JPH1081676A - Production of optically active 2-halogeno-3-hydroxypropionic ester compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as e.g. an intermediate for synthesizing medicines such as calcium channel blockers in an industrially advantageous way by reaction of an aldehyde compound with a silyl keteneacetal compound in the presence of a Lewis acid. SOLUTION: This optically active compound of formula III is obtained by reaction of an aldeheyde compound of the formula R-CHO [R is a lower alkyl, lower alkenyl, (substituted) aryl or cycloalkyl].. with a silyl keteneacetal compound of formula I [X<1> and X<2> are each CL or Br, or such groups that one of them is H and the other CL or Br; R<1> to R<3> are each H, a lower alkyl or (substituted) aryl; R<4> is a lower alkyl or (substituted) alkyl] in the presence of a Lewis acid consisting of a chiral titanium compound of e.g. formula II [R<5> and R<6> are each H, a lower alkyl or (substituted) aryl, or joined into a lower alkylene or oxo; R<7> is H, a lower alkyl, (substituted) aryl or cycloalkyl; R<8a> and R<8b> are each a halogen, lower alkoxy, etc.].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel process for producing an optically active 2-halogeno-3-hydroxypropionate compound useful as a synthetic intermediate for a pharmaceutical compound.

[0002]

2. Description of the Related Art Optically active 2-halogeno-3-hydroxypropionate compounds are known as diltiazem hydrochloride [chemical name: (2S, 3S) -3-acetoxy-5- [] which is useful as various pharmaceuticals, for example, calcium channel blockers. 2-
(Dimethylamino) ethyl] -2,3-dihydro-2- (4
-Methoxyphenyl) -1,5-benzothiazepine-4
(5H) -one hydrochloride].

Heretofore, the following method has been disclosed as a method for producing an optically active 2-halogeno-3-hydroxypropionate compound. (1) A method of reacting a halogenoacetic acid ester with a benzaldehyde compound in the presence of a chiral lithium amide compound and an alkyl lithium (JP-A 1-222681)
issue). (2) A method of asymmetrically reducing a 2-halogeno-3-oxopropionate compound with an alkali metal borohydride or an alkali metal aluminum hydride in the presence of a chiral amino acid derivative and a lower aliphatic alcohol (Japanese Unexamined Patent Publication No. 190865). (3) A method of asymmetrically reducing a 2-halogeno-3-oxopropionate compound with a microorganism capable of asymmetrically reducing a carbonyl group (JP-A-3-272691). (4) A method of reacting a halogenoacetic acid t-butyl ester with a benzaldehyde compound in the presence of a chiral boron compound [Tetrahedron Letters]
32, 2857-2860 (1991)]. However, the methods described in the above (1) to (4) all have problems such as the use of expensive reagents and a large number of steps, and a new industrially advantageous production method is desired.

In recent years, a silyl ketene acetal compound derived from an acetate compound and an aldehyde compound have been reacted in the presence of a chiral Lewis acid to give a highly optically pure 3
A method for obtaining a hydroxypropionate compound has been reported. For example, a method using a chiral titanium compound as a chiral Lewis acid [Kaleira et al. (E.M.
eira et al), J. Am. Chem. Soc., 1994, 116, 8837;
And Keck et al., J. Am. Chem. So
c., 1995, 117, 2363], a method using a chiral boron compound [S. Kiyooka et al., J. Org. Chem.,
1991, 56, 2276; Masamune et al., J.
Am. Chem. Soc., 1991, 113, 9365; Yamamoto et al.
amoto et al), Synlett, 1991, 439; and Rietz (M.
T. Reetz), Tetrahedron Lett., 1986, 27, 4721], a method using a chiral copper compound [DA Evans,
J. Am. Chem. Soc., 1996, 118, 5814], a method using a chiral aluminum compound [MT Reetz, Ch.
em. Ind. 824, 1986] and a method using a chiral tin compound [T. Mukaiyama, J. Am. Chem. So
c., 1991 113, 4247]. However, when the silyl ketene acetal compound derived from a halogenoacetic acid ester such as chloroacetate or dichloroacetate is reacted with an aldehyde compound in the presence of the chiral Lewis acid, the silylketene acetal compound However, since it has a high electronegativity and a sterically bulky halogen atom in the molecule, it cannot be predicted whether a 2-halogeno-3-hydroxypropionate compound with high optical purity can be obtained in a high yield.

[0005] In addition, there have been some reports on conversion of chloroacetate or dichloroacetate to silylketene acetal [for example, see Nakai et al.
etal), Tetrahedron Asymmetry, 1991, 2, 993; G. Simchen, Liebigs Ann. Chem., 1983, 81.
6; Wilcox et al. (CS Wilcox et al), Tetrahedr
on Lett., 1984, 25, 699; Lion et al. (C. Lion et a
l), Bull. Chim. Belg., 1988, 97, 227; and Vep Schepin et al., Zh. Obshch. Khim., 1990,
60, 2805]. However, these methods have many problems such as a high cost of a silylating agent and a base to be used, a low yield, and a by-product of a C-silyl form in addition to a necessary O-silyl form. Have.

Further, as an asymmetric synthesis method of a 2-halogeno-3-hydroxypropionate compound, a method of reacting an aldehyde compound with a difluorosilylketene acetal compound in the presence of a chiral boron compound is disclosed [Tetra. Tetrahedron Le
tters) 38, 1447-1448 (1997)
Year)]. However, when a silyl ketene acetal compound containing a chloro atom (or bromo atom) is used instead of the silyl ketene acetal compound containing a fluorine atom, the atomic radius or electronegativity between the fluorine atom and the chloro atom (or bromo atom) is increased. Due to such a large difference, the steric environment and the reactivity of the compound are greatly different, and it is not expected at all that the optical activity of the target compound is similarly controlled and the asymmetric reaction proceeds.

[0007]

DISCLOSURE OF THE INVENTION The present invention provides an optically active compound having a high optical purity by reacting an aldehyde compound and a silyl ketene acetal compound in the presence of a chiral Lewis acid.
-Halogeno-3-hydroxypropionate compound is provided.

[0008]

According to the present invention, the general formula
[III]

[0009]

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Wherein R is a lower alkyl group, a lower alkenyl group, an aryl group or a cycloalkyl group, and X ¹ and X ² are each a hydrogen atom and the other is a chlorine or bromine atom, or both are a chlorine or bromine atom. Atom, R ⁴ represents a lower alkyl group or an aryl group, and * represents an asymmetric carbon atom). The optically active 2-halogeno-3-hydroxypropionate compound represented by the general formula [I]

An aldehyde compound represented by R-CHO [I] (wherein the symbols have the same meanings as described above) and a general formula [II]

[0011]

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Wherein R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a lower alkyl group or an aryl group, and other symbols have the same meanings as described above. It can be produced by reacting a compound with a chiral Lewis acid.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, as the aldehyde compound [I], R represents a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a t-butyl group, an n-butyl group; Lower alkenyl groups such as vinyl group, propenyl group and butenyl group; aryl groups such as phenyl group and naphthyl group; and cycloalkyl groups such as cyclopropyl group, cyclobutyl group and cyclopentyl group. Aryl groups such as phenyl and naphthyl are halogen atoms such as fluorine, chlorine and bromine; methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl and the like. Lower alkyl group; methoxy group, ethoxy group, n-propyloxy group,
It may be substituted with a lower alkoxy group such as an isopropyloxy group, a t-butyloxy group and an n-butyloxy group. Of these, an aldehyde compound [I] in which R is a lower alkylphenyl group or a lower alkoxyphenyl group is preferred, and those in which R is either a 4-methylphenyl group or a 4-methoxyphenyl group are most preferred.

As the silyl ketene acetal compound [II], ^one of X ¹ and X ² is a hydrogen atom and the other is a chlorine or bromine atom, or both are a chlorine or bromine atom, and R ¹ , R ² and R ³ is the same or different and is a hydrogen atom; a methyl group, an ethyl group, an n-propyl group,
An isopropyl group, a lower alkyl group such as a t-butyl group or an n-butyl group or an aryl group such as a phenyl group or a naphthyl group, wherein R ⁴ is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a t-butyl group; And a lower alkyl group such as a n-butyl group or an aryl group such as a phenyl group or a naphthyl group. The aryl group represented by R ^{1 to} R ³ is a methyl group, an ethyl group, an n-propyl group,
The aryl group for R ⁴ may be substituted with a lower alkyl group such as an isopropyl group, a t-butyl group, and an n-butyl group; a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom; a methyl group and an ethyl group , N-propyl group, isopropyl group, t-butyl group, lower alkyl groups such as n-butyl group; methoxy group, ethoxy group, n-propyloxy group,
Lower alkoxy groups such as isopropyloxy group, t-butyloxy group and n-butyloxy group; halogeno lower alkyl groups such as trifluoromethyl group; di-lower alkylamino groups such as dimethylamino group and diethylamino group; nitro group;
It may be substituted with a cyano group or the like.

In the silyl ketene acetal compound [II], one of X ¹ and X ² is a hydrogen atom and the other is a bromine or chlorine atom, or both are a chlorine or bromine atom, and R ¹ , R ² and R ³ is the same and is a methyl group, an ethyl group, an n-propyl group, an isopropyl group or an n-butyl group, or ^{two of} R ¹ , R ² and R ³ are a methyl group and one is a t-butyl group; Two methyl groups, one isopropyl group, two methyl groups, one phenyl group, two methyl groups, one 1,1,2,2-tetramethylpropyl group, or two One of the methyl groups is any combination of hydrogen atoms, and R ⁴ is a methyl group, an ethyl group or n
Those which are -propyl groups are preferred. Among them, one of X ¹ and X ² is a hydrogen atom and the other is a chlorine atom or both are chlorine atoms, and R ¹ , R ² and R ³ are the same methyl group,
Ethyl group, n-propyl group or n-butyl group, a compound in which R ⁴ is a methyl group, ethyl group or n-propyl group is more preferable, and in particular, ^one of X ¹ and X ² is a hydrogen atom and the other is a chlorine atom or Both are chlorine atoms and R ¹ , R ² ,
R ³ and R ⁴ are all methyl groups or R ¹ , R ² and R ³
Is a methyl group and R ⁴ is an ethyl group.

The chiral Lewis acid used in the method of the present invention includes a chiral Lewis acid usable for the aldol reaction, and includes, for example, a metal selected from titanium, copper, aluminum or tin, or a boron and a ligand. And chiral complexes. The ligands constituting the chiral complex include the following compounds. (1) 1,2,3,4-tetrahydroxybutane which has a substituent at the 1- and 4-positions and may have a protected hydroxyl group at the 2- and 3-positions. Examples of the substituents at the 1- and 4-positions include a lower alkyl group, a lower alkylphenyl group, a lower alkylnaphthyl group, a cycloalkyl group, and the like. And lower alkylene groups formed together. (2) [1,1′-binaphthalene] which may have a substituent
-2,2'-diol. Examples of the substituent include one or two groups selected from a halogen atom and a lower alkylene group. (3) An α-amino acid having a substituent at the carbon at the α-position and an α-amino group optionally protected. The substituent may be substituted with, for example, a carboxyl group; and 1 to 2 groups selected from a phenylcarbonyloxy group which may be substituted with 1 to 2 lower alkyl groups or lower alkoxy groups. A lower alkyl group, a phenyl lower alkyl group which may be substituted with a lower alkyl group, and a protecting group which may be substituted with a group selected from a nitro group, a halogen atom, a lower alkyl group and a lower alkoxy group Good phenylsulfonyl or naphthylsulfonyl groups are mentioned. (4) α-hydroxycarboxylic acid having a substituent at the carbon at the α-position. The substituent may be substituted with, for example, a carboxyl group; and 1 to 2 groups selected from a phenylcarbonyloxy group which may be substituted with 1 to 2 lower alkyl groups or lower alkoxy groups. A lower alkyl group and a phenyl lower alkyl group which may be substituted with a lower alkyl group are exemplified. (5) 1- (optionally protected amino) -2-hydroxycycloalkane optionally having a substituent at the 1- or 2-position. Examples of the substituent include a lower alkyl group and a phenyl lower alkyl group. Examples of the protecting group include a lower alkylsulfonyl group, a trifluoromethanesulfonyl group, a lower alkylphenylsulfonyl group, and a lower alkylnaphthylsulfonyl group. (6) A crosslinked 1,2-dihydroxycycloalkane which may have a substituent. Examples of the substituent include a lower alkyl group, a lower alkylphenyl group, and a lower alkylnaphthyl group. Examples of the crosslinked cycloalkane include a cycloalkane ring cross-linked by a lower alkylene group. (7) 1,2- having a substituent at the 1- and / or 2-position
Dihydroxycycloalkane. Examples of the substituent include a lower alkyl group, a lower alkylphenyl group, and a lower alkylnaphthyl group.

Specific examples of the chiral Lewis acid include the following. (1) Chiral titanium compound represented by the general formula [IV]:

[0018]

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Wherein R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a lower alkyl group, an aryl group, or together form a lower alkylene group or an oxo group, and R ⁷ is a lower alkyl group; A group, an aryl group or a cycloalkyl group, R ^8a and R ^8b are the same or different and are a halogen atom, a trifluoromethanesulfonyloxy group or a lower alkoxy group, and * represents an asymmetric carbon atom). R ⁵ , R ⁶ and R ⁷ Is an halogen group such as a fluorine atom, a chlorine atom, and a bromine atom; a lower alkyl group such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a t-butyl group, and an n-butyl group; Halogeno lower alkyl groups such as methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, t-butyloxy group, n-butyl A lower alkoxy group such as a ruoxy group; a phenyl group optionally substituted with a phenyl group; a naphthyl group;

(2) A chiral titanium compound represented by the general formula [Va] or [Vb]:

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Wherein R ^9a , R ^9b , R ^9c and R ^9d are
The same or different and represents a hydrogen atom, 1-2 halogen atoms or a lower alkyl group)

(3) Chiral titanium compound represented by the general formula [VI-a] or [VI-b]:

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(Wherein R ^10a and R ^10b are the same or different, and are a hydrogen atom, 1 to 2 halogen atoms or lower alkyl groups, R ^10c and R ^10d are the same or different, and are a halogen atom, trifluoro (Represents a methanesulfonyloxy group or a lower alkoxy group)

(4) A chiral boron compound represented by the general formula [VII]:

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(Wherein X ³ is an oxygen atom, a nitrogen atom substituted with a lower alkylsulfonyl group, a nitrogen atom substituted with a trifluoromethanesulfonyl group, or a nitrogen atom substituted with an arylsulfonyl group, R ¹¹ and R ¹² are different from each other, and a lower alkyl group which may have a group or an aralkyl group, or optionally substituted lower alkylene group which may have a substituent together, * represents an asymmetric carbon atom) this X ^3, And the aryl group moiety of the nitrogen atom substituted with an arylsulfonyl group is a nitro group in addition to the phenyl or naphthyl group substituents of R ⁵ , R ⁶ and R ⁷ above.
Cyano group; methoxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group, isopropyloxycarbonyl group, t-butyloxycarbonyl group, n-
Examples include a phenyl group and a naphthyl group which may be substituted with a substituent such as a lower alkoxycarbonyl group such as a butyloxycarbonyl group. The aralkyl group for R ¹¹ or R ¹² is a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a t-butyl group, an n-butyl group; a methoxy group, an ethoxy group, an n-propyloxy group. A phenyl lower alkyl group or a naphthyl lower alkyl group which may be substituted with a lower alkoxy group such as a group, an isopropyloxy group, a t-butyloxy group, or an n-butyloxy group. Examples of the substituent of the lower alkyl group represented by R ¹¹ and R ¹² include a carboxyl group; and one or two phenylcarbonyloxy groups optionally substituted with one or two lower alkyl groups or lower alkoxy groups. Substituents and the like are mentioned, and as a substituent of the lower alkylene group, 1 to 2 lower alkyl groups are mentioned.

(5) Chiral copper compound represented by the general formula [VIII]:

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Wherein R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are
Identical or different, lower alkyl groups, X ⁻ represents a counter anion)

(6) Chiral aluminum compound represented by the general formula [IX]:

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(Wherein X ⁴ is an oxygen atom or an arylsulfonyl group-substituted nitrogen atom, ring A is a bridged cycloalkane ring which may have a substituent, a cycloalkane ring which may have a substituent, * Represents an asymmetric carbon atom, provided that X ⁴
If is an oxygen atom, ring A is not unsubstituted cycloalkane ring) the aryl portion of arylsulfonyl group substituted nitrogen atom in the X ⁴ are the same as the aryl moiety of the arylsulfonyl group substituted nitrogen atom in the X ³ Examples include a phenyl group or a naphthyl group which may be substituted with a substituent. Examples of the substituent in the bridged cycloalkane ring and the cycloalkane ring in the ring A include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a t-butyl group, and a
Lower alkyl groups such as -butyl group; lower alkylphenyl groups; lower alkylnaphthyl groups and the like. Examples of the crosslinked cycloalkane ring include a cycloalkane ring crosslinked with a lower alkylene group.

(7) Chiral tin compound represented by the general formula [X]:

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(Wherein R ¹⁹ and R ²⁰ are different from each other and are a hydrogen atom or an aryl group which may have a substituent, or a lower alkylene group which may have a substituent together. , R ²¹ is a lower alkyl group, R ²² and R ²³ are a trifluoromethanesulfonyloxy group or a chlorine atom, and * represents an asymmetric carbon atom.) The aryl group in R ¹⁹ and R ²⁰ is a methyl group,
Examples include a phenyl group or a naphthyl group which may be substituted with a lower alkyl group such as an ethyl group, a propyl group, an isopropyl group, a t-butyl group and an n-butyl group.
Examples of the substituent in the lower alkylene group in R ¹⁹ and R ²⁰ include a lower alkyl group and a lower alkoxy lower alkyl group. These chiral Lewis acids are preferably chiral titanium compounds when the silyl ketene acetal compound [II] is a monohalogeno compound ( ^one of X ¹ and X ² is a hydrogen atom and the other is a chlorine atom or a bromine atom). Ketene acetal compound [II]
Is a dihalogeno compound (both X ¹ and X ² are chlorine atoms or bromine atoms), a chiral boron compound is preferred.

In the chiral titanium compound [IV], R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom; methyl, ethyl, n-propyl, isopropyl, t-
A lower alkyl group such as a butyl group or an n-butyl group; an aryl group such as a phenyl group or a naphthyl group, or a lower alkylene group such as a methylene group, an ethylene group, a trimethylene group, a propylene group or a tetramethylene group; form a group or an oxo group, R ⁷ is a methyl group, an ethyl group, n- propyl group, an isopropyl group, t- butyl group, a lower alkyl group such as n- butyl group; a phenyl group, or an aryl group such as phenyl or naphthyl Cyclopropyl group, cyclobutyl group, cycloalkyl group such as cyclopentyl group, R ^8a and R ^8b are the same or different, fluorine atom, chlorine atom, halogen atom such as bromine atom, trifluoromethanesulfonyloxy group or methoxy group, ethoxy group, Lower such as n-propyloxy group, isopropyloxy group, t-butyloxy group, n-butyloxy group There may be mentioned those which are alkoxy groups. Further, the aryl group is a methyl group in R ⁵ and R ^6, an ethyl group, n- propyl group, an isopropyl group, t- butyl group which may be substituted with a lower alkyl group such as n- butyl group, the R ⁷ Examples of the aryl group include a phenyl group or a naphthyl group which may be substituted with one or two substituents selected from a halogen atom, a trifluoromethyl group, a phenyl group and a lower alkyl group. Substituted phenyl groups are preferred. In the chiral titanium compound [IV], R ⁵ and R ⁶ are the same lower alkyl group, R ⁷ is a halogen atom,
A phenyl group or a naphthyl group which may be substituted with one or two groups selected from a trifluoromethyl group, a phenyl group and a lower alkyl group, and a compound in which R ^8a and R ^8b are both halogen atoms are more preferable. Particularly preferred are those in which ⁵ and R ⁶ are methyl groups, R ⁷ is a methylphenyl group, and R ^8a and R ^8b are both chlorine atoms. The chiral titanium compound [IV] is any of the chiral titanium compounds [IV-a] and [IV-b] represented by the following formula, and is a desired optically active 2-halogeno-3-hydroxypropionate. Depending on the 3-position absolute configuration of [III], it can be appropriately selected and used.

[0033]

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(Wherein the symbols have the same meanings as described above) In the chiral boron compound [VII], X ³ is an oxygen atom; a lower alkylsulfonyl group-substituted nitrogen atom; a trifluoromethanesulfonyl group-substituted nitrogen atom; An arylsulfonyl group-substituted nitrogen atom such as a group-substituted nitrogen atom, a naphthylsulfonyl group-substituted nitrogen atom, and the like, wherein R ¹¹ and R ¹² are different from each other; and a hydrogen atom; , T
A lower alkyl group such as -butyl group and n-butyl group; an aralkyl group such as a phenyl lower alkyl group and a naphthyl lower alkyl group, or having together with a substituent such as one or two lower alkyl groups; A methylene group which may be
Examples thereof include lower alkylene groups such as an ethylene group, a trimethylene group, and a tetramethylene group.

The substituent in the lower alkyl group for R ¹¹ and R ¹² includes a carboxyl group and 1-2.
And one or two groups selected from a phenylcarbonyloxy group which may be substituted with a lower alkyl group or a lower alkoxy group. The aryl group moiety of the arylsulfonyl group-substituted nitrogen atom in X ³ is a nitro group; a cyano group; a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom; a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Lower alkyl groups such as -butyl group and n-butyl group; lower alkoxy groups such as methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, t-butyloxy group and n-butyloxy group; trifluoromethyl group and the like A lower alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propyloxycarbonyl group, an isopropyloxycarbonyl group, a t-butyloxycarbonyl group or an n-butyloxycarbonyl group; a phenyl group or the like Substituents. The aralkyl group for R ¹¹ and R ¹² is a methyl group, an ethyl group, an n-propyl group, an isopropyl group,
A lower alkyl group such as -butyl group, n-butyl group and the like; substituted by a lower alkoxy group such as methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, t-butyloxy group and n-butyloxy group. And phenyl lower alkyl and naphthyl lower alkyl.

Among the chiral boron compounds [VII], X
³ is a nitro group, a halogen atom, a lower alkyl group, a nitrogen atom substituted with a phenylsulfonyl group or a naphthylsulfonyl group which may be substituted with 1 to 3 groups selected from a halogeno lower alkyl group and a lower alkoxy group, It is preferable that R ¹¹ and R ¹² are different from each other and are a hydrogen atom, a lower alkyl group or a phenyl lower alkyl group, and X ¹ is a nitro group, a chlorine atom, a methyl group, a trifluoromethyl group and a methoxy group. 3 of optionally substituted phenylsulfonyl also be sulfonyl a group group or naphthylsulfonyl-substituted nitrogen atom in groups, R ¹¹ and R ¹² are different from each other a hydrogen atom, an isopropyl group, an isobutyl group, sec- butyl group, tert- butyl more preferably those wherein group or a benzyl group, X ³ is of a nitro phenylsulfonyl group Nitrogen atom, R ¹¹ and R
Those in which ¹² is different from each other and is a hydrogen atom or an isopropyl group are particularly preferred. The amount of the chiral Lewis acid used in the method of the present invention is not particularly limited, and is usually about 1 to 200 mol%, preferably 10 to 120 mol%, relative to compound [I].
About mol% is preferable.

The solvent used in the method of the present invention includes:
There is no limitation as long as the solvent does not hinder the reaction. Examples thereof include ethers such as dioxane and tetrahydrofuran; nitriles such as acetonitrile; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; chlorobenzene, o- Halogenated aromatic hydrocarbons such as dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene and trichlorobenzene; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; n Aliphatic hydrocarbons such as -hexane and n-heptane; alicyclic hydrocarbons such as cyclohexane; aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide and nitroethane; Hydrocarbons or halogenated aliphatic hydrocarbons are preferred. Toluene and methylene chloride are preferred. These solvents may be used alone,
If necessary, two or more kinds may be mixed and used at an appropriate ratio. The reaction is -100 ~ 20 ° C,
It is particularly preferred to carry out at -78 to -10C.

The optically active 2-halogeno thus obtained
Among the 3-hydroxypropionic acid ester compounds [III], monohalogeno compounds ( ^one of X ¹ and X ² is a hydrogen atom and the other is a chlorine atom or a bromine atom) are described in, for example, JP-A-3-190865 or JP-A-3-56471. By performing intramolecular ring closure by the method described, the compound represented by the general formula [XI]

[0039]

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(Wherein * represents an asymmetric carbon atom and other symbols have the same meanings as described above), and can be converted to an optically active trans-2,3-epoxypropionate compound represented by the formula: . That is, the halogeno compound is dissolved in a suitable solvent (for example, lower alkanol) in the presence of a base (for example, alkali metal alkoxide, 1,8-diazabicyclo [5.4.0] -7-undecene, etc.) for -10 to -10.
By reacting at 50C, especially at 0C to room temperature,
It can lead to compound [XI].

In this case, the 3S-type (ie, (2R, 3S) -type and (2S, 3S) -type) optically active 2-halogeno-3-hydroxypropionate compound [III] does not depend on the absolute configuration at the 2-position. (2R, 3S) -type trans-2,3-epoxypropionate compound by intramolecular ring closure reaction
[XI] is generated. On the other hand, the 3R type [ie (2R, 3R) type and (2S, 3R) type] optically active 2-halogeno-3-hydroxypropionate compound [III] has an intramolecular ring closure regardless of the absolute configuration at the 2-position. The reaction produces a (2S, 3R) -type trans-2,3-epoxypropionate compound [XI].

The compound [III] is replaced with the compound [XI]
Is converted to a dihalogeno compound (X ¹
And X ² are both a chlorine atom or a bromine atom), it is necessary to reduce by a known method and convert it to a monochloro or monobromo compound before the intramolecular ring closure reaction. This conversion can be performed, for example, using compound [III] (X ¹
And X ² are both chlorine atoms or bromine atoms) in zinc-acetic acid at room temperature for about one and a half hours to easily lead to the desired monohalogeno compound (C
hem. Pharm. Bull., 41 (4), 643-648, 1993).

The thus obtained optically active transformer-2,
When the 3-epoxypropionic acid ester compound [XI] is used, an optically active 1,5-benzothiazepine derivative useful as a pharmaceutical compound can be produced, for example, by the following known method.

[0044]

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(Wherein, R ²⁴ represents a hydrogen atom, a halogen atom or a lower alkyl group, and R ²⁵ represents a 2-dimethylaminoethyl group or a 3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl group. , The other symbols have the same meanings as described above. That is, the optically active trans-2,3-epoxypropionate compound [XI] is reacted with the aminothiophenol compound [XII-a], or nitrothiophenol is used. After reacting with compound [XII-b], the nitro group is reduced to obtain an optically active threo-3- (2-aminophenylthio) -2-hydroxypropionate compound [X
III-a] is hydrolyzed, if necessary, followed by intramolecular ring closure to obtain optically active cis-3-hydroxy-1,
A 5-benzothiazepine compound [XIV-a] was added to the 5-nitrogen atom in any order onto a 2-dimethylaminoethyl group or 3- [4- (2-methoxyphenyl)
An optically active cis-3-acetoxy-1,5-benzothiazepine compound [XV] can be produced by introducing a -1-piperazinyl] propyl group and acetylating the 3-position hydroxyl group.

The above process is described in JP-A-60-202871.
JP-A-2-286672 and JP-A-3-157378.
Nos. 4-234866, 5-201865, JP-B-46-16988, 46-43785, and 4
Nos. 7-813, 53-18038 and 63-139
No. 94, 63-17832, 46-8982 and the like.

At this time, it is obtained from 3S-type 2-halogeno-3-hydroxypropionate compound [III].
When the (2R, 3S) type trans-2,3-epoxypropionic acid ester compound [XI] is used, the (2S, 3S) type threo-3- (2-aminophenylthio) -2-hydroxypropionic acid ester compound [ XIII-a],
(2S, 3S) -type cis-3-acetoxy-1,5-benzothiazepine compound [XV] can be obtained.

On the other hand, it is obtained from 3R type 2-halogeno-3-hydroxypropionate compound [III].
When the (2S, 3R) type trans-2,3-epoxypropionate compound [XI] is used, the (2R, 3R) type threo-3- (2-aminophenylthio) -2-hydroxypropionate compound [ XIII-a],
(2R, 3R) -type cis-3-acetoxy-1,5-benzothiazepine compound [XV] can be obtained.

When the optically active trans-2,3-epoxypropionic acid ester compound [XI] is used, an optically active 1,5-benzothiazepine derivative useful as a pharmaceutical compound is produced by the following known method. You can also.

[0050]

Embedded image

(Wherein the symbols have the same meanings as described above) That is, the optically active trans-2,3-epoxypropionic acid ester compound [XI] is reacted with an N-alkylaminothiophenol compound [XII-c]. Optically active threo-3- [2- (N-alkylamino) phenylthio] -2-hydroxypropionic acid ester compound [X
III-b] is hydrolyzed, if necessary, to obtain an optically active cis-5-alkyl-3-hydroxy-1,5-benzothiazepine compound [XIV-b] obtained by intramolecular ring closure. By acetylating the 3-hydroxyl group of the compound, an optically active cis-3-acetoxy-1,5-benzothiazepine compound [XV] can be produced, and this step is described in JP-A-6-279398. It can be carried out according to the method described.

Here, cis-3-acetoxy-1,5-
The following are particularly preferred as the benzothiazepine compound [XV]. (a) R is a 4-methoxyphenyl group, R ²⁴ is a hydrogen atom, R
²⁵ is a 2-dimethylaminoethyl group, and the absolute configuration is
A compound which is (2S, 3S). (b) R is a 4-methylphenyl group, R ²⁴ is a methyl group, R ²⁵
Is a 2-dimethylaminoethyl group, and the absolute configuration is (2
R, 3R). (c) R is a 4-methoxyphenyl group, R ²⁴ is a chlorine atom, R
^A compound in which ²⁵ is a 3- [4- (2-methoxyphenyl) -1-piperazinyl] propyl group and the absolute configuration is (2S, 3S).

Further, optically active cis-3-acetoxy-
Pharmaceutically acceptable salts of the 1,5-benzothiazepine compound [XV] include addition salts of inorganic acids (for example, hydrochloride,
Sulfates, phosphates, hydrobromides) and addition salts of organic acids (e.g., methanesulfonate, acetate, fumarate, maleate, oxalate, benzenesulfonate). .

The silyl ketene acetal compound of the present invention
[II] wherein one of X ¹ and X ² is a hydrogen atom and the other is a chlorine atom or a bromine atom is, for example, Liebigs Annalen der Chemy
hemie), p. 687 (1987), and has the general formula [XVI]

[0055]

Embedded image A haloacetic acid ester compound represented by X ⁵ —CH ₂ —CO ₂ R ⁴ [XVI] (wherein X ⁵ represents a chlorine atom or a bromine atom, and other symbols have the same meanings as described above) And the general formula [XVII]

[0056]

Embedded image

(Wherein the symbols have the same meanings as described above) and a suitable solvent (for example,
Ethers such as dioxane, tetrahydrofuran and diethyl ether; nitriles such as acetonitrile; aromatic hydrocarbons such as benzene and toluene; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane ) In or without solvent, base
(Eg, triethylamine, diisopropylethylamine, dimethylethylamine, tetramethylethylenediamine) in the presence of 0 ° C. to room temperature.

The silyl ketene acetal compound [II]
Wherein X ¹ and X ² are both chlorine atoms or bromine atoms, for example, those represented by the general formula [XVIII]

[0059]

Embedded image

(Wherein X ⁶ represents a chlorine atom or a bromine atom, and other symbols have the same meanings as described above) and a general formula [XIX]

[0061]

Embedded image

(Wherein X ⁷ represents a halogen atom or a trifluoromethanesulfonyloxy group, and other symbols have the same meanings as described above) and a suitable solvent (for example, ethers such as tetrahydrofuran) In the presence of zinc in the solution at room temperature to the reflux temperature of the solvent. The chiral titanium compound [IV] used in the production method of the present invention is, for example, Chimia
Vol. 45, p. 238 (1991), Journal of
Organic Chemistry (J. Org. Chem.) Vol. 60,
1788 (1995) and 57, 6825
Page (1992), Helvetica Kimika Acta
Chimica Acta), vol. 70, p. 954 (1987) and the like, according to the general formula [XX].

[0063]

Embedded image Br-Mg-R ⁷ [XX]

(Wherein the symbols have the same meanings as described above) and a general formula [XXI]

[0065]

Embedded image

(Wherein the symbols have the same meanings as described above), and a chiral dimethoxycarbonyldioxolane compound represented by the following formula: and a suitable solvent (for example, ethers such as tetrahydrofuran and diethyl ether; benzene, toluene,
General formula [XXII] obtained by reacting at 0 to 100 ° C in an aromatic hydrocarbon such as xylene).

[0067]

Embedded image

(Wherein the symbols have the same meanings as described above), and a chiral dihydroxymethyldioxolane compound represented by the general formula [XXIII]

^{Embedded image} Ti (R ^8a ) _m (R ^8b ) _4-m [XXIII] (where m represents 0, 1, 2, 3 or 4 and other symbols have the same meanings as described above) And optionally a general formula [XXIV]

[0069]

Embedded image A silane compound represented by Si (R ^8c ) ₄ [XXIV] (where R ^8c represents a halogen atom) and a suitable solvent (for example, aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene, etc.) Class), 0-50
It can also be produced by reacting at ° C. The chiral boron compound [VII] used in the production method of the present invention is, for example, a compound represented by the general formula [XXV]

[0070]

Embedded image

(Wherein the symbols have the same meanings as described above) and borane (BH ₃ ) are reacted with a suitable solvent (for example, ethers such as tetrahydrofuran, halogenated aliphatic carbons such as methylene chloride, etc.). (Hydrogens) at room temperature.

Other chiral Lewis acids used in the process of the present invention include, for example, Chemistry L.
etters) pp. 807-810 (1990), Chemistry Express, Vol. 5, 335.
338 (1991), Journal of American Chemical Society (J. Am. Chem. Soc.) 116
887-8838 (1994), Journal of American Chemical Society (J. Am. Che.
m. Soc.) 117, 2363-2364 (199
5 years), Journal of Organic Chemistry
(J. Org. Chem.) Vol. 56, pp. 2276-2278 (1
991), Journal of American Chemical Society (J. Am. Chem. Soc.) 113, 9365
9366 (1991), Synlett No. 4
39-440 (1991), Tetrahedron Letters
(Tetrahedron Letters) Vol. 27, 4721-472
4 (1986), Journal of American Chemical Society (J. Am. Chem. Soc.) Vol. 118, pp. 5814-5815 (1996), Chemistry and Industry (82)
4 (1986), Journal of American Chemical Society (J. Am. Chem. Soc.), Volume 113,
It can be produced according to the description on pages 4247 to 4252 (1991) and the like.

In the present specification, the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.
As a lower alkylene group, a linear or branched alkylene group having 1 to 6 carbon atoms, as a lower alkoxy group,
A linear or branched alkoxy group having 1 to 6 carbon atoms is a lower alkenyl group, a linear or branched alkenyl group having 2 to 7 carbon atoms is a cycloalkyl group and a cycloalkane ring, Is a cycloalkyl group and a cycloalkane ring of 3 to 8, as a halogen atom,
Examples include a chlorine atom, a bromine atom, a fluorine atom, an iodine atom and the like. As counter anions, SbF ₆ ⁻ , CN ⁻ , C
_{^{l -, Br -, CH 3}} COO -, ClO 4 -, CF 3 SO 3 - , and the like.

Hereinafter, the present invention will be described more specifically with reference to examples.
The present invention is not limited by these.

[0075]

【Example】

Example 1 (4S, 5S) -2,2-dimethyl-α, α,
To a solution of 313 mg of α ′, α′-tetrakis (p-tolyl) -1,3-dioxolane-4,5-dimethanol in 5 ml of toluene was added dropwise a solution of 170 mg of tetraisopropyl orthotitanate in 1 ml of toluene at room temperature. Stir at temperature for 30 minutes. The solution is concentrated under reduced pressure at room temperature, and the obtained colorless solid is dissolved by adding 5 ml of toluene in argon. A solution of 306 mg of silicon tetrachloride in 1.5 ml of toluene was added dropwise thereto, and the mixture was stirred at room temperature for 30 minutes. This solution was concentrated at room temperature under reduced pressure to obtain the following formula

[0076]

Embedded image

In argon, 5 ml of toluene was added to and dissolved in the red solid of the chiral titanium compound represented by the above formula, and this solution was used for the reaction as it was.

The toluene solution of the chiral titanium compound obtained by the above method is cooled to -78 ° C., and a solution of 68 mg of p-anisaldehyde in 1 ml of toluene is added dropwise and stirred at the same temperature for 15 minutes. To this was added dropwise a solution of 135 mg of 2-chloro-1-methoxy-1-trimethylsilyloxyethene in 1 ml of toluene, and the mixture was stirred at the same temperature for 1 hour.
30 ml of saturated saline was added to this reaction solution, and ethyl acetate 30 ml was added.
Then, the aqueous layer is extracted again with 30 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue obtained, 2 ml of tetrahydrofuran was added to dissolve the residue, and 1 ml of 1N hydrochloric acid was added thereto, followed by stirring at room temperature for 5 minutes. 30 ml of a saturated saline solution was added thereto, and the mixture was extracted with 30 ml of ethyl acetate.
Re-extract with ml. The organic layers were combined, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (solvent; hexane:
By purifying with ethyl acetate = 8: 1 to 3: 1),
2-chloro-3-hydroxy-3- (4-methoxyphenyl) propionic acid methyl ester, a threo form [(2R, 3
S) and (2S, 3R)] and erythro [[2S, 3S)
63 mg (threo-form: erythro-form = 1: 16) of a mixture of the isomer and the (2R, 3R) -isomer] are obtained as colorless crystals. When the component ratio of the mixture was analyzed by HPLC, the 3S type compound [(2R,
3S) type and (2S, 3S) type]: 3R type compound [(2R, 3
R) type and (2S, 3R) type] = 93.0: 7.0.

Melting point: 63-65 ° C. ¹ H-NMR (CDCl ₃ , δ): 2.94 (1H, brs), 3.8
1 (6H, s), 4.36 (0.94H, d, J = 8.0, erythro form), 4.42 (0.06H, d, J = 6.7, threo form), 5.0
1 (0.94H, d, J = 8.0, erythro), 5.07 (0.0
6H, d, J = 6.7, threo), 6.86-6.97 (2H,
m), 7.25-7.38 (2H, m).

HPLC conditions Column: Chiral Cell OJ (4.6 × 250 mm) [manufactured by Daicel Chemical Industries] Moving layer: n-hexane: ethanol = 90: 10 Flow rate: 1.0 ml / min UV detection: 254 nm Column temperature: 35 ° C.

Example 2 (4R, 5R) -2,2-dimethyl-α, α,
To a solution of 313 mg of α ', α'-tetrakis (o-tolyl) -1,3-dioxolane-4,5-dimethanol in 5 ml of toluene was added dropwise a solution of 170 mg of tetraisopropyl orthotitanate in 1 ml of toluene at room temperature. Stir at temperature for 30 minutes. The solution is concentrated under reduced pressure at room temperature, and the obtained colorless solid is dissolved by adding 5 ml of toluene in argon. A solution of 306 mg of silicon tetrachloride in 1.5 ml of toluene was added dropwise thereto, and the mixture was stirred at room temperature for 30 minutes. This solution was concentrated at room temperature under reduced pressure to obtain the following formula

[0082]

Embedded image

5 ml of toluene was added to and dissolved in a red solid of a chiral titanium compound represented by the above in argon, and this solution was used for the reaction as it was.

The toluene solution of the chiral titanium compound obtained by the above method is cooled to -78 ° C., and a solution of 68 mg of p-anisaldehyde in 1 ml of toluene is added dropwise and stirred at the same temperature for 15 minutes. To this was added dropwise a solution of 135 mg of 2-chloro-1-methoxy-1-trimethylsilyloxyethene in 1 ml of toluene, and the mixture was stirred at the same temperature for 1 hour.
30 ml of saturated saline was added to this reaction solution, and ethyl acetate 30 ml was added.
Then, the aqueous layer is extracted again with 30 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue obtained, 2 ml of tetrahydrofuran was added to dissolve the residue, and 1 ml of 1N hydrochloric acid was added thereto, followed by stirring at room temperature for 5 minutes. 30 ml of a saturated saline solution was added thereto, and the mixture was extracted with 30 ml of ethyl acetate.
Re-extract with ml. The organic layers were combined, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (solvent; hexane:
By purifying with ethyl acetate = 8: 1 to 3: 1),
2-chloro-3-hydroxy-3- (4-methoxyphenyl) propionic acid methyl ester, a threo form [(2R, 3
S) and (2S, 3R)] and erythro [[2S, 3S)
98 mg (threo-form: erythro-form = 11: 1) of a mixture of the compound (2R, 3R) -isomer] as colorless crystals. When the component ratio of the mixture was analyzed by HPLC under the same conditions as in Example 1, it was found that the 3S type compound [(2R, 3S) type and (2S, 3S)
Type]: 3R type compound [(2R, 3R) type and (2S, 3R)
Type] = 78.7: 21.3.

Examples 3 to 14 p-anisaldehyde, 2-chloro-1-methoxy-1
By treating trimethylsilyloxyethene and the chiral titanium compound described in Tables 1 and 2 in the same manner as in Example 1 or 2, 3S-type or 3R-type optically active 2- Chloro-3-hydroxy-
3- (4-Methoxyphenyl) propionic acid methyl ester is obtained.

[0086]

[Table 1]

[0087]

[Table 2]

Example 15 N- (p-toluenesulfonyl) -L-tert in a stream of nitrogen
1 ml of a 1M borane-THF solution is added dropwise to a solution of 285 mg of leucine in 10 ml of tetrahydrofuran at room temperature, and the mixture is stirred at the same temperature for 30 minutes. Then, it was cooled to -70 ° C or less,
-136 mg of anisaldehyde 1 ml of tetrahydrofuran
After the solution was added dropwise, a solution of 285 mg of 2-chloro-1-ethoxy-1-trimethylsilyloxyethene in 1 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, 10 ml of 0.2N phosphate buffer (pH 7) was added, and the temperature was raised to room temperature. Separate into a methylene chloride layer and an aqueous layer, and extract the aqueous layer with ethyl acetate. The organic layers are combined, and washed with saturated aqueous sodium hydrogen carbonate and saturated saline in this order. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and 5 ml of tetrahydrofuran and 1 ml of 2N hydrochloric acid were added to the obtained residue, followed by stirring for 30 minutes. After distilling off tetrahydrofuran under reduced pressure, ethyl acetate is added, and the mixture is washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order. After drying over anhydrous magnesium sulfate and concentration under reduced pressure, the resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 8:
1-3: 1) to give 2-chloro-3-
Ethyl hydroxy-3- (4-methoxyphenyl) propionate [(2R, 3S) form and (2S, 3R) form] and erythro form [(2S, 3S) form and (2R, 3R) form] 168 mg of a mixture (threo form: erythro form = 67: 33) is obtained as a colorless powder. When the component ratio of the mixture was analyzed by HPLC, the 3S type compound [(2R, 3S) type and (2S, 3S)
Type]: 3R type compound [(2R, 3R) type and (2S, 3R)
Type] = 77.3: 22.7.

¹ H-NMR (CDCl ₃ , δ): 1.15 (2
H, t, J = 7.1, erythro body), 1.29 (1H, t, J = 7.
1,1 threo), 2.91 (1H, d, J = 3.7), 3.80 (3
H, s), 4.10 (1.34H, q, J = 7.1, erythro body),
4.25 (0.67H, q, J = 7.1, threo), 4.34
(0.33H, d, J = 7.9, threo), 4.40 (0.67
H, d, J = 7.9, erythro body), 4.99 (0.33H, dd, J
= 4.3, 7.9, threo), 5.07 (0.67H, dd, J =
4.3, 7.9, erythro body), 6.87 (2H, d, J = 8.7),
7.30 (2H, d, J = 8.7).

HPLC conditions Column: Chiral Cell OJ (4.6 × 250 mm) [manufactured by Daicel Chemical Industries] Moving layer: n-hexane: 2-propanol = 80: 20 Flow rate: 1.0 ml / min UV detection: 254 nm Column temperature: 40 ℃

Examples 16 to 21 p-anisaldehyde, 2-chloro-1-ethoxy-1
By treating trimethylsilyloxyethene and the chiral boron compound described in Table 3 in the same manner as in Example 15, the optically active 2-chloro-3-hydroxy-forms of 3S type and 3R type were obtained in the proportions shown in Table 3 below. 3- (4-Methoxyphenyl) propionic acid ethyl ester is obtained.

[0092]

[Table 3]

Example 22 Under a nitrogen stream, 1 ml of a 1M borane-THF solution was added dropwise to a solution of 271 mg of N- (p-toluenesulfonyl) -L-valine in 10 ml of methylene chloride at room temperature, followed by stirring at the same temperature for 30 minutes. . Then, the mixture was cooled to -70 ° C or lower, and a solution of 136 mg of p-anisaldehyde in 1 ml of methylene chloride was added dropwise.
A solution of 237 mg of 2,2-dichloro-1-methoxy-1-trimethylsilyloxyethene in 1 ml of methylene chloride was added dropwise, and the mixture was stirred at the same temperature for 9 hours. The reaction solution was added at pH 7 0.2.
Add 10 ml of N phosphate buffer and warm to room temperature. Separate into a methylene chloride layer and an aqueous layer, and extract the aqueous layer with ethyl acetate. The organic layers are combined, and washed with saturated aqueous sodium hydrogen carbonate and saturated saline in this order. After drying over anhydrous magnesium sulfate and concentration under reduced pressure, 5 ml of tetrahydrofuran and 1 ml of 2N hydrochloric acid were added to the resulting residue.
And stir for 30 minutes. After distilling off tetrahydrofuran under reduced pressure, ethyl acetate is added, and the mixture is washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform: hexane: ethyl acetate = 5: 5: 1).
To give 2,2-dichloro-colorless crystals.
198 mg of methyl 3-hydroxy-3- (4-methoxyphenyl) propionate are obtained. Formation ratio (%) of 3S-form and 3R-form 3S: 3R = 2.
5: 97.5

Melting point: 69 ° C. ¹ H-NMR (CDCl ₃ , δ): 3.18 (3H, br), 3.8
2 (3H, s), 3.91 (3H, s), 5.38 (1H, s), 6.90
(2H, d, J = 8.9), 7.45 (2H, d, J = 8.7).

HPLC conditions Column: Chiral Cell OJ (4.6 × 250 mm) [manufactured by Daicel Chemical Industries] Moving layer: n-hexane: 2-propanol = 70: 30 Flow rate: 0.6 ml / min UV detection: 230 nm Column temperature: 35 ° C

Example 23 N- (o-Nitrobenzenesulfonyl) -L under a nitrogen stream
1 in a solution of 60 mg of valine in 10 ml of methylene chloride at room temperature.
0.2 ml of M borane-THF solution was added dropwise, and the solution was heated at the same temperature for 30 minutes.
Stir for minutes. Then, the mixture was cooled to -70 ° C or less, and a solution of 136 mg of p-anisaldehyde in 1 ml of methylene chloride was added.
A solution of 237 mg of dichloro-1-methoxy-1-trimethylsilyloxyethene in 1 ml of methylene chloride was simultaneously added to 10
After dropping over time, the mixture is further stirred at the same temperature for 3 hours. To the reaction mixture, 10 ml of 0.2N phosphate buffer (pH 7) was added, and the temperature was raised to room temperature. Separate into a methylene chloride layer and an aqueous layer, and extract the aqueous layer with ethyl acetate. The organic layers are combined, and washed with saturated aqueous sodium hydrogen carbonate and saturated saline in this order. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and 5 ml of tetrahydrofuran and 1 ml of 2N hydrochloric acid were added to the obtained residue, followed by stirring for 30 minutes. After distilling off tetrahydrofuran under reduced pressure, ethyl acetate is added, and the mixture is washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order. After drying over anhydrous magnesium sulfate and concentration under reduced pressure, the obtained residue was quantitatively analyzed by HPLC. As a result, methyl 2,2-dichloro-3-hydroxy-3- (4-methoxyphenyl) propionate 2 was obtained.
06 mg are obtained. Formation ratio (%) of 3S-form and 3R-form 3S: 3R = 1
9:81

Examples 24 to 37 Treatment of p-anisaldehyde, 2,2-dichloro-1-methoxy-1-trimethylsilyloxyethene and the chiral boron compounds described in Tables 4 to 5 in the same manner as in Examples 22 or 23 By doing so, 3S-type or 3R-type optically active 2,2-dichloro-3 at the ratios shown in Tables 4 and 5 below.
-Hydroxy-3- (4-methoxyphenyl) propionic acid methyl ester is obtained.

[0098]

[Table 4]

[0099]

[Table 5]

Reference Example 1 Under a nitrogen atmosphere and under ice cooling, 11.1 g of trimethylsilyl trifluoromethanesulfonate was added dropwise to a solution of 5.43 g of methyl chloroacetate in 50 ml of triethylamine over 30 minutes. After stirring at the same temperature for 2 hours, 50 ml of n-pentane was added to the reaction solution, and the mixture was allowed to stand at room temperature. About 60 ml of the upper layer separated into two layers is taken, concentrated under reduced pressure, and the residue is distilled under reduced pressure to obtain 2.56 g of 2-chloro-1-methoxy-1-trimethylsilyloxyethene.

Boiling point: 62-63 ° C. (5 mmHg) ¹ H-NMR (CDCl ₃ , δ): 0.27 (9H, s), 3.55
(3H, s), 4.55 (1H, s) Reference Example 2 A suspension of 7.57 g of 3-bromotoluene in a suspension of 1.07 g of magnesium and 50 ml of anhydrous iodine in 50 ml of anhydrous tetrahydrofuran in argon was used. Is dropped. The remainder is diluted with 50 ml of anhydrous tetrahydrofuran and added dropwise. After completion of the dropwise addition, the mixture is heated to reflux for 30 minutes. The Grignard reagent (4.4 equivalents) was cooled to 10 ° C, and (2R, 3R)-
2,3-O-isopropylidene-L-dimethyl tartrate 2.
A solution of 18 g of 10 ml of anhydrous tetrahydrofuran is added dropwise. After the dropwise addition, the mixture is stirred at the same temperature for 2 hours and then at room temperature overnight. The reaction mixture is poured into ice-cooled saturated aqueous ammonium chloride (500 ml), extracted with ethyl acetate, and the aqueous layer is re-extracted with ethyl acetate. The organic layers were combined, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 10: 1) to give (4R, 5R) -2,2-dimethyl-
1.3 g of α, α, α ′, α′-tetrakis (m-tolyl) -1,3-dioxolan-4,5-dimethanol are obtained as a colorless powder.

IR (Nujol): 3300, 2930, 14
60, 1380 (cm ^-1 ) ¹ H-NMR (CDCl ₃ , δ): 1.06 (6H, s), 2.26
(6H, s), 2.33 (6H, s), 3.84 (2H, s), 4.56
(2H, s), 7.00-7.40 (16H, m).

MS (m / z): 522.5 (M ⁺ ), 521.6
(MH) [α] _D ²⁴ : -53.7 ゜ (C = 1.00, chloroform)

Reference Example 3 A suspension of 535 mg of magnesium and one piece of iodine in 25 ml of anhydrous tetrahydrofuran in argon was added to 1-bromo-3,
About one-fifth of 4.85 g of 5-dichlorobenzene is added dropwise. The remainder is diluted with 25 ml of anhydrous tetrahydrofuran and added dropwise. After completion of the dropwise addition, the mixture is heated to reflux for 30 minutes. The Grignard reagent (4.4 equivalents) is cooled to 10 ° C., and a solution of 1.09 g of dimethyl (2R, 3R) -2,3-O-isopropylidene-L-tartrate in 10 ml of anhydrous tetrahydrofuran is added dropwise thereto. After the dropwise addition, the mixture is stirred at the same temperature for 50 minutes and then at room temperature overnight. The reaction mixture is poured into ice-cooled saturated aqueous ammonium chloride (500 ml), extracted with ethyl acetate, and the aqueous layer is re-extracted with ethyl acetate. The organic layers were combined, washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 50: 1) to obtain 1.7 g of a colorless powder. This was crystallized from hexane and recrystallized from hexane to give (4R, 5R) -2,2-dimethyl-α, α, α ′, α′-tetrakis (3,5-dichlorophenyl) -1,3. 630 mg of dioxolane-4,5-dimethanol are obtained as colorless crystals.

IR (Nujol): 3160, 2930, 15
80, 1570, 1460 (cm ^-1 ) ¹ H-NMR (CDC
l ₃ , δ): 1.25 (6H, s), 3.98 (2H, s), 4.38 (2
H, s), 7.14 (4H, d, J = 1.83), 7.26 (2H, t,
J = 1.83), 7.35 (2H, t, J = 1.83), 7.39
(4H, d, J = 1.83) MS (m / z): 742 (M ⁺ ), 741 (MH) [α] _D ²⁴ : -84.3 ゜ (C = 1.00, chloroform) Melting point: 124.3-126.7C.

Reference Example 4 A mixture of 7.6 ml of trimethylsilyl chloride and 7.15 g of methyl dichloroacetate was added dropwise to a suspension of 4.9 g of zinc in 50 ml of THF at room temperature under a nitrogen atmosphere, and the mixture was heated under reflux for 1 hour. The reaction is cooled to room temperature and 50 ml of hexane are added. The insolubles were filtered under reduced pressure, the filtrate was concentrated, and the residue was distilled under reduced pressure to obtain 5.62 g of 2-chloro-1-methoxy-1-trimethylsilyloxyethene. Boiling point: 47-51 ° C (2 mmHg) ¹ H-NMR (CDCl ₃ , δ): 0.27 (9H, s), 3.55
(3H, s), 4.55 (1H, s).

Reference Example 5 17.7 g of zinc in 100 ml of THF at room temperature under a nitrogen atmosphere.
To the suspension was added dropwise a mixture of 15.2 ml of trimethylsilyl chloride and 17.7 g of methyl trichloroacetate. During the dropwise addition, reflux starts as the reaction proceeds. After dropwise addition over 15 minutes, the reaction solution is cooled to room temperature, and 100 ml of hexane is added. The insolubles were filtered under reduced pressure, the filtrate was concentrated, and the residue was distilled under reduced pressure to give 2,2-dichloro-1-methoxy-.
18.3 g of 1-trimethylsilyloxyethene are obtained. Boiling point: 64-65 ° C. (2 mmHg) ¹ H-NMR (CDCl ₃ , δ): 0.31 (9H, s), 3.65
(3H, s).

[0108]

According to the method of the present invention, the aldehyde compound [I] and the silyl ketene acetal compound [II] are reacted in the presence of a chiral Lewis acid to stereoselectively form the 3R-form in one step. Or 3S-type 2-halogeno-3-
Hydroxypropionate compound [III] can be produced, and there is no need to use expensive metals and optically active reagents, complicated reaction operations, and no environmentally harmful waste liquid treatment problems. Synthetic intermediates can be produced industrially advantageously.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location C07D 303/48 C07D 303/48 // B01J 31/22 B01J 31/22 X C07B 61/00 300 C07B 61/00 300 C07C 319/14 7419-4H C07C 319/14 323/51 7419-4H 323/51 C07M 7:00

Claims (13)

[Claims] A compound represented by the general formula [I]: wherein R is a lower alkyl group, a lower alkenyl group, an aryl group which may have a substituent or a cycloalkyl group; And an aldehyde compound represented by the general formula [II]: (In the formula, X ¹ and X ² are each a hydrogen atom and the other is a chlorine atom or a bromine atom, or both are a chlorine atom or a bromine atom, and R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom A lower alkyl group or an aryl group which may have a substituent, R ⁴ represents an aryl group which may have a lower alkyl group or an optionally substituted substituent)) and a chiral Lewis General formula [III] characterized by reacting in the presence of an acid (Wherein * represents an asymmetric carbon atom, and other symbols have the same meanings as described above).
-A method for producing a hydroxypropionate compound. 2. The process according to claim 1, wherein the chiral Lewis acid is a metal selected from titanium, copper, aluminum or tin, or a chiral complex comprising boron and a ligand. 3. The method according to claim 2, wherein at least one of the ligands is a compound selected from the following: (1) a hydroxyl group at the 2- or 3-position having a substituent at the 1- or 4-position; 1,2,3,4-tetrahydroxybutane which may have (2) an optionally substituted [1,1′-binaphthalene]
-2,2'-diol, (3) an α-amino acid having a substituent at the carbon at the α-position and an α-amino group optionally protected, (4) α having a substituent at the carbon at the α-position -Hydroxycarboxylic acid, (5) 1- (optionally protected amino) -2-hydroxycycloalkane optionally having a substituent at the 1- and 2-positions, (6) having a substituent (7) 1,2-dihydroxycycloalkane having a substituent at the 1- and / or 2-position
Dihydroxycycloalkane. 4. The process according to claim 1, wherein the chiral Lewis acid is a chiral complex selected from the following: (1) A chiral titanium compound represented by the following formula [IV]: (Wherein, R ⁵ and R ⁶ are the same or different and each represent a hydrogen atom,
A lower alkyl group or an aryl group which may have a substituent, or together form a lower alkylene group or an oxo group, and R ⁷ may have a lower alkyl group or a substituent Aryl or cycloalkyl, R
^8a and R ^8b are the same or different and each is a halogen atom, a trifluoromethanesulfonyloxy group or a lower alkoxy group, and * represents an asymmetric carbon atom.) (2) Formula (Va) or (Vb) Chiral titanium compound: (Wherein R ^9a , R ^9b , R ^9c and R ^9d are the same or different and represent a hydrogen atom, 1 to 2 halogen atoms or a lower alkyl group). (3) The following formula [VI-a] or A chiral titanium compound represented by [VI-b]: (Wherein, R ^10a and R ^10b are the same or different, and are a hydrogen atom, one or two halogen atoms or a lower alkyl group, R ^10c and R ^10d are the same or different, a halogen atom, trifluoromethanesulfonyloxy (4) a chiral boron compound represented by the following formula [VII]: (In the formula, X ³ is an oxygen atom, a lower alkylsulfonyl group-substituted nitrogen atom, a trifluoromethanesulfonyl group-substituted nitrogen atom or an optionally substituted arylsulfonyl group-substituted nitrogen atom, and R ¹¹ and R ¹² are different from each other. A hydrogen atom, a lower alkyl group which may have a substituent or an aralkyl group which may have a substituent, or a lower alkylene group which may have a substituent together , * Represents an asymmetric carbon atom.) (5) Chiral copper compound represented by the following formula [VIII]: (In the formula, R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different and are a lower alkyl group, X ⁻ is a counter anion, and * is an asymmetric carbon atom.) (6) The following formula [IX] A chiral aluminum compound represented by the following formula: (In the formula, X ⁴ is an oxygen atom or an optionally substituted arylsulfonyl group-substituted nitrogen atom, ring A is an optionally substituted bridged cycloalkane ring, And * represents an asymmetric carbon atom, provided that when X ⁴ is an oxygen atom, ring A is not an unsubstituted cycloalkane ring.) (7) Chiral tin represented by the following formula [X] Compound: (In the formula, R ¹⁹ and R ²⁰ are different from each other, and may be a hydrogen atom or an aryl group which may have a substituent, or a lower alkylene group which may have a substituent together;
²¹ represents a lower alkyl group, R ²² and R ²³ represent a trifluoromethanesulfonyloxy group or a chlorine atom, and * represents an asymmetric carbon atom). 5. A compound of the general formula [III] obtained by the process according to claim 1, 2, 3 or 4. (Wherein, R is a lower alkyl group, a lower alkenyl group, an aryl group or a cycloalkyl group which may have a substituent, X ¹ and X ² are each a hydrogen atom and the other is a chlorine atom or a bromine atom, or Both are a chlorine atom or a bromine atom, R ⁴ is a lower alkyl group or an aryl group which may have a substituent, * represents an asymmetric carbon atom), and an optically active 2-halogeno-3-hydroxypropionic acid When both X ¹ and X ² in the ester compound are a chlorine atom or a bromine atom, one of them is reduced to a hydrogen atom, and then subjected to an intramolecular ring closure reaction, characterized by the general formula [XI] Embedded image (Wherein the symbols have the same meanings as described above), a process for producing an optically active trans-2,3-epoxypropionate compound represented by the formula: 6. A general formula [XI] obtained by the process according to claim 5. (Wherein, R is a lower alkyl group, a lower alkenyl group, an aryl group or a cycloalkyl group which may have a substituent, R ⁴ is a lower alkyl group or an aryl group which may have a substituent, * Represents an asymmetric carbon atom) and an optically active trans-2,3-epoxypropionate compound represented by the general formula [XII-a]: (Wherein R ²⁴ represents a hydrogen atom, a halogen atom or a lower alkyl group), or reacted with an aminothiophenol compound represented by the general formula [XII-b]: (Wherein the symbols have the same meanings as described above), and then reacting with a nitrothiophenol compound and reducing the nitro group to obtain a compound of the general formula [XIII-a] (Wherein the symbols have the same meaning as described above), after hydrolyzing the optically active threo-3- (2-aminophenylthio) -2-hydroxypropionic acid ester compound, if necessary, The ring is closed to give a compound of the general formula [XIV-a] (Wherein the symbols have the same meanings as described above) represented by the formula (1), and the compound is placed on the nitrogen atom at the 5-position in any order. Dimethylaminoethyl group or 3- [4- (2
-Methoxyphenyl) -1-piperazinyl] propyl group, acetylating the hydroxyl group at the 3-position and, if desired, converting the product into a pharmaceutically acceptable salt.
[XV] embedded image (Wherein R ²⁵ is a 2-dimethylaminoethyl group or 3-
An optically active cis-3-acetoxy-1,5-benzothiazepine compound represented by [4- (2-methoxyphenyl) -1-piperazinyl] propyl group, and other symbols having the same meaning as described above; Preparation of the pharmaceutically acceptable salt. 7. A compound of the general formula [XI] obtained by the process according to claim 5. (Wherein, R is a lower alkyl group, a lower alkenyl group, an aryl group or a cycloalkyl group which may have a substituent, R ⁴ is a lower alkyl group or an aryl group which may have a substituent, * Represents an asymmetric carbon atom) and an optically active trans-2,3-epoxypropionate compound represented by the general formula [XII-c]: (Wherein R ²⁴ is a hydrogen atom, a halogen atom or a lower alkyl group, R ²⁵ is a 2-dimethylaminoethyl group or 3-
[Representing a 4- (2-methoxyphenyl) -1-piperazinyl] propyl group) represented by the general formula [XIII-
b] (Wherein the symbols have the same meanings as described above), wherein the optically active threo-3- [2- (N-alkylamino) phenylthio] -2-hydroxypropionate compound was hydrolyzed, if necessary. Then, the compound represented by the general formula [XIV-b] is obtained by intramolecular ring closure. (Wherein the symbols have the same meanings as described above) represented by the formula: cis-5-alkyl-3-hydroxy-1,5-benzothiazepine compound represented by the formula: General formula [XV] wherein the product is a pharmacologically acceptable salt. (Wherein the symbols have the same meanings as described above). A process for producing an optically active cis-3-acetoxy-1,5-benzothiazepine compound or a pharmaceutically acceptable salt thereof. 8. A lower alkyl group wherein R ⁵ and R ⁶ are the same,
R ⁷ is a halogen atom, a trifluoromethyl group, one to two phenyl group or a naphthyl group optionally substituted by a group selected from a phenyl group and a lower alkyl group, R ^8a
The method according to claim 4, wherein R ^8b and R ^8b are both halogen atoms. 9. X ³ is a phenylsulfonyl group or a naphthylsulfonyl group optionally substituted with 1 to 3 groups selected from a nitro group, a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group. substituted nitrogen atom, a process according to claim 4 R ¹¹ and R ¹² are mutually different and represent a hydrogen atom, a lower alkyl group or a phenyl-lower alkyl group. 10. The method according to claim 1, wherein R is a lower alkylphenyl group or a lower alkoxyphenyl group, R ¹ , R ² and R ³ are the same lower alkyl group, and R ⁴ is a lower alkyl group.
10. The method according to any one of items 9 to 9. 11. R is a 4-methoxyphenyl group, R ¹ ,
10. All of R ² and R ³ are a methyl group, R ⁴ is a methyl group or an ethyl group, R ⁵ and R ⁶ are both a methyl group, R ⁷ is a methylphenyl group, and R ^8a and R ^8b are both a chlorine atom. Production method described in 1. 12. An optical activity 2 represented by the general formula [III]
The process according to any one of claims 1 to 11, wherein the 3-position of the -halogeno-3-hydroxypropionate compound has an absolute configuration of R. 13. The optical activity 2 represented by the general formula [III]
The process according to any one of claims 1 to 11, wherein the 3-position of the halogeno-3-hydroxypropionate compound has an absolute configuration of S.