JP2714315B2 - Optically active epoxy propionic acid derivative and its preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active epoxypropionic acid derivative, a method for producing the same, and a method for obtaining a 1,5-benzothiazepine derivative from the epoxypropionic acid derivative.

[0002]

BACKGROUND OF THE INVENTION Optically active epoxypropionic acid derivatives and 1,5-benzothiazepine derivatives obtainable by the present invention are useful as coronary vasodilator diltiazem hydrochloride: (2S, 3S) -cis-3-acetoxy. −
Extremely important as an intermediate such as 2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one hydrochloride Compound.

Heretofore, methods for producing optically active epoxypropionic acid derivatives and benzothiazepine derivatives include: (i) (±)-(2RS, 3SR) -2,3-epoxy-3- (4-methoxyphenyl) propion An acid or an alkali metal salt thereof is reacted with an optically active organic amine or a mineral acid salt thereof, and the resulting diastereomer salt is converted into (-)-(2R, 3S) using the difference in solubility in a solvent.
-Isomer and then reacted with 2-aminothiophenol to give (2S, 3S) -3- (2-aminophenylthio)
Method for producing 2-hydroxy-3- (4-methoxyphenyl) propionic acid (JP-A-60-13775,
JP-A-60-13776, JP-A-61-145159
No., JP-A-61-145160),

(Ii) Stereoselective condensation of 4-methoxybenzaldehyde and halogenoacetic acid (-)-menthyl ester to give (2R, 3S) -2,3-epoxy-3-
(4-Methoxyphenyl) propionic acid (-)-menthyl ester was obtained and further reacted with 2-aminothiophenol to give (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3- ( Method for obtaining 4-methoxyphenyl) propionic acid (JP-A-61-26866)
No. 3), or

(Iii) Anti (+)-(2S, 3S)
-Or syn (-)-(2R, 3S) -2-chloro-3
-Hydroxy-3- (4-methoxyphenyl) propionate was synthesized and reacted in the presence of an organic base to give (-)-(2R, 3S) -2,3-epoxy-3-.
(4-methoxyphenyl) propionic acid ester is obtained,
A method for leading to diltiazem (see JP-A-3-56471) is known.

[0006]

However, (i)
In this method, an expensive optical resolving agent such as optically active α-methylbenzylamine must be used, and the yield of the diastereomer salt obtained is low. In the method (ii), expensive optically active menthol must be used, and the asymmetric yield is not sufficient. Further, (ii)
The method i) has disadvantages such as the necessity of using an expensive and special asymmetric catalyst reagent to obtain the optically active α-chloro-β-hydroxyester compound as a raw material. It was not a manufacturing method.

[0007]

Means for Solving the Problems The present inventors have made intensive studies to overcome the disadvantages of the prior art, and as a result, have found that an optically active epoxypropionic acid derivative [I] can be produced economically by a preferential crystallization optical resolution method. And it was found that it can be obtained with high yield by industrially easy operation.

That is, according to the present invention, general formula [I]:

Embedded image Wherein ring A is a benzene ring substituted at the 4-position with a methoxy group. The optically active epoxypropionic acid derivative represented by the formula:
It can be obtained by inoculating crystals of the (S, 3R) -form or (2R, 3S) -form and preferentially crystallizing the same optically active epoxypropionic acid derivative.

In general, in a method for obtaining an optically active substance by optically resolving a racemic body, one optically active body is inoculated into a supersaturated solution of the racemic body, and the same kind of optically active body as the inoculated optically active body is separated. The principle of the so-called preferential crystallization method is described in, for example, Jeques, A. Colette, S.M.
H. Entitled "Enantiomers, racemates, and resolution" by Wylen [J. Willie and Sun, New York (1981)]. This method is industrially advantageous because it does not require a special and expensive optically active resolving agent unlike the diastereomer method. However, this method is advantageously applicable only generally when the racemic crystals form a racemic mixture, and which compounds crystallize and form a racemic mixture, and whether preferential crystallization is possible. It is unknown, and there is no regularity.

That is, in order to find a racemic mixture to which this optical resolution method can be applied, it is necessary to prepare and confirm crystals of various epoxypropionate esters.
Usually, the probability of forming a racemic mixture is very low, and it is rather a special case. Therefore, great effort is required to find a compound that satisfies such conditions.

Conventionally, (2R, 3S) -2,3-epoxy-3- (substituted-phenyl) propionic acid ester and (2S, 3R) -2,3-epoxy-3- (substituted-phenyl) propionic acid ester There has been no known method of optically resolving a mixture of the above by a preferential crystallization method to obtain each optically active substance. This is because the carboxylic acid form and the lower alkyl ester form of the compound are unstable and easily decomposed, and thus are disadvantageous for repeated preferential crystallization resolution. The present inventors have studied various ester forms of (2RS, 3SR)-and (2R, 3S)-or (2S, 3R) -2,3-epoxy-3- (substituted-phenyl) propionic acid. When the compound was converted to a 4-chloro-3-methylphenyl ester, it was found that the compound was excellent in stability, formed a racemic mixture, and could be repeatedly subjected to preferential crystallization, and completed the present invention.

According to the optical resolution method of the epoxypropionic acid derivative of the present invention, both (2R, 3S) -coordinated compound and (2S, 3R) -coordinated compound can be obtained. The optically active epoxy propionate [I] thus obtained is represented by the following general formula [II]:

Embedded image [Wherein ring B is a benzene ring which may have a substituent (s)]
I] to give the general formula [III]:

Embedded image [In the formula, ring A and ring B are as defined above] to obtain an optically active propionic acid derivative [III]. This compound [III] is further subjected to a ring closure reaction to give a compound of the general formula [IV]:

Embedded image [Wherein ring A and ring B are as defined above], an optically active 1,5-benzothiazepine derivative [IV]
Can be obtained.

In the present invention, ring A and / or ring B
Is a benzene ring having a substituent, examples of such a substituent include a lower alkyl group, a lower alkoxy group, and a halogen atom.

2,3-Epoxy-3- (substituted or unsubstituted-phenyl) propionic acid 4 as a raw material used in the present invention
-Chloro-3-methylphenyl ester is obtained by converting 2,3-epoxy-3- (substituted or unsubstituted-phenyl) propionic acid using 4-chloro-3-methylphenol, for example, as described in JP-A-61-145159. It can be easily obtained by subjecting it to a general esterification reaction such as the method described above.

The optically active 2,3-epoxy-3 of the present invention
-(Substituted or unsubstituted-phenyl) propionic acid 4-chloro-3-methylphenyl ester is obtained by the above-mentioned method, (2R, 3S) -epoxypropionic acid ester and (2S, 3R) -epoxypropionic acid ester Can be obtained by optical resolution. More specifically, a supersaturated solution of the mixture is prepared, and the solution is inoculated with crystals of an optically active (2S, 3R) -epoxypropionate or (2R, 3S) -epoxypropionate, It can be obtained by preferentially crystallizing the same optically active substance as the crystal.

A supersaturated solution of a mixture of (2R, 3S) -epoxypropionate and (2S, 3R) -epoxypropionate is (±)-(2RS,
The 3SR) -epoxypropionate is dissolved in an appropriate solvent by heating and then cooled, concentrated, or used to prepare a general supersaturated solution such as a method of adding a solvent that reduces the solubility of the epoxypropionate. It can be prepared by a method such as

As the solvent, methanol, ethanol,
Alcohol solvents such as isopropanol, acetone, ketone solvents such as methyl ethyl ketone or ethers such as ethyl ether, isopropyl ether, dioxane, tetrahydrofuran, n-hexane, n-heptane,
Aliphatic or aromatic hydrocarbons such as benzene, toluene, and xylene; and halogenated hydrocarbons such as chloroform, bromoform, carbon tetrachloride, 1,2-dichloroethane, and monochlorobenzene; and esters such as ethyl acetate. And nitriles such as acetonitrile, amides such as acetamide and dimethylformamide, or a mixed solvent thereof. Particularly, tetrahydrofuran (THF) and dimethylformamide (DMF) are preferable for efficient optical resolution.

When the solute of the supersaturated solution of the epoxypropionic acid derivative in the present invention is an optically pure racemate, it is necessary to inoculate a seed crystal from the outside in the resolution, but the solute is optically impure. In such a case, that is, when one of the optically active substances is present in a large amount, the active substance spontaneously crystallizes and acts in the same manner as when a seed crystal is inoculated, so that external inoculation is not necessarily required. The amount of inoculation is not particularly limited, but the larger the number, the easier the splitting is facilitated, but usually, the inoculating amount of about 10% by weight or less of the epoxypropionate in the split solution may be used.
It is desirable that the optically active substance to be inoculated be of high purity for the purpose of use.

In the mother liquor in which the one optically active epoxy propionate was crystallized by the above operation, the opposite optically active epoxy propionate was excessively dissolved. By repeating the above operation, the enantiomer can be selectively crystallized.
For example, after additionally dissolving the (±) -epoxypropionic acid ester, the solution is cooled to prepare a supersaturated solution, and an appropriate amount of the enantiomer is inoculated into the solution. Obtainable. In the method of the present invention,
Optically active epoxy propion, which is not only in a so-called batch type one-sided division where only one optically active substance is crystallized from a supersaturated solution but also in a divided tank having two divided towers or sections connected in parallel or in series. By inoculating one of the acid esters, two kinds of optically active epoxy propionates can be obtained at the same time.

In carrying out the method for obtaining an optically active epoxy propionate of the present invention, a compound soluble in a supersaturated solution of a racemic form of the compound is added to increase the degree of supersaturation and increase stability. Is also possible.

The optically active epoxypropionic acid derivative [I] of the present invention and the 2-aminothiophenol derivative [I]
I] to react with an optically active propionic acid derivative [II
The reaction for obtaining the optically active 1,5-benzothiazepine derivative [IV] via I] suitably proceeds in the presence of a solvent.

The solvent is not particularly limited as long as it does not hinder the progress of the reaction. Examples of the solvent include hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene and xylene, and methylene chloride, chloroform and monochlorobenzene. Halogenated hydrocarbons, ethers such as ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, and esters such as ethyl acetate can be used, and preferred solvents are hydrocarbons.

The reaction temperature can be raised to the boiling point of the solvent, but is usually 50 to 150 ° C., preferably 70 to 14 ° C.
0 ° C., and the reaction time varies depending on the starting material, the reaction temperature and the like, but is usually 4 to 48 hours, preferably 4 to 24 hours.

After completion of the reaction, the optically active propionic acid derivative [III] can be separated from the reaction solution by a conventional method. For example, the reaction solution is cooled, or an aliphatic hydrocarbon such as hexane is added, and the precipitated crystals are collected by filtration, or water is added and extracted with an organic solvent, followed by distilling off the solvent. can do. Further, if necessary, it can be further purified by, for example, recrystallization, column chromatography or the like.

Next, the obtained optically active propionic acid derivative [III] is dissolved in a solvent, a catalytic amount of an organic acid such as methanesulfonic acid or p-toluenesulfonic acid is added, and the mixture is heated to 110 to 140 ° C. at 1 to 3 ° C. After the heating reaction for a period of time, if the same treatment is performed as described above, an optically active 1,5-benzothiazepine compound [IV] can be obtained in a high yield.

Further, an optically active propionic acid derivative [I
II], a catalytic amount of an organic acid such as methanesulfonic acid or p-toluenesulfonic acid is directly added to the reaction solution produced above and reacted by heating, and treated in the same manner as described above to obtain an optically active epoxypropionic acid derivative [I]. Thus, an optically active 1,5-benzothiazepine compound [IV] can be obtained at once.

The optically active 1,5-benzothiazepine derivative [IV] represented by the general formula [IV] can be produced by a known method, for example, as described in JP-B-46-16749 and JP-B-sho-4.
6-43785, JP-B-47-813, JP-B-53
No.-18038, JP-B-63-13994 or JP-A-3-157378 according to the general formula [V]:

Embedded image Wherein R ¹ is a lower alkanoyl group or a lower alkoxycarbonyl lower alkyl group, R ² is a lower alkyl group,
R ³ is a lower alkyl group or a lower alkoxyphenyl lower alkyl group, Y is a lower alkylene group, and ring A and ring B are as defined above.
-A benzothiazepine derivative [V].

For example, a 1,5-benzothiazepine derivative [V] can be obtained by converting a compound [IV] into a compound of the general formula [VI]: R ¹ OH [VI] wherein R ¹ is a lower alkanoyl group or a lower alkoxycarbonyl lower compound. Which is an alkyl group] or a reaction derivative thereof, by condensation reaction.
I]:

Embedded image Wherein the symbols are as defined above, and an optically active 1,5-benzothiazepine derivative [VII],
Further, after converting the compound into an alkali metal salt at the 5-position nitrogen site, the compound [VIII]:

Embedded image [Wherein X is a halogen atom, and other symbols are as defined above.]
Can be manufactured.

In the above method, the general formula [V
The condensation reaction with the compound of the formula [I] and the condensation reaction with the general formula [VIII] may be performed in a different order. That is, the alkali metal salt of the compound [IV] may be condensed with the compound [VIII], and then condensed with the compound [VI].

For example, to obtain diltiazem from the above optically active 1,5-benzothiazepine compound [IV],
Compound [IV] in which ring A is a 4-methoxyphenyl group and ring B is an unsubstituted phenyl group can be prepared, for example, by reacting 2-
By reacting with (dimethylamino) ethyl halide and then acetylating the hydroxyl group, diltiazem having high optical purity can be easily obtained.

In the present invention, the lower alkyl group, lower alkoxy group and lower alkylene group have 1 to 1 carbon atoms.
6, especially 1-4, and lower alkanoyl groups include those having 1-6, especially 1-4.

[0032]

EXAMPLES Next, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Determination of Optical Purity The optical purity of the compound [I] obtained by the optical resolution method of the present invention was calculated from the specific rotation of the pure optically active compound [I] based on the following formula (1). . The specific optical rotation of the pure optically active compound [I] is [α] ²⁵ _D : -193.4 ° (c = 1.0, THF) in the (−) form, and the (+) form is [ α] ²⁵ _D : + 193.4 ° (c = 1.0, THF).

## EQU1 ## Equation (1): The resolution of the compound obtained by the optical resolution method of the present invention was calculated based on the formula (2).

## EQU2 ## Equation (2):

Reference Example 1 (±)-(2RS, 3SR) -2,3-epoxy-3-
(4-methoxyphenyl) propionic acid 4-chloro-3
Synthesis of -methylphenyl ester (±)-(2RS, 3SR) -2,3-epoxy-3-
(4-methoxyphenyl) propionic acid potassium salt 4
0.7 g (0.175 mol) and triethylamine 1
7.7 g (0.175 mol) are suspended in 200 ml of DMF and stirred at 40 ° C. To the mixture was added 25.0 g (0.175 mol) of 4-chloro-3-methylphenol / DMF
100 ml solution and 1 M 1-methyl-2-chloropyridinium methyl sulfate dichloromethane solution 193 ml
And stirred for 30 minutes. After adding ethyl acetate and extracting, the mixture is washed with water and saturated saline and dried over anhydrous magnesium sulfate. After concentrating the solvent, the precipitate was filtered, washed with cold ethyl acetate, and dried, and 28.1 g of the title compound (yield: 5
0.3%). Melting point: 123-124 ° C IR spectrum (KBr tablet) cm ^-1 : 1750,16
12,1517,1476,1403,1249,11
75, 1158, 1051, 1033, 896, 83
6,810,780,694,528 NMR spectrum (200 MHz, CDCl ₃ ) δ:
7.4 to 6.8 (m, 7H), 4.19 (d, 1H),
3.82 (s, 3H), 3.70 (d, 1H), 2.3
7 (s, 3H)

Reference Example 2 (-)-(2R, 3S) -2,3-epoxy-3- (4
Synthesis of (-methoxyphenyl) propionic acid 4-chloro-3-methylphenyl ester (-)-(2R, 3S) -2,3-epoxy-3- (4
-Methoxyphenyl) propionic acid potassium salt 23.2
g (0.100 mol) in the same manner as in Reference Example 1 to obtain 17.3 g (yield: 54.3%) of the title compound. Melting point: 139-141 ° C [α] ²⁵ _D : -193.4 ° (c = 1.0, THF)
Or [α] ²⁵ _D : -191.4 ° (c = 1.0, ethyl acetate) IR spectrum (KBr tablet) cm ⁻¹ : 1751, 16
12, 1517, 1477, 1404, 1248, 11
76, 1158, 1052, 1031, 896, 83
7,808,780,694,527 NMR spectrum (200 MHz, CDCl ₃ ) δ:
7.4 to 6.8 (m, 7H), 4.19 (d, 1H),
3.82 (s, 3H), 3.71 (d, 1H), 2.3
8 (s, 3H)

Reference Example 3 (+)-(2S, 3R) -2,3-epoxy-3- (4
Synthesis of (-methoxyphenyl) propionic acid 4-chloro-3-methylphenyl ester (+)-(2S, 3R) -2,3-epoxy-3- (4
-Methoxyphenyl) propionic acid potassium salt 1.08
g (4.65 mmol) and the reaction treatment was carried out in the same manner as in Reference Example 1 to obtain 0.74 g (yield: 50.0%) of the title compound. Melting point: 138-140 ° C [α] ²⁵ _D : + 190.3 ° (c = 1.0, ethyl acetate) The IR spectrum and NMR spectrum are the same as those of Reference Example 2.

Example 1 (±)-(2RS, 3SR) -2,3-epoxy-3-
(4-methoxyphenyl) propionic acid 4-chloro-3
-Resolution by preferential crystallization of -methylphenyl ester (THF solution) (A) (±)-(2RS, 3SR) -2,3-epoxy-3- (4-methoxyphenyl) propionic acid 4-chloro-3 8.58 g of -methylphenyl ester and 0.40 g of the (-)-(2R, 3S) -form thereof in THF 50m
After heating and dissolving in 1 l, the mixture is cooled to 30 ° C. (-)-(2
(R, 3S) -body is inoculated and cooled to 25 ° C. in about 20 minutes with stirring. The precipitate was filtered, washed with cold THF, and dried to give the (-)-(2R, 3S) -isomer 0.5
1 g is obtained. [Α] ²⁵ _D : -193 ° (c = 1.0, THF) Optical purity: 99.9% IR spectrum and NMR spectrum are the same as those of Reference Example 2. (B) 0.22 g of the (±)-(2RS, 3SR) -form and THF are added to the mother liquor of (A) and dissolved by heating, and then cooled to 30 ° C. Next, 3 mg of the (+)-(2S, 3R) -isomer was inoculated and treated in the same manner as in (A) to obtain 0.35 g of the (+)-(2S, 3R) -isomer. [Α] ²⁵ _D : + 190 ° (c = 1.0, THF) Optical purity: 98.1% IR spectrum and NMR spectrum are identical with those of Reference Example 3.

Thereafter, the (+)-isomer and THF are appropriately added each time, and the preferential crystallization is further repeated four times to obtain the optically active isomers shown in Table 1 below.

[Table 1]

Example 2 (±)-(2RS, 3SR) -2,3-epoxy-3-
(4-methoxyphenyl) propionic acid 4-chloro-3
-Resolution by preferential crystallization of -methylphenyl ester (DMF solution) (A) (±)-(2RS, 3SR) -2,3-epoxy-3- (4-methoxyphenyl) propionic acid 4-chloro-3 -Methylphenyl ester (8.10 g) and its (-)-(2R, 3S) -form (0.31 g) in DMF (50 m)
After heating and dissolving in 1 l, the mixture is cooled to 30 ° C. (-)-(2
(R, 3S) -body is inoculated and cooled to 25 ° C. in about 20 minutes with stirring. The precipitate is filtered and cold DMF
And then dried to obtain the (-)-(2R, 3S) -isomer.
62 g are obtained. [Α] ²⁵ _D : -176 ° (c = 1.0, THF) Optical purity: 91.1% IR spectrum and NMR spectrum are the same as those of Reference Example 2. (B) 2.26 g of (±)-(2RS, 3SR) -form and DMF are appropriately added to the mother liquor of (A) and dissolved by heating, and then 30 ° C.
Cool. Then (+)-(2S, 3R) -body 3mg
And treated in the same manner as (A) (+)-(2S, 3R)
-Obtain 0.72 g of body. [Α] ²⁵ _D : + 181 ° (c = 1.0, THF) Optical purity: 93.5% IR spectrum and NMR spectrum are identical with those of Reference Example 3.

Thereafter, the (+)-form and DMF are appropriately added each time, and the preferential crystallization is further repeated four times to obtain the optically active forms shown in Table 2 below. The amount of DMF was increased with each crystallization,
Make 9 ml.

[Table 2]

Example 3 (1) (-)-(2R, 3S) -2,3-epoxy-3
-(4-methoxyphenyl) propionic acid 4-chloro-
1.91 g (6.00 mmol) of 3-methylphenyl ester is added to 12 ml of chlorobenzene and dissolved by heating.
At 110 ° C, 0.77 g of 2-aminothiophenol (6.
18 mmol) and stir for 30 minutes. After cooling to room temperature, the precipitated crystals were washed with cold chlorobenzene and dried, and dried (2S, 3S) -3- (2-aminophenylthio) -2.
-Hydroxy-3- (4-methoxyphenyl) propionic acid 4-chloro-3-methylphenyl ester 2.03
g (76.4% yield). Melting point: 157 to 159 ° C [α] ²⁵ _D : + 223 ° (c = 0.5, DMF) IR spectrum (KBr tablet) cm ^-1 : 3455,33
58, 1736, 1608, 1511, 1480, 13
84,1299,1238,1179,1105,10
52, 1031, 906, 816, 746, 457 NMR spectrum (200 MHz, CDCl ₃ ) δ:
7.4-6.5 (m, 11H), 4.8-4.0 (m,
5H), 3.81 (s, 3H), 2.33 (s, 3H)

(2) (2S, 3S) -2-hydroxy-
1.33 g (3.00 mmol) of 3- (4-methoxyphenyl) -3- (2-aminophenylthio) propionic acid 4-chloro-3-methylphenyl ester is added to 6 ml of chlorobenzene and stirred with heating. At 110 ° C., 5.6 mg of methanesulfonic acid are added, and the mixture is further stirred at 140 ° C. for 1 hour. After cooling to room temperature, the precipitated crystals were washed with cold chlorobenzene and dried, and then dried (2S, 3S) -cis-2,3-
0.85 g (yield: 94%) of dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one is obtained. Melting point: 199-200 ° C [α] ²⁵ _D : + 109 ° (c = 0.5, DMF) IR spectrum (KBr tablet) cm ^-1 : 3191,16
82, 1512, 1476, 1338, 1307, 12
56, 1179, 1103, 1025, 814, 765 NMR spectrum: (200 MHz, CDCl ₃ ) δ:
9.34 (s, 1H), 7.7 to 6.7 (m, 8H),
5.08 (d, 1H), 4.47 (q, 1H), 3.7
2 (s, 3H), 3.15 (d, 1H)

Example 4 (-)-(2R, 3S) -2,3-epoxy-3- (4
-Methoxyphenyl) propionic acid 4-chloro-3-methylphenyl ester 1.91 g (6.00 mmol)
Is added to 12 ml of chlorobenzene and stirred with heating. 110
After adding 0.77 g (6.18 mmol) of 2-aminothiophenol at 30 ° C. and stirring for 30 minutes, methanesulfonic acid 1 was added.
1 mg is added and further stirred at 140 ° C. for 1 hour. After cooling to room temperature, the precipitated crystals were washed with cold chlorobenzene and dried, and then dried (2S, 3S) -cis-2,3-dihydro-3.
-Hydroxy-2- (4-methoxyphenyl) -1,5
-Benzothiazepine-4 (5H) -one (1.00 g, yield: 55.2%) is obtained. Melting point: 198-200 ° C. [α] ²⁵ _D : + 110 ° (c = 0.5, DMF) The IR spectrum and the NMR spectrum are those of Example 3.
Consistent with the compound of (2).

Example 5 (-)-(2R, 3S) -2,3-epoxy-3- (4
-Methoxyphenyl) propionic acid 4-chloro-3-methylphenyl ester 1.91 g (6.00 mmol)
Is added to 12 ml of xylene and stirred with heating. 2 at 110 ° C
After adding 0.77 g (6.18 mmol) of -aminothiophenol and stirring for 2 hours, methanesulfonic acid 11m
g and stirred for a further 30 minutes. After cooling to room temperature, the precipitated crystals were washed with cold xylene and then dried (2S, 3
S) -cis-2,3-dihydro-3-hydroxy-2-
1.04 g (yield: 57.5%) of (4-methoxyphenyl) -1,5-benzothiazepine-4 (5H) -one is obtained. Melting point: 195-198 ° C. [α] ²⁵ _D : + 111 ° (c = 0.5, DMF) The IR spectrum and the NMR spectrum are those of Example 3.
Consistent with the compound of (2).

[0045]

According to the method of the present invention, 1,5 such as diltiazem can be used.
-An optically active 2,3-epoxypropionic acid derivative which is important as an intermediate of the benzothiazepine derivative [V] can be obtained with high optical purity by the above-mentioned preferential crystallization optical resolution method without using an expensive optically active reagent. Moreover, the compound can be obtained with high reproducibility, and the compound can be easily prepared from 1,1, such as diltiazem.
It can lead to a 5-benzothiazepine derivative [V]. Therefore, the optically active epoxypropionic acid derivative [I] of the present invention and its production method are suitable for an industrial scale.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location // A61K 31/55 ABS A61K 31/55 ABS (56) References JP-A-3-56471 (JP) , A)

Claims (5)

(57) [Claims] 1. A compound of the general formula [I]: [Wherein ring A is a benzene ring substituted at the 4-position with a methoxy group]. 2. A compound of the general formula [I]: Wherein ring A is a benzene ring substituted at the 4-position with a methoxy group, wherein the racemic epoxypropionic acid derivative is optically resolved by a preferential crystallization method. Production method of acid derivative [I]. 3. A compound of the general formula [I]: [Wherein ring A is a benzene ring substituted with a methoxy group at the 4-position] The optically active epoxypropionic acid derivative obtained by optically resolving a racemic epoxypropionic acid derivative represented by the following formula: [I] and the general formula [I
I]: embedded image [Wherein ring B is a benzene ring which may have a substituent (s)]
I] to give a compound of the general formula [III]: Wherein ring A and ring B are as defined above, to obtain an optically active propionic acid derivative [III], and subjecting the compound [III] to a ring closing reaction, IV]: [Wherein ring A and ring B are as defined above], a method for producing an optically active 1,5-benzothiazepine derivative. 4. A compound of the general formula [I]: [Wherein ring A is a benzene ring substituted with a methoxy group at the 4-position] The optically active epoxy obtained by optically resolving a racemic epoxypropionic acid derivative [I] represented by the following formula: Propionic acid derivative [I] and general formula [II]: [Wherein ring B is a benzene ring which may have a substituent (s)]
I] is subjected to a ring-closing reaction at once, characterized by the general formula [IV]: [Wherein ring A and ring B are as defined above], a method for producing an optically active 1,5-benzothiazepine derivative. 5. A compound of the general formula [I]: [Wherein ring A is a benzene ring substituted with a methoxy group at the 4-position] The optically active epoxypropionic acid derivative obtained by optically resolving a racemic epoxypropionic acid derivative represented by the following formula: [I] and the general formula [I
I]: embedded image [Wherein ring B is a benzene ring which may have a substituent (s)]
I] to give a compound of the general formula [III]: Wherein ring A and ring B are as defined above, to obtain an optically active propionic acid derivative [III], and then subjecting the compound [III] to a ring-closing reaction or a compound [I] And the compound [II] are subjected to a ring-closing reaction at once to give a compound of the general formula [IV]: [Wherein ring A is a benzene ring substituted at the 4-position with a methoxy group, and ring B is a benzene ring which may have a substituent]. After obtaining the thiazepine derivative [IV], the compound [IV] is converted to a compound of the general formula [VI]: R ¹ OH [VI] wherein R ¹ is a lower alkanoyl group or a lower alkoxycarbonyl lower alkyl group. The compound of the formula [VI]
I]: embedded image Wherein the symbols are as defined above, and an optically active 1,5-benzothiazepine derivative “VII”,
Further, after converting the compound into an alkali metal salt at the nitrogen position at the 5-position, compound [VIII]: Wherein R ² is a lower alkyl group, R ³ is a lower alkyl group or a lower alkoxyphenyl lower alkyl group, Y is a lower alkylene group, and X is a halogen atom. The alkali metal salt of the compound [IV] is condensed with the compound [VIII] and then condensed with the compound [VI] to give a compound of the general formula [V]: Wherein the symbols are as defined above, and wherein the product is a pharmacologically acceptable salt thereof, if desired. A method for producing a 1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof.