KR100730767B1 - New method for preparing dibenzothiepin derivatives - Google Patents

Abstract

The present invention relates to a novel process for the preparation of dibenzothiepine derivatives, and more particularly, to a 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid, an intermediate compound prepared by a simple and novel method, under an acid catalyst. The present invention relates to a method for preparing 2- (10,11-dihydro-10-oxobenzo [b, f] thiinpin-2-yl) propionic acid of Chemical Formula 1, wherein the reaction is carried out.

[Formula 1]

According to the preparation method of the present invention, 2- (10,11-dihydro-10-oxobenzo [b, f], a propionic acid-based anti-inflammatory analgesic agent, which is easily applied industrially and has pharmaceutical activity, is simpler than the conventional method. Thiefin-2-yl) propionic acid can be provided in high purity and high yield.

2- (10,11-dihydro-10-oxobenzo [b, f] thiin-2-yl) propionic acid, 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid, acid, cyclization , Pharmaceutical activity

Description

New manufacturing method of dibenzothiene derivatives {NEW METHOD FOR PREPARING DIBENZOTHIEPIN DERIVATIVES}

[Industrial use]

The present invention relates to a method for preparing a dibenzothiepine derivative, more particularly 2- (10,11-dihydro-10-oxobenzo [b, f] thipin-2-yl) which is a propionic acid anti-inflammatory analgesic agent. In preparing propionic acid, 2- (1-carboxyethyl) 2-phenylpiophenyl-acetic acid, which is a key intermediate prepared by a simple and novel method, is easily applied industrially, and 2- can be obtained with high yield and high purity. A method for producing (10,11-dihydro-10-oxobenzo [b, f] thiin-2-yl) propionic acid.

[Prior art]

2- (10,11-dihydro-10-oxobenzo [b, f] thipin-2-yl) propionic acid is known as a compound having anti-inflammatory analgesic action. Various methods have been reported for preparing the 2- (10,11-dihydro-10-oxobenzo [b, f] thipin-2-yl) propionic acid.

Japanese Patent Laid-Open No. 55-53282 discloses a method for preparing dibenzothione derivatives by hydrolysis of 3- (α-cyanoethyl) -6-phenylthio-phenylacetic acid followed by a hydrolysis reaction. .

In addition, Japanese Patent Application Laid-open No. 57-106678 discloses a method for producing a dibenzothiene derivative by subjecting a dicarboxylic acid derivative obtained by hydrolyzing a phenyl acetate having a nitrile group to undergo a cyclization reaction using a condensing agent.

Japanese Patent Application Laid-open No. Hei 8-253472 describes a method of preparing the desired compound via an hydroxyacetal intermediate after acylating dibenzothiene without introducing a nitrile group.

In addition, Korean Patent Publication No. 2000-68251 discloses diazotizing 2- (4-amino-3-carboxymethylphenyl) propionic acid or a salt thereof and reacting with thiophenol to react 2- (3-carboxymethyl-4-phenylpiophenyl. A method for producing 2- (10,11-dihydro-10-oxobenzo [b, f] thipin-2-yl) propionic acid by obtaining propionic acid or a salt thereof and cyclizing the product is disclosed. .

However, the above methods are industrially employed using toxic reagents such as KCN to obtain the desired compound 2- (10,11-dihydro-10-oxobenzo [b, f] thipin-2-yl) propionic acid. It is difficult to apply, or the production process is low because the production process is low and takes a lot of manufacturing time due to a complicated post-reaction treatment process after a plurality of reactions.

In consideration of the problems of the prior art, the present invention provides a 2- (10,11-dihydro-) using 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid, which is an intermediate compound prepared by a simpler method. It is an object of the present invention to provide a method for preparing 10-oxobenzo [b, f] thienpin-2-yl) propionic acid.

Another object of the present invention is 2- (10,11-dihydro-10-oxobenzo [b, f] thiefine-2, which is a propionic acid type anti-inflammatory analgesic that can be industrially applied and can be manufactured in high purity and high yield. -To provide a method for producing propionic acid.

In order to achieve the above object, the present invention

In the method for preparing 2- (10,11-dihydro-10-oxobenzo [b, f] thiin-2-yl) propionic acid,

a) Substituting the compound of formula 5 with sodium salt, methyl magnesium halide is added to the green yard (grignard) reaction to the intermediate of 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid of formula 2 Manufacturing step; And

b) cyclizing the 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid under an acid catalyst

It provides a method for preparing 2- (10,11-dihydro-10-oxobenzo [b, f] thipin-2-yl) propionic acid of Formula 1 comprising a.

[Formula 1]

[Formula 2]

[Formula 5]

In Formula 5, R is methyl, ethyl, phenyl or substituted phenyl.

Hereinafter, the present invention will be described in more detail.

The present invention relates to 2- (10,11-dihydro-10-oxobenzo [b, f] using 5- (1-carboxymethyl) -2-phenylthiophenyl-acetic acid, a novel intermediate compound prepared by a simple method. It is to provide a method for producing thiefin-2-yl) propionic acid. According to the present invention, unlike the conventional method using a toxic reagent such as KCN, it is safe and easy to apply industrially, by preparing a intermediate compound by a simple method to eliminate the hassle of going through several steps and the final compound after the reaction 1, the process is simple, the production yield can be increased.

The present invention prepares an intermediate compound of 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid by a new method, and then cyclizes it under an acid catalyst to give 2- (10,11-dihydro of Chemical Formula 1). Prepare -10-oxobenzo [b, f] thiin-2-yl) propionic acid.

In particular, 5- (1-carboxymethyl) -2-phenylthiophenyl-acetic acid of Chemical Formula 2 used as an intermediate in the present invention is prepared by the following method.

In the present invention, 2-hydroxy- (4-thiophenyl- (3-carboxyethyl)) phenylacetic acid of the following Chemical Formula 4 is reacted by reacting 1-carboxyethyl-2-phenylthiobenzene of the following Chemical Formula 3 with glycoic acid in a basic aqueous solution. To prepare a step.

[Formula 3]

[Formula 4]

It is preferable to use the sodium hydroxide aqueous solution for the said basic aqueous solution. The glyoxy acid is used in an excess of 1 equivalent or more, preferably 1 to 4 equivalents, and the pH of the aqueous solution of glyoxylic acid is adjusted to neutral to weak base with an aqueous sodium hydroxide solution.

The reaction is preferably carried out for 1 to 24 hours at a temperature of -5 to 100 ℃. After the reaction was completed, the solution was acidified, extracted with an organic solvent such as ethyl acetate, ether, benzene, toluene, nitrobenzene, methylene chloride, chloroform and concentrated under reduced pressure to obtain the compound of Chemical Formula 4 in high yield and high purity. Can be.

Subsequently, the compound of Formula 5 is prepared by substituting the hydroxy group of 2-hydroxy- (4-thiophenyl- (3-carboxyethyl)) phenylacetic acid with an alkyl or arylsulfonate derivative. In the present invention, the compound of Formula 4 is reacted with an alkyl or arylsulfonyl chloride compound to replace the hydroxy group in the compound with an alkylsulfone or an arylsulfone derivative and used in the next reaction. As the alkyl or arylsulfonyl chloride compound, methane sulfonyl chloride (mesyl chloride), p-toluenesulfonyl chloride, and the like may be used. The amount of the alkyl or arylsulfonyl chloride compound is preferably used in 1 to 2 equivalents.

[Formula 5]

In Formula 5, R is methyl, ethyl, phenyl or substituted phenyl.

Thereafter, the present invention is to prepare a 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid of the formula (2) as a core intermediate by adding a magnesium magnesium halide to the compound of formula (5) to the green yard (grignard) reaction Carry out the steps.

The green yard reaction is preferably carried out using methyl magnesium halide after replacing the compound of Formula 4 with sodium salt. As the methyl magnesium halide, it is preferable to use methyl magnesium bromide. The amount of the methylmagnesium halide is preferably 1 to 4 equivalents based on the compound of Formula 4. As a solvent used for reaction, organic solvents, such as tetrahydrofuran, an ether, and isopropyl ether, can be used. The reaction temperature is carried out at -30 to 100 ℃, preferably at -10 to 30 ℃.

Finally, 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid of Chemical Formula 2 was cyclized under an acid catalyst to give 2- (10,11-dihydro-10-oxobenzo [b] of Chemical Formula 1 , f] thiefin-2-yl) propionic acid.

In the present invention, when the reaction for preparing 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid is completed, an acid is added to the reaction solution, an organic solvent is extracted, or an alkali is added to separate the aqueous layer, and then acidified again. Extraction with an organic solvent, and a cyclization reaction to give the desired compound of formula (1).

The extraction solution is concentrated and then crystallized by adding an organic solvent, and the solvent used for crystallization may be an organic solvent such as ethyl acetate, ether, acetone, benzene, toluene, 1,4-dioxane, tetrahydrofuran, etc. have.

Acids used in the present invention include polyphosphoric acid, sulfuric acid, hydrochloric acid, acetic acid and the like, and the amount of acid used is preferably 2 to 10 equivalents. Ethyl acetate, ether, benzene, toluene, nitrobenzene, methylene chloride, chloroform, ethylene dichloride and the like may be used as the extraction solvent.                     

As such, the present invention does not use toxic reagents as compared to the conventional method, and thus is not only easy to apply industrially, but also to simplify the production process of the intermediate and greatly shorten the production time, thereby improving the yield. In addition, there is an advantage in economical production of the dibenzothiene derivative of Formula 1 by excellent in terms of yield and purity.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are provided to help the understanding of the present invention, and the scope of the present invention is not limited thereto.

EXAMPLE

Example 1

Preparation of 2-hydroxy- (4-thiophenyl- (3-carboxyethyl)) phenyl acetic acid

15 g of 50% aqueous solution of glyoxylic acid was added to 500 ml of pure water, and the pH was adjusted to neutral with 25% aqueous solution of sodium hydroxide. 23.5 g of 1-carboxyethyl-2-phenylthiobenzene and 10 g of a 25% aqueous sodium hydroxide solution were added at room temperature and reacted at 30 ° C. for 6 hours. At the end of the reaction, the pH was adjusted to 1-2 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 30.0 g (yield: 98%) of the title compound 2-hydroxy- (4-thiophenyl- (3-carboxyethyl)) phenyl acetic acid.

Example 2

Preparation of 2- (p-toluenesulfonyl)-(4-thiophenyl- (3-carboxyethyl)) phenylacetic acid sodium salt

30.0 g of 2-hydroxy- (4-thiophenyl- (3-carboxyethyl)) phenyl acetic acid and 20.4 g of triethyl amine were dissolved in 200 ml of toluene, and p-tulloensul was maintained at a temperature of 10 to 15 ° C. 20.2 g of vinyl chloride was added in portions. After about 1 hour and 30 minutes, the reaction solution was raised to 20 ° C. and poured into pure water to separate layers. 40 g (yield: 88%) of sodium salt of 2- (p-toluenesulfonyl)-(4-thiophenyl- (3-carboxyethyl)) phenyl acetate was added to the organic layer by adding 40% aqueous sodium hydroxide solution. .

Example 3

Preparation of 2- (10,11-dihydro-10-oxobenzo [b, f] thiin-2-yl) propionic acid

40 g of 2- (p-toluenesulfonyl)-(4-thiophenyl- (3-carboxyethyl)) phenyl acetate sodium salt was dissolved in 200 ml of tetrahydrofutan while maintaining a nitrogen atmosphere. 3 mol of methylmagnesium bromide and 28.5 g of ether solution were added dropwise over 30 minutes while maintaining the temperature of the reaction solution at 10 ° C. or lower, and stirred for 1 hour after the completion of the addition. An additional 100 ml of pure water was added and acidified with 10 ml of concentrated hydrochloric acid and layered. The organic layer was washed with water and distilled under reduced pressure to obtain 19.5 g (yield: 73%) of 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid oil as an intermediate compound.

The 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid concentrate was dissolved in 100 ml of ethylenedichloride solution, 30 g of polyphosphoric acid was added thereto, heated to reflux for 6 hours, water was added thereto, and the layers were separated. Was concentrated under reduced pressure. Acetonitrile was added to the concentrate for crystallization, followed by filtration. 13.3 g of 2- (10,11-dihydro-10-oxobenzo [b, f] thiin-2-yl) propionic acid (yield: 72%, purity: 99%) )

As described above, according to the preparation method of the present invention, 2- (10,11-dihydro-10-oxo, which is a propionic acid-based anti-inflammatory analgesic agent, which is easily applied industrially and has a pharmaceutical activity, is simpler than the conventional method. Benzo [b, f] thipin-2-yl) propionic acid can be provided in high purity and high yield.

Claims (4)

In the method for preparing 2- (10,11-dihydro-10-oxobenzo [b, f] thiin-2-yl) propionic acid, a) p-toluene sulfonyl chloride was added to the compound of formula 5 to react with triethylamine and toluene at 10-15 ° C., and an aqueous sodium hydroxide solution was added to the organic layer obtained after layer separation to obtain a compound of formula 5 After replacing the compound with sodium salt, methyl magnesium halide was added, and then a green yard reaction was carried out at -10 to 30 ° C. under an organic solvent selected from tetrahydrofuran, ether, or isopropyl ether. Preparing 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid; And b) cyclizing the 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid under an acid catalyst selected from polyphosphoric acid, sulfuric acid, hydrochloric acid, and acetic acid Method for preparing 2- (10,11-dihydro-10-oxobenzo [b, f] thiin-2-yl) propionic acid of Formula 1 comprising: [Formula 1]

[Formula 2]

[Formula 5]

In Formula 5, R is methyl, ethyl, or phenyl. According to claim 1, wherein the compound of Formula 5 a) 1-carboxyethyl-2-phenylthiobenzene of Formula 3 is reacted for 1 hour to 24 hours at a temperature of -5 to 100 ℃ under aqueous solution of glycoic acid and aqueous sodium hydroxide solution which is a basic aqueous solution. -Hydroxy- (4-thiophenyl- (3-carboxyethyl)) phenylacetic acid; And b) reacting the 2-hydroxy- (4-thiophenyl- (3-carboxyethyl)) phenylacetic acid with alkyl or arylsulfonylchloride, which is methane sulfonyl chloride or p-toluene sulfonyl chloride. Method for preparing 2- (10,11-dihydro-10-oxobenzo [b, f] thiin-2-yl) propionic acid [Formula 3]

[Formula 4]

The method of claim 1, 2- (10,11-dihydro-10-oxobenzo [b, f] thiepin-2-yl), characterized in that the amount of methyl magnesium halide used in step a) is 1 to 4 equivalents based on Chemical Formula 5. A method of producing propionic acid. delete