quinone carboxylic acid for 16 hours.

The property of obtained (-)-dianthracene quinone carboxylic acid is as follows：Decomposition point (dp)：196.8-220.6℃[α]_D ²⁵：- 225 ° of (C=0.8, MeOH) IR (atoleine) ν_max(cm^-1)：3490,1721,1670,1584LC-MS (ESI) m/z：501(M-H)¹H-NMR(DMSO-d₆)：δ 7.80-7.95 (m, 6H), 8.21-8.26 (m, 2H), 8.33 (d, J=8Hz, 2H), 8.41 (d, J=8Hz, 2H), 13.0 (brs, 2H)

Analyze the crystallization with HPLC under the following conditions again.As a result show not finding (+)-type impurity.LiChro CART 250-4 Chira Dec 5μmMeOH：The preparation of liquid (pH6.5) (50/50) (2) chiral ketone compound during 1/45M phosphate is slow

Under logical argon gas, 0.144ml oxalyl chlorides and 1 drop dimethylformamide are added into the 8ml tetrahydrofuran solutions containing 331mg (-)-dianthracene quinone carboxylic acid, at room temperature stirs the mixed liquor 1 hour.

The reaction mixture is diluted with 102ml tetrahydrofurans, the 1,3-Dihydroxyacetone dimer that 20ml contains the representative of 89mg following formulas is added dropwise into the mixed liquor with 40 minutes：

With the tetrahydrofuran solution (suspension) of 0.551ml triethylamines.Then, the 1,3-Dihydroxyacetone dimer being retained in dropping funel is rinsed with 20ml tetrahydrofurans.

At room temperature, the mixed liquor is stirred 22 hours, then decompression boils off solvent.Dichloromethane and water are added into the residue, then obtained mixed liquor is extracted with dichloromethane.

Organic layer boils off solvent through anhydrous sodium sulfate drying.The residue is through silica gel rapid column chromatography [solvent：Ethyl acetate: hexane (1: 2-2: 1)] purifying, solvent is evaporated off from extract solution and obtains 199mg (yields：54%) the chiral ketone compound that following formula is represented, is noncrystalline powder：

The property of obtained chiral ketone compound is as follows：IR (atoleine) ν_max(cm^-1)：1756,1737,1672LC-MS (APCI adds ammonium acetate) m/z=574 (M+NH₄)⁺ ¹H-NMR(CDCl₃)：δ 4.20 (d, J=15Hz, 2H), 5.49 (d, J=15Hz, 2H), 7.64-7.80 (m, 4H), 7.91-7.96 (m, 2H), 8.01 (d, J=8Hz, 2H), 8.29-8.33 (m, 2H), (8.58 d, J=8Hz, 2H).Reference implementation example 2

Under logical argon gas, to containing 750mg (-) -1,0.37ml oxalyl chlorides and a few drop dimethylformamides are added in the 35ml dichloromethane solutions of 1 '-bis- (2- anthracene carboxylic acids) (being referred to as dianthracene carboxylic acid later).The mixed liquor that this is obtained is stirred 2 hours at room temperature.

By reaction mixture 420ml dchloromethanes, then the dichloromethane solution (suspension) that 80ml contains 230mg 1,3-Dihydroxyacetones dimer and 1.4ml triethylamines is added dropwise with 1 hour 30 minutes into the mixed liquor.Then the 1,3-Dihydroxyacetone dimer in dropping funel is retained in 20ml dichloromethanes.

At room temperature, the mixed liquor is stirred 42 hours, then decompression boils off solvent.Add chloroform and sodium bicarbonate aqueous solution into the residue, then by obtained mixed liquor chloroform recovery.

Organic layer is washed with water and saturated brine, then through anhydrous sodium sulfate drying.Then solvent is boiled off.The residue is through silica gel column chromatography [solvent：Chloroform] purifying, solvent is evaporated off from eluent and obtains 671mg (yields：78%) the chiral ketone compound that following formula is represented, is noncrystalline powder：

The property of obtained chiral ketone compound is as follows：IR (atoleine) ν_max(cm^-1)：1753,1735,1239LC-MS (APCI adds ammonium acetate) m/z=514 (M+NH₄)⁺ ¹H-NMR(CDCl₃)：δ 4.21 (d, J=15Hz, 2H), 5.59 (d, J=15Hz, 2H), 7.29 (ddd, J=1.7,8Hz, 2H), 7.46 (ddd, J=1.7,7.9Hz, 2H), 7.52 (d, J=9Hz, 2H), 7.67 (d, J=9Hz, 2H), 7.89 (s, 2H), 8.03 (d, J=8Hz, 2H), 8.26 (d, J=9Hz, 2H), 8.59 (s, 2H).Reference implementation example 3

To containing 2.37g (R)-(+) -6,6 '-two chloro- 2,16.9ml triethylamines are added in 2 '-diphenic acid (prepared by the method according to " Chem.Pharm.Bull.; 37 (8); 2207-2208 (1989) ") and the 700ml anhydrous acetonitriles of 2.05g1,3- dihydroxyacetone (DHA) dimer.The mixed liquor is stirred 15 minutes at room temperature.The chloro- 1- picolines of 15.5g iodate 2- are added into the solution, then under room temperature, logical nitrogen, the mixed liquor is stirred 12 hours.Then the mixed liquor is heated to reflux 1 hour again.Decompression boils off the solvent in reaction mixture.Dichloromethane and water are added into the residue, then obtained mixed liquor is extracted with dichloromethane.Organic layer boils off solvent through anhydrous sodium sulfate drying.The residue is through silica gel rapid column chromatography [solvent：Ethyl acetate: hexane (2: 1) (volume ratio)] purifying, solvent is evaporated off from eluent and obtains 450mg (yields：16%) the chiral ketone compound that following formula is represented, is noncrystalline powder：

The property of obtained chiral ketone compound is as follows：¹H-NMR(CDCl₃)：δ 4.19 (d, J=15Hz, 2H), 5.50 (d, J=15Hz, 2H), 7.40-7.73 (m, 6H).Reference implementation example 4

The methanol solution (28%, 65mmol) of 6.81g (50mmol) anisaldehyde, 35.2g (400mmol) ethyl acetate and 12.5g sodium methoxides is mixed together, at 60 DEG C, obtained mixed liquor stirred 6 hours.Decompression boils off solvent from reaction mixture, and the 30ml methanol solutions containing 8.8g (90mmol) concentrated sulfuric acid are added into the residue.Obtained mixed liquor is heated to reflux 8 hours.Solvent is boiled off from reaction mixture, 30ml methanol is added into the residue, obtained mixed liquor is reheated into backflow 9 hours.Solvent is boiled off from reaction mixture.30ml methanol is added into the residue, the mixed liquor is reheated into backflow 4 hours.Then water and ethyl acetate are added into the mixed liquor, ethyl acetate layer is collected.Portion of ethyl acetate layer is taken to carry out HPLC analyses.As a result infer：Contain 8.01g (83.4%) trans- 4- p-Methoxymethylcinnamates in the ethyl acetate layer.The ethyl acetate layer is concentrated, then residue is heated, is re-dissolved in water of the 30ml 70% containing methanol.The solution is stirred, room temperature is cooled to, then obtained mixed liquor is cooled to 4 DEG C overnight.The crystallization of precipitation is collected by filtration, the crystallization is washed with ice-cold methanol, the trans- 4- p-Methoxymethylcinnamates (yields of 7.58g are isolated in drying at 50 DEG C：78.9%).Reference implementation example 5

It is mixed together by 6.81g (50mmol) anisaldehyde, 35.2g (400mmol) ethyl acetate and by the ethanol solution that 1.61g (70mmol) metallic sodium is dissolved in obtained caustic alcohol in 25ml ethanol.At room temperature, obtained mixed liquor is stirred 13 hours, then stirred 3 hours at 50 DEG C.Decompression boils off solvent from reaction mixture.30ml methanol is added into the residue, the reaction mixture is reacted at room temperature 5 hours.Decompression boils off solvent from reaction mixture again, and 30ml methanol is added into the residue, then the mixed liquor is reacted 18 hours at 50 DEG C.4.2g acetic acid terminating reactions are added into the reaction mixture.Then water and ethyl acetate are added into the mixed liquor, ethyl acetate layer is collected.Portion of ethyl acetate layer is taken to carry out HPLC analyses.As a result infer：Contain 7.78g (81.0%) trans- 4- p-Methoxymethylcinnamates in the ethyl acetate layer.Reference implementation example 6-9

In addition to the ethanol solution for the methanol solution or caustic alcohol that sodium methoxide is replaced with different alkali carries out condensation reaction, carried out by the identical method of reference implementation example 1 or 2, the result shown in table 2 is then obtained by the identical method of reference implementation example 1 or 2 progress transesterification.

Table 2 numbers 18 hours ethanol solution room temperatures without 5 days 75.17 caustic alcohols of room temperature of (eq) reaction time (eq) (%) 6 metallic sodium (1.1) room temperature 40 hours with reference to condensation reaction transesterification embodiment alkali reaction temperature acid reaction time yield, and sulfuric acid (1.9) flows back 14 hours 79.9

The tert-butyl alcohol room temperature 3 hours of (1.4) 50 DEG C of 3 hours 8 potassium tert-butoxides was without room temperature 37 hours 77.0

Tert-butyl alcohol room temperature sulfuric acid (1.8) backflow in 5 hours of the potassium tert-butoxide of solution (1.3) 9 16 hours 78.9

Solution (1.3) reference implementation example 10

The chiral dicarboxylic acid compound that 160mg (0.48mmol) following formula is represented (in Bull.Chem.Soc.Jpn, reported in 57,1943-1947)：

It is dissolved in 6ml tetrahydrofurans.Under room temperature, logical nitrogen, 0.105ml (1.20mmol) oxalyl chlorides and 1 drop dimethylformamide are added into the solution.The mixed liquor is stirred 1 hour at the same temperature.The reaction mixture is diluted with 80ml tetrahydrofurans, then with the 20ml tetrahydrofuran solutions for being added dropwise to 65mg (0.36mmol) 1,3-Dihydroxyacetone dimers and 0.4ml (2.88mmol) triethylamine for about 40 minutes into the mixed liquor.At the same temperature, the mixed liquor is stirred overnight.Evaporate reaction solution and remove solvent, dissolve the residue in chloroform.The solution is washed with saturated brine, dried and evaporation of solvent.Obtained crude product [uses n-hexane: triethylamine (100: 1) is pre-processed through silica gel rapid column chromatography；Solvent：N-hexane: ethyl acetate (1: 1)] purifying obtain 41mg (yields：22%) the chiral ketone compound that following formula is represented：

As described above, finding：Handled by the styrene derivative (I) that represents formula (I) with the asymmetric oxidation agent obtained from chiral ketone compound and oxidant, prepare highly-solid selectively and optically active phenyloxirane compounds of formula (II) representative in high yield.

It is used as the example by Oxone and the asymmetric oxidation of chiral ketone compound, it is known that the asymmetric Epoxidation effect [J.Am.Chem.Soc., 118,11311 (1996)] of trans- 1,2- talan.With used herein trans- 1,2- talan is C2 symmetrical compounds conversely, because styrene derivative (I), i.e. starting compound of the invention are the complex compounds without symmetrical factor, asymmetric reaction control is considered as being more difficult to than the reaction controlling of trans- 1,2- talan.Moreover, it has been found that optically active phenyloxirane compounds of very high optical yield can be prepared.

In addition, usually, in asymmetric reaction, to obtain highly-solid selectively, the reaction is often carried out at about -78 DEG C extremely low of temperature.But in the methods of the invention, due under 0 DEG C to ambient temperature, the asymmetric oxidation of highly-solid selectively can be carried out, therefore, the present invention is easily applied in industrial use.

In styrene derivative (I), i.e. starting compound of the invention, because electrophilic ester group is directly combined with double bond, therefore assert that the asymmetric oxidation for using the asymmetric oxidation agent obtained from chiral ketone compound and oxidant is difficult progress.In addition, the asymmetric oxidation reaction can even be carried out in low temperature and in the relatively short time.

In addition, in the methods of the invention, due to the asymmetric oxidation agent obtained from chiral ketone compound and oxidant (i.e. mild oxidizing agent) can be used, it therefore, it can obtain optically active phenyloxirane compounds with labile oxirane ring in high yield.

In addition, in the methods of the invention, when using chiral ketone compound and in reaction system with oxidizing to form asymmetric oxidation agent when, and when with the asymmetric oxidation agent carrying out the asymmetric oxidation of styrene derivative (I) present in same reaction system, the chiral ketone compound generated by the asymmetric oxidation agent of asymmetric reaction as asymmetric oxidation agent can be reoxidized by oxidant present in reproducible reaction system.Therefore, the asymmetric oxidation reaction only can be carried out with the chiral ketone compound of catalytic amount.Furthermore, because the chiral ketone compound is chemically stable compound, therefore the recyclable repeated application chiral ketone compound.

Commercial Application

Because the present invention can prepare optically active phenyloxirane compounds and reusable chiral catalyst in preparation in high yield, therefore display can reach high yield and economically prepare the ability of the optical activity phenyloxirane compounds.

Hence it is evident that finding out that many changes may be present in invention described above.These changes are without departing from the spirit and scope of the present invention, and all these changes are it will be apparent that it is included within the scope of following claims for those skilled in the art.

Claims

1. A method for preparing an optically active phenyloxirane compound represented by the following formula (II):

Where ring A is a substituted or unsubstituted benzene ring; R is a -CO ₂ R ^q group, or a group that can be converted into -CO ₂ R ^q , where R ^q is an ester residue; ^* represents an asymmetric carbon atom , the method comprises the styrene derivative (I) represented by formula (I):

Wherein the rings A and R are as defined above, treated with an asymmetric oxidizing agent formed from a chiral ketone compound and an oxidizing agent.

2. The method according to claim 1, wherein the chiral ketone compound is an optical isomer of the ketone compound (V) represented by formula (V): Wherein the ring Ar is a monocyclic, bicyclic or tricyclic aromatic ring that may have a substituent; Y is a group represented by the following formula:

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii)-Alk ³ -O-Alk ^4- , (iv)-O-Alk ^5- ,

(v) -NR ¹ -Q-Alk ¹ -, (vi)-Q-NR ¹ -Alk ² -,

(vii)-Alk ³ -NR ¹ -Alk ⁴ - or (viii)-NR ¹ -Alk ⁵ -,

Wherein Q is -CO- or -SO ₂ -group;

R ¹ is a hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group; and

Each of Alk ¹ , Alk ² , Alk ³ , Alk ⁴ and Alk ⁵ is a lower alkylene group, respectively.

3. The method according to claim 1 or 2, wherein the chiral ketone compound is an optical isomer of the ketone compound (VI) represented by formula (VI): Wherein R ^a and R ^b are each a hydrogen atom or a substituent; and R ^c and R ^d satisfy one of the following (I)-(III):

(1) R ^and ^R are each a hydrogen atom or a substituent; or

(II) R ^c and R ^d are combined with each other to form a group represented by the following formula:

Where R ^e , R ^f , R ^g and ^Rh satisfy one of the following (a) and (b):

(a) two adjacent groups combine with each other to form a benzene ring which may have substituents together with two interconnected carbon atoms, and the remaining two groups are each hydrogen or a substituent; or

(b) each of these groups is a hydrogen atom or a substituent; or

(III) R ^c and R ^d are combined with each other to form a group represented by the following formula:

wherein each of R ⁱ , R ^j , R ^k and R ^m is a hydrogen atom or a substituent; and Y is a group represented by the following formula:

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii) -Alk ³ -O-Alk ⁴ -, (iv) -O-Alk ⁵ -,

(v) -NR ¹ -Q-Alk ¹ -, (vi) -Q-NR ¹ -Alk ² -,

(vii) -Alk ³ -NR ¹ -Alk ⁴ - or (viii) -NR ¹ -Alk ⁵ -, wherein Q is a -CO- or -SO ₂ - group; R ¹ is a hydrogen atom, an alkylsulfonyl group or Arylsulfonyl; Alk ¹ , Alk ² , Alk ³ , Alk ⁴ and Alk ⁵ are each lower alkylene groups, respectively.

4. The method according to any one of claims 1-3, wherein the reaction of the chiral ketone compound with the oxidant and the reaction of the obtained asymmetric oxidant with the styrene derivative (I) are carried out in the same reaction system.

5. A method for preparing an optically active phenyloxirane compound represented by the following formula (II): Where ring A is a substituted or unsubstituted benzene ring; R is a -CO ₂ R ^q group, or a group that can be converted into -CO ₂ R ^q , where R ^q is an ester residue; ^* represents an asymmetric carbon atom , the method comprises the styrene derivative (I) represented by formula (I):

Wherein the rings A and R are as defined above, treated with a chiral dioxirane compound.

6. The method according to claim 5, wherein the chiral dioxirane compound is an optical isomer of the dioxirane compound (III) represented by formula (III):

Wherein the ring Ar is a monocyclic, bicyclic or tricyclic aromatic ring that may have a substituent; Y is a group represented by the following formula:

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii) -Alk ³ -O-Alk ⁴ -, (iv) -O-Alk ⁵ -,

(v) -NR ¹ -Q-Alk ¹ -, (vi) -Q-NR ¹ -Alk ² -,

(vii) -Alk ³ -NR ¹ -Alk ⁴ - or (viii) -NR ¹ -Alk ⁵ -, wherein Q is a -CO- or -SO ₂ - group; R ¹ is a hydrogen atom, an alkylsulfonyl group or arylsulfonyl; and Alk ¹ , Alk ² , Alk ³ , Alk ⁴ and Alk ⁵ are each lower alkylene, respectively.

7. The method according to claim 5 or 6, wherein the chiral dioxirane compound is an optical isomer of the dioxirane compound (IV) represented by formula (IV):

Wherein R ^a and R ^b are each a hydrogen atom or a substituent; and R ^c and R ^d satisfy one of the following (I)-(III):

(1) R ^and ^R are each a hydrogen atom or a substituent; or

(II) R ^c and R ^d are combined with each other to form a group represented by the following formula: Where R ^e , R ^f , R ^g and ^Rh satisfy one of the following (a) and (b):

(b) each of these groups is a hydrogen atom or a substituent; or

(III) R ^c and R ^d are combined with each other to form a group represented by the following formula: wherein each of R ⁱ , R ^j , R ^k and R ^m is a hydrogen atom or a substituent; and Y is a group represented by the following formula:

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii) -Alk ³ -O-Alk ⁴ -, (iv) -O-Alk ⁵ -,

(v) -NR ¹ -Q-Alk ¹ -, (vi) -Q-NR ¹ -Alk ² -,

(vii) -Alk ³ -NR ¹ -Alk ⁴ - or (viii) -NR ¹ -Alk ⁵ -, wherein Q is a -CO- or -SO ₂ - group; R ¹ is a hydrogen atom, an alkylsulfonyl group or Arylsulfonyl; Alk ¹ , Alk ² , Alk ³ , Alk ⁴ and Alk ⁵ are each lower alkylene.

8. A method according to any one of claims 5-7 comprising the steps of:

The optical isomer of the ketone compound (VI) represented by the following formula (VI) is reacted with an oxidizing agent:

(1) R ^and ^R are each a hydrogen atom or a substituent; or

(a) two adjacent groups combine with each other to form a benzene ring which may have a substituent together with two interconnected carbon atoms, and the remaining two groups are each a hydrogen atom or a substituent; or

(b) each of these groups is a hydrogen atom or a substituent; or

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii) -Alk ³ -O-Alk ⁴ -, (iv) -O-Alk ⁵ -,

(v) -NR ¹ -Q-Alk ¹ -, (vi) -Q-NR ¹ -Alk ² -,

(vii) -Alk ³ -NR ¹ -Alk ⁴ - or (viii) -NR ¹ -Alk ⁵ -, wherein Q is a -CO- or -SO ₂ - group; R ¹ is a hydrogen atom, an alkylsulfonyl group or Arylsulfonyl; Alk ¹ , Alk ² , Alk ³ , Alk ⁴ and Alk ⁵ are each a lower alkylene group; and reacting the styrene derivative (I) with the generated chiral dioxirane compound (IV) .

9. The method according to claim 8, wherein the reaction of the ketone compound (VI) of the optical isomer with the oxidizing agent and the obtained chiral dioxirane compound (IV) with styrene derivatives are carried out in the same reaction system The reaction of substance (I).

10. The method according to any one of claims 1-9, wherein the styrene derivative (I) is a trans isomer, and the optically active phenyloxirane compound (II) is (2R, 3S )-isomers or (2S,3R)-isomers.

11. The method according to any one of claims 1-4, wherein the styrene derivative (I) is a trans isomer; the chiral ketone compound is a chiral ketone compound represented by formula (VI-a) (VI-a):

(1) R ^and ^R are each a hydrogen atom or a substituent; or

(b) each of these groups is a hydrogen atom or a substituent; or (III) R ^c and R ^d are combined with each other to form a group represented by the following formula:

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii) -Alk ³ -O-Alk ⁴ -, (iv) -O-Alk ⁵ -,

(v) -NR ¹ -Q-Alk ¹ -, (vi) -Q-NR ¹ -Alk ² -,

(vii) -Alk ³ -NR ¹ -Alk ⁴ - or (viii) -NR ¹ -Alk ⁵ -, wherein Q is a -CO- or -SO ₂ - group; R ¹ is a hydrogen atom, an alkylsulfonyl group or Arylsulfonyl; Alk ¹ , Alk ² , Alk ³ , Alk ⁴ and Alk ⁵ are each lower alkylene; and the optically active phenyloxirane compound (II) is (2R, 3S)-isomeric body.

12. The method according to any one of claims 1-4, wherein the styrene derivative (I) is a trans isomer, and the chiral ketone compound is a chiral ketone compound represented by formula (VI-b) (VI-b):

Wherein R ^a and R ^b are each a hydrogen atom or a substituent; and R ^c and R ^d satisfy one of the following (I)-(III): (I) R ^c and R ^d are each a hydrogen atom or a substituent; or (II) R ^c and R ^d are combined with each other to form a group represented by the following formula:

Where R ^e , R ^f , R ^g and ^Rh satisfy one of the following (a) and (b):

(b) each of these groups is a hydrogen atom or a substituent; or

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii) -Alk ³ -O-Alk ⁴ -, (iv) -O-Alk ⁵ -,

(v) -NR ¹ -Q-Alk ¹ -, (vi) -Q-NR ¹ -Alk ² -,

(vii) -Alk ³ -NR ¹ -Alk ⁴ - or (viii) -NR ¹ -Alk ⁵ -, wherein Q is a -CO- or -SO ₂ - group; R ¹ is a hydrogen atom, an alkylsulfonyl group or Arylsulfonyl; Alk ¹ , Alk ² , Alk ³ , Alk ⁴ and Alk ⁵ are each lower alkylene; and the optically active phenyloxirane compound (II) is (2S, 3R)-isomeric body.

13. The method according to any one of claims 5-9, wherein the styrene derivative (I) is a trans isomer; the chiral dioxirane compound is represented by formula (IV-a) Chiral dioxirane compound (IV-a):

(1) R ^and ^R are each a hydrogen atom or a substituent; or

Where R ^e , R ^f , R ^g and ^Rh satisfy one of the following (a) and (b):

(b) each of these groups is a hydrogen atom or a substituent; or

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii) -Alk ³ -O-Alk ⁴ -, (iv) -O-Alk ⁵ -,

(v) -NR ¹ -Q-Alk ¹ -, (vi) -Q-NR ¹ -Alk ² -,

14. The method according to any one of claims 5-9, wherein the styrene derivative (I) is a trans isomer; the chiral dioxirane compound is represented by formula (IV-b) Chiral dioxirane compound (IV-b):

(1) R ^and ^R are each a hydrogen atom or a substituent; or

(b) each of these groups is a hydrogen atom or a substituent; or

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii) -Alk ³ -O-Alk ⁴ -, (iv) -O-Alk ⁵ -,

(v) -NR ¹ -Q-Alk ¹ -, (vi) -Q-NR ¹ -Alk ² -,

15. The method according to claim 3, 4, 7, 8, 9, 11, 12, 13 or 14, wherein Y represents a -CO-O- _CH2- group; R ^a , R ^b , R ^c and R ^d One of the following (a) and (b) is met:

(a) R ^a and R ^b are each a hydrogen atom; R ^c and R ^d are combined with each other to form a group represented by the following formula:

R ^c is a hydrogen atom and R ^d is a halogen atom; or

R ^c is a hydrogen atom and R ^d is a nitro group; or

(b) R ^a is a halogen atom; R ^b is a hydrogen atom; R ^c and R ^d are combined with each other to form a group represented by the following formula:

16. The method according to claim 15, wherein R ^and ^R are each a hydrogen atom; R ^and ^R are combined with each other to form a group represented by the following formula:

17. The method according to claim 5, wherein the reaction of the styrene derivative (I) represented by the chiral dioxirane compound can be processed by the chiral dioxirane compound by utilizing the separation process of the difference in the solubility of the organic solvent In the mixed liquid, the ketone compound obtained by reducing the chiral dioxirane compound and the optically active phenyloxirane compound (II) are recovered in high purity.

18. The method according to claim 1, wherein the ketone obtained by reducing the asymmetric oxidant contained in the reaction mixture can be recovered with high purity from the reaction mixture by a separation process utilizing a difference in solubility to an organic solvent Compound and the optically active phenyloxirane compound (II).

19. The method according to claim 17 or 18, wherein the ketone compound is a ketone compound (V) of an optical isomer represented by the following formula (V):

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii) -Alk ³ -O-Alk ⁴ -, (iv) -O-Alk ⁵ -,

(v) -NR ¹ -Q-Alk ¹ -, (vi) -Q-NR ¹ -Alk ² -,

20. The method according to any one of claims 17-19, wherein the ketone compound is a ketone compound (VI) of an optical isomer represented by the following formula (VI):

(1) R ^and ^R are each a hydrogen atom or a substituent; or

(b) each of these groups is a hydrogen atom or a substituent; or

(i) -OQ-Alk ¹ -, (ii) -QO-Alk ² -,

(iii) -Alk ³ -O-Alk ⁴ -, (iv) -O-Alk ⁵ -,

(v) -NR ¹ -Q-Alk ¹ -, (vi) -Q-NR ¹ -Alk ² -,

21. The method according to any one of claims 1-20, wherein ring A is a phenyl group having 1-3 substituents selected from lower alkyl, lower alkoxy and halogen atoms, and R is -CO ₂ R A group represented by ^q , wherein R ^q is an ester residue.

22. The method according to claim 21, wherein ring A is 4-lower alkylphenyl or 4-lower alkoxyphenyl, and ^Rq is lower alkyl.

23. The method according to claim 22, wherein Ring A is 4-methoxyphenyl and ^Rq is methyl.

24. A method for preparing a 1,5-benzothiazepine derivative represented by formula (VII) or a pharmaceutically acceptable salt thereof:

Wherein Ring A is a substituted or unsubstituted benzene ring; Ring B is a substituted or unsubstituted benzene ring; ^R2 is a hydrogen atom or a substituted alkyl group; ^R3 is a lower alkanoyl group; ^* represents an asymmetric carbon atom , the method adopts the optically active phenyloxirane compound (II) represented by formula (II) as raw material:

wherein R represents a -CO ₂ R ^q group, or a group that can be converted into -CO ₂ R ^q , wherein R ^q is an ester residue; ring A and ^* are as defined above, wherein the optically active phenyloxirane Compound (II) can be prepared using a process according to any one of claims 1-23.

25. A method for preparing a nitrocarboxylic acid compound represented by the following formula or a salt thereof: Wherein Ring A is a substituted or unsubstituted benzene ring; Ring B is a substituted or unsubstituted benzene ring; ^* represents an asymmetric carbon atom, and the method adopts the optically active phenyloxirane represented by formula (II) Compound (II) is raw material: