WO2001096321A1

WO2001096321A1 - Process for the preparation of thiazolidinedione derivatives

Info

Publication number: WO2001096321A1
Application number: PCT/JP2001/004989
Authority: WO
Inventors: Michiro Ohnota; Kazuo Orita; Yasuhiro Aizawa; Noriyuki Yoshida; Takashi Sakamaki
Original assignee: Kyorin Pharmaceutical Co., Ltd.
Priority date: 2000-06-14
Filing date: 2001-06-13
Publication date: 2001-12-20
Also published as: AU2001274502A1

Abstract

An industrially advantageous process for the preparation of a benzylthiazolidinedione derivative useful as an intermediate in the preparation of N-benzyldioxothiazolidinyl-benzamide derivatives serving as antihyperglycemics. Specifically, a process for the preparation of a thiazolidinedione derivative of formula (1), characterized by forming a Co complex catalyst in a specified pH range in a reaction system where the subsequent reduction is to be carried out, and reducing a compound of the general formula (2) with a reducing agent in the resulting reaction system (2) (wherein R is hydrogen or lower alkyl).

Description

Satsuki Itoda Method for producing thiazolidinedione derivative Technical field

The present invention is useful as a hypoglycemic agent and an insulin sensitivity enhancer.

The present invention relates to a method for producing a benzylthiazolidinedione derivative represented by the general formula (2), which is a synthetic intermediate for producing an N-benzyldioxothiazolidinyl benzamide derivative.

Background art

The N-benzyldioxothiazolidinyl benzamide derivative is known as a compound having an excellent hypoglycemic effect and hypolipidemic effect (Japanese Patent Application Laid-Open No. Hei 9-48771). In order to produce these series of compounds, it was necessary to reduce the benzylidenethiazolidinedione derivative represented by the general formula (1) to a benzylthiazolidinedione derivative. Conventionally, as a method for reducing this form of thiazolidinedione derivative, a high-pressure catalytic reduction method using palladium carbon as a catalyst has been known (Japanese Patent Application Laid-Open No. H08-106468). It was done.

However, this method required a large amount of catalyst and a high-pressure catalytic reduction unit, and was not suitable for safe mass synthesis.

On the other hand, another method for reducing such thiazolidinedione derivatives For example, an example of reduction using sodium borohydride and a cobalt complex (Japanese Patent Application Laid-Open No. 7-520530) has been known. However, it was unknown whether it could be used for the reduction of the benzylidenethiazolidinedione derivative according to the present invention. Furthermore, when the method described in JP-T-Hei 7-5202530 is directly applied to the benzylidene thiazolidinedione derivative according to the present invention, the yield and purity vary greatly and the reproducibility of the reaction increases. Therefore, it was not an industrially advantageous method, and it was necessary to devise and improve it. · Disclosure of the invention

The present inventors have conducted intensive studies on the production of raw materials for establishing an industrial production method of an N-benzyldioxothiazolidinyl benzamide derivative.

General formula (1)

[In the formula, R represents hydrogen or a lower alkyl group. ]

By forming a Co complex catalyst in the same reaction system within a specific pH range and then using a reducing agent in the same reaction system, the reduction reaction proceeds rapidly at room temperature. , 'General formula (2)

The present inventors have found that a benzylthiazolidinedione derivative represented by the formula (1) can be obtained with good yield, high purity and stability, and have completed the present invention.

The compound represented by the general formula (1) of the present invention can be synthesized by the method described in JP-A-9-48771. In the general formula (1), the group defined as R is hydrogen or a lower alkyl group, which is a methyl group, an ethyl group, or an isopropyl group. R of the compound of the general formula (1), which is a raw material, may be either hydrogen or a lower alkyl group. In the case of a lower alkyl group, hydrolysis proceeds easily in the reaction system, and as a result, carboxylic acid is produced. Changes to acid groups.

Examples of the reaction solvent in the production method of the present invention include aqueous solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, and these aqueous solutions and dimethylformamide, tetrahydrofuran. A mixed solvent with an organic solvent such as drofuran, methanol, ethanol, and isopropyl alcohol can be used. Preferably, it is a 0.5 to 1 mol / L aqueous sodium hydroxide solution.

The temperature range of the reaction is 0-50 ° C. Preferably, it is 20 to 40 ° C.

Examples of the Co complex catalyst used in the present invention include, for example, black (pyridyl) covaloxime (III) synthesized by the method described in In 0 rg. Synth. 11, 61 (19668). Can be used, but there is the trouble of separately preparing the catalyst. The feature of the present invention is the same reaction In the system, C 0 (Π) and dimethylglyoxime are used to form a C 0 complex catalyst within a specific pH range, and a reduction reaction is performed.

The donor of the Co (II) ion is preferably cobalt chloride, and the preferred ligand is dimethylglyoxime. This ligand is preferably used in an amount of about 4 mol% with respect to cobalt.

The preparation amount of the C0 catalyst used in the reaction is 0.1 to 1.5 fflol% based on the compound represented by the general formula (1). Preferably, it is 0.5 to 1.0 mol%.

As the reducing agent, borohydride compounds such as sodium borohydride, lithium borohydride, and borohydride can be used. Preferably, sodium borohydride can be used at low cost. In carrying out this reaction, the pH of the reaction system can be set arbitrarily, but the reaction speed or the like changes significantly depending on the pH, which greatly affects the result of the reaction. In the compound of the present invention, for example, although the reduction reaction proceeds even at pH 9.5 or more, the raw material compound (1) does not completely disappear. In order to completely eliminate the raw materials, it is necessary to add a catalyst and a reducing agent again, and it takes a long time to complete the reaction. In general, the thiazolidine-2,4-dione ring is relatively unstable under basic conditions, and therefore, it is disadvantageous to leave it under strong basic conditions for a long time.

In order to solve the above-mentioned problems, when reducing the compound of the general formula (1), the pH at the time of forming a C 0 complex catalyst in the reaction solution, then adding a reducing agent and performing reduction is examined. As a result, it was found that high-purity benzylthiazolidinedione derivative (2) can be obtained with high yield and high reproducibility when the reaction is performed at pH 8.0 to 9.5. .

That is, the compound of the general formula (1) is prepared in a reaction system at a pH of 8.0 to 9.5 with a C 0 complex catalyst, and the reduction reaction is carried out. This is a major feature of the invention. As a result, the reduction reaction is completed in a short time, and the compound of the general formula (2) is produced with good reproducibility and good quality, which is an excellent method for industrial production. . BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by these Examples.

(Reference example 1)

Synthesis of 5-[(2,4-dioxothiazolidine-1-5-ylidene) methyl] -1-2-methoxybenzoic acid methyl ester

1) 52.3-Formylsalicylic acid was suspended in 1.66 L of acetone, and then cooled to 10 ° C or lower. 52.8 g (4.0 Omol) of lithium carbonate was added, and dimethyl sulfate (purity: 95%) 53.1 (4.0 Omol) was added dropwise at 10 ° C or lower. After the addition, the mixture was stirred for 2 hours and refluxed for another 1 hour. The reaction solution was cooled to room temperature, poured into 3.32 L of cold water, and 3.32 L of water was added dropwise, followed by stirring at room temperature for 1 hour. The crystals were collected by filtration, washed with 3.32 L of water, and dried by blowing air at 40 ° C overnight to give 33.5.4 g (86.4%) of methyl 3-formyl-6-methoxybenzoate. ) Obtained.

m.p. 84-86 ° C.

2) 3-Formyl-l-6-methoxybenzoic acid methyl ester 30.7 g (1.6 Oraol) was suspended in 1.55 L of ethanol, and then 2,4-thiazolidinedione was 24.9 g. (1.92 mol) and 13.6.3 g (1.6 Omol) of piperidine were added, and the mixture was reacted under reflux for 6 hours. did. After cooling to room temperature, the reaction solution was poured into 3.11 L of cold water, and concentrated hydrochloric acid was added dropwise while cooling to adjust the pH to 2-3. After stirring for 30 minutes, the crystals were collected by filtration and washed with water until the filtrate became neutral. The obtained wet crude crystals were suspended in 4.69 L of methanol for 30 minutes under reflux. After cooling to room temperature, the crystals were collected by filtration and washed with 1.41 L of methanol. Blow-dry at 60 ° C and dry with 5-[(2,4-dioxothiazolidin-1-5-ylidene) methyl] -12-methoxybenzoic acid methyl ester 37.7.7 g (80.5%) I got

m.p. 273-276 ° C.

(Reference example 2)

Synthesis of 2-Methoxy-5-[(2,4-Dioxothiazolidine-1-lylidene) methyl] benzoic acid

5-[(2,4-Dioxothiazolidine-1-5-ylidene) methyl] methyl 2--1-methoxybenzoate 370.0 g (1.26 mol) of l-mol / L hydroxylation The solution was added to 3.78 L (3.78 mol) of a sodium aqueous solution, and stirred at room temperature for 3 hours. Thereafter, 3.7 g of activated carbon was added, and the mixture was further stirred for 1 hour. The activated carbon was filtered off using celite and washed with 3.78 L of water. After adding 3.78 L of water to the filtrate, 6 mol / L hydrochloric acid was added to adjust the pH to 2-3. After stirring for 1 hour, the crystals were collected by filtration and washed with water until the filtrate became neutral. The wet crude crystals were suspended in 3.5 L of acetone for 30 minutes under reflux. After cooling to room temperature, the crystals were collected by filtration and washed with 1.6 L of acetone. Dry with air at 50 ° C and dry 5-([2,4-dioxothiazolidine-1-5-ylidene) methyl] -12-methoxybenzoic acid 28.5.3 g (81.0%) I got

mp 268-270. C. (Reference example 3)

Preparation of black mouth (pyridine) covaloxime (III)

To 400 mL of 95% ethanol, 10.0 g of cobalt chloride (II) hexahydrate and 11.0 g of dimethyldalioxime were added and dissolved by heating. g was added and stirred. After cooling to 20 ° C, air was blown into the reaction solution for 30 minutes and left at the same temperature for 1 hour.

The precipitated crystals were collected by filtration and washed with water, ethanol, and getyl ether (50 mL each). The crystals were dried under reduced pressure at room temperature to obtain kuroguchi (pyridine) kovaloxim (III) 8.6.

(Reference example 4)

5-[(2,4-Dioxothiazolidine-1-5-ylidene) methyl] 1-2-Methoxybenzoic acid 50.0 0.5 mol / L sodium hydroxide aqueous solution at 25 ° C It was poured into 720 mL to dissolve. After charging 6.8 g of sodium borohydride, 0.36 g of chlorinated (pyridine) covaloxime (III) was added, and the mixture was reacted at 25 ° C for 6.5 hours. The reaction solution was cooled with ice water, 50% isopropyl alcohol and water (720 mL) were added, and 6 mol / L hydrochloric acid was added dropwise to adjust the pH to 2. The mixture was stirred for 1 hour while being cooled with ice water, and the precipitated crystals were collected by filtration and washed with 500 mL of a 10% aqueous isopropyl alcohol solution.

It was dried by blowing air at 50 ° C to obtain 43.5 g (86.4) of 5-[(2,4-dioxothiazolidine-l-yl) methyl] -2-methoxybenzoic acid.

mp 187-189 ° C. (Reference example 5)

0.5 mol / L aqueous sodium hydroxide solution 4.0 — 5 — [(2,4 dioxothiazolidine_5—ylidene) methyl] 1-2-methoxybenzoic acid in 0.0L 2 7 9.3 g (1.0 Omol) was added and dissolved, and the mixture was cooled to 10 ° C or lower. This was followed by 0.65 (5.0 Ommol) of sodium chloride chloride, 2.32 g (20.0 mmol) of dimethyldalioxime, 41.6 g (1.1 Omol) of sodium borohydride. ) And 400 mL of DMF. Stirring was continued at room temperature, but unreacted raw materials were found.Three hours later, sodium borohydride 41.6 g (1.1 Omol) was added, and after another one hour, hydrogenation was performed. 3.78 g (0.1 Omol) of sodium boron was added. After adding 4.00 L of a cold 50% isopropyl alcohol aqueous solution to the reaction solution under cooling, 6 mol / L hydrochloric acid was added dropwise at 20 ° C. or lower to adjust the pH to 2-3.

After stirring for 1 hour under cooling, the crystals were collected by filtration and washed with 2.81 L of a 10% aqueous solution of isopropyl alcohol. It was blow-dried at 50 ° C. to obtain 229.2 g of crude crystals. To this, 2.29 L of ethyl acetate was added, suspended under reflux for 30 minutes, cooled to 20 ° C or lower, and the crystals were collected by filtration. The crystals were washed with 1.15 L of ethyl acetate, blown dry at 40 ° C, and dried with 5 — [(2,4 dioxothiazolidine-1-yl) methyl] 1-2—methoxybenzoic acid 2 15.2 g (76.5%) were obtained.

m.p. 187-189 ° C., HPLC purity 98.0%.

(Example)

5-[(2,4-Dioxothiazolidine-1-5-ylidene) methyl] —2—Methoxybenzoic acid methyl ester 37.6 g (0.128 mol) was added to 1 mol / L sodium hydroxide. The solution was added to 28 mL of the stream solution, and the mixture was stirred at 30 to 35 ° C for 2 hours. 2 mol / L hydrochloric acid was added dropwise to adjust the pH to 9.13. Was. This was followed by a solution of 83 mg (0.640 mmol) of cobalt chloride in 5.3 mL of water, and 298 g (2.56 mmol) of dimethylglyoxime in 3.0 mL of dimethylformamide (DMF). mL solution and sodium borohydride (2.91 g, 76.9 marl ol) were sequentially added, and the mixture was stirred at 30 to 35 ° C for 2 hours. After adding 282 mL of isopropyl alcohol to the reaction solution, 6 mol / L hydrochloric acid was added dropwise at 20 to 30 ° C to adjust the pH to 7.81. After charging 0.38 g of activated carbon, the mixture was stirred at 20 to 30 ° C for 30 minutes. The insoluble matter was removed by filtration. 6 mol / L hydrochloric acid was added dropwise to the filtrate at 20 to 30 ° C., and the pH was adjusted to 2.01. After the cooled crystals were precipitated, the mixture was stirred at 0 to 5 ° C. for 1 hour, and the crystals were collected by filtration and washed with 1076% aqueous isopropyl alcohol solution (376 mL). 46.7 g was obtained as wet crude crystals. 46.1 g of the wet crude crystals were suspended in 157 mL of water, and dissolved by adding 83.6 mL of a 2 mol / L sodium hydroxide aqueous solution. Add 12.0 mL of isopropyl alcohol and 1.1 mL of DMF (water: isopropyl alcohol: DMF = 10: 5: 1), add 6 mol / L hydrochloric acid dropwise, and adjust the pH to 2.02. Was adjusted to The mixture was stirred at 20 ° C or lower for 1 hour, and the crystals were collected by filtration and washed with 62.7 mL of water. Blow dry at 60 ° C for 23 hours, and dry 30.1 g (83.6%) of 5 — [(2,4-dioxothiazolidine-1-yl) methyl] —2—methoxybenzoic acid. ) Obtained.

m.p. 18 88 ° C, HPLC purity 99.3 3%. Industrial applicability

In order to establish an industrial process for the production of N-benzyldioxothiazolidinyl benzamide derivatives, which are being developed as antidiabetic agents, an industrially superior process for producing a benzylthiazolidinedione derivative having a carboxyl group as a raw material Was found. That is, the benzylidene zolidinedione derivative was used in the same reaction system, and the pH range was 8.0 to 9.5. When a Co complex catalyst is formed in the above and the reduction is performed with a reducing agent, the reaction is completed in a short time, and a benzylthiazolidinedione derivative of good quality with good reproducibility can be obtained. The method for producing a thiazolindione derivative of the present invention is a simple and highly reproducible industrial method that does not require the use of a special device such as a high-pressure catalytic reduction device, and is suitable for mass synthesis. To provide.

Claims

Speculation of Word

1. General formula (1)

[In the formula, R represents hydrogen or a lower alkyl group. ]

A compound represented by the general formula (2) characterized in that, in the same reaction system, a Co complex catalyst is formed within a specific pH range and then reduced by the action of a reducing agent.

For producing thiazolidinedione derivative represented by formula

2. The method according to claim 1, wherein the specific pH range is 8.09.5.

3. The production method according to claim 1, wherein the reducing agent is a borohydride compound.