JP2001354664A - Method for producing thiazolidinedione derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a thiazolidinedione derivative. which is a synthetic intermediate for N-benzyldioxythiazolidinylbenzamide derivatives useful as a hypoglycemic agent. SOLUTION: This method for producing a thiazolidinedione derivative represented by general formula (2), wherein R1 and R2 are each same or different and denote each hydrogen or a lower alkyl group is characterized by reacting a compound represented by general formula (1), wherein R1 and R2 are each as described above; and X denotes a leaving group with thiazolidine-2,4- dione in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the general formula (2), which is an intermediate for the synthesis of N-benzyldioxothiazolidinylbenzamide derivatives useful as hypoglycemic agents and insulin sensitivity enhancers. (Wherein, R ₁ and R ₂ are the same or different and each represent hydrogen or a lower alkyl group.) A method for producing a thiazolidinedione derivative represented by the formula:

[0002]

2. Description of the Related Art As a method for synthesizing a 5-benzylthiazolidinedione derivative, a 5-benzylidenethiazolidinedione derivative obtained by condensation of a benzaldehyde derivative and a thiazolidinedione is catalytically reduced (Japanese Patent Application Laid-Open No. H08-1010).
4688) or a method of reducing with a metal hydride (Japanese Patent Application Laid-Open No. 7-502530).

However, when a 5-benzylthiazolidinedione derivative is produced on an industrial scale, the catalytic reduction requires a large amount of a catalyst under a high-pressure hydrogen stream, which may be dangerous. Further, in the reduction with a metal hydride, it is difficult to set the reaction conditions, and the reproducibility of the purity, yield, and the like may be lacking.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for producing a 5-benzylthiazolidinedione derivative which is an intermediate for synthesizing an N-benzyldioxothiazolidinylbenzamide derivative. Equation (1) (Wherein, R ₁ and R ₂ are the same or different and each represent hydrogen or a lower alkyl group, and X represents a leaving group). The compound represented by the formula (I) is reacted with thiazolidine-2,4-dione in the presence of a base. By reacting, the general formula (2) (Wherein R ₁ and R ₂ are the same or different and represent hydrogen or a lower alkyl group), and the present invention has been completed.

Several examples of the alkylation of the thiazolidinedione ring of the present invention are known (JP-A-1-272573, Synthesis 31).
0, 1971 . Etc.), but alkylation with an aralkyl group having a carboxylic acid derivative as a substituent has not been known so far.

The compound represented by the general formula (1) is known (JP-A-48-19539, Bull. Soc. Chim.
Fr. , 1969 (5), 1698. ) Or can be synthesized by known methods.

Here, the lower alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl and propyl, and is preferably a methyl group, and the leaving group is halogen, sulfonyl. It represents an oxy group and is preferably halogen.

[0008] Among the benzoic acid derivatives represented by the general formula (1), 5-iodomethyl-2- useful especially as a synthesis starting material for the thiazolidinedione derivative represented by the general formula (2).
Methyl methoxybenzoate is a novel compound not described in the literature.

Alkylation of thiazolidine-2,4-dione with the compound of the general formula (1) is carried out in a solvent inert to a reaction such as tetrahydrofuran, such as n-butyllithium, sec-butyllithium or sodium amide. It is carried out in the presence of a base in a temperature range between -78 ° C and the boiling point of the solvent. Usually, after completion of the reaction, the target compound of the general formula (2) can be easily obtained by decomposing the excess base with water to make it acidic.

Heretofore, the compound of the general formula (2) has been produced by catalytic reduction of a 5-benzylidenethiazolidinedione derivative obtained by condensation of a benzaldehyde derivative with a thiazolidinedione (JP-A-9-048771).
On the other hand, according to the method of the present invention, the compound of the general formula (1), which is the starting compound, can be obtained at a lower cost than the benzaldehyde derivative, and does not require a reduction step after the condensation. It is a feature of the present invention that an industrially advantageous method is provided because the number of steps can be greatly reduced.

[0011]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

<Example 1>5-iodomethyl-2-me
Methyl oxybenzoate  16.4 g (109.4 mmol) of sodium iodide in acetone
5-Chloromethyl-2 was added to a 100 mL solution under ice-cooling and stirring.
Of methyl 2-methoxybenzoate (20.0 g, 99.7 mmol)
Seton 25 mL of solution was added. After stirring at room temperature for 14 hours,
The insolubles were removed by filtration and the solvent was distilled off. The residue was ethyl acetate 15
It was dissolved in 0 mL and washed with 100 mL of water. Magnesium sulfate
After drying over, the solvent was distilled off to give the title compound 2 as brown crystals.
4.5 g (80.2%) were obtained.¹ H-NMR (CDCl_Three, 60MHz) δ: 3.90 (6H, s), 4.47 (2H, s), 6.90
(1H, d, J = 8.0Hz), 7.48 (1H, dd, J = 2.0,8.0Hz), 7.82 (1H, d, J
= 2.0Hz) .IR (KBr): 1264,1298,1698cm^-1 .

<Embodiment 2>5- (2,4-dioxochi)
Azolidine-5-yl) methyl-2-methoxybenzoic acid
Methyl  Thiazolidine-2,5-dione 250 mg (2.13 mmol
l) was dissolved in 10 mL of anhydrous tetrahydrofuran, and
2.9 mL of 1.47 mol / L n-butyllithium solution at ℃
(4.26 mmol) was added and stirred at room temperature for 30 minutes. Reaction liquid
After cooling with ice, 5-iodomethyl-2-methoxybenzoic acid
650 mg (2.12 mmol) of tyl in anhydrous tetrahydrofuran
10 mL of the solution was added. Then stir at 50 ° C for 2 hours and 20 minutes
Was. After completion of the reaction, 10 mL of 0.6 mol / L hydrochloric acid was added, and salt was added.
Extracted with methylene chloride (10 mL × 2). Organic layer anhydrous sulfur
After drying over magnesium acid, it was concentrated. Silica gel residue
Column chromatography (hexane: ethyl acetate = 3: 2)
To give 310 mg (49%) of the title compound.
m. p. 150-152 ° C.

[0014]

According to the process for producing a thiazolidinedione derivative provided by the present invention, a 5-thiazolidinedione derivative obtained by condensing a benzaldehyde derivative with a thiazolidinedione can be used.
Although the benzylidene thiazolidinedione derivative was produced by catalytic reduction, a less expensive halogenomethylbenzene derivative was used, and no reduction step was required during production. It provides a method which is economically advantageous.

Claims (4)

[Claims] 1. General formula (1) (Wherein R ₁ and R ₂ are the same or different and each represent hydrogen or a lower alkyl group, and X represents a leaving group) in the presence of a base with a thiazolidine-2,4-dione General formula (2) (In the formula, R ₁ and R ₂ are as described above.) A method for producing a thiazolidinedione derivative represented by the formula: 2. The method for producing a thiazolidinedione derivative according to claim _1, wherein R ₁ and R ₂ are methyl, X is halogen, and the base is n-butyllithium. 3. A benzoic acid derivative represented by the general formula (1) used in the method for producing a thiazolidione derivative according to claim 1 or 2. 4. The benzoic acid derivative according to claim 3, which is methyl 5-iodomethyl-2-methoxybenzoate.