JP2676720B2 - Method for producing 1,5-benzothiazepine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a process for producing a 1,5-benzothiazepine derivative useful as a synthetic intermediate for pharmaceutical compounds.

[0002]

2. Description of the Related Art General formula (I)

[0003]

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The 1,5-benzothiazepine derivative represented by (wherein R represents a lower alkyl group) is a pharmaceutical compound such as (+)-cis-2- (4-) having an excellent coronary vasodilatory action. Methoxyphenyl) -3-acetoxy-5
-(Β-Dimethylaminoethyl) -2,3-dihydro-
It is a compound useful as a synthetic intermediate for 1,5-benzothiazepin-4 (5H) -one (generic name: diltiazem).

Conventionally, as a method for producing the 1,5-benzothiazepine derivative (I), for example, 2-hydroxy-3-
A method is known in which (2-aminophenylthio) -3- (4-methoxyphenyl) propionic acid is heated and refluxed in xylene to perform intramolecular ring closure (Japanese Patent Publication No. 53-1803).
8). However, this method has a drawback that it takes a long time (12 hours in the examples of the above publications) to complete the reaction, and it is not always satisfactory as an industrial production method of the compound (I).

[0006]

DISCLOSURE OF THE INVENTION The present invention is a synthetic intermediate of a pharmaceutical compound having an excellent coronary vasodilator action 1,
A method for producing a 5-benzothiazepine derivative is provided.

[0007]

Means for Solving the Problems As a result of various studies conducted by the present inventors, if the intramolecular ring-closing reaction of compound (II) is carried out in the presence of a specific sulfonic acid compound, the reaction time is significantly shortened. It was found that the compound (I) can be produced with good yield and the present invention was completed.

That is, according to the present invention, the target compound (I) is represented by the general formula (II)

[0009]

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(However, R has the same meaning as described above.)
The propionic acid derivative represented by the general formula (III)

[0011]

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(Wherein R ¹ represents a substituted or unsubstituted phenyl group),
It can be produced by subjecting it to an intramolecular ring closure reaction.
(However, if the intramolecular ring-closing reaction is carried out with an organic solvent such as benzene,
A mixture of zen, toluene, or more preferably xylene.
Reaction mixture with nitrogen at about the reflux temperature of the solvent
While bubbling through something, let's look at organic acid catalysts, for example
For example, in the presence of p-toluenesulfonic acid monohydrate
Argon in xylene at reflux temperature.
In the presence of p-toluenesulfonic acid monohydrate under an atmosphere
Except when implementing) .

Examples of the sulfonic acid compound (III) used in the method of the present invention include those represented by the general formula (III)
Examples thereof include compounds in which R ¹ is a phenyl group which may be substituted with an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group or a butyl group. Among these, toluenesulfonic acid is more preferable. The amount of the sulfonic acid compound used is not particularly limited, but is usually 0.5 to 10 w / w% with respect to the compound (II),
It is preferable to use it at a ratio of about 1 to 6 w / w%.

This reaction is preferably carried out in a high boiling point solvent such as xylene, toluene, dichlorobenzene or the like under heating under reflux.

The desired compound (I) thus produced is subjected to a simple operation such as cooling the reaction solution, collecting the precipitated crystals by filtration, and washing with a suitable solvent (eg ethanol, hydrous ethanol). It can be isolated as a pure product without III).

Experimental Example 12.75 g of (+)-threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) propionic acid was dissolved in 52 ml of xylene or toluene to produce water. Heat to reflux while separating and evaporating (+)
-Cis-2- (4-methoxyphenyl) -3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4
When the effect of the presence of a sulfonic acid compound in the reaction system in producing (5H) -one was examined, the results shown in Tables 1 and 2 below were obtained.

The amount used in the table represents the amount of the sulfonic acid compound used with respect to the raw material compound, and p-toluenesulfonic acid was used as a hydrate.

[0018]

[Table 1]

[0019]

[Table 2]

From Tables 1 and 2 above, it can be seen that by allowing p-toluenesulfonic acid to be present in the reaction system, the desired product can be obtained in a very short time with good yield.

[0021]

【Example】

Example 1 12.75 g of (+)-threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) propionic acid, p-toluenesulfonic acid hydrate 14
A mixture of 0 mg and xylene 52 ml is heated to reflux for about 1 hour and 15 minutes.

During this time, the water produced in the reaction is separated and distilled off. After cooling, the precipitated crystals were collected by filtration, washed with cold ethanol and dried (+)-cis-2- (4-methoxyphenyl)-.
11.5 g of 3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one are obtained.

Yield: 95.9% M. P. : 203 to 204 ° C. [α] _D ²⁰ : + 116 ° (C = 0.5, dimethylformamide) Example 2 (+)-threo-2-hydroxy-3- (2-aminophenylthio) -3- (4 -Methoxyphenyl) propionic acid 12.75 g, p-toluenesulfonic acid hydrate 69
A mixture of 0 mg and 52 ml toluene is heated to reflux for about 5 hours. During this time, water generated in the reaction is separated and distilled off. After cooling, the precipitated crystals were collected by filtration, washed with cold ethanol and dried to obtain (+)-cis-2- (4-methoxyphenyl) -3-hydroxy-2,3-dihydro-1,5-benzothiazepine- 11 g of 4 (5H) -one are obtained.

Yield: 92% P. : 203 to 204.5 ° C. [α] _D ²⁰ : + 118 ° (C = 0.5, dimethylformamide)

[0025]

INDUSTRIAL APPLICABILITY The method of the present invention can significantly shorten the time required for the intramolecular ring closure reaction as compared with the known method, and can obtain the target compound with high yield and high purity. Is an extremely excellent method.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masashi Kitano North 4 Nara Prefecture ▲ Katsura ▼ 1-4-3 Kumigaoka, Kawai-cho, Castle-gun (72) Inventor Sadao Maeda 3- 13 Mizuo, Ibaraki-shi, Osaka No. 605

Claims (3)

(57) [Claims] 1. A compound represented by the general formula (II): (However, R represents a lower alkyl group.) The propionic acid derivative represented by the general formula (III): (Wherein R ¹ represents a substituted or unsubstituted phenyl group), the compound is subjected to an intramolecular ring closure reaction in the presence of a sulfonic acid compound, and the product is converted to a salt thereof if desired. (I) (However, R represents the same meaning as described above.) 1,
Preparation of 5-benzothiazepine derivative or salt thereof (however,
The intramolecular ring closure reaction in an organic solvent such as benzene, toluene, or more preferably a mixture of xylenes,
At about the reflux temperature of the solvent, while bubbling nitrogen through the reaction mixture, the catalyst for the organic acid, eg p-
When carried out in the presence of toluenesulfonic acid monohydrate,
Alternatively, it is performed in xylene at reflux temperature under an argon atmosphere in the presence of p-toluenesulfonic acid monohydrate). 2. The method according to claim 1, wherein the sulfonic acid compound (III) is p-toluenesulfonic acid. 3. (+)-Threo-2-hydroxy-3-
(2-Aminophenylthio) -3- (4-methoxyphenyl) propionic acid has the general formula (III): (Wherein R ¹ represents a substituted or unsubstituted phenyl group), and subjected to an intramolecular ring closure reaction in the presence of a sulfonic acid compound to obtain (+)-cis-2- (4-methoxyphenyl). ) -3-Hydroxy-2,3-dihydro-
At the 5-position of 1,5-benzothiazepin-4 (5H) -one
Reaction for introducing β-dimethylaminoethyl group and 3-position hydrid
Performs a reaction to acetylate the Roxy group, and if desired,
By converting the product into a pharmacologically acceptable salt , (+)
-Cis-2- (4-methoxyphenyl) -3-acetoxy-5- (β-dimethylaminoethyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one or pharmacologically A method for producing a 1,5-benzothiazepine derivative or a salt thereof, which comprises converting the intramolecular ring-closing reaction into an organic solvent such as benzene, toluene, or more preferably xylene. When carried out in the presence of a catalyst of an organic acid, for example p-toluenesulfonic acid monohydrate, with bubbling nitrogen through the reaction mixture at about the reflux temperature of the solvent in the mixture, or in xylene. , Except at the reflux temperature in the presence of p-toluenesulfonic acid monohydrate under an argon atmosphere).