JP3252900B2 - Method for producing (2R, 3S) type 3- (4-lower alkoxyphenyl) glycidic acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a (2R, 3S) -type 3- (4) compound obtained by asymmetric amidation of racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester.
The present invention relates to a method for producing (lower alkoxyphenyl) glycidic acid ester and a method for producing (2S, 3S) type 1,5-benzothiazepine derivatives using the same.

[0002]

2. Description of the Related Art As a calcium channel blocker, diltiazem hydrochloride (chemical name: (2S, 3S) -2- (4-), which is widely used for the treatment of angina pectoris and essential hypertension.
(Methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-1,5-
(2) such as benzothiazepine-4 (5H) -one hydrochloride).
(S, 3S) -type 1,5-benzothiazepine derivatives are (2
It is known that the compound can be advantageously produced using an (R, 3S) -3-phenylglycidic acid ester compound (JP-A-60-13776, JP-A-61-145174,
JP-A-2-231480).

[0003] Also, lipase SP523 [Novo Nord, Denmark] is used for racemic trans-3- (4-methoxyphenyl) glycidic acid methyl ester.
isk)] to give (2S, 3R) -3- (4-
Asymmetric amidation of methyl methoxyphenyl) glycidate is known (International Publication No. W.
O95 / 07359), the activity and selectivity of the enzyme were not sufficient with this method.

[0004]

SUMMARY OF THE INVENTION The present inventors have studied a method for amidating racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester with a high reaction rate and a high stereoselectivity. Stacked.

[0005]

According to the study of the present inventors, racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester was converted to ammonia or lower in the presence of an enzyme produced by a microorganism of the genus Serratia. By reacting with an alkylamine to form an asymmetric amidation and separating and obtaining the remaining ester from the reaction solution, the (2R, 3S) type 3-
They have found that (4-lower alkoxyphenyl) glycidic acid esters can be efficiently produced in a short time, and have completed the present invention.

[0006]

According to the present invention, the compound represented by the general formula (I)

[0007]

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(Wherein R ¹ represents a lower alkyl group, and R represents an ester residue).
(4-Lower alkoxyphenyl) glycidic acid ester and general formula (II)

[0009]

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(Wherein R ² represents a hydrogen atom or a lower alkyl group) with an (2S, 3
R) -type 3- (4-lower alkoxyphenyl) glycidic acid ester was reacted in the presence of an enzyme derived from a microorganism belonging to the genus Serratia and capable of asymmetrically amidating (2S, 3)
The (2R, 3S) type 3- (4-lower alkoxyphenyl) which remains after amidating the R) type optical isomer selectively
By separating and collecting glycidic acid ester from the reaction solution,
General formula (III)

[0011]

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(However, R ¹ and R have the same meanings as described above.) (2R, 3S) type 3- (4-lower alkoxyphenyl) glycidic acid ester can be produced.

In the method of the present invention, examples of the lower alkyl group of R ¹ in the general formula (I) include an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group and an n-butyl group. And is preferably a methyl group. Examples of the ester residue of R include an alkyl group which may have a substituent. Examples of the substituent of the alkyl group include an alkoxy group having 1 to 4 carbon atoms and a halogen atom. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, and a hexyl group. And other alkyl groups having 1 to 6 carbon atoms. R is preferably a lower alkyl group such as a methyl group and an ethyl group, and particularly preferably a methyl group.

On the other hand, examples of the lower alkyl group of R ² in the general formula (II) include an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group and an n-butyl group. A group is preferable, and as the amine compound (II), a compound in which R ² is a hydrogen atom is preferable.

In the present invention, the racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester (I), which is the starting compound, is composed of (2R, 3S) form and (2S, 3R) form in equivalent amounts. Not only those containing these but also any of these optical isomers can be used.

The enzymes that can be used in the method of the present invention include:
(2S, 3R) type 3- (4-lower alkoxyphenyl)
From a microorganism of the genus Serratia having the ability to asymmetrically amidate glycidic acid esters, for example, Serratia marcescens
lipase, esterase and the like produced by s). Such Serratia microorganisms may be wild strains or mutant strains, and may be those derived from these microorganisms by biotechnological techniques such as gene recombination and cell fusion.

These enzymes are usually used after being separated and purified from a culture of a microorganism producing the enzyme. Instead of using these separated enzymes, a culture of the microorganism, cells, cell extracts, A crushed cell, an ultrasonically treated cell, or the like may be used.

The enzymes derived from the microorganism of the genus Serratia used in the method of the present invention include, for example, a polyacrylamide method, a sulfur-containing polysaccharide gel method (carrageenan gel method), an alginic acid gel method, an agar gel method, and a photocrosslinkable resin. It can also be used after immobilization by a known method such as the method, polyethylene glycol method, and celite fixing method.

The asymmetric amidation reaction according to the method of the present invention is represented by the following reaction formula.

[0020]

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(However, R, R ¹ and R ² have the same meanings as described above.) That is, racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester (I) is added to a suitable solvent by adding The amine compound (II) is reacted in the presence of an enzyme derived from a microorganism belonging to the genus Serratia which has the ability to asymmetrically amidate the (2S, 3R) type 3- (4-lower alkoxyphenyl) glycidic acid ester to give (2S, 3R) -type (3R) type optical isomers remain after selective amidation (2R, 3S)
The desired (2R, 3S) type 3- (4-lower alkoxyphenyl) glycidic acid ester can be obtained by separating and collecting the type 3- (4-lower alkoxyphenyl) glycidic acid ester from the reaction solution. .

Racemic trans-3- (4-lower alkoxyphenyl) which is one of the substrates in the method of the present invention
The concentration of the glycidic acid ester (I) in the reaction solution is generally from 0.1 to 80% (w / w), especially from 1 to 20% (w / w).
/ W). The other substrate, amine compound (II), is a racemic trans-3- (4-lower alkoxyphenyl) glycidate (I) 1
0.5 to 3.0 moles per mole, especially 0.6 to 3.0 moles
It is preferred to use 2.0 moles. The concentration of the amine compound (II) in the reaction solution is generally 0.1 to 5% (w
/ W), particularly preferably 0.2 to 2% (w / w). When the concentration of the amine compound (II) in the reaction solution is reduced, it may be added sequentially. The reaction suitably proceeds at room temperature or under heating, preferably at 10 to 50 ° C, particularly preferably at 20 to 40 ° C.

Examples of the solvent include aromatic hydrocarbon solvents which may be halogenated such as benzene, toluene, xylene and chlorobenzene; halogenated solvents such as hexane, cyclohexane, heptane, isooctane, dichloroethane, trichloroethane and carbon tetrachloride. Aliphatic hydrocarbon solvents which may be used; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as methyl isobutyl ketone;
t-butyl methyl ether, isopropyl ether,
Ether solvents such as 1,4-dioxane and tetrahydrofuran; nitrile solvents such as acetonitrile; alcohol solvents such as isopropanol and t-butanol; and aromatic hydrocarbon solvents, ether solvents, and ester solvents. It is preferable to use a solvent, and particularly preferable to use toluene, t-butyl methyl ether, ethyl acetate, and butyl acetate. In order to suppress the hydrolysis of the racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester (I), the method of the present invention is preferably carried out in an organic solvent substantially free of water. preferable.

From the reaction solution thus obtained, (2R, 3
The separation and collection of S) type 3- (4-lower alkoxyphenyl) glycidic acid ester (III) can be easily carried out according to a conventional method. For example, after completion of the enzyme reaction, the enzyme is filtered off, the solvent is distilled off from the filtrate under reduced pressure, the residue is dissolved in an aromatic hydrocarbon solvent (for example, toluene), and the precipitate is filtered off. The (2S, 3R) type 3- (4-lower alkoxyphenyl) glycidic acid amide compound is removed, the solvent is distilled off from the filtrate, and the mixture is crystallized by adding an alcoholic solvent (eg, methanol). The (2R, 3S) type 3- (4-lower alkoxyphenyl) glycidic acid ester (III) can be obtained by filtration.

(2R, 3S) obtained as described above
Type 3- (4-lower alkoxyphenyl) glycidic acid ester (III) is represented by the following general formula (IV)

[0026]

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(Wherein, ring A represents a benzene ring which may be substituted, and R ³ represents a hydrogen atom or a di-lower alkylamino-lower alkyl group). Accordingly, after hydrolyzing the ester site of the product, and performing an intramolecular ring closure reaction, the compound represented by the general formula (V)

[0028]

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(However, R ¹ , R ³ and ring A have the same meanings as described above.) Can be led to a (2S, 3S) type 1,5-benzothiazepine derivative represented by the following formula:

(2R, 3S) type 3- (4-lower alkoxyphenyl) glycidic acid ester (III)
The reaction with the aminothiophenol derivative (IV) can be carried out in a suitable organic solvent in the presence or absence of an iron catalyst.

As the solvent, an aromatic hydrocarbon solvent which may be halogenated (for example, benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, trichlorobenzene), an alcohol solvent (for example, methanol, ethanol, Propanol) and the like, with methanol, xylene, chlorobenzene and dichlorobenzene being particularly preferred.

Examples of the iron catalyst include inorganic or organic salts or complexes containing divalent or trivalent iron ions. Specific examples of such an iron catalyst include ferric nitrate and iron hydroxide oxide. Ferric chloride, ferrous chloride, ferrous sulfate, ferrous iodide, iron sulfide, iron 4-cyclohexylbutyrate, ferric oxide, ferric bromide, ferrous fluoride, ferric fluoride Iron and the like can be mentioned, and it is particularly preferable to use ferric chloride, iron sulfate, ferric nitrate and the like.

The reaction is carried out at 60 to 200 ° C., especially at 100
Properly proceeds at ~ 150 ° C.

The hydrolysis of the ester moiety of the product is
According to a general ester hydrolysis method, for example, the product is a base or a mineral acid such as an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide), an alkaline earth metal hydroxide (eg, calcium hydroxide). (For example, hydrolysis using an acid such as hydrochloric acid, nitric acid, and sulfuric acid).

The subsequent intramolecular ring closure reaction is carried out in a suitable solvent in the presence or absence of an acid or base in the range of 0 to 250.
C, especially at 80-200C.

The solvent may be any solvent which does not hinder the reaction, and may be an aromatic hydrocarbon solvent which may be halogenated (for example, benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene,
Trichlorobenzene, naphthalene), an aliphatic hydrocarbon solvent which may be halogenated (for example, methylene chloride, carbon tetrachloride, dichloroethane, cyclohexane),
Aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide), ketone solvents (eg, acetone, methyl ethyl ketone), ester solvents (eg, ethyl acetate, butyl acetate), ether solvents (eg, 1 , 4-dioxane, tetrahydrofuran), nitrile solvents (eg, acetonitrile), alcohol solvents (eg, methanol, ethanol, propanol) and the like. These solvents may be used in a single-phase or two-phase form, if necessary, by mixing two or more kinds in an appropriate ratio. Among these solvents, alcohol solvents, aromatic hydrocarbon solvents which may be halogenated, and ether solvents are preferable, and chlorobenzene, dichlorobenzene, toluene, xylene and mesitylene are particularly preferable. The intramolecular ring closure reaction is preferably performed in the absence of water so as not to cause hydrolysis.

As the acid, both Bronsted acid and Lewis acid can be used. As the Bronsted acid, any organic or inorganic acid can be used, and mineral acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid, phosphonic acid, hydrofluoric acid, hydrobromic acid, perchloric acid), Lower alkanoic acids (eg, formic acid, acetic acid, propionic acid, butyric acid), hydroxy-substituted lower alkanoic acids (eg, citric acid), halogeno lower alkanoic acids (eg, trifluoroacetic acid), lower alkanesulfonic acids (eg, methanesulfonic acid) Acid, ethanesulfonic acid), arylsulfonic acid (e.g., p-toluenesulfonic acid, benzenesulfonic acid), oxalic acid, and the like. On the other hand, as the Lewis acid, titanium tetrachloride, aluminum chloride, boron trifluoride, tin chloride and the like can be used. Of these acids, mineral acids, lower alkanoic acids or arylsulfonic acids are preferred, especially methanesulfonic acid, p-
Preferred are toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid and hydrobromic acid.

As the base, any inorganic or organic base can be used. Examples of such a base include alkali metal hydrogencarbonates (eg, sodium hydrogencarbonate, potassium hydrogencarbonate) and alkali metal carbonates (eg, sodium carbonate). , Potassium carbonate), alkali metal hydroxide (for example,
Sodium hydroxide, potassium hydroxide), alkali metal amides (eg, sodium amide, lithium amide, potassium amide), alkali metal alkoxides (eg,
Sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide), alkali metals (eg, lithium metal, sodium metal, potassium potassium), alkaline earth metals (eg, calcium), organic bases (eg, 1,8) -Diazabicyclo [5.4.0]
Undec-7-ene, diisopropylamine, triethylamine, pyridine).

(2R, 3S) type 3- (4-lower alkoxyphenyl) glycidic acid ester (III)
The reaction with the aminothiophenol derivative (IV) and the intramolecular ring closure reaction can also be performed in one pot, (2R, 3
S) After the reaction of the 3- (4-lower alkoxyphenyl) glycidic acid ester (III) with the 2-aminothiophenol derivative (IV), an acid or a base is directly added to the reaction solution to effect an intramolecular ring closure reaction. Can also be implemented.

[0040] In the above method, R is a lower alkyl group (e.g., methyl group, ethyl group), are preferred when the ring A is an unsubstituted benzene ring or a halogen-substituted benzene ring, especially, R and R ¹ is a methyl group, R ³ is a hydrogen atom,
Preferably, ring A is an unsubstituted benzene ring.

The (2S, 3S) type 1,
The 5-benzothiazepine derivative is subjected to O-alkanoylation and, in the case where R ³ is a hydrogen atom, introduction of a di-lower alkylamino-lower alkyl group by N-alkylation according to a conventional method. Is converted into a pharmaceutically acceptable salt thereof to obtain a compound represented by the general formula (VI):

[0042]

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(Where R ⁴ is a di-lower alkylamino lower alkyl group, R ⁵ is a lower alkanoyl group, R ¹ and ring A have the same meanings as described above) (2S, 3S)
A type 1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof can be produced.

The O-alkanoylation in the above is described, for example, in JP-B-46-16749 and JP-B-63-1399.
4, JP-B-2-28594, JP-A-58-9947.
It can be easily carried out according to the method described in No. 1 or the like.

The introduction of di-lower alkylamino lower alkyl groups by N-alkylation when R ³ is a hydrogen atom is described, for example, in JP-B-46-16749 and JP-B-6-16749.
3-13994, JP-B-2-28594, JP-A-5
It can be easily carried out according to the methods described in JP-A-8-99471, JP-A-61-118377, JP-A-2-78673, JP-A-6-228117, JP-A-8-26926 and the like.

In the above conversion method, R ¹ is a methyl group,
Preferably, R ³ is a hydrogen atom, R ⁴ is a dimethylaminoethyl group, R ⁵ is an acetyl group, and ring A is an unsubstituted benzene ring.

In the present invention, examples of the lower alkyl group include a linear or branched alkyl group having 1 to 4 carbon atoms.

[0048]

According to the present invention, the method of (2S, 3R) type 3-
By using an enzyme derived from a microorganism belonging to the genus Serratia having the ability to asymmetrically amidate (4-lower alkoxyphenyl) glycidic acid ester, International Publication No. WO95
Compared with the method described in US Pat. No. 5,073,359, the (2) of racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester is remarkably fast and remarkably stereoselective.
(S, 3R) type optical isomer can be amidated,
(2R, 3S) type-3- (4-lower alkoxyphenyl) glycidic acid ester can be efficiently separated and obtained.

The thus obtained (2R, 3S) type-3-
(4-Lower alkoxyphenyl) glycidic acid esters are useful for producing (2S, 3S) type 1,5-benzothiazepine derivatives such as diltiazem hydrochloride. (2S, 3S) -type 1,5-benzothiazepine derivatives can be efficiently produced from 3- (4-lower alkoxyphenyl) glycidic acid esters.

[0050]

Example 1 In a 200 ml eggplant flask, toluene (86 ml), racemic trans-3- (4-methoxyphenyl) glycidic acid methyl ester (hereinafter referred to as racemic ester,
g), a solution of ammonia in t-butanol (2.65 mol / L, 14 ml) and Serratia marcescens (Se
lipase (hereinafter referred to as Lipase SM) (1 g) derived from S. cerevisiae (rratia marcescens) Sr41 [FERM-BP No. 487] was added, and the container was hermetically sealed.
The reaction is performed for 4.5 hours at 300 rpm at ° C.

The lipase SM used in this reaction was
Was prepared by culturing according to the method described in Reference Example of JP-A-6-78790, removing bacteria with an MF membrane [EMP-313, Asahi Kasei Corporation], and freeze-drying. The olive oil decomposition activity described in Reference Example of the same publication,
4.95 × 10 ⁵ units / g (the same applies to the following examples). Further, a t-butanol solution of ammonia (2.65 mol / L) was added to t-butanol under ice cooling,
Ammonia gas was prepared by bubbling for 4 hours, and the ammonia concentration was measured using an automatic potentiometric titrator (Kyoto Electronics).

The reaction solution was measured using the following apparatus and conditions for high performance liquid chromatography (HPLC) and quantified in comparison with the pure product.
(The molar number of the substrate is set to 100%, the same applies hereinafter).
(2R, 3S) type ester] 49.4%, (2S, 3
R) -type 3- (4-methoxyphenyl) glycidamide [hereinafter, (2S, 3R) -type amide] 49.6% was confirmed to be contained.

Column: Daicel Chemical Industries, Ltd. Chiral Cell OB-H Mobile phase: n-hexane-isopropanol (9: 1) Flow rate: 1.0 ml / min Temperature: 40 ° C. Detection: 235 nm From the reaction solution thus obtained, The enzyme is filtered, the collected matter is washed with acetone, the filtrate and the washing liquid are combined, and the solvent is distilled off under reduced pressure. Toluene (26 ml) was added to the residue to dissolve it, filtered, filtered through a glass filter, and the collected matter was washed with toluene. The filtrate and washing solution were combined, and toluene was distilled off.
The obtained candy was crystallized by adding methanol (10 ml), and then filtered through a glass filter, and washed twice with methanol (5 ml) to obtain (2R, 3S).
The type ester (2.07 g, yield: 41%) is obtained as crystals. After combining the filtrate and the washing solution, the mixture was further cooled on ice, and the precipitated crystals were collected by filtration to obtain a (2R, 3S) type ester (0.
15 g, yield: 3%) as crystals. Total isolated yield: 44%. When both crystals were quantified by HPLC in the same manner as described above, it was confirmed that the optical purity was 99.9% or more.

Example 2 Test tubes (6 pieces) having a diameter of 1.5 cm and a length of 12.3 cm
Respectively, toluene (1.72 ml), racemic ester (100 mg), t-butanol solution of ammonia (2.65 mol / L, 0.28 ml) and lipase S
M (20 mg) was added, and the reaction was carried out at 30 ° C. and 300 rpm with a screw cap.

At 0 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, and 5 hours after the start of the reaction, one test tube was taken out, and N, N-dimethylformamide was added to stop the enzyme reaction. When the sample was sampled from the solution and quantified by HPLC in the same manner as described above, 29.3 hours after the start of the reaction, the racemic ester of the substrate was decomposed by 49.3%, and the reaction solution contained the (2R, 3S) ester 49.9%,
Contains (2S, 3R) type 3- (4-methoxyphenyl) glycidic acid methyl ester [hereinafter, (2S, 3R) type ester] 0.8% and (2S, 3R) type amide 46.7%. It was confirmed that.

Based on this, E, which indicates the stereoselectivity of the enzyme,
When the value was calculated according to the following equation, the E value calculated from the component ratio 2 hours after the start of the reaction was 3457.

[0057]

(Equation 1)

1-C: the amount of trans-3- (4-methoxyphenyl) glycidic acid methyl ester (including any optical isomers, hereinafter referred to as residual ester) (calculated assuming that the amount of the racemic ester used is 1) ee: Optical purity of the (2R, 3S) ester type in the residual ester (calculated as 1 when the optical purity is 100%) Table 1 shows the time course of the reaction progress.

[0059]

[Table 1]

Example 3 Toluene (1.72 ml) and racemic ester (100 m) were placed in a test tube having a diameter of 1.5 cm and a length of 12.3 cm.
g), a solution of ammonia in t-butanol (2.65 mol / L, 0.28 ml), 1,3-dimethoxybenzene (internal standard, 5 μL) and lipase SM (50 mg). ° C, 300
The reaction was performed at rpm for 15 minutes. N, N-dimethylformamide was added to the test tube to stop the enzymatic reaction, a part of the reaction solution was sampled, and quantified by HPLC as described above. Racemic ester used as substrate is 4
It was decomposed by 9.4%, and it was confirmed that the reaction solution contained 48.2% of (2R, 3S) type ester, but contained only 2.3% of (2S, 3R) type ester. Was.

Example 4 An organic solvent (1.72 ml) and a racemic ester (100 m) were placed in a test tube having a diameter of 1.5 cm and a length of 12.3 cm.
g), a solution of ammonia in t-butanol (3.0 mol /
L, 0.28 ml), 1,3-dimethoxybenzene (internal standard, 5 μL) and lipase SM (10 mg), sealed with a screw cap, and 30 ° C., 300 r
The reaction was performed at pm for 4 hours. N, N-dimethylformamide was added to the test tube to stop the enzymatic reaction, a part of the reaction solution was sampled, and quantified by HPLC as described above. The amounts of (2R, 3S) type ester and (2S, 3R) type ester contained in the reaction solution are as shown in Table 2.

[0062]

[Table 2]

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Akiko Dei 2- 18-4, 505, Miyakojima Kitadori, Miyakojima-ku, Osaka-shi, Osaka (56) References JP-A-6-78790 (JP, A) (58) Surveyed field (Int. Cl. ⁷ , DB name) C12P 41/00 BIOSIS (DIALOG)

Claims (8)

(57) [Claims] 1. A compound of the general formula (I) (Where R ¹ represents a lower alkyl group and R represents an ester residue) and a racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester represented by the general formula (I
I) (However, R ² represents a hydrogen atom or a lower alkyl group.)
With an amine compound represented by the formula (2S, 3R)
Reacting in the presence of a lipase or esterase derived from a microorganism of the genus Serratia having the ability to asymmetrically amidate (4-lower alkoxyphenyl) glycidic acid ester,
After selectively amidating the (2S, 3R) type optical isomer, the remaining (2R, 3S) type 3- (4-lower alkoxyphenyl) glycidic acid ester is separated from the reaction solution.
General formula (III) characterized by being collected: (However, R ¹ and R have the same meanings as described above.) A method for producing (2R, 3S) type 3- (4-lower alkoxyphenyl) glycidic acid ester represented by the formula: 2. The method according to claim 1, wherein R is a lower alkyl group. 3. The method according to claim 1, wherein R ² is a hydrogen atom. 4. The method according to claim ^1, wherein R ¹ and R are methyl groups.
Or the method of 3. 5. A method according to claim 1, 2, 3 or 4 The method according Serratia microorganism is Serratia marcescens (Serratiamarcescens). 6. A compound of the general formula (I) (Where R ¹ represents a lower alkyl group and R represents an ester residue) and a racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester represented by the general formula (I
I) (However, R ² represents a hydrogen atom or a lower alkyl group.)
With an amine compound represented by the formula (2S, 3R)
Reacting in the presence of a lipase or esterase derived from a microorganism of the genus Serratia having the ability to asymmetrically amidate (4-lower alkoxyphenyl) glycidic acid ester,
After selectively amidating the (2S, 3R) type optical isomer, the remaining (2R, 3S) type 3- (4-lower alkoxyphenyl) glycidic acid ester is separated from the reaction solution.
Collect the compound of general formula (III) (Wherein, R ¹ and R have the same meanings as described above.) A (2R, 3S) -type 3- (4-lower alkoxyphenyl) glycidic acid ester represented by the general formula (I)
V) (However, ring A is an optionally substituted benzene ring, R ³
Represents a hydrogen atom or a di-lower alkylamino lower alkyl group. )), And if necessary, the product is subjected to ester hydrolysis, followed by an intramolecular ring closure reaction. (However, R ¹ , R ³ and ring A have the same meanings as described above.) A method for producing a (2S, 3S) type 1,5-benzothiazepine derivative represented by the formula: 7. A compound of the general formula (I) (Where R ¹ represents a lower alkyl group and R represents an ester residue) and a racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester represented by the general formula (I
I) (However, R ² represents a hydrogen atom or a lower alkyl group.)
With an amine compound represented by the formula (2S, 3R)
Reacting in the presence of a lipase or esterase derived from a microorganism of the genus Serratia having the ability to asymmetrically amidate (4-lower alkoxyphenyl) glycidic acid ester,
After selectively amidating the (2S, 3R) type optical isomer, the remaining (2R, 3S) type 3- (4-lower alkoxyphenyl) glycidic acid ester is separated from the reaction solution.
Collecting the compound of the general formula (III) (Wherein, R ¹ and R have the same meanings as described above), and a (2R, 3S) -type 3- (4-lower alkoxyphenyl) glycidic acid ester represented by the general formula (I)
V) (However, ring A is an optionally substituted benzene ring, R ³
Represents a hydrogen atom or a di-lower alkylamino lower alkyl group. ) And, if necessary, ester hydrolysis of the product, followed by an intramolecular ring closure reaction to give the compound of the general formula (V) (However, R ¹ , R ³ and ring A have the same meaning as described above.) A (2S, 3S) type 1,5-benzothiazepine derivative represented by the formula
^{When 3} is a hydrogen atom, a di-lower alkylamino lower alkyl group is introduced by N-alkylation to give a compound of the general formula (VI) (However, R ⁴ is a di-lower alkylamino lower alkyl group,
R ⁵ represents a lower alkanoyl group, and R ¹ and ring A have the same meaning as described above. And (2S, 3S) type 1,5-benzothiazepine derivatives or pharmacologically acceptable salts thereof, characterized in that the compound represented by the formula (1) is optionally converted into a pharmaceutically acceptable salt thereof. Method of producing salt. 8. Ring A is an unsubstituted benzene ring, R ¹ is a methyl group, R ⁴ is dimethylaminoethyl group, method according to claim 7, wherein R ⁵ is an acetyl group.