WO2009148195A1

WO2009148195A1 - 5-(4-hydroxybenzyl)thiazolidine-2,4-dione as intermediate for synthesis of thiazolidinedione based compounds and process for preparing the same

Info

Publication number: WO2009148195A1
Application number: PCT/KR2008/003102
Authority: WO
Inventors: Jin Oh Park; Yong Gil Kim; Han Il Son; Yun Jeong Lee; Eun Mi Kim
Original assignee: Daebong Ls, Ltd.
Priority date: 2008-06-02
Filing date: 2008-06-03
Publication date: 2009-12-10

Abstract

The present invention relates to 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by the following Chemical Formula [1], which is useful as an intermediate for synthesis of thiazolidinedione based compounds, a method for preparing the compound, and a method for preparing pioglitazone or pioglitazone hydrochloride, which is a thiazolidinedione based drug and useful in treating and preventing diabetes, using the 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula [1] as an intermediate:

Description

[DESCRIPTION] [Invention Title]

5-(4-HYDROXYBENZYL)THIAZOLIDINE-2_/4-DIONE AS INTERMEDIATE FOR SYNTHESIS OF THIAZOLIDINEDIONE BASED COMPOUNDS AND PROCESS FOR PREPARING THE SAME

[Technical Field]

The present invention relates to 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1, which is useful as an intermediate for synthesis of thiazolidinedione based compounds, a method for preparing the compound, and a method for preparing pioglitazone or pioglitazone hydrochloride, which is a thiazolidinedione based drug and useful in treating and preventing diabetes, using 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1 as an intermediate. Chemical Formula 1

[Background Art]

Thiazolidinedione (TZD) based drugs are treatments for type 2 diabetes, facilitating absorption and consumption of glucose in muscles and adipose tissues without increasing insulin secretion in the pancreas and reducing glucose production in the liver. They are prescribed for diabetics with large insulin resistance whose blood sugar level cannot be easily controlled through diet or exercise. Glitazone based drugs including pioglitazone, ciglitazone, troglitazone, englitazone, rosiglitazone, pioglitazone, etc., are included in the thiazolidinedione based.

Ciglilaionø

EngWβzonβ

Troflϊtarøe

Rflfifllltawβ Pioglitazone, which is representative of the thiazolidinedione based drugs, has a structure formula of Chemical Formula 2. Its compound name is 5-{4-[2-(5- ethylpyridin-2-yl)ethoxy]benzyl}thiazolidine-2,4-dione. Chemical Formula 2

Previously known preparation processes of pioglitazone represented by

Chemical Formula 2 or a hydrochloride thereof are as follows.

Reaction Scheme 1 showis a preparation process of pioglitazone disclosed in European Patent Publication No. 193256 and U.S. Patent No. 4,687,777. Reaction Scheme 1 comprises: reacting 2-(5-ethyl-2-pyridyl)ethanol represented by Chemical

Formula I with 4-fluoro-l-benzene to obtain 4-[2-(5-ethyl-2-pyridyl)-ethoxy]-l- benzene represented by Chemical Formula II; reducing the compound represented by Chemical Formula II with hydrogen in the presence of palladium on carbon (Pd- C) catalyst to obtain a compound represented by Chemical Formula III; subjecting the compound represented by Chemical Formula III to diazotization in an aqueous bromic acid solution and Meerwein arylation by acrylic ester in the presence of cuprous oxide (Cu₂O) catalyst to obtain a compound represented by Chemical

Formula IV; reacting the compound represented by Chemical Formula IV with thiourea in ethanol in the presence of sodium acetate to obtain a compound represented by Chemical Formula V; and hydrolyzing the compound represented by

Chemical Formula V in an inorganic acid solvent to obtain pioglitazone represented by Chemical Formula 2.

Reaction Scheme 1

In the preparation process based on Reaction Scheme 1, Meerwein arylation is used in the synthesis of the compound represented by Chemical Formula IV. However, since the Meerwein arylation is an exothermic reaction accompanied by the generation of a large quantity of nitrogen, the process may be dangerous. The production of a large amount of impurities may lead to a very low yield, and the use of bad-smelling acrylic esters as reactant may be harmful to health. Further, since it leaves wastes including heavy metals, the post-process is complicated. Therefore, this process is limited to be applied for industrial synthesis.

Reaction Scheme 2 is another preparation process of pioglitazone disclosed in European Patent No. 506273 and Korean Patent Laid-open No. 95-008312. Reaction Scheme 2 comprises: reacting 2-(5-ethyl-2-pyridyl)ethanol represented by Chemical Formula I with p-toluenesulfonyl chloride represented by represented by Chemical Formula VI in the presence of an organic or inorganic base using a phase transition catalyst benzyltributylammonium chloride to prepare 2-(5-ethylpyridin-2-yl)ethyl-4- methylbenzenesulfonate represented by Chemical Formula VII; reacting the compound represented by Chemical Formula VII with p-hydroxybenzaldehyde to obtain a compound represented by Chemical Formula VIII; reacting the compound represented by Chemical Formula VIII with thiazolidine-2,4-dione represented by Chemical Formula 4 to obtain 5-[[4-[2-(5-ethyl-2- pyridyl)ethoxy]phenyl]methylene]thiazolidine-2,4-dione represented by Chemical Formula IX; and reducing the compound represented by Chemical Formula IX with pressurized hydrogen on Pd-C catalyst to obtain pioglitazone represented by Chemical Formula 2.

Reaction Scheme 2

( Vi )

M )

(VHI)

PX) (2)

European Patent No. 506273 and Korean Patent Laid-open No. 95-008312 disclose that 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde represented by Chemical Formula VIII, which is an intermediate in the preparation process of Reaction

Scheme 2, can be prepared by Reaction Scheme 3. Reaction Scheme 3 comprises: reacting 2-(5-ethyl-2-pyridyl)ethanol represented by Chemical Formula I with 4- fluorobenzonitrile represented by Chemical Formula X in the presence of sodium hydride to obtain 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzonitrile represented by Chemical Formula XI; and reducing the compound represented by Chemical

Formula XI in formic acid with Raney nickel to obtain 4-[2-(5-ethylpyridin-2- yl)ethoxy]benzaldehyde represented by Chemical Formula VIII. Reaction Scheme 3

(1) <x) (XI)

Reaction Scheme 4 is another preparation process of pioglitazone disclosed in WO 93/13095 and Korean Patent No. 214908. Reaction Scheme 4 comprises reducing 5- [ [4- [2-(5-ethy 1-2-py r idy l)ethoxy ] phenyl] methylene] thiazolidine-2_/4-dione represented by Chemical Formula IX using a catalyst system consisting of a cobalt ion, a bidentate ligand and a reducing agent sodium borohydride (NaBH₄) to prepare pioglitazone represented by Chemical Formula 2.

Reaction Scheme 4

The preparation process of pioglitazone based on Reaction Scheme 4 comprises: synthesizing 5-substitued methylene-thiazolidinedione represented by Chemical Formula IX as a reaction intermediate; and reducing the methylene unsaturated bond of the intermediate to convert it into 5-substitued methyl- thiazolidinedione, using a catalyst system including NaBH₄ as a reducing agent. Besides, many preparation processes of pioglitazone are disclosed in literatures [Chem. Pharm. Bull, 39:1440 (1991); Japanese Paten No. 139182 (1988); Chem. Abstr., 109:6504h (1988); /. Med. Chem. 1998, Vol. 41, No. 10; /. Med. Chem. 1999, Vol. 42, No. H]. In these methods, pioglitazone represented by Chemical Formula 2 is obtained by performing reduction using Pd-C catalyst, performing hydrogenation under pressure in the presence of a metal catalyst, or performing reduction using magnesium in methanol. These reduction methods require the use of high-pressure hydrogen gas, which is difficult to handle, in the presence of a metal catalyst. Accordingly, a special manufacturing apparatus and a special technique to operate the same are required.

Therefore, there is an urgent need for the development of an improved preparation process of pioglitazone, which enables mass production in commercial scale.

The inventors of the present invention have worked for the development of a new preparation process of pioglitazone represented by Chemical Formula 2, which avoids the need of special manufacturing apparatus and special technique and is applicable to industrial or commercial scale production. As a result, they identified that 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1 is an intermediate useful for the preparation of glitazone drugs having a thiazolidinedione structure, and completed the present invention through intensive researches on the preparation method of the intermediate compound.

[Chemical Formula 1]

[Disclosure]

[Technical Problem]

The present invention provides a use of 5-(4-hydroxybenzyl)thiazolidine-2,4- dione represented by Chemical Formula 1 as an intermediate for synthesis of thiazolidinedione based compounds.

The present invention also provides an effective preparation process of preparation process of 5-(4-hydroxybenzyl)thiazolidine-2_/4-dione represented by Chemical Formula 1. The present invention further provides an effective preparation process of pioglitazone represented by Chemical Formula 2 or pioglitazone hydrochloride by way of synthesis of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1 as reaction intermediate.

[Technical Solution]

In an aspect to achieve the aforesaid objects, the present invention provides 5- (4-hydroxybenzyl)thiazolidine-2_/4-dione represented by Chemical Formula 1 as an intermediate for synthesis of thiazolidinedione based compounds.

[Chemical Formula 1]

In another aspect, the present invention provides a preparation process of 5-

(4-hydroxybenzyl)thiazolidine-2,4-dione comprising: condensating p-hydroxybenzaldehyde represented by Chemical Formula 3 with thiazolidine-2,4-dione represented by Chemical Formula 4 to prepare 5-(4- hydroxybenzylidene)thiazolidine-2,4-dione represented by Chemical Formula 5; and

(3) {4) (5) reducing 5-(4-hydroxybenzylidene)thiazolidine-2_/4-dione represented by Chemical Formula 5 to prepare 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1.

In another aspect, the present invention provides a preparation process of pioglitazone represented by Chemical Formula 2 comprising performing substitution of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1 and 2-(5-ethylpyridin-2-yl)ethyl 4-methylbenzenesulfonate represented by Chemical Formula 6.

(1) m G)

[Best Mode]

Hereinafter, reference will now be made in detail to various embodiments of the present invention, examples of which are described below. While the invention will be described in conjunction with exemplary embodiments, it will be understood by that the present description is not intended to limit the invention to those exemplary embodiments. On the contrary, the invention is intended to cover not only the exemplary embodiments, but also various alternatives, modifications, equivalents and other embodiments, which may be included within the spirit and scope of the invention as defined by the appended claims. The present invention relates to 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1, which is a useful intermediate in the synthesis of thiazolidinedione (TZD) based diabetic drugs, a preparation process thereof, and a preparation process of pioglitazone or pioglitazone hydrochloride using the compound represented by Chemical Formula 1 as an intermediate.

Reaction Scheme 5 briefly shows the preparation process of 5-(4- hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1. The preparation process based on Reaction Scheme 5 comprises: condensating γ- hydroxybenzaldehyde represented by Chemical Formula 3 with thiazolidine-2,4- dione represented by Chemical Formula 4 to prepare 5-(4- hydroxybenzylidene)thiazolidine-2,4-dione represented by Chemical Formula 5; and reducing 5-(4-hydroxybenzylidene)thiazolidine-2,4-dione represented by Chemical Formula 5 to prepare 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1. [ Reaction Scheme 5 ]

(3) {4} (5) (1)

According to Reaction Scheme 5, at first, 4-hydroxybenzaldehyde represented by Chemical Formula 3 is reacted with thiazolidine-2,4-dione represented by Chemical Formula 4 to prepare 5-(4-hydroxybenzylidene)thiazolidine-2,4-dione represented by Chemical Formula 5. That is, 5-(4- hydroxybenzylidene)thiazolidine-2,4-dione represented by Chemical Formula 5 may be obtained from condensation of a carbonyl compound and an activated methylene compound in the presence of an amine based basic catalyst. The reaction may be carried out in the presence of a catalyst such as piperidinium acetate, piperidinium benzoate or pyrrolidine. More specifically, condensation of aldehyde (R-CHO) and thiazolidinedione may be carried out using a small amount of piperidinium acetate or piperidinium benzoate as catalyst in an aromatic hydrocarbon solvent, e.g. toluene, or using pyrrolidine as catalyst in an alcohol solvent, e.g. methanol. Reaction temperature may be within the reflux temperature range of the solvent. Specifically, the reaction temperature may be from about 100 to about 250 ⁰C, more preferably from about 100 to about 150⁰C. Then, 5-(4-hydroxybenzylidene)thiazolidine-2,4-dione represented by

Chemical Formula 5 is reduced to prepare 5-(4-hydroxybenzyl)thiazolidine-2,4- dione represented by Chemical Formula 1.

As described earlier, in existing preparation processes, in order to convert unsaturated carbon chain such as alkene or olefin bonding into alkane bonding, high-pressure hydrogenation is preformed in the presence of Adams' catalyst (prepared by supporting precious metal catalyst such as platinum or palladium on inactive material such as charcoal) Pd/ C or PtCb, or reduction is performed using magnesium in methanol. Although such hydrogenation or reduction may be effective in laboratories, special manufacturing apparatus and process are required for their application in an industrial scale. In the existing process based on Reaction Scheme 4, 5-sustituted methylene-thiazolidinedione represented by Chemical Formula IX is reduced using a catalyst system consisting of a reducing agent sodium borohydride (NaBH₄), a cobalt ion and a bidentate ligand to obtain pioglitazone represented by Chemical Formula 2. An organic solvent such as methanol, ethanol, isopropanol, acetone, dimethylformamide (DMF) and tetrahydrofuran (THF), or a mixture solvent of water and THF is used as reaction solvent. That is, since 5-sustituted methylene-thiazolidinedione represented by Chemical Formula IX is not well dissolved in water, a mixture solvent of water and THF is used. Further, in order to obtain the target material following the reduction, a complicated separation and purification process such as extraction using ethyl acetate is necessary.

In contrast, the present invention provides a preparation process highly applicable industrially, by which reduction can be sufficiently performed without requiring a special manufacturing apparatus.

In accordance with the present invention, the target compound 5-(4- hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1 may be prepared by easily reducing the methylene group at the C-5 position of thiazolidinedione in 5-(4-hydroxybenzylidene)thiazolidine-2,4-dione represented by Chemical Formula 5 using a reducing agent, a metal catalyst and a ligand in a basic aqueous solution. That is, the present invention is characterized in that reduction is performed using water as a solvent, and thus, the target compound can be obtained as solid through a simple control of acidity following the reduction. Accordingly, the preparation process of the present invention is applicable to industrial-scale mass production. In the present invention, sodium borohydride, lithium borohydride, potassium borohydride, tetraalkylammonium borohydride, zinc borohydride, lithium aluminum hydride, etc. may be used as the reducing agent. Among them, sodium borohydride may be preferred, because it exists as a white, crystalline solid, making it safely treatable in the industrial field, and can be weighed in the air, making it easily treatable, and water or alcohol may be used as a solvent. An effective amount of the reducing agent may be 2-10 molar equivalents based on the compound represented by Chemical Formula 5. The metal catalyst may be a cobalt compound. A typical example is cobalt chloride. An effective amount of the metal catalyst may be 0.01-0.02 molar equivalent based on the compound represented by Chemical Formula 5. The ligand may be dimethylglyoxime. An effective amount of the ligand may be 10-50 molar equivalents based on the metal catalyst.

The reduction may be carried out at a temperature below room temperature. Preferably, the reducing agent may be added while maintaining the temperature at 0-10 ⁰C, and, after the addition of the reducing agent is completed, the reduction may be carried out while maintaining the temperature at around the room temperature (20-30⁰C).

To describe the reduction according to the present invention in more detail, the compound represented by Chemical Formula 5, the metal catalyst and the ligand may be added to the reaction solvent to prepare a basic aqueous solution. Then, the reducing agent may be added. It is preferred that the reducing agent be added dropwise as slowly as possible, in order to prevent vigorous reaction. Preferably, a solution in which the reducing agent is dissolved in water or purified water maintained at a temperature below the room temperature (specifically 0-20 ⁰C). An inorganic base or an organic base may be added further to prepare the basic aqueous solution. Preferably, the inorganic base may be selected from hydroxide, carbonate, bicarbonate, phosphate, sulfate, etc., of an alkali metal or an alkaline earth metal.

Specifically, the inorganic base may be sodium hydroxide, sodium carbonate, sodium bicarbonate or potassium phosphate. More preferably, the base may be an alkali metal hydroxide. Particularly, sodium hydroxide may be preferred. The base may be added as dissolved in water, and the concentration of the base solution is not particularly limited. The base may be used in an amount by which the pH of the reaction solution may be controlled to be from 8 to 11, more preferably 10.5.

During the reduction, the solution exhibits a yellowish brown color. But, after the reduction is completed, it turns into a slightly black, transparent solution. The reaction may be terminated by controlling the pH of the reaction solution to become neutral using an acid. The acid used to terminate the reaction may be generally selected from an organic acid such as formic acid, acetic acid, etc., and an inorganic acid such as hydrochloric acid, sulfuric acid, etc. The reaction is terminated as slowly as possible. The reaction product, 5-(4- hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1, may be precipitated using an acid such as acetic acid at pH 6-7. Thus precipitated compound represented by Chemical Formula 1 may be purified by solvent extraction using ethyl acetate and hexane. Alternatively, the precipitated compound represented by Chemical Formula 1 may be purified through repeated dissolution and precipitation. For example, the compound represented by Chemical Formula 1 may be dissolved in water or purified water. Then, after adjusting the pH of the solution to 8-11 by adding an alkali metal salt, acetic acid may be used to adjust the pH to 6-7. Then, the compound represented by Chemical Formula 1 is precipitated again. The purification process according to the present invention is very useful in a commercial-scale mass production.

Further, the present invention provides a preparation process of pioglitazone represented by Chemical Formula 2 or pioglitazone hydrochloride using 5-(4- hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1 prepared by the preparation process based on Reaction Scheme 5 as an intermediate.

Reaction Scheme 6 briefly describes the preparation process of pioglitazone represented by Chemical Formula 2 or pioglitazone hydrochloride. The preparation process based on Reaction Scheme 6 comprises: reacting 5-(4- hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1 with 2-(5- ethylpyridin-2-yl)ethyl 4-methylbenzenesulfonate represented by Chemical Formula 6 to prepare pioglitazone represented by Chemical Formula 2; and, optionally, treating pioglitazone represented by Chemical Formula 2 with hydrogen chloride to prepare pioglitazone hydrochloride: [Reaction Scheme 6]

m (βj

m (2) » HCI SaIl

5-(4-Hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1 is a phenolic compound with a hydroxy group bonded to a benzene ring. Accordingly, pioglitazone represented by Chemical Formula 2 may be synthesized through Williamson ether synthesis, i.e. alkylation of alkyl halide and alkoxide via nucleophilic substitution (SN2). That is, after converting the hydroxy (-OH) group bonded to the benzene ring of the compound represented by Chemical Formula 1 into a phenoxy anion in the presence of an inorganic base, pioglitazone represented by Chemical Formula 2 may be synthesized via nucleophilic substitution with 2-(5- ethylpyridin-2-yl)ethyl 4-methylbenzenesulfonate represented by Chemical Formula 6. At this moment, C2-C10 ketones such as acetone and Ci-C₆ alcohols such as ethanol may be used as reaction solvent. The base may be an inorganic base selected from hydroxide or carbonate of an alkali metal such as K2CO3, KOH and NaOH. Specifically, the substitution may be performed in ethanol solvent using potassium hydroxide (KOH), or in anhydrous ethanol solvent using potassium carbonate (K₂CO₃). Pioglitazone represented by Chemical Formula 2 obtained from the substitution may be converted into pharmaceutically acceptable salts. As a typical example, it may be converted into pioglitazone hydrochloride. Preparation of acid addition salts is well known in the art. In the present invention, pioglitazone represented by Chemical Formula 2 may be reacted with strong hydrochloric acid in methanol and precipitated using acetone to prepare pioglitazone hydrochloride.

As described earlier with respect to Reaction Scheme 2, 2-(5-Ethylpyridin-2- yl)ethyl 4-methylbenzenesulfonate represented by Chemical Formula 6, another starting material in the preparation process based on Reaction Scheme 6, may be synthesized from 2-(5-ethyl-2-pyridyl)ethanol represented by Chemical Formula I and p-toluenesulf onyl chloride represented by Chemical Formula VI in the presence of an organic or inorganic base using benzyltributylammonium chloride as a phase transition catalyst.

More conveniently, in the present invention, 2-(5-ethyl-2-pyridyl)ethanol represented by Chemical Formula I may be reacted with p-toluenesulf onyl chloride represented by Chemical Formula VI at room temperature in the presence of an organic or inorganic base, without using a phase transition catalyst, to synthesize 2- (5-ethylpyridin-2-yl)ethyl 4-methylbenzenesulfonate represented by Chemical Formula 6. That is, whereas the compound represented by Chemical Formula 6 is synthesized in the presence of a phase transition catalyst in the existing preparation processes, it can be synthesized with a sufficiently high production yield in the absence of a phase transition catalyst in accordance with the present invention. At this moment, halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as diethyl ether and THF, and acetates such as ethyl acetate and isopropyl acetate may be used as reaction solvent. The base may be an organic base such as triethylamine, diethylamine and trimethylamine, or an inorganic base such as Na₂CO₃, NaCO₃, NaHCO₃, KOH, K₂CO₃, NaOH, etc. Preferably, a mixture of an organic solvent and purified water, and an inorganic base may be used. Most preferably, a mixture solvent of THF or dichloromethane and purified water may be used, and sodium hydroxide may be used as the inorganic base. Since the reaction gives a very high production yield and byproducts other than the compound represented by Chemical Formula 6 can be easily removed in the purification process following the synthesis of pioglitazone according to Reaction Scheme 6, the compound represented by Chemical Formula 6 may be used immediately as starting material for the preparation process based on Reaction Scheme 6 with no additional purification process. If necessary, a simple purification process such as silica gel column chromatography may be used. In this case, a mixture solution of ethyl acetate and n-hexane (2:1, v/v) or ethyl acetate may be used as mobile phase. [Mode for Invention]

The following examples further illustrate the present invention, but they are not intended to limit the present invention in any means.

Example 1. Preparation of 5-(4-hydroxybenzylidene)thiazolidine-2_/4-dione

20 g of 4-hydroxybenzaldehyde and 23 g of thiazolidine-2,4-dione were added to 400 mL of toluene and stirred at room temperature. 4.46 mL of piperidine and 5 g of benzoic acid were added. After dissolving 4-hydroxybenzaldehyde and thiazolidine-2,4-dione, the mixture was stirred for 5 hours under reflux. After cooling the mixture slowly at room temperature, 50 mL of methanol was added and then stirred for 30 minutes. The resultant was washed with methanol, filtrated and then dried at 60 ⁰C with hot air and finally obtained 35 g of bright yellow 5-(4- hydroxybenzylidene)thiazolidine-2,4-dione.

¹H NMR (300 MHz, CD₃OD) δ 6.90-6.93 (2H), 7.40-7.43 (2H), 7.72 (IH). HPLC [column: C18 (ODS), mobile phase: acetonitrile/0.1 M ammonium acetate/ acetic acid = 25/25/1 (v/v/v), wavelength: 269 nm, flow rate: 0.7 mL/min, temperature: 35 ⁰C] 99.37%.

Example 2. Preparation of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione Example 2-1

0.61 g of cobalt chloride -6H₂O and 2.98 g of dimethylglyoxime were added to 600 mL of purified water and stirred. After adding 30 g of 5-(4- hydroxybenzylidene)thiazolidine-2,4-dione to the mixture, its pH was adjusted to

10.5 by adding 10% aqueous sodium hydroxide solution. After stirring at room temperature for 30 minutes, the mixture was cooled down to 0 ⁰C and stirred. A solution prepared by dissolving 51.3 g of sodium borohydride in 200 mL of purified water and 1 mL of 1 N NaOH was drop wisely added. After the addition was completed, the resultant was stirred at room temperature for 24 hours. After identifying that the reaction solution turned into a slightly black, transparent solution, the pH of the reaction mixture was adjusted to 6 by dropwisely adding acetic acid. After the product was precipitated, it was stirred for 1 additional hour. After filtration, the product was washed with water. After filtration, it was dried at 60 ⁰C under reduced pressure, and obtained 19.75 g of 5-(4- hy droxybenzyl)thiazolidine-2,4-dione.

Thus obtained 5-(4-hydroxybenzyl)thiazolidine-2,4-dione was dissolved at room temperature in 200 mL of ethyl acetate. After adding activated charcoal, the mixture was refluxed for 2 hours. After removing the activated charcoal by filtration, the reaction solution was concentrated under reduced pressure until the volume became one third of its original volume. 50 mL of hexane was added at room temperature while stirring, and stirried for 1 hour. After filtration and washing with hexane followed by drying at 50 ⁰C with hot air, 17.26 g of 5-(4- hydroxybenzyl)thiazolidine-2,4-dione was obtained.

¹H NMR (400 MHz, DMSO) δ 3.02-3.24 (2H), 4.82 (IH), 6.70-7.02 (4H), 9.34 (IH), 11.99 (IH); mp. (BI/UK 9200) 157 ⁰C; GCMS m/z 223 107(100), 91(3.85), 77(16.91).

EA (Thermofinnigan EA1108, C₁₀H₉NO₃S) C 53.91 H 3.81 N 6.23 S 15.00.

HPLC [column: C18 (ODS), mobile phase: acetonitrile/0.1 M ammonium acetate/ acetic acid = 25/25/1 (v/v/v), wavelength: 269 nm, flow rate: 0.7 mL/min, temperature: 35⁰C] 99.38%.

Example 2-2

0.61 g of cobalt chloride 6H₂O and 2.98 g of dimethylglyoxime were added to 600 rrvL of purified water and stirred. After adding 30 g of 5-(4- hydroxybenzylidene)thiazolidine-2_/4-dione to the mixture, its pH was adjusted to 10.5 by adding 10% aqueous sodium hydroxide solution. After stirring at room temperature for 30 minutes, the mixture was cooled down to 0 ⁰C and stirred. A solution prepared by dissolving 51.3 g of sodium borohydride in 200 mL of purified water and 1 mL of 1 N NaOH was dropwisely added. After the addition was completed, the mixture was stirred at room temperature for 24 hours. After identifying that the reaction solution turned into a slightly black, transparent solution, the pH of the reaction mixture was adjusted to 6 by dropwisely adding acetic acid. After the product was precipitated, the mixture was stirred for 1 additional hour. After filtration, the product was washed with water. After filtration, it was dried at 60 ⁰C under reduced pressure, and obtained 19.75 g of 5-(4- hydroxybenzyl)thiazolidine-2,4-dione was obtained.

Thus obtained 5-(4-hydroxybenzyl)thiazolidine-2,4-dione was added to purified water and, after adjusting the pH to 10-11 by adding aqueous sodium hydroxide solution, stirred for 3 hours. When the pH was adjusted to 6 by adding acetic acid, 5-(4-hydroxybenzyl)thiazolidine-2,4-dione was precipitated. The precipitate was filtered, washed with hexane, and dried at 50 ⁰C with hot air to obtain 18.09 g of purified 5-(4-hydroxybenzyl)thiazolidine-2,4-dione. Example 3. Preparation of 2-(5-ethylpyridin-2-yl)ethyl 4- methylbenzenesulfonate

150 mL of purified water was cooled and 29.12 g of sodium hydroxide was slowly added and dissolved by stirring. A solution prepared by dissolving 50 g of 2-(5-ethyl-2-pyridyl)ethanol in 100 mL of dichloromethane was added dropwise to the reaction solution, and stirring was performed for 2 hours. A solution prepared by dissolving 69.35 g of 4-toluenesulfonyl chloride in 120 mL of dichloromethane was added dropwise to the reaction solution, and stirring was performed at room temperature for 4 hours. Phase separation was performed after stopping the stirring. Thus organic layer was washed for 3 times with excess purified water.

The resultant reaction solution was dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 2-(5- ethylpyridin-2-yl)ethyl 4-methylbenzenesulfonate as yellow oil. Then, column chromatography [solvent: ethyl acetate/ n-hexane = 2/1 (v/v)] was performed to obtain 45 g purified 2-(5-ethylpyridin-2-yl)ethyl 4-methylbenzenesulfonate.

Example 4. Preparation of pioglitazone

Example 4-1

3.42 g of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione and 2.58 g of potassium hydroxide were added to 50 mL of ethanol and stirred at room temperature for 1 hour. A solution prepared by dissolving 6.88 g of 2-(5-ethylpyridin-2-yl)ethyl 4- methylbenzenesulfonate in 20 mL of ethanol was added dropwise. After the addition was completed, the mixture was stirred for 5 hours under reflux. After cooling the resultant room temperature, its salt was removed by filtration. The filtrate was removed by concentration under reduced pressure. After adding 20 mL of acetone and 10 niL of purified water followed by stirring, it was neutralized by using dilute hydrochloric acid. Thus produced precipitate was filtered, washed with acetone, and dried at 45 ⁰C with hot air to obtain 1.5 g of pioglitazone.

Example 4-2

2.68 g of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione and 5 g of potassium carbonate were added to 50 mL of anhydrous ethanol and stirred at room temperature for 1 hour. A solution prepared by dissolving 5.5 g of 2-(5- ethylpyridin-2-yl)ethyl 4-methylbenzenesulfonate in 20 mL of anhydrous ethanol was drop wisely added. After the addition was completed, the mixture was stirred for 5 hours under reflux. After cooling at room temperature, its salt was removed by filtering. The filtrate was removed by concentration under reduced pressure. After adding 20 mL of acetone and 10 mL of purified water followed by stirring, it was neutralized by using dilute hydrochloric acid and 0.1 N sodium hydroxide. Thus produced precipitate was filtered, washed with acetone, and dried at 45 ⁰C with hot air to obtain 0.28 g of pioglitazone.

Example 5. Preparation of pioglitazone hydrochloride 1.47 g of pioglitazone was added to 10 mL of methanol and stirred. Strong hydrochloric acid was added in small amounts until pioglitazone was dissolved. After dissolvign pioglitazone, the mixture was stirred for 1 hour at room temperature. The reaction mixture was removed by concentration under reduced pressure. 20 mL of acetone was added to thus obtain yellow oil and stirred for 1 hour at room temperature. After filtration, the resultant was washed with acetone and dried at 45 ⁰C with hot air and finally obtained 1.41 g of pioglitazone hydrochloride.

¹H NMR (300 MHz, CD₃OD) δ 1.29-1.35 (3H), 2.84-2.91 (2H), 3.08 (IH), 3.29 (IH), 3.49-3.53 (2H), 4.36-4.40 (2H), 4.65-4.69 (IH), 6.83-6.88 (2H), 7.13 (2H), 8.03 (IH), 8.44 (IH), 8.65 (IH).

HPLC [column: C18 (ODS), mobile phase: acetonitrile/ 0.1 M ammonium acetate/ acetic acid = 25/25/1 (v/v/v), wavelength: 269 nm, flow rate: 0.7 mL/min, temperature: 25 ⁰C] 90.5%.

[Industrial Applicability]

The present invention provides a use of 5-(4-hydroxybenzyl)thiazolidine-2,4- dione represented by Chemical Formula 1 as an intermediate for synthesis of thiazolidinedione based compounds. According to the present invention, pioglitazone or pioglitazone hydrochloride and other various glitazone based drugs such as ciglitazone, troglitazone, rosiglitazone and rivoglitazone, which are useful as diabetic treatments, may be prepared in an industrial scale. Accordingly, the preparation process provided by the present invention is of significant industrial value. The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the accompanying claims and their equivalents.

Claims

[CLAIMS] [Claim 1]5-(4-Hydroxybenzyl)thiazolidine-2/4-dione represented by the following Chemical Formula 1,

[Chemical Formula 1]

which is an intermediate for the synthesis of thiazolidinedione based compounds.

[Claim 2] A preparation process of 5-(4-hydroxybenzyl)thiazolidine-2_/4-dione comprising: condensating p-hydroxybenzaldehyde represented by Chemical Formula 3 with thiazolidine-2,4-dione represented by Chemical Formula 4 to prepare 5-(4- hydroxybenzylidene)thiazolidine-2,4-dione represented by Chemical Formula 5; and

reducing 5-(4-hydroxybenzylidene)thiazolidine-2_/4-dione represented by Chemical Formula 5 to prepare 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1.

[Claim 3]

The preparation process according to claim 2, wherein the condensation is performed in the presence of a catalyst selected from piperidinium acetate, piperidinium benzoate and pyrrolidine.

[Claim 4]

The preparation process according to claim 2, wherein the reduction is performed using water as a solvent, NaBH₄ as a reducing agent, cobalt chloride (CoCb) as a metal catalyst, and dimethylglyoxime as a ligand.

[Claim 5]

The preparation process according to claim 4, wherein the reduction is performed using 2-10 molar equivalents of NaBH₄ as a reducing agent and 0.01-0.02 molar equivalent of cobalt chloride as a metal catalyst, based on 5-(4- hydroxybenzylidene)thiazolidine-2,4-dione represented by Chemical Formula 5, and using 10-50 molar equivalents of dimethylglyoxime as a ligand, based on cobalt chloride.

[Claim 6]

The preparation process according to any of claims 2, 4 or 5, wherein the reduction is performed in the presence of alkali metal hydroxide base.

[Claim 7]

The preparation process according to claim 4, wherein the reduction is performed using an aqueous sodium hydroxide solution of pH 8-11 as a solvent.

[Claim 8]

The preparation process according to claim 2, which, further comprises a step of adjusting the pH to 6-7 using acetic acid to precipitate the compound represented by Chemical Formula 1 upon completion of the reduction.

[Claim 9]

The preparation process according to claim 8, further comprising purifying the precipitated compound represented by Chemical Formula 1 consecutively with ethyl acetate and hexane.

[Claim 10]

The preparation process according to claim 8 or 9, further comprising purifying the precipitated compound represented by Chemical Formula 1 by: dissolving the compound in purified water; adjusting the pH to 9-11 by adding sodium hydroxide; and adjusting the pH to 6-7 using acetic acid to precipitate the compound.

[Claim 11]

A preparation process of pioglitazone represented by Chemical Formula 2 comprising performing substitution of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione represented by Chemical Formula 1 and 2-(5-ethylpyridin-2-yl)ethyl 4- methylbenzenesulfonate represented by Chemical Formula 6.

Ei) (6} {2}

[Claim 12]

The preparation process according to claim 11, further comprising: reacting pioglitazone represented by Chemical Formula 2 with hydrochloric acid to convert it into pioglitazone hydrochloride.

[Claim 13]

The preparation process according to claim 11, wherein the substitution is performed using C₁-C₆ alcohol as a solvent, and an inorganic base selected from hydroxide and carbonate of an alkali metal.

[Claim 14]

The preparation process according to claim 11, wherein the substitution is performed using ethanol as a solvent and potassium hydroxide (KOH) as a base.

[Claim 15] The preparation process according to claim 11, wherein the substitution is performed using anhydrous ethanol as a solvent and potassium carbonate (K2CO3) as a base.