KR0161552B1 - Intermediates in the preparation of aromatic amino-alcohol derivatives having anti-diabetic and anti-obesity properties - Google Patents

Abstract

Novel intermediate compounds of the formula and methods for their preparation and uses.

[Wherein R ⁷ is a hydrogen atom or an acetyl group]

Description

Intermediates useful in the preparation of antidiabetic and anti-obesity aromatic amino-alcohol derivatives

The present invention relates to two intermediate compounds useful for the preparation of a series of compounds characterized by a 2- [2- (substituted phenyloxy) -1-methylethyl] aminoethanol structure and having high antidiabetic and anti-obesity activity. In addition, these compounds can inhibit the action of aldose reducing element to prevent and treat hyperlipidemia and hyperglycemia, and is also effective in the prevention and treatment of diabetic complications. They are also effective in the prophylaxis of obesity hypertension and osteoporosis. The present invention also provides a method for preparing the compound of the present invention.

We now find two novel intermediate compounds useful for the preparation of a series of novel 2- [2-substituted phenyloxy-1-methylethyl] aminoethanol derivatives with high antidiabetic and anti-obesity activity, low toxicity and few side effects. It was done; These compounds can also inhibit the action of aldose reductase and thus are effective in the prevention of diabetic complications. They are also effective in the prophylaxis of obesity hypertension and osteoporosis.

That is, it is an object of the present invention to provide compounds of this type.

It is also an object of the present invention to provide such compounds which have antidiabetic and anti-obesity activity and are preferably used as intermediates in the preparation of compounds having low toxicity and little side effects.

Compounds of the present invention are compounds of the formula:

[Wherein R ⁷ is a hydrogen atom or an acetyl group]

These intermediates are particularly useful for the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof:

[In the above meal,

R ⁰ is a hydrogen atom, a methyl group or a hydroxymethyl group;

R ¹ is a 5-methyl-thiazolidine-2, 4-dione group;

R ² and R ³ are each hydrogen atoms

X is an oxygen atom;

Ar is a group of the following formula (II) or (III):

Wherein R ⁴ represents a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, a C 1-5 alkoxy group, a C 1-5 alkyl group, a C 1-6 aliphatic carboxyl acyloxy group, a nitro group, a cyano group Aralkyloxy group (where the aralkyl moiety is defined below), aryloxy group (where the aryl moiety is defined below), an aryl group defined below or a haloalkyl group having 1 to 4 carbon atoms;

R ⁵ is a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group having 1 to 5 carbon atoms, an alkyl group having 1 to 5 carbon atoms, or a nitro group; R ⁶ is a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms; The aralkyl moiety is an alkyl group having 1 to 3 carbon atoms substituted with one or two aryl groups defined below;

The aryl group is unsubstituted or one or more substituted ring carbon atoms having 6 to 10 carbon ring aryl groups selected from the group consisting of substituents B defined below;

The substituent B is selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy key having 1 to 3 carbon atoms, a nitro group, a haloalkyl group having 1 to 4 carbon atoms, and a hydroxy group)]

These compounds of formula (I) are described as novel compounds and claimed in Korean Patent Application No. 21899/1992.

In addition, the present invention

(Iii) reacting p-hydroxybenzaldehyde with thiazolidine-2, 4-dione to form 5- (4-acetoxybenzylidene) thiazolidine-2, 4-dione;

(Ii) hydrogenating the 5- (4-acetoxybenzylidene) thiazolidine-2, 4-dione thus formed to form 5- (4-acetoxybenzyl) thiazolidine-2, 4-dione;

(Iii) 5- (4-acetoxybenzyl) thiazolidine-2,4-dione thus produced is reacted with triphenylmethyl chloride to give 5- (4-acetoxybenzyl) -3-triphenylmethyl-thiazoli Dine-2, 4-dione; (Iii) providing a process for the preparation of a compound of the formula: characterized in that the compound so obtained is optionally hydrolyzed:

[Wherein R ⁷ is a hydrogen atom or an acetyl group]

The present invention also provides a compound of the formula used as an intermediate in the preparation of the compound of formula (I):

[In the above meal,

R ⁷ , Ar, R ⁰ , X, R ¹ , R ² and R ³ are as defined above]

The intermediate compound of the present invention is converted into a compound of the following formula (XI) as described below, and then reacted with a compound of the following formula (XIII) [Step A] to produce a compound of the following formula (XIV). The compound of formula (XIV) was reduced [step B] to prepare a compound of formula (XV), and then, if necessary, a compound of formula (I) was deprotected by deprotecting the compound wherein Z ³ is a hydroxy-protecting group. Can be obtained.

[In the above meal,

R ⁷ , Ar, R ¹ , R ² , R ³ and X are as defined above; Z ³ is a hydrogen atom or a hydroxy-protecting group]

The kind of hydroxy-protecting group represented by Z ³ is not important in the present invention, and any type of hydroxy-protecting group commonly used in the present invention may be used in the present invention. Examples of such groups include tetrahydropyranyl, methoxymethyl, diphenylmethyl, trityl, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups. According to processes A and B, if the protecting group is to be removed, the type of removal reaction depends on the type of protecting group and is also known as used in the art. Examples of such removal reactions are described in TW Green, Protective Groups in Organic Synthesis, John Wiley Sons; And JFW McOmie, Protective Groups in Organic Chemistry, Plenum Press.

In step A of the above reaction, a compound of formula (XIV) is prepared by reacting an amino compound of formula (XI) with a carbonyl compound of formula (XIII). The reaction can be carried out in the presence or absence of a dehydrating agent such as anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous calcium chloride, anhydrous magnesium sulfate or a dehydrated molecular sieve.

In general, the reaction is preferably carried out in the presence of a solvent, and the kind of solvent is not important as long as there is no adverse effect on the reaction and the reagent can be dissolved to some extent or more. Examples of suitable solvents include: hydrocarbons which may be aliphatic or aromatic, such as benzene, toluene, xylene, hexane and heptane; Halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride, in particular halogenated aliphatic hydrocarbons: ethers such as diethyl ether, tetrahydrofuran and dioxane; Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; Alcohols such as methanol and ethanol; Sulfoxides such as dimethyl sulfoxide; Sulfolane; And mixtures of two or more kinds of the aforementioned solvents.

The reaction is carried out over a wide range of temperatures, and the exact reaction temperature chosen is not critical to the invention. In general, it is convenient to carry out the reaction at a temperature ranging from the freezing point to the boiling point of the solvent used. The time required for the reaction can vary widely depending on many factors, mainly the reaction temperature and the type of reagent. However, in most cases where the reaction is carried out under the preferred conditions outlined above, 0.5-10 hours will suffice.

The reaction is preferably carried out in the presence of a solvent such as a hydrocarbon or an alcohol for 1 to 5 hours at an ice cold point to reflux temperature. More preferably, the reaction is carried out in benzene by heating under reflux for 1-3 hours and the resulting water is removed.

In process B of the said reaction, the compound of formula (XV) is manufactured by reducing the compound of formula (XIV) which can be manufactured as described in process A. The reaction is usually carried out using a reducing agent or by hydrogenation in the presence of a catalyst. When the reduction is carried out using a reducing agent, the kind of reducing agent used is not critical to the present invention, and the reducing agent generally used for this kind of reaction can be used equally here. Examples of suitable reducing agents include metal hydrides such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or diisobutylaluminum hydride. In general, the reaction is preferably carried out in the presence of a solvent, the kind of which is not important so long as it has no adverse effect on the reaction and can dissolve the reagent to some extent. Examples of suitable solvents are: hydrocarbons which may be aliphatic or aromatic, such as benzene, toluene, xylene, hexane or heptane; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; Alcohols such as methanol, ethanol or isopropanol; And mixtures of two or more kinds of the solvents described above.

The reaction is carried out over a wide range of temperatures, and the exact reaction temperature chosen is not critical to the invention. In general, it is convenient to carry out the reaction at an ice cold point to a heating temperature of, for example, 50 ° C. or higher. The time required for the reaction can vary widely depending on many factors, mainly the reaction temperature and the type of reagent. In most cases, however, usually 0.5 hours to several days will be sufficient.

The reaction is preferably carried out using sodium borohydride or sodium cyanoborohydride in the presence of an alcoholic solvent at an ice cold point to a temperature of 50 ° C. for 1 to 24 hours.

When the reduction is carried out by hydrogenation in the presence of a catalyst, the catalyst used may be a catalyst generally used for catalytic reduction, and the type of catalyst is not important to the present invention. Examples of preferred catalysts are palladium / charcoal or platinum oxide. In general, the reaction is preferably carried out in the presence of a solvent, and the type of solvent is not important as long as there is no adverse effect on the reaction and the reagent can be dissolved to some extent. Examples of suitable solvents include: ethers such as diethyl ether, tetrahydrofuran or dioxane; Amides such as dimethylformamide or dimethylacetamide; Alcohols such as methanol, ethanol or isopropanol; Esters such as methyl acetate or ethyl acetate; And mixtures of two or more kinds of the aforementioned solvents. When using a palladium catalyst, catalytic hydrogenation is preferably carried out under medium to high pressure, preferably at 1 to 5 kg / cm ² . When using a platinum catalyst, the hydrogenation is preferably carried out at atmospheric pressure. The reaction takes place over a wide range of temperatures, and the exact reaction temperature chosen is not critical. In general, it is convenient to carry out the reaction at a temperature in the range from room temperature to 50 ° C. It is also preferred to carry out in the presence of alcoholic solvents, in particular methanol or ethanol.

A compound of formula (XIII) wherein R ⁰ is a hydrogen atom, ie a compound of formula (XVI), can be prepared by the method of Scheme B below:

[In the above meal,

Ar and Z ³ are the same as the above definition;

R is preferably a lower alkyl group having 1 to 4 carbon atoms as exemplified with respect to substituent B above]

In step 1 of this scheme, the compound of formula (f) can be prepared by conventional methods such as Organic Syntheses I, pp. 336] to yield the compound of formula (g).

This reaction is usually carried out by reacting a compound of formula (f) with hydrogen cyanide or trimethylsilyl cyanide in the presence or absence of zinc iodide and preparing a cyanohydrin derivative, followed by acid catalytic hydrolysis of the resulting cyanohydrin compound. To do it. The cyanohydrin compound formation reaction is usually carried out over a wide range of temperatures such as, for example, ice-cold temperature to heating temperature, preferably room temperature to 100 ° C. Acid catalyzed hydrolysis is usually carried out for several tens to tens of hours at room temperature to the reflux temperature of the reaction mixture in the presence of excess water, using known acids such as inorganic acids such as hydrochloric acid or sulfuric acid or organic acids such as p-toluene sulfonic acid or acetic acid. This reaction is preferably carried out by heating under reflux for 30 minutes to 10 hours in the presence of hydrochloric acid or sulfuric acid.

The esterification of the compound of formula (g) thus obtained can then be carried out by acid catalyzed esterification or treatment of an esterifying agent such as diazoalkane or alkyl halide + alkali to prepare the compound of formula (h).

The acid catalyzed esterification is carried out by the compound of formula (g) in the presence or absence of a solvent, preferably in the presence of an inorganic acid such as hydrogen chloride or sulfuric acid or an organic acid such as p-toluenesulfonic acid, at a suitable temperature such as room temperature to heating temperature, For example, several hours to several days, for example by reaction with excess alcohol.

Esterifications using diazoalkanes include solvents such as alcohols such as methanol or ethanol; Aliphatic or aromatic hydrocarbons such as benzene, toluene, xylene, hexane or heptane; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Or in the presence of a mixture of two or more solvents. This reaction can be carried out over a wide range of temperatures and the exact reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at an ice cooling temperature to a heating temperature, more preferably at an ice cooling temperature to 60 ° C. The time required for the reaction may also vary greatly depending on various factors, in particular the reaction temperature and the type of reagent and solvent used.

Examples of alkalis usable in esterification reactions using alkalis and alkyl halides may include alkali metal carbonates such as potassium carbonate or sodium carbonate. In general, this reaction is preferably carried out in the presence of a solvent. The type of solvent used is not particularly limited as long as it can dissolve the reagent at least to some extent without adversely affecting the reaction or the reagent used. Examples of suitable solvents include alcohols such as methanol or ethanol; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Aliphatic or aromatic hydrocarbons such as benzene, toluene, xylene, hexane or heptane; Amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; And mixtures of two or more of these solvents. This reaction can be carried out over a wide range of temperatures and the exact reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at or near room temperature and heating temperature. The time required for the reaction may also vary greatly depending on various factors, in particular the reaction temperature and the type of reagent and solvent used. However, several hours to several days are sufficient when the reaction is carried out under the above preferred conditions.

In step 3, the compound of formula (h) obtained above is protected using a known hydroxy-protecting group to give a compound of formula (VII). Examples of hydroxy-protecting groups that can be used are described, for example, in T. W. Green, Protective Groups in Organic Syntheses, John Wiley Sons; And tetrahydropyranyl, methoxymethyl, diphenylmethyl, trityl, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl groups as described in JFW McOmie, Protective Groups in Organic Chemistry, Plenum Press. do.

In step 4, the compound of formula (XVI) is reacted with diisobutylaluminum hydride, for example, in a hydrocarbon solvent previously cooled with an acetone-dry ice bath such as hexane, heptane, benzene, toluene or xylene It can be manufactured by a conventional method in the compound of Formula (i).

Compounds of formula (XVI) can also be prepared by the methods shown in Scheme C below:

[Wherein Ar, Z ³ and R are the same as the above definition]

In step 1 of this scheme, the compound of formula (VII) is reacted conventionally with a metal hydride such as lithium aluminum hydride or diisobutylaluminum hydride to produce the compound of formula (j). In general, this reaction is preferably carried out in the presence of a solvent. The type of solvent used is not particularly limited as long as it can dissolve the reagent at least to some extent without adversely affecting the reaction or the reagent used. Examples of suitable solvents include ethers such as diethyl ether, tetrahydrofuran and dioxane.

The compound of formula (j) thus obtained is then oxidized in process 2, for example by the sulfur trioxide / pyridine complex or chromium oxidant or by a one-way oxidation reaction to give the compound of formula (XVI).

When the compound of formula (XVI) is optically active, stereoisomers of the compound of formula (IV) having a subsidiary carbon atom represented by ^* 1 can be obtained. That is, when the amino compound of formula (XIV) is optically active and R ⁰ is a hydrogen atom, ( ^* 1R, ^* 3R), ( ^* 1R, ^* 3S), ( ^* 1S, ^* 3R) or ( ^* 1S, ^* Compounds of formula (IV) having stereochemistry consisting of the desired combinations of 3S) can be prepared separately.

In addition, compounds of formula (g) may be prepared using optically active amines, such as (+)-or (-)-ephedrine or (d) -or (1) -1-phenylethylamine, which can be used for conventional optical separation Into (R) and (S) compounds.

The following examples illustrate the preparation of intermediate compounds of the invention, and the preparations described below show the conversion of these intermediates to the compounds of formula (I) as defined above.

Example 1

5- (4-acetoxybenzyl) -3-triphenylmethylthiazolidine-2, 4-dione

1 (a) 5- (4-acetoxybenzylidene) thiazolidine-2, 4-dione

A mixture containing 200 g of p-hydroxybenzaldehyde, 229 g of thiazolidine-2, 4-dione, 280 g of sodium acetate and 660 ml of dimethylacetamide is stirred at 150 ° C. for 1 hour. It is then cooled and 540 ml of dimethylacetamide and 370 ml of acetic anhydride are added to the reaction mixture. The resulting mixture is then stirred at 50 ° C. for 1.5 hours and then poured into water. The precipitated solid is collected by filtration, washed with water and dried over anhydrous sodium sulfate to give the title compound.

1 (b) 5- (4-acetoxybenzyl) thiazolidine-2, 4-dione

2.0 g of 5- (4-acetoxybenzyl) thiazolidine-2,4-dione (prepared as described in step (a) above) are dissolved in 80 ml of acetic acid and 10% w / v palladium / charcoal 2.0 Hydrogenation is carried out by passing hydrogen under atmospheric pressure through a solution for 5 hours at 90 ° C. in the presence of g. The catalyst is then filtered off and the filtrate is diluted with toluene. The acetic acid solvent is then distilled off as a toluene azeotrope. Toluene and hexane were added to the concentrate, and the crystals separated off were collected by filtration and dried to obtain the title compound.

1 (c) 5- (4-acetoxybenzyl) -3-triphenylmethylthiazolidine-2, 4-dione

To a solution of 9.0 g of 5- (4-acetoxybenzyl) thiazolidine-2, 4-dione (prepared as described in step (b) above) in 70 ml of methylene chloride, 3.43 g of trimethylamine was added and 30 ml of methylene chloride A solution of 9.45 g of triphenylmethyl chloride in was added dropwise to the resulting mixture. The mixture is then stirred at room temperature for 1 hour and then left at the same temperature overnight. The reaction mixture is then mixed with water and ethyl acetate and the organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The crystals which were separated by distilling off the solvent under reduced pressure were washed with a mixture of hexane and ethyl acetate to give the title compound.

Example 2

5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2, 4-dione

A solution of 2.99 g of a 28% w / v methanolic solution of sodium methoxide in 10 ml of methanol was subjected to 5- (4-acetoxybenzyl) -3-triphenylmethylthiazolidine-2, 4-dione in 70 ml of toluene [the above practice. Prepared as described in Example 1] 7.86 g of a solution is added dropwise under ice-cooling, and the resulting mixture is stirred at room temperature for 1 hour and then left at the same temperature overnight. Then, the pH of the mixture is adjusted to 4 by adding 1N aqueous hydrochloric acid solution, and the mixture is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate.

The solvent is then distilled off under reduced pressure and the crystals appearing in the residue are collected, washed with hexanes and dried to afford the title compound.

[Preparation 1]

5- {4- [2 (R) -aminopropoxy] benzyl]} thiazolidine-2, 4-dione trifluoroacetate

1 (a) 5- {4- [2 (R) -t-butoxycarbonylaminopropoxy] benzyl} -3-triphenylmethylthiazolidine-2, 4-dione

13.2 g of diethyl azodicarboxylate is added dropwise to a solution of 20.7 g of triphenylphosphine in 300 ml of benzene and the mixture is stirred at room temperature for 30 minutes. Subsequently, 35.0 g of 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2, 4-dione (prepared as described in Example 2 above) was added to the mixture, and the resulting mixture was stirred at room temperature. Stir for 1 hour. 13.2 g of (R) -2-t-butoxycarbonylamino-1-propanol is added to the mixture, and then allowed to stand overnight. At the end, 40.9 g of triphenylphosphine, 23.68 ml of diethylazodicarboxylate and 33 g of (R) -2-t-butoxycarbonylamino-1-propanol were added to the reaction mixture in three or four portions in turn. After addition, the mixture is stirred for 2 days. The benzene solvent is then distilled off under reduced pressure in the reaction mixture and the residue is subjected to silica gel column chromatography [eluent; 1: 3 volume mixture of ethyl acetate and hexane] to give the title compound as a crystal having a melting point of 153 ~ 157 ℃.

[α] _D ²³ + 19.5 ° (c = 1.000, chloroform).

1 (b) 5- {4- [2 (R) -aminopropoxy] benzyl)} thiazolidine-2,4-dione trifluoroacetate

5- {4- [2 (R) -t-butoxycarbonylaminopropoxy] benzyl} -3-triphenylmethylthiazolidine-2, 4-dione in 700 ml of methylene chloride [described in the above step (a) As prepared] to 85.5 g of a solution is added dropwise 500 ml of trifluoroacetic acid under ice-cooling, and the resulting mixture is stirred at room temperature for 4 hours. At the end, the reaction mixture is distilled off under reduced pressure in methylene chloride solvent and trifluoroacetic acid and a mixture of benzene and a small amount of ethyl acetate is added to the residue. The precipitated crystals are collected by filtration and recrystallized in a mixture of methanol and ethyl acetate to give the title compound as crystals having a melting point of 162 to 166 캜.

^{_{[α] D 23 - 13.0 °}} (c = 0.885, methanol).

[Method 2]

Methyl (R) -α-t-butyldimethylsilyloxy-3-chlorophenyl acetate

A solution of 31.6 g of t-butyldimethylsilylchloride in 200 ml of dimethylformamide was prepared from 28 g of methyl (R) -3-chloromandelate (prepared as described in Preparation 7) and 28.5 g of imidazole in 300 ml of dimethylformamide. The solution was added dropwise to an ice-cold port, and the resulting mixture was stirred at the same temperature for 30 minutes and then left at 40 ° C. overnight. At the end, the reaction mixture is evaporated under reduced pressure and the residue is mixed with water and ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [eluent; 1: 15 volume mixture of ethyl acetate and hexane] to give the title compound as a crystal having a melting point of 36 ~ 38 ℃.

^{_{[α] D 23 - 39.1 °}} (c = 1.014, chloroform).

[Process 3]

(R) -α-t-butyldimethylsilyloxy-α- (3-chlorophenyl) acetaldehyde

After cooling a solution of 26 g of methyl (R) -α-t-butyldimethylsilyloxy-3-chlorophenylacetate (prepared as described in Preparation 2) in a mixture of 1000 ml of anhydrous hexane and 500 ml of dry toluene was cooled to -60 ° C. 124 ml of a 1M solution of diisobutylaluminum hydride in hexane is added dropwise to the cooled solution. The resulting mixture is stirred at the same temperature for 3 hours, then 10 ml of water is added and the temperature of the mixture is slowly raised to room temperature. The reaction mixture is then mixed with water and ethyl acetate and stirred for 30 minutes. The insolubles are filtered using a Celite (trade name) filter aid and the ethyl acetate layer is separated from the filtrate and dried over anhydrous sodium sulfate. The ethyl acetate solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [eluent; 1: 60 volume mixture of ethyl acetate and hexane] to give Rf = 0.36 [silica gel thin layer chromatography, developing solvent; 1: 60 vol. Mixture of ethyl acetate and hexane] to give the title compound.

[Process 4]

5- {4- [2 (R)-[2 (R)-(3-chlorophenyl) -2-t-butyldimethylsilyloxyethylamino] propoxy} benzyl] thiazolidine-2, 4-dione

5- {4- [2 (R) -aminopropoxy] benzyl)} thiazolidine-2,4-dione trifluoroacetate (prepared as described in Preparation 1) 36.5 g, (R) -α- A mixture containing 98.4 g of (t-butyldimethylsilyloxy) -α- (3-chlorophenyl) -acetaldehyde (prepared as in Preparation 3) and 400 ml of anhydrous methanol was stirred at room temperature for 2.5 hours, and then the mixture was 29.0 g of sodium cyanoborohydride is added in portions under cooling in an ice-sodium chloride bath. The reaction mixture is then left at room temperature overnight and then the methanol solvent is distilled off under reduced pressure. The resulting residue is mixed with water and ethyl acetate. The ethyl acetate layer was separated, washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Subsequently, the ethyl acetate solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent; 2: 1 volume mixture of ethyl acetate and hexane] to give the title compound.

^{_{[α] D 23 - 26.3 °}} (c = 0.988, chloroform).

[Method 5]

3-chloromandelic acid

A mixture of 158 g of 3-chlorobenzaldehyde, 111.6 g of trimethylsilylnitrile and the amount of zinc iodide catalyst is heated at 90 ° C. for 2 hours with stirring. The reaction mixture is ice-cooled and 350 ml of concentrated aqueous hydrochloric acid solution is added. The resulting mixture is then heated under reflux for 1 hour and then mixed with water and ethyl acetate. The ethyl acetate layer is separated and mixed with 30% w / v aqueous sodium hydroxide solution. The aqueous layer was separated, washed three times with ethyl acetate, acidified with concentrated aqueous hydrochloric acid solution and extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure to afford the title compound as a crystal having a melting point of 110 to 114 ° C.

[Preparation 6]

(R) -3-chloromandelic acid and (S) -3-chloromandelic acid

A mixture of 100 g of 3-chloromandelic acid (prepared as described in Preparation 5) and 32.7 g of (R)-(+)-1 -phenethylamine is dissolved in methanol and diethyl ether and recrystallized. The resulting crystals are collected by filtration and recrystallized three times in a mixture of methanol and diethyl ether and mixed with aqueous hydrochloric acid solution. The mixture is then extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure to give (R) -3-chloromandelic acid as a crystal having a melting point of 102 to 105 캜.

[α] _D ²³ -153.7 ° (c = 1.026, chloroform).

Hydrochloric acid is added to the filtrate obtained and the mixture is extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The resulting residue was mixed with 32.7 g of (S)-(-)-1-phenethylamine and recrystallized three times in a mixture of methanol and diethyl ether to give (S) -3-chloro as a crystal having a melting point of 101-104 ° C. Obtain mandelic acid.

[α] _D ²³ + 151.9 ° (c = 1.008, chloroform).

[Process 7]

Methyl (R) -3-chloromandelate

18.3 g of a 10% w / v solution of trimethylsilyldiazomethane in hexane was added dropwise to a solution of 28 g of (R) -3-chloromandelic acid (prepared as described in Preparation 6) in a mixture of 300 ml methanol and 700 ml benzene. The resulting mixture is stirred for 1 hour. At the end, the solvent was distilled off under reduced pressure to give [α] _D ²³ -119.3 ° (c = 1.00, chloroform) and Rf = 0.36 [silica gel thin layer chromatography, developing solvent; 1: 5 volume mixture of ethyl acetate and hexane] is obtained as a crude product.

[Process 8]

5- {4- [2 (R)-[2 (R)-(3-chlorophenyl) -2-hydroxyethylamino] propoxy]} benzyl] thiazolidine-2, 4-dione [formula (I Compound of

5- [4- {2 (R)-[2 (R)-(3-chlorophenyl) -2-t-butyldimethylsilyloxyethylamino] propoxy} benzyl] thiazolidine-2 in 500 ml tetrahydrofuran. To 46.2 g of 4-dione (prepared as in Preparation 4), 88 g of tetrabutylammonium fluoride was added under ice cooling, and the resulting mixture was stirred at room temperature for 15 hours. At the end, the tetrahydrofuran solvent is distilled off under reduced pressure, and the residue is mixed with water and extracted with ethyl acetate. The extract is washed with an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate.

The ethyl acetate solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [eluent; 5: 1 volume mixture of ethyl acetate and ethanol]. The crude crystal thus obtained is recrystallized from a mixture of ethyl acetate and ethanol to give 27.1 g of the title compound as a crystal having a melting point of 100 to 112 ° C.

^{_{[α] D 23 - 4.4 °}} (c = 1.005, methanol).

Claims (5)

1. Compounds of the formula: [Wherein R 7 is a hydrogen atom or an acetyl group] The compound of claim 1, which is 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2, 4-dione. The compound of claim 1, which is 5- (4-acetoxybenzyl) -3-triphenylmethylthiazolidine-2, 4-dione. (Iii) reacting p-hydroxybenzaldehyde with thiazolidine-2, 4-dione to form 5- (4-acetoxybenzylidene) thiazolidine-2, 4-dione; (Ii) hydrogenating the 5- (4-acetoxybenzylidene) thiazolidine-2, 4-dione thus formed to form 5- (4-acetoxybenzyl) thiazolidine-2, 4-dione; (Iii) 5- (4-acetoxybenzyl) thiazolidine-2, 4-dione thus produced is reacted with triphenylmethyl chloride to give 5- (4-acetoxybenzyl) -3-triphenylmethyl-thiazoli Dine-2, 4-dione; (Iii) A process for producing the compound of claim 1, characterized in that the compound thus obtained is optionally hydrolyzed. The compound of claim 1 used in the preparation of the compound of formula (I) or a pharmaceutically acceptable salt thereof. [Wherein, R ⁰ is a hydrogen atom, a methyl group or a hydroxymethyl group; R ¹ is a 5-methyl-thiazolidine-2, 4-dione group; R ² and R ³ are each a hydrogen atom; X is an oxygen atom; Ar is a group of the following formula (II) or (III): Wherein R ⁴ represents a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, a C 1-5 alkoxy group, a C 1-5 alkyl group, a C 1-6 aliphatic carboxyl acyloxy group, a nitro group, a cyano group , An aralkyloxy group (where the aralkyl moiety is defined below), an aryloxy group (where the aryl moiety is defined below), an aryl group defined below or a haloalkyl group having 1 to 4 carbon atoms; R ⁵ is hydrogen An atom, a halogen atom, a hydroxy group, a C1-5 alkoxy group, a C1-5 alkyl group or a nitro group; R ⁶ is a hydrogen atom, a halogen atom, a hydroxy group, a C1-5 alkoxy group or a C1-5 An aralkyl moiety is an alkyl group having 1 to 3 carbon atoms substituted with one or two aryl groups as defined below; the aryl group is unsubstituted or substituted with one or more substituents selected from the group consisting of substituents B as defined below Substituted ring carbon source Embroidery 6-10 carbon cyclic aryl group; The substituent B in the group consisting of a halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 3 carbon atoms, a nitro group, a haloalkyl group and a hydroxyl group of 1 to 4 carbon atoms Is selected)].