JPH0429990A - Production of optically active cis-thiazolidin-4-one derivative - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the subject derivative useful as a preventive and treating agent for inflammations and allergic diseases by reacting a mixture of the d-with the l-isomers of a cis-thiazolidin-4-one derivative with optically active 10-camphor-sulfonic acid and optically resolving the resultant product. CONSTITUTION:A mixture of the d-with l-isomers of a compound expressed by the formula is made to react with optically active D- or L-10-camphor- sulfonic acid as an optical resolving agent preferably in a solvent such as THF by heating to the vicinity of the boiling point of the solvent to provide two kinds of diastereomer salts. The resultant two kinds of the salts are separated by utilizing, e.g. a solubility difference, reacted with a base such as sodium hydrogencarbonate and converted into a salt, which is then passed into an aqueous layer, extracted with toluene, etc., and isolated to afford the objective compound expressed by the formula.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention provides the above-mentioned This invention relates to a method for producing an optically active compound of the formula [E].

The cis-thiazolidin-4one derivative represented by formula [I] has excellent platelet activating factor (hereinafter abbreviated as PAF) antagonistic activity, and is effective against PAF-induced diseases such as various inflammatory and allergic diseases, cardiovascular diseases, etc. It is known to be extremely useful as a prophylactic and therapeutic drug for systemic diseases, digestive system diseases, etc. (Japanese Patent Application Laid-open No. 1-279882).

<Prior art and problems> As a method for obtaining an optically active form of cis-thiazolidin-4-one derivative represented by formula CI), optically active α-mercaptopropionic acid and N-nicotinylidenemethylamine are used. There is a known method to obtain it by condensing the
279882). However, this method cannot be said to be a practical method at present, as there are problems in obtaining optically active α-mercaptopropionic acid as a raw material.

<Problems to be Solved by the Invention> The present invention provides cis-thiazolidine-4 represented by formula [I]
The purpose of this study is to establish a practical method for producing optically active -one derivatives.

Means for Solving the Problem> A compound represented by the above formula [I] produced from a mixture of the d-mercaptopropionic acid and the 1-mercaptopropionic acid and N-nicotinylidenemethylamine, which is industrially easily available. It has been found that the objective can be achieved by optically resolving a mixture of the d-form and the β-form of the cis-thiazolidin-4-one derivative with optically active 10-camphorsulfonic acid.

That is, the present invention provides a mixture of the d-form and the β-form of the cis-thiazolidin-4-one derivative represented by formula [I],
The present invention relates to a method for obtaining an optically active cis-thiazolidin-4-one derivative of formula [I] by optically resolving using optically active 10-camphorsulfonic acid as an optical resolving agent.

More specifically, the present invention provides a method for preparing a mixture of a d-form and a cis-thiazolidin-4-one derivative represented by formula [I] and D- or L-10-camphorsulfonic acid in an appropriate solvent. to generate two types of diastereomeric salts, which are separated by utilizing the difference in solubility of these salts in the solvent, and the resulting desired diastereomeric salt is decomposed to form the formula [ This is a method for obtaining an optically active cis-thiazolidin-4-one derivative represented by [I].

Specifically, the present invention is carried out by the following method.

A mixture of the d-form and β-form of the cis-thiazolidin-4-one derivative of formula [I] and D-10-camphorsulfonic acid or L-10-camphorsulfonic acid are dissolved in a solvent to form a salt. .

Next, one of the two resulting diastereomeric salts is preferentially crystallized.

An example of a mixture consisting of the d-form and the 1-form is a racemate.

Examples of the solvent include aromatic solvents such as benzene, toluene, and chlorobenzene, such as tetrahydrofuran,
Ether solvents such as dioxane, e.g. acetone, 2
- Ketone solvents such as butanone, highly polar aprotic solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide, halogen solvents such as dichloromethane, chloroform, 2-dichloroethane, e.g. methanol, ethanol, isopropyl alcohol, t -Alcoholic solvents such as butyl alcohol can be mentioned. Particularly preferred solvents include:
Examples include solvents such as tetrahydrofuran, benzene, and isopropyl alcohol. Moreover, these can also be mixed and used in arbitrary ratios.

The temperature for dissolving and forming a salt can be in the range from room temperature to the boiling point of the solvent, but it is possible to form the salt easily and preferentially precipitate one diastereomeric salt due to the difference in solubility. In order to facilitate the reaction, it is preferable to heat the solvent to a temperature close to its boiling point. Before separating the precipitated salt, it is possible to cool the precipitated salt as necessary to increase the number of precipitated crystals.

The appropriate amount of D-10-camphorsulfonic acid or L-10-camphorsulfonic acid used as a resolving agent is 0.5 to 2.0 equivalents, preferably around 1 equivalent, relative to the substrate.

Note that it is also possible to inoculate a previously prepared salt with high optical purity at the time of crystallization.

It is also possible to further improve optical purity by recrystallizing the obtained crystals in the above-mentioned solvent, or by suspending and stirring the crystals in the same solvent and filtering them. The solvent used at this time may be the same as that used for the initial salt formation, or a different solvent may be used.

In addition, in the method of the present invention, a mixture of two types of diastereomer salts is isolated in advance, and this is recrystallized using the above-mentioned solvent, or suspended in the same solvent, stirred, and then filtered.
It is also possible to extract only one of the diastereomeric salts.

The diastereomeric salts obtained by these methods can be subjected to conventional salt decomposition methods to isolate optically active cis-thiazolidin-4-one derivatives.

That is, for example, by neutralizing the diastereomeric salt with a base,
Optically active 10-camphorsulfonic acid is transferred to the aqueous layer as a salt with a base, and optically active cis-thiazolidine-
A suitable organic solvent for separating the 4-one derivative from water, such as dichloromethane, 1°2-dichloroethane, toluene,
It can be separated and isolated by extraction with ethyl acetate, ether, etc. Examples of the base include inorganic bases and organic bases. Examples of the inorganic base include alkali metal carbonates such as sodium hydrogen carbonate, sodium carbonate, and potassium carbonate, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Examples of the organic base include amines such as triethylamine.

Furthermore, the enantiomer can also be obtained from the filtrate obtained when one diastereomeric salt is obtained.

That is, the concentrated residue of the filtrate is subjected to salt decomposition by the above method, and the resulting cis-thiazolidin 4-one derivative represented by formula CI) has an optical rotation opposite to that of the optically active 10-camphorsulfonic acid used previously. An optically active cis-thiazolidin-4-one derivative can be obtained by reacting optically active 10-camphorsulfonic acid having 10-camphorsulfonic acid and applying the above-mentioned method. Therefore, by the method of the invention, -
From a mixture of the 6-isomer and the β-isomer of the cis-thiazolidin-4-one derivative represented by Formation [I], it is possible to obtain the 6-isomer and the 1-isomer with high optical purity in high yields, respectively.

Next, the present invention will be explained with reference to the following examples, but these are merely examples and are not intended to limit the invention in any way.

In addition, in the examples, the optical purity is measured as follows.

Optical purity: cis-3,5-dimethyl-2-(3-pyridyl)-thiazolidin-4-one is dissolved in dichloromethane, and cis-3,5-dimethyl-2(3-pyridyl)-thiazolidin-4-one is dissolved in dichloromethane. The camphor sulfonate of 100% was salt-decomposed with an aqueous sodium bicarbonate solution, and then extracted with dichloromethane. This solution was analyzed under the following liver LC conditions to determine the optical purity (%e, e, ). HPLC condition column:
Chiralcel OD■ (manufactured by Daicel) 4.6
X260mm Mobile phase n-hexane/IPA=9/1 1.0ml/
min Column temperature: Room temperature detection: UV-264 nm Retention time: (+)cis-3,5-dimethyl-2(3-pyridyl)thiazolidin-4-one 16.6mln (-)-cis-3,5dimethyl-2 ( 3-pyridyl)thiazolidin-4-one 31.2 m1n Example I 5.0 g of racemic cis-3,5-dimethyl 2-(3
-pyridyl)thiazolidin-4-one 5.58g D-
25 ml of tetrahydrofuran was added to camphorsulfonic acid (anhydride) and dissolved at room temperature.

Add (10)-cis-3,5-dimethyl-2(3-
A small amount of D camphorsulfonate of pyridyl)thiazolidin-4-one was added as a seed crystal, and the mixture was stirred at room temperature for 5 hours. The precipitated product was collected by filtration, washed with tetrahydrofuran 6-, and dried under reduced pressure to give (+)cis-3,5-dimethyl-2-(3-
4.61 g of D-camphorsulfonate of pyridylthiazolidin-4-one was obtained.

Melting point 145-150°C [α] Otsu'-134.5° (c = 1.0.methanol) Optical purity 85.0% e, e.

Example 2 5.0 g of racemic cis-3,5-dimethyl 2-(3
-pyridyl)thiazolidin-4-one, 5.58 g of D-camphorsulfonic acid (anhydride) and 50 m of benzene
1 was added and dissolved at room temperature. Add (+)-cis-3 to this solution.
,5-dimethyl-2-(3pyridyl)thiazolidine-4
A small amount of D-camphorsulfonate of -one was added as a seed crystal, and the mixture was stirred at room temperature for 5 hours. The precipitated product was collected by filtration, washed with 10 mg of benzene, and dried under reduced pressure to obtain (+)-cis-3,5
4.55 g of D-camphorsulfonate of dimethyl-2-(3-pyridyl)thiazolidin-4-one was obtained.

Melting point 144-148°C [α] Otsu' = +33.6° (c = 1.0.methanol) Optical purity 83.6% e, e.

Example 3 Racemic cis-3,5-dimethyl 2-(3
-pyridyl)thiazolidin-4-one, 15 ml of isopropyl alcohol was added to 58 g of D-camphorsulfonic acid (anhydride) and dissolved by heating to about 50°C. This solution was cooled to room temperature and (+)-cis-3,5-
A small amount of D-camphorsulfonate of dimethyl-2-(3-pyridyl)thiazoridin-4-one was added as a seed crystal, and the mixture was stirred at room temperature for 5 hours. The precipitate was collected by filtration, washed with 3 ml of isopropyl alcohol cooled to 5°C, and dried under reduced pressure. - 4.14 g of camphorsulfonate were obtained.

Melting point 145-150°C [α] Otsu'-+34.1° (c=1.0.methanol) Optical purity 8.6.4% e, e.

Example 4 Using L-camphorsulfonic acid instead of D-camphorsulfonic acid, the same treatment as in Example 1 was performed to obtain (-)-cis-3,5-dimethyl-2-(3pyridyl)thiacyridine-4. -onoshiichi camphor sulfonate 4.48g
I got it.

Melting point 145-148°C [α] Otsu0=-34.1° (c=1.0.Metatsuru) Optical purity 82.6%e, e.

Example 5 The divided filtration and washing liquid of Example 1 was concentrated under reduced pressure to remove the solvent. Add 30ml of water and 34% 5% sodium bicarbonate aqueous solution to the residue.
7 g was added to decompose the salt, and the mixture was extracted twice with 25 g of dichloromethane. The organic layer was concentrated under reduced pressure to obtain 81 g of residue 2.

The residue was dissolved in 25 ml of tetrahydrofuran, 3.14 g of L-camphorsulfonic acid (anhydride) was added, and the mixture was stirred at room temperature for 16 hours. The precipitated crystals were collected by filtration, washed with 5 rnl of tetrahydrofuran, and dried under reduced pressure to give (-)-cis-3,5
4.49 g of camphorsulfonate of -dimethyl-2(3-pyridyl)thiazolidin-4-one was obtained.

Melting point 149-153°C [α)B'-35.4° (c=1.0.methanol)
Optical purity 94.2%e, e.

Example 6 1700 g of toluene was added to 134 g of D-camphorsulfonic acid monohydrate and heated to distill off 1250 g of a mixture of water and toluene at normal pressure. The residue was cooled to room temperature, and 110 g of racemic cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one and 820 g of tetrahydrofuran were added and dissolved therein. To this solution, a small amount of D-camphorsulfonate of (+)cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one was added as a seed crystal, and the mixture was incubated at room temperature for 1 hour.
It was kept warm at 0°C for 1 hour and at 0-5°C for 2 hours.

The precipitated crystals were filtered, washed with 300 g of tetrahydrofuran cooled to 0 to 5°C, and dried to form D-camphorsulfone of (+)-3°5-dimethyl-2-(3-pyridyl)thiazolidin-4-one. 113 g of the acid salt was obtained.

Optical purity 90.0%e, e.

Example 7 (+)-cis-3,5-dimethyl- obtained in Example 6
To 110 g of D-camphorsulfonate of 2-(3-pyridyl)thiazolidin-4one was added 49 g of tetrahydrofuran.
Add 0g, heat and keep warm under reflux for 1 hour, then 0 to 5
It was kept warm at °C for 2 hours. The crystals were filtered, washed with 140 g of tetrahydrofuran cooled to 0-5°C, and (+)-
99 g of D-camphorsulfonate of cis-35-dimethyl-2-(3-pyridyl)thiazolidin-4-one was obtained.

Melting point 151-153°C [α]'D = +35.0° (c = 1.0.methanol) Optical purity 98.5% e, e.

Example 8 (+)-cis-3,5-dimethyl- obtained in Example 7
5.0 g of D-camphorsulfonate of 2-(3-pyridyl)thiazolidin-4one was dissolved in 25 ml of water, and 285 g of a 5% thorium bicarbonate aqueous solution was added thereto for salt decomposition. This solution was extracted twice with 25 mf of dichloromethane, the dichloromethane layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and (+)-cis-3,5-dimethyl-2-
(3-pyridyl)thiazolidin-4-one 2.32 g
I got it.

Optical purity 99.0%e, e.

Melting point 66-67°C [α] Otsu'-139.7° (c=1.0.methanol) <Effects of the present invention> According to the present invention, the optically active cis- It has become possible to obtain thiazolidin-4-one derivatives by an industrially advantageous method.

Claims (4)

[Claims] (1) Formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Optically active 10-camphorsulfonic acid in a mixture consisting of the d-form and l-form of the cis-thiazolidin-4-one derivative represented by [I] The optically active cis-
Method for producing thiazolizon-4-one derivative. (2) In claim 1, after salt decomposition of the other diastereomer salt contained in the residue obtained by crystallizing one diastereomer salt, the salt decomposed cis- An optical method comprising the step of acting on a thiazolidin-4-one derivative with optically active 10-camphorsulfonic acid having an optical rotation opposite to that of the optically active 10-camphorsulfonic acid used in claim 1. Method for producing active cis-thiazolidin-4-one derivatives. (3) A salt of an optically active form of a cis-thiazolidin-4-one derivative represented by the formula [I] ▼Mathematical formulas, chemical formulas, tables, etc.▼[I] and optically active 10-camphorsulfonic acid. (4) Salt of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one and D-10-camphorsulfonic acid.