JPH09216874A - Optically active benzothiazepine derivative and process for producing the same - Google Patents

Abstract

(57) Abstract: An optically active 1,5-benzothiazepine derivative salt and a method for producing the same are provided. SOLUTION: The general formula [I] or [II] [In the formula, ring A and ring B represent a benzene ring which may have a substituent, and R ¹ and R ² are the same or different and represent a lower alkyl group. ] The method of obtaining optically active said compound salt by optically resolving the racemic 1,5-benzothiazepine derivative salt shown by these by the preferential crystallization method.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an optically active 1,5-benzothiazepine derivative and a method for producing the same.

[0002]

The optically active 1,5-benzothiazepine derivative obtainable by the present invention is a diltiazem hydrochloride useful as a coronary vasodilator [Chemical name: (2S, 3S)-
Cis-3-acetoxy-5- [2- (dimethylamino)
Ethyl] -2,3-dihydro-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one hydrochloride] and the like are extremely important compounds as intermediates.
As a method for producing an optically active 1,5-benzothiazepine derivative, for example, the following production methods (i) and (ii) are known.

(I) Two types of diastereomers produced by reacting racemic 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid or its ester with optically active tartaric acid. After obtaining a sparingly soluble diastereomer salt [(-)-(2S, 3S) -diastereomer salt] by utilizing the difference in solubility of the mer salt in a solvent, the salt is used as an optically active 1,5-benzothiol salt. A method of leading to an azepine derivative (JP-A-3-115273).

(Ii) Racemic-cis-3-acetoxy-2,3-dihydro-5- [2- (dimethylamino) ethyl] -2- (4-methoxyphenyl) -1,5-benzothiazepine- The 4 (5H) -one was treated with d-tartaric acid, quinic acid, dibenzoyl-d-tartaric acid or d-10-camphor-sulfonic acid, and the difference in the solubility of the two diastereomeric salts formed in the solvent was used. To obtain a sparingly soluble diastereomer salt, and then from the salt, the optically active 1,5
-A method for obtaining a benzothiazepine derivative (Inoue et al., Pharmaceutical Journal, 93 (6), 729-732 (1973)).

However, racemic-cis-5- [2
-(Di-lower alkylamino) ethyl] -2,3-dihydro-3-hydroxy-2- (substituted or unsubstituted phenyl)
-1,5-substituted or unsubstituted benzothiazepine-4 (5
There is no known method of optically resolving H) -one in the form of a salt with a compound having no optical activity by a preferential crystallization method to obtain each optically active salt.

Generally, in a method of optically resolving a racemate, so-called preferential crystallization in which a supersaturated solution of the racemate is inoculated with one of the optically active substances and the optically active substance of the same species as the inoculated optically active substance is separated. The principle of law is, for example,
J. Jeques, A. Colette, S.M. H. By wilen
"Enantiomers, racemates, and resolutions" [J. Wiley and Sons, New York (1981)].

This method does not require a special and expensive optically active resolving agent as in the diastereomer method, and is an industrially advantageous resolving method. However, the compounds to which this method can be advantageously applied are generally limited to those in which the racemate forms a racemic mixture in solution. Moreover, it is not clear what racemates form a racemic mixture, and whether preferential crystallization is applicable, nor is there any 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 benzothiazepine derivatives. However, the probability of forming a racemic mixture is usually very low,
It is rather rare to form, and great effort is required to find a compound satisfying such conditions.

[0009]

The present invention provides a method for producing an optically active 1,5-benzothiazepine derivative by a preferential crystallization method industrially advantageously and in high yield.

[0010]

As a result of earnest studies, the present inventors have found that (2RS, 3RS)-and (2R, 3R)-or (2S, 3S) -cis-5- [2- (di-lower alkyl). Amino) ethyl] -2,3-dihydro-3-hydroxy-2- (substituted or unsubstituted phenyl) -1,5-substituted or unsubstituted benzothiazepin-4 (5H) -one various salts were investigated. As a result, the 1-naphthalenesulfonic acid addition salt or the 2-aminophenol-4-sulfonic acid addition salt of the compound is excellent in stability, and the acid addition salt forms a racemic mixture, and is optically resolved by the preferential crystallization method. The present invention has been completed by finding out that it is possible.

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

[0012]

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[In the formula, ring A and ring B represent a benzene ring which may have a substituent, and R ¹ and R ² are the same or different and represent a lower alkyl group. ] The optically active salt of 1,5-benzothiazepine derivative salt [I] is obtained by optically resolving the racemic salt of 1,5-benzothiazepine derivative salt [I] You can

The general formula [II]

[0015]

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[Wherein the symbols have the same meanings as described above. ] The optically active salt of the 1,5-benzothiazepine derivative salt [II] is obtained by optically resolving the racemic salt of the 1,5-benzothiazepine derivative salt [II] by the preferential crystallization method. You can

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, ring A and / or ring B of the 1,5-benzothiazepine compound represented by the above general formulas [I] and [II] have no substituent. Or may have a substituent selected from a lower alkyl group, a lower alkoxy group and a halogen atom at an arbitrary substitution position.

As such a lower alkyl group, a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a lower alkoxy group. As, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group and the like, a straight or branched chain alkoxy group having 1 to 6 carbon atoms, the halogen atom, a chlorine atom, a bromine atom, a fluorine atom, Examples thereof include iodine atom.

Of these, the ring A has the general formula [V]

[0020]

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[Wherein R represents a hydrogen atom, a methyl group, a methoxy group or a chlorine atom. ] The benzene ring shown by the above is preferable, and as the ring B, a benzene ring having a methoxy group or a methyl group at the 4-position is preferable.

Particularly, ring A is preferably an unsubstituted benzene ring, and ring B is preferably a benzene ring having a methoxy group at the 4-position.

Further, examples of the lower alkyl group represented by R ¹ and R ² include the lower alkyl groups exemplified as the substituents on the ring A and / or ring B, and the methyl group is particularly preferable.

In the method of the present invention, the optical resolution of the racemic 1,5-benzothiazepine derivative salt [I] or [II] salt by the preferential crystallization method is the racemic salt [I] or [II]. Of supersaturated solution of
1,5-benzothiazepine derivative salt [I] or [II]
An optically active salt of [that is, (2S, 3S)-or (2S
R, 3R) -body salt], and an optically active salt of the same kind as the seeded crystal can be preferentially crystallized.

1,5-Benzothiazepine derivative salt [I]
Alternatively, the supersaturated solution of the racemic salt of [II] is prepared by heating and dissolving the racemic salt of 1,5-benzothiazepine derivative [I] or [II] in a suitable solvent, followed by cooling, concentration, or The 5-benzothiazepine derivative salt [I] or [II] can be prepared by a method commonly used for the preparation of a general supersaturated solution, such as a method of adding an appropriate amount of a solvent that reduces the solubility.

It is also possible to add a compound soluble in the supersaturated solution (for example, hydrochloric acid, ammonium chloride or methylamine hydrochloride) to increase the degree of supersaturation or the stability of the supersaturated solution.

As the solvent, in addition to water, alcohol solvents such as methanol, ethanol and isopropanol, ketone solvents such as acetone and methyl ethyl ketone, ethers such as dioxane and tetrahydrofuran, amides such as acetamide and dimethylformamide, or the like. Mixed solvents are used.

Regarding the seed crystal inoculation, when the solute of the supersaturated solution of the 1,5-benzothiazepine derivative salt [I] or [II] is a completely racemic salt, the seed crystal is inoculated from the outside during the separation. However, if one of the optically active salts is present in excess, the active salt will spontaneously crystallize, and this will have the same effect as when seed crystals were inoculated. Does not need

The inoculation amount is not particularly limited, and the larger the amount, the easier and facilitates the resolution. Usually, the 1,5-benzothiazepine derivative salt [I] or [II] in the resolution solution is used.
Inoculation amount of about 10% by weight or less may be used. It is desirable that the optically active salt to be inoculated has a high purity for the purpose of use.

Further, according to the method of the present invention, the racemic salt of the same kind is added to the mother liquor after the preferential crystallization of the 1,5-benzothiazepine derivative salt [I] or [II], and the preceding preferential crystal is added. After the supersaturated solution is prepared by the same method as the precipitation, the optical resolution can be continued by inoculating the crystals of the optically active salt opposite to the crystals inoculated in the prior preferential crystallization and preferentially crystallizing the crystals. . The racemate after the preferential crystallization may be added as crystals or after being dissolved in a solvent. By repeating the addition of such racemic salt and the operation of preferential crystallization,
1,5-benzothiazepine derivative salt [I] or [II]
Both optically active salts [ie (2S, 3S) -body salts and (2
R, 3R) -form salt] can be obtained in the form of crystals.

When the method of the present invention is carried out industrially, not only so-called batch-type one-sided division in which only one optically active substance is crystallized from a supersaturated solution, but also two division columns connected in parallel or in series. Alternatively, two kinds of optically active 1,5-benzothiazepine derivative salts can be simultaneously obtained by inoculating one of the optically active 1,5-benzothiazepine derivative salts which are opposite to each other in a divided tank having compartments. it can.

The optically active isomer of the 1,5-benzothiazepine derivative salt [I] or [II] thus obtained is decomposed to give a compound of the general formula [III]

[0033]

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[In the formula, ring A, ring B and other symbols have the same meanings as described above. ] The optically active substance of the 1,5-benzothiazepine derivative [III] can be obtained.

1,5-Benzothiazepine derivative salt [I]
Alternatively, to decompose the optically active salt of [II] to obtain an optically active 1,5-benzothiazepine derivative [III],
It may be carried out by a known method, for example, by dissolving the optically active salt in a suitable solvent and adding a base to obtain precipitated crystals, or by extracting with a different solvent after adding the base,
It can be easily carried out by an operation such as distilling off the solvent.

The solvent used for the decomposition reaction is 1,5
-It is not particularly limited as long as it can dissolve the optically active salt of benzothiazepine derivative salt [I] or [II]. For example, in addition to water, alcohol solvents such as methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, etc. The above ketone solvents, ethers such as dioxane and tetrahydrofuran, amides such as acetamide and dimethylformamide, or a mixed solvent thereof is used.

As the base, either an inorganic base or an organic base can be used. As the inorganic base, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, ammonia and the like, as the organic base, methylamine, dimethylamine, Trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, diisopropylamine,
Pyrrolidine, piperidine, piperazine and the like can be used.

The amount of the base used is usually 1.0-1.5 mol ratio, preferably 1.0, with respect to the 1,5-benzothiazepine derivative salt [I] or [II] optically active salt. It is a molar ratio.

Any solvent can be used as the extraction solvent as long as it dissolves the 1,5-benzothiazepine derivative [III] but does not dissolve the sulfonate formed. Examples of such a solvent include methyl acetate and Examples thereof include ethyl acetate, dichloromethane, chloroform, benzene and toluene.

The optically active substance of the 1,5-benzothiazepine derivative [III] obtained as described above can be obtained by the general method [IV] according to a known method.

[0041]

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[In the formula, R ³ represents a lower alkanoyl group, and other symbols have the same meanings as described above. ] The optically active substance of the 1,5-benzothiazepine derivative [IV] represented by or its pharmacologically acceptable salt can be used.

That is, the optically active isomers of the 3-hydroxy-1,5-benzothiazepine derivative [III] are, for example, Japanese Patent Publication Nos. 46-16988, 46-43785, 47-813 and 53. -18038, JP-B-63-13994 or JP-A-3-157378, according to a known method, conversion to an optically active 1,5-benzothiazepine derivative [IV] or a pharmacologically acceptable salt thereof. You can

For example, compound [IV] is compound [II]
I] in the general formula [VI]

[0045]

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[In the formula, R ³ is a lower alkanoyl group. ] It can manufacture by carrying out a condensation reaction with the compound shown by these, or its reactive derivative.

The lower alkanoyl is acetyl,
It represents a straight or branched chain alkanoyl having 2 to 6 carbon atoms such as propionyl, isopropionyl, butanoyl, pentanoyl, hexanoyl and the like.

The 1,5-benzothiazepine derivative salt [I] or [II], which is the starting material compound of the present invention, is a novel substance. -It can be produced by treating with naphthalenesulfonic acid or a salt thereof or 2-aminophenol-4-sulfonic acid or a salt thereof.

For example, 1,5-benzothiazepine derivative [III] and 1-naphthalenesulfonic acid or 2-aminophenol-4-sulfonic acid are heated and dissolved in an appropriate solvent, cooled, and the precipitated crystals are separated by filtration. Can be obtained.

Suitable examples of the solvent used for the production of the starting compound [I] or [II] include water and alcohols such as methanol, ethanol and propanol. These solvents may be used alone, or may be used by mixing two kinds or more kinds at an appropriate ratio, if necessary, and a mixed solvent of water and alcohols is particularly preferable.

The 1,5-benzothiazepine derivative [III] was used in the chemical and pharmaceutical bulletin (Chem. Pharm.
l. ) 19, 595 (1971) and the like.

The optical purity of the compound [I] [II] [III] obtained by the optical resolution method of the present invention was determined by HPLC using a chiral column.

HPLC conditions Column: Daicel Chemical Industries, Ltd. CHIRALCEL
OD 4.6 × 250 mm Carrier: n-hexane / ethanol / diethylamine = 85/15 / 0.1 Flow rate: 0.5 ml / min Detection: UV-254 nm Temperature: 35 ° C.

[0054]

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.

Reference Example 1 (±)-(2RS, 3RS) -cis-5- [2- (dimethylamino) ethyl] -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1 Synthesis of 5,5-benzothiazepine-4 (5H) -one-1-naphthalene sulfonate 1-naphthalene sulfonic acid sodium salt 6.91 g
(30 mmol) was dissolved in 35 ml of water by heating to give 1 mol.
/ L hydrochloric acid 30 ml and (±)-(2RS, 3RS)-
Cis-5- [2- (dimethylamino) ethyl] -2,3
-Dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one 9.31 g (25 mmol) of hot methanol 47 ml
Add solution. After crystallization under ice cooling for 20 hours, the precipitated crystals were filtered off,
13.50 g of the title compound (93.0
%).

Melting point: 136-138 ° C. IR spectrum (KBr tablet) cm ⁻¹ : 3425, 30
45, 1660, 1500, 1465, 1295, 11
75, 1105, 1040, 770, 680, 610 NMR spectrum (200 MHz, CDCl ₃ ) δ:
2.88 (s, 3H), 2.95 (s, 3H), 3.0
4 to 3.09 (m, 1H), 3.25 to 3.55 (m,
2H), 3.80 (s, 3H), 4.17 to 4.35.
(M, 2H), 4.43 to 4.58 (m, 1H), 4.
87 (d, 1H), 6.86 to 8.89 (m, 15H) Reference Example 2 (±)-(2RS, 3RS) -cis-5- [2- (dimethylamino) ethyl] -2,3- Synthesis of dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one 2-aminophenol-4-sulfonate (±)-(2RS, 3RS ) -Cis-5- [2- (Dimethylamino) ethyl] -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one 7 Methanol (16%, 20 mmol) and 2-aminophenol-4-sulfonic acid (content: 95%) (4.38 g, 22 mmol) were added to methanol (16).
It is dissolved by heating in a mixed solvent of 48 ml of water and 48 ml of water. Under ice cooling 2
After crystallization for 0 hour, the precipitated crystals are filtered off and dried at 50 ° C. to obtain 10.42 g (92.8%) of the title compound.

Melting point: 134-137 ° C. IR spectrum (KBr tablet) cm ^-1 : 1660, 16
00, 1505, 1465, 1280, 1245, 11
70, 1100, 1020, 760, 685, 595 NMR spectrum (200 MHz, DMSOd ₆ ) δ:
2.81 (s, 6H), 3.05 to 3.20 (m, 2
H), 3.76 (s, 3H), 3.94 to 4.10.
(M, 1H), 4.24 (t, 1H), 4.35-4.
55 (m, 1H), 4.83 (d, 1H), 4.92
(D, 1H), 6.52 to 7.75 (m, 11H) Example 1 (±)-(2RS, 3RS) -cis-5- [2- (dimethylamino) ethyl] -2,3-dihydro. Optical Resolution of 3-Hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4 (5H) -one.1-naphthalene sulfonate by preferential crystallization method (A) (±)- (2RS, 3RS) -cis-5- [2
-(Dimethylamino) ethyl] -2,3-dihydro-3
-Hydroxy-2- (4-methoxyphenyl) -1,5
-Benzothiazepine-4 (5H) -one / 1-naphthalene sulfonate 5.01 g and its (+)-(2S,
3S) -body salt 0.18 g was added to 50% DMF-H ₂ O (w /
w) Heat and dissolve in 20 g, and then cool to 25 ° C. 20 mg of the above (+)-(2S, 3S) -form salt is inoculated into the solution and crystallized for 19 hours with stirring. The precipitate was filtered, washed with cold 50% DMF-H ₂ O (w / w) and then dried at 50 ° C. to give the (+)-(2S, 3S) -form salt 0.55.
g.

[Α] ²⁵ _D : + 67.6 ° (C = 1, DM
F) Optical purity: 98.4% ee IR spectrum and NMR spectrum were in agreement with the compound of Reference Example 1.

(B) 0.7 g of the starting material (±)-(2RS, 3RS) -form salt was added to the mother liquor obtained after the operation of (A), and the mixture was heated and dissolved, and then cooled to 25 ° C.
Then, the (-)-(2R, 3R) -form salt 2 of the starting material
Inoculate 0 mg and crystallize for 15 hours with stirring. The precipitate was filtered, washed with cold 50% DMF-H ₂ O (w / w) and then dried at 50 ° C. to obtain the (-)-(2R, 3R)-.
0.15 g of body salt is obtained.

[Α] ²⁵ _D : -65.4 ° (C = 1, DM
F) Optical purity: 95.2% ee IR spectrum and NMR spectrum were consistent with the compound of Reference Example 1.

Example 2 (±)-(2RS, 3RS) -cis-5- [2- (dimethylamino) ethyl] -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1 Resolution of 5,5-benzothiazepine-4 (5H) -one / 1-naphthalenesulfonate by the preferential crystallization method (±)-(2RS, 3RS) -cis-5- [2- (dimethylamino) ethyl ] -2,3-Dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4 (5H) -one.1-naphthalenesulfonate 5.37 g and its (-) -(2R, 3R)-
0.21 g of body salt was added to 50% DMF-H ₂ O (w / w) 20
After heating and dissolving in g, the mixture is cooled to 25 ° C. 20 mg of the above (-)-(2R, 3R) -form salt is inoculated into the solution and crystallized for 3 hours with stirring. The precipitate is filtered and cold 50% DM
After washing with F-H ₂ O (w / w), drying at 50 ° C,
0.37 g of the above (-)-(2R, 3R) -form salt is obtained.

[Α] ²⁵ _D : -63.4 ° (C = 1, DM
F) Optical purity: 92.3% ee IR spectrum and NMR spectrum were consistent with the compound of Reference Example 1.

Example 3 (±)-(2RS, 3RS) -cis-5- [2- (dimethylamino) ethyl] -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1 Resolution of 5,5-benzothiazepine-4 (5H) -one-2-aminophenol-4-sulfonate by the preferential crystallization method (A) (±)-(2RS, 3RS) -cis-5- [ Two
-(Dimethylamino) ethyl] -2,3-dihydro-3
-Hydroxy-2- (4-methoxyphenyl) -1,5
-Benzothiazepine-4 (5H) -one-2-aminophenol-4-sulfonic acid salt 5.02 g and its (+)-(2S, 3S) -form salt 0.25 g were added to water 160 g.
After heating and melting, the mixture is cooled to 40 ° C. The solution is inoculated with 30 mg of the above (+)-(2S, 3S) -form salt and crystallized for 7 hours with stirring. The precipitate is filtered, washed with cold water and then dried at 50 ° C. to obtain the above (+)-(2S, 3S)-.
0.49 g of body salt is obtained.

[Α] ²⁵ _D : + 86.0 ° (C = 1, Me
OH) Optical purity: 97.1% ee IR spectrum and NMR spectrum are in agreement with the compound of Reference Example 2.

(B) After adjusting the amount of water in the mother liquor obtained after the operation of (A) to 160 g, the starting material (±)-
0.42 g of (2RS, 3RS) -form salt is added and dissolved by heating, and then cooled to 40 ° C. Subsequently, 30 mg of the (-)-(2R, 3R) -form salt of the starting material is inoculated and crystallized for 5 hours with stirring. The precipitate is filtered, washed with cold water, and then dried at 50 ° C. to obtain the (-)-(2R, 3R)-.
0.40 g of body salt is obtained.

[Α] ²⁵ _D : -83.2 ° (C = 1, Me
OH) Optical purity: 96.3% ee IR spectrum and NMR spectrum are consistent with the compound of Reference Example 2.

Thereafter, in the same manner as in the above-mentioned operations (A) and (B), the mother liquor after the preferential crystallization had a starting material of (±)-(2).
RS, 3RS) -body salt was added, and then seed crystals were inoculated, (+)
-(2S, 3S) -body salt and (-)-(2R, 3R)-
Each optically active salt is obtained by repeating the operation of obtaining the body salt alternately up to 8 times (detailed resolution conditions are shown in Table 1 below) (the yield, optical purity and resolution of each salt are shown below). It is shown in Table 2.).

[0068]

[Table 1]

[0069]

[Table 2]

Example 4 (+)-(2S, 3S) -cis-5- [2- (dimethylamino) ethyl] -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1 , 5-Benzothiazepine-4 (5H) -one-2-aminophenol-4
-Decomposition of sulfonate (+)-(2S, 3S) -cis-5- [2- (dimethylamino) ethyl] -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1 , 5-Benzothiazepine-4 (5H) -one-2-aminophenol-4
-Sulfonate 0.56 g (1 mmol, 97.8% e)
e) is dissolved by heating in 30 ml of water, 0.09 g (1.1 mmol) of sodium hydrogen carbonate is added, and the mixture is extracted with ethyl acetate. The ethyl acetate layer was washed with water and then concentrated to dryness to give (+)-(2S, 3S) -cis-5- [2- (dimethylamino) ethyl] -2,3-dihydro-3-hydroxy-2- (. 4-Methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one 0.35 g (93.0
%).

Melting point: 84-86 ° C. [α] ²⁵ _D : + 166.1 ° (C = 1, MeOH) Optical purity: 98.0% ee IR spectrum (KBr tablet) cm ^-1 : 2825, 16
70, 1610, 1510, 1470, 1440, 13
65, 1305, 1255, 1180, 1130, 77
0 NMR spectrum (200 MHz, DMSOd ₆ ) δ:
2.14 (s, 6H), 2.22 to 2.35 (m, 1
H), 2.49 to 2.62 (m, 1H), 3.63 to
3.76 (m, 1H), 3.76 (s, 3H), 4.2
0 (t, 1H), 4.26 to 4.41 (m, 1H),
4.50 (d, 1H), 4.89 (d, 1H), 6.8
7 to 7.70 (m, 8H)

[0072]

According to the method of the present invention, an optically active 1,5-benzothiazepine derivative, which is important as an intermediate of diltiazem, can be obtained by a preferential crystallization optical resolution method without using an expensive optically active reagent. Obtained in purity. Therefore,
The method of the present invention is an industrially excellent optically active benzothiazepine derivative and a method for producing the same.

Claims (11)

[Claims] 1. A compound of the general formula [I] [In the formula, ring A and ring B represent a benzene ring which may have a substituent, and R ¹ and R ² are the same or different and represent a lower alkyl group. ] The optically active substance of 1,5-benzothiazepine derivative salt [I] characterized by optically resolving a racemic salt of 1,5-benzothiazepine derivative salt [I] by a preferential crystallization method. How to make salt. 2. A compound represented by the general formula [II]: [In the formula, ring A and ring B represent a benzene ring which may have a substituent, and R ¹ and R ² are the same or different and represent a lower alkyl group. ] The optically active substance of 1,5-benzothiazepine derivative salt [II] characterized by optically resolving a racemic salt of 1,5-benzothiazepine derivative salt [II] by a preferential crystallization method. How to make salt. 3. The process according to claim 1, wherein ring A is an unsubstituted benzene ring, ring B is a benzene ring having a methoxy group at the 4-position, and R ¹ and R ² are both methyl groups. 4. The optically active 1,5-benzothiazepine derivative salt obtained is a (2S, 3S) -form salt.
The manufacturing method according to 2 or 3. 5. The process according to claim 1, 2 or 3, wherein a racemic salt of 1,5-benzothiazepine derivative salt is added to the mother liquor after preferential crystallization, and further preferential crystallization is continued. 6. A compound of the general formula [III]: embedded image which is obtained by decomposing an optically active 1,5-benzothiazepine derivative salt obtained by the process according to claim 1, 2, 3, 4 or 5. [In the formula, ring A and ring B represent a benzene ring which may have a substituent, and R ¹ and R ² are the same or different and represent a lower alkyl group. ] The manufacturing method of the optically active substance of the 1, 5- benzo thiazepine derivative [III] shown by these. 7. The 1,5-obtained by the method of claim 6.
The optically active benzothiazepine derivative [III] is prepared according to a known method by the general formula [IV] [Wherein, ring A and ring B are a benzene ring which may have a substituent, R ¹ and R ² are the same or different and are a lower alkyl group, R 1
³ represents a lower alkanoyl group. ] 1,5
-A method for producing an optically active 1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof, which is an optically active benzothiazepine derivative [IV] or a pharmaceutically acceptable salt thereof. 8. A compound represented by the general formula [I]: [In the formula, ring A and ring B represent a benzene ring which may have a substituent, and R ¹ and R ² are the same or different and represent a lower alkyl group. ] The 1,5-benzothiazepine derivative salt shown by these. 9. A compound represented by the general formula [II]: [In the formula, ring A and ring B represent a benzene ring which may have a substituent, and R ¹ and R ² are the same or different and represent a lower alkyl group. ] The 1,5-benzothiazepine derivative salt shown by these. 10. The 1,5-benzothi group according to claim 8 or 9, wherein ring A is an unsubstituted benzene ring, ring B is a benzene ring having a methoxy group at the 4-position, and R ¹ and R ² are both methyl groups. An optically active salt of an azepine derivative salt. 11. The 1,5-benzothiazepine derivative salt according to claim 8, which is a (2S, 3S) -form salt.