JPH1171358A - Production of 5-benzylthiazolidine-2,4-dione derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as an intermediate for synthesizing compounds having insulin resistance-improving effect, by reaction of a benzylidene-thiazolidine-2,4-dione with a metal hydride. SOLUTION: This new compound, a 5-benzylthiazolidine-2,4-dione derivative of formula II, is obtained in high yield by reaction of a compound of formula I [R is a (substituted) arylheterocycle, heteroaromatic ring or the like; X is an amino-protecting group] with 1-10 equivalents, based on the compound of formula I, of a metal hydride (e.g. sodium borohydride) in a mixed solvent of an amide- or ether-based organic solvent (e.g. dimethylformamide) and water or an alcohol-based organic solvent (e.g. ethanol) at 0-80 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 5-benzylthiazolidine-2,4-dione derivative useful as a synthetic intermediate for a compound having an insulin resistance improving action.

[0002]

2. Description of the Related Art As a method of synthesizing a 5-benzylthiazolidine-2,4-dione derivative, for example, a hydrogenation method of a 5-benzylidenethiazolidine-2,4-dione derivative with palladium carbon (C. Hatanaka, Chem. Pharm. .Bull.3
6,1440 (1991)), reduction using sodium amalgam (B. Hulin, J. Med. Chem. 39, 3897 (1996)) or reduction using sodium borohydride catalyzed by a cobalt salt (Upjon Co. WO93) / 13095) is known. However, in these methods, for example, the hydrogenation method using palladium carbon requires high temperature and high pressure in the reaction conditions and uses a large amount of palladium carbon. In the method using sodium amalgam, highly toxic mercury is used. Reduction with sodium borohydride using a cobalt salt as a catalyst is not suitable for an industrial production method such as using a cobalt salt of a heavy metal.

[0003]

SUMMARY OF THE INVENTION The present inventors have sought to solve these problems by using 5-benzylthiazolidine.
As a result of intensive studies on the industrial production method of the 2,4-dione derivative, a compound of the following formula (1) is reacted with a metal hydride in a mixed solvent of an amide-based or ether-based organic solvent and water or an alcohol-based organic solvent. Thereby, 5-benzylthiazolidine-2,4- of the following formula (2) can be obtained in high yield.
The present inventors have found that a dione derivative can be obtained and completed the present invention.

[0004]

According to the present invention, there is provided a compound of the general formula

[0005]

Embedded image Wherein R is an aryl group having 6 to 10 carbon atoms which may have a substituent selected from the following α group, and a heterocyclic group which may have a substituent selected from the following α group Alternatively, it represents a heteroaromatic ring group which may have a substituent selected from the following α group, and X represents a protecting group for an amino group. Wherein the compound represented by the general formula (1) is reacted with a metal hydride in an organic solvent.

[0006]

Embedded image [Wherein, R and X are as defined above. And a process for producing a 5-benzylthiazolidine-2,4-dione derivative having the formula: (Α group) includes an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, a halogenated alkyl group having 1 to 4 carbon atoms, and 1 to 4 carbon atoms. An acyloxy group having, an alkylenedioxy group having 1 to 4 carbon atoms,
An aralkyl group having 7 to 11 carbon atoms, an aralkyloxy group having 7 to 12 carbon atoms, and 1 to 4 carbon atoms
An alkylsulfonyl group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a halogen atom, a nitro group, an amino group, a monoalkylamino group having 1 to 4 carbon atoms, the same or different, each alkyl having 1 carbon atom To 4
Dialkylamino group, thiol group, carbon number 1
An alkylsulfinyl group having 1 to 4 carbon atoms, an alkylsulfonylamino group having 1 to 4 carbon atoms, an alkylsulfonylalkylamino group having the same or different and each alkyl having 1 to 4 carbon atoms, a sulfone group, a sulfonamide group, 1 to 4 carbon atoms having a heterocyclic or heteroaromatic ring which may have a substituent selected from the following β group:
An alkoxythio group having 1 to 4 carbon atoms, or an alkylthio group having 1 to 4 carbon atoms having a heterocyclic or heteroaromatic ring which may have a substituent selected from the following β group.
(Β group) includes an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms,
Halogenated alkyl group having 1 to 4 carbon atoms, acyloxy group having 1 to 4 carbon atoms, 1 to 4 carbon atoms
An alkylenedioxy group having 7 to 11 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, an aralkyloxy group having 7 to 12 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, and 1 to 4 carbon atoms. Alkylthio group, halogen atom, nitro group, amino group, monoalkylamino group having 1 to 4 carbon atoms, dialkylamino group having the same or different alkyl having 1 to 4 carbon atoms, thiol group, carbon number Alkylsulfinyl group having 1 to 4 carbon atoms, alkylsulfonylamino group having 1 to 4 carbon atoms, alkylsulfonylalkylamino group having the same or different and each alkyl having 1 to 4 carbon atoms, sulfone group or sulfonamide group Is shown. The present invention has the general formula

[0007]

Embedded image [Where R is

[0008]

Embedded image

[0009]

Embedded image And X represents a protecting group for an amino group. Wherein the compound represented by the general formula (1) is reacted with a metal hydride in an organic solvent.

[0010]

Embedded image [Wherein, R and X are as defined above. And a process for producing a 5-benzylthiazolidine-2,4-dione derivative having the formula: In compounds (1) and (2),
R has 6 carbon atoms which may have a substituent selected from α group
When referring to an aryl group having from 1 to 10 unsubstituted aryl groups are, for example, phenyl, 1-naphthyl, or 2
-A naphthyl group, preferably a phenyl group. When a substituted aryl group is shown, it may be substituted with 1 to 4 substituents. It is preferably one or two, and more preferably one. When R represents a heterocyclic group and a heteroaromatic group which may have a substituent selected from α group, 1 to 3 nitrogen atoms may be the same or different from the heterocyclic group,
It is a 5- or 6-membered saturated or unsaturated ring containing an oxygen atom and a sulfur atom. A heteroaromatic group consists of a monocyclic or bicyclic ring system. When it comprises a two-ring system, at least one ring is at least a heterocyclic ring. In the case of a two-ring system, the ring is a condensed ring, and one ring may be a heterocyclic ring and the other ring may be a carbocyclic ring, or a bicyclic coheterocyclic ring. The heterocycle is a 5- or 6-membered saturated or unsaturated ring, and the carbocycle is an aryl group having 6 to 10 carbon atoms. The unsubstituted heterocyclic group and unsubstituted heteroaromatic ring group include, for example, a pyrrolyl group such as 2-pyrrolyl and 3-pyrrolyl; a furyl group such as 2-furyl and 3-furyl; a 2-thienyl and 3-thienyl group. Such a thienyl group;
Pyridyl groups such as 2-pyridyl, 3-pyridyl or 4-pyridyl; imidazolyl groups such as 2-imidazolyl and 4-imidazolyl; pyrazolyl groups such as 3-pyrazolyl and 4-pyrazolyl; 2-oxazolyl; An oxazolyl group such as oxazolyl or 5-oxazolyl; an isoxazolyl group such as 3-isoxazolyl, 4-isoxazolyl or 5-oxazolyl; a thiazolyl group such as 2-thiazolyl, 4-thiazolyl or 5-thiazolyl; Isothiazolyl, 4
An isothiazolyl group such as -isothiazolyl or 5-isothiazolyl; a pyrazinyl group; 3-pyridazinyl;
Pyridazinyl groups such as 4-pyridazinyl; indol-4-yl, indol-5-yl, indole-6
Yl, or an indolyl group such as indol-7-yl; benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, or benzofuran-7.
Benzofuranyl groups such as -yl; benzothiophene-
A benzothiophenyl group such as 4-yl, benzothiophen-5-yl, benzothiophen-6-yl or benzothiophen-7-yl; benzimidazole-4
-Benzimidazolyl groups such as -yl, benzimidazol-5-yl, benzimidazol-6-yl or benzimidazol-7-yl; benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl Or benzoxazole-7
A benzothiazolyl group such as benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, or benzothiazol-7-yl; chromen-5-yl; ,
A chromenyl group such as chromen-6-yl, chromen-7-yl or chromen-8-yl; 2-quinolyl,
Quinolyl groups such as 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl; 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7
-An isoquinolyl group such as isoquinolyl or 8-isoquinolyl; a chromanyl group such as 5-chromanyl, 6-chromanyl, 7-chromanyl or 8-chromanyl; 5-isochromanyl, 6-isochromanyl, 7-isochromanyl or 8- An isochlamanyl group such as isochromanyl; preferably a benzofuranyl group, a benzothiophenyl group, a quinolyl group, a chromenyl group, or a chromanyl group, and more preferably a benzofuranyl group or a chromanyl group. When a substituted heterocyclic group and a substituted heteroaromatic ring group are shown, they may be substituted with 1 to 4 substituents. It is preferably one or two, and more preferably one. In the definition of the substituted α group: 1) An alkyl group having 1 to 4 carbon atoms is, for example,
It is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, or t-butyl group, preferably methyl, ethyl, propyl, and more preferably a methyl group.

2) Alkoxy groups having 1 to 4 carbon atoms include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy,
Or t-butoxy, preferably a methoxy group.

3) The halogenated alkyl group having 1 to 4 carbon atoms is, for example, chloromethyl, difluoromethyl, trifluoromethyl, iodomethyl, bromomethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, or 2,2,2-trichloroethyl,
Preferably it is trifluoromethyl.

4) The acyloxy group having 1 to 4 carbon atoms is, for example, a formyloxy, acetyloxy, propionyloxy, butyryloxy or t-butyryloxy group, preferably acetyloxy or t-butyryloxy.
Butyryloxy group.

5) The alkylenedioxy group having 1 to 4 carbon atoms is, for example, a methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy or propylenedioxy group. A dioxy or ethylenedioxy group.

6) The aralkyl group having 7 to 11 carbon atoms is, for example, a benzyl, phenethyl, 1-naphthylmethyl or 2-naphthylmethyl group.
It is a benzyl or phenethyl group.

7) The aralkyloxy group having 7 to 12 carbon atoms is, for example, a benzyloxy, phenethyloxy, 3-phenylpropoxy, 4-phenylbutoxy, 1-naphthylmethoxy or 2-naphthylmethoxy group, Preferably, it is a benzyloxy or phenethyloxy group.

8) Alkylsulfonyl groups having 1 to 4 carbon atoms include, for example, methylsulfonyl, ethylsulfonyl, propionylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-
A butylsulfonyl or t-butylsulfonyl group, preferably a methylsulfonyl or ethylsulfonyl group.

9) The alkylthio group having 1 to 4 carbon atoms includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,
It is an s-butylthio or t-butylthio group, preferably a methylthio or ethylthio group.

10) The halogen atom is, for example, fluorine,
A chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.

11) The monoalkylamino group having 1 to 4 carbon atoms is, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, or t-butylamino.
A butylamino group, preferably a methylamino or ethylamino group.

12) The same or different dialkylamino groups in which each alkyl has 1 to 4 carbon atoms include, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, N-methyl-N-ethylamino Or an N-ethyl-N-isopropylamino group, preferably a dimethylamino or diethylamino group.

13) The alkylsulfinyl group having 1 to 4 carbon atoms is, for example, a methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, s-butylsulfinyl or t-butylsulfinyl group. And preferably a methylsulfinyl or ethylsulfinyl group.

14) The alkylsulfonylamino group having 1 to 4 carbon atoms is, for example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino, s-butylsulfonylamino Or a t-butylsulfonylamino group, preferably a methylsulfonylamino or ethylsulfonylamino group.

15) The same or different alkylsulfonylalkylamino groups in which each alkyl has 1 to 4 carbon atoms include, for example, N-methylsulfonyl-N-methylamino, N-ethylsulfonyl-N-ethylamino,
N-propylsulfonyl-N-propylamino, N-isopropylsulfonyl-N-propylamino, N-butylsulfonyl-N-butylamino, N-methylsulfonyl-N-ethylamino, or N-ethylsulfonyl-
An N-isopropylamino group, preferably an N-methylsulfonyl-N-methylamino or N-ethylsulfonyl-N-ethylamino group.

16) a heterocyclic or heteroaromatic ring having 1 to 4 carbon atoms which may have a substituent selected from the β group
Among the alkoxy groups having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogenated alkyl group having 1 to 4 carbon atoms, An acyloxy group having 4 carbon atoms, an alkylenedioxy group having 1 to 4 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, an aralkyloxy group having 7 to 12 carbon atoms, and 1 to 4 carbon atoms. Alkylsulfonyl group having 1 to 4 carbon atoms
Alkylthio group, halogen atom, monoalkylamino group having 1 to 4 carbon atoms, dialkylamino group having the same or different alkyl group having 1 to 4 carbon atoms, thiol group, 1 to 4 carbon atoms An alkylsulfinyl group having 1 to 4 carbon atoms, an alkylsulfonylamino group having 1 to 4 carbon atoms, or an alkylsulfonylalkylamino group having the same or different and each alkyl having 1 to 4 carbon atoms has the same meaning as the α group described above. .
It is preferably an alkyl group having 1 to 4 carbon atoms, a hydroxy group, or an aralkyl group having 7 to 11 carbon atoms.

The heterocyclic ring may be the same or different from 5 or 6 containing 1 to 3 nitrogen, oxygen and sulfur atoms.
It is a membered saturated or unsaturated ring.

The heteroaromatic ring comprises a monocyclic or bicyclic ring system. When it comprises a two-ring system, at least one ring is at least a heterocyclic ring. In the case of a two-ring system, the ring is a condensed ring, and one ring may be a heterocyclic ring and the other ring may be a carbocyclic ring, or a bicyclic coheterocyclic ring. The heterocycle is a 5- or 6-membered saturated or unsaturated ring, and the carbocycle is an aryl group having 6 to 10 carbon atoms.

The alkoxy group having 1 to 4 carbon atoms having a heterocyclic ring or a heteroaromatic ring which may have a substituent selected from the β group is, for example, 1-substituted methoxy, 1-substituted methoxy,
Substituted ethoxy, 2-substituted ethoxy, 1-substituted propoxy, 2-substituted propoxy, 3-substituted propoxy, 1-substituted isopropoxy, 2-substituted isopropoxy, 1-substituted butoxy, 2-substituted butoxy, 3-substituted butoxy, 4-
A substituted butoxy, 1-substituted isobutoxy, 2-substituted isobutoxy, 3-substituted isobutoxy, 1-substituted s-butoxy, 2-substituted s-butoxy, or 3-substituted s-butoxy group, preferably 1-substituted methoxy Or a 2-substituted ethoxy group.

Examples of the unsubstituted heterocyclic ring or unsubstituted heteroaromatic ring include a pyrrolyl group such as 2-pyrrolyl and 3-pyrrolyl; a furyl group such as 2-furyl and 3-furyl; 2-thienyl; A thienyl group such as thienyl;
Pyridyl groups such as 2-pyridyl, 3-pyridyl or 4-pyridyl; imidazolyl groups such as 2-imidazolyl and 4-imidazolyl; pyrazolyl groups such as 3-pyrazolyl and 4-pyrazolyl; 2-oxazolyl; An oxazolyl group such as oxazolyl or 5-oxazolyl; an isoxazolyl group such as 3-isoxazolyl, 4-isoxazolyl or 5-oxazolyl; a thiazolyl group such as 2-thiazolyl, 4-thiazolyl or 5-thiazolyl; Isothiazolyl, 4
An isothiazolyl group such as isothiazolyl or 5-isothiazolyl; 1,3,4-oxadiazole-2
Oxadiazolyl groups such as -yl; tetrazolyl groups such as 5-tetrazolyl; pyridazinyl groups such as 3-pyridazinyl and 4-pyridazinyl; 2-pyrimisols;
A pyrimidinyl group such as -pyrimidinyl or 5-pyrimidyl; a pyridinyl group; an oxazinyl group such as 1,4-oxazin-2-yl and 1,4-oxazin-3-yl; 1,4-thiazin-2-yl Thiazinyl groups such as, 1,4-thiazin-3-yl; pyran-2-yl;
A pyranyl group such as pyran-3-yl, pyran-4-yl, pyran-5-yl or pyran-6-yl; indol-2-yl, indol-3-yl, indol-4-yl, indol- 5-yl, indole-6
Yl or an indolyl group such as indol-7-yl; benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, or benzofuran-7.
Benzofuranyl groups such as -yl; benzothiophene-
2-yl, benzothiophen-3-yl, benzothiophen-4-yl, benzothiophen-5-yl, benzothiophen-6-yl, or benzothiophen-7-
A benzothiophenyl group such as yl; a benzimidazolyl group such as benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, or benzimidazol-7-yl; Benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5
Benzoxazolyl groups such as -yl, benzoxazol-6-yl or benzoxazol-7-yl; benzothiazol-2-yl, benzothiazol-
Benzothiazolyl groups such as 4-yl, benzothiazol-5-yl, benzothiazol-6-yl or benzothiazol-7-yl; chromen-2-yl, chromen-3-yl, chromen-4-yl, chromene −5-
Chromenyl groups such as yl, chromen-6-yl, chromen-7-yl or chromen-8-yl; 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6
A quinolyl group such as quinolyl, 7-quinolyl or 8-quinolyl; 1-isoquinolyl, 3-isoquinolyl,
Isoquinolyl groups such as 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl or 8-isoquinolyl; indazol-2-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl; An indazolyl group such as indazol-6-yl or indazol-7-yl; a benzoxazinyl group such as 1,4-benzoxazin-2-yl, 1,4-benzoxazin-3-yl; 4-benzothiazin-2-yl, 1,4-benzothiazin-3
Benzothiazinyl groups such as -yl; 1,8-naphthyridin-2-yl, 1,8-naphthyridin-3-yl,
Naphthyridinyl groups such as 1,5-naphthyridin-2-yl or 1,5-naphthyridin-3-yl; 2-chromanyl, 3-chromanyl, 4-chromanyl, 5-chromanyl, 6-chromanyl, 7-chromanyl, or A chromanyl group such as 8-chromanyl; 1-isochromanyl,
3-isochromanyl, 4-isochromanyl, 5-isochromanyl, 6-isochromanyl, 7-isochromanyl,
Or an isokuramanyl group such as 8-isochromanyl;
And the like, preferably a pyridyl group, a benzofuranyl group,
It is a benzothiophenyl group, a benzimidazolyl group or a chromanyl group, more preferably a pyridyl group or a chromanyl group.

Accordingly, α has 1 carbon atom having a heterocyclic ring or a heteroaromatic ring which may have a substituent selected from the β group.
The alkoxy group having from 1 to 4 is an arbitrary combination of a heterocyclic or heteroaromatic ring which may have a substituent selected from the above-mentioned β group and an alkoxy group having from 1 to 4 carbon atoms. For example, (pyridin-2-yl) methoxy, (5-methoxypyridin-2-yl) methoxy, (5-acetoxypyridin-2-yl) methoxy,
(Benzofuran-2-yl) methoxy, (6-methoxybenzofuran-2-yl) methoxy, (6-acetoxybenzofuran-2-yl) methoxy, (benzothiophen-2-yl) methoxy, (6-methoxybenzothiophene-) 2-yl) methoxy, (6-acetoxybenzothiophen-2-yl) methoxy, (benzimidazol-2-yl) methoxy, (5-methoxybenzimidazol-2-yl) methoxy, (5-acetoxybenzimidazole) -2-yl) methoxy, (chroman-2-yl) methoxy, (2,5,7,8-tetramethyl-6-
(Hydroxychroman-2-yl) methoxy, (6-acetoxy-2,5,7,8-tetramethylchroman-2-
Yl) methoxy, 2- (pyridin-2-yl) ethoxy, 2- (5-ethylpyridin-2-yl) ethoxy,
2- (5-methoxypyridin-2-yl) ethoxy, 2
-(Benzofuran-2-yl) ethoxy, 2- (6-methoxybenzofuran-2-yl) ethoxy, 2- (6-
Acetoxybenzofuran-2-yl) ethoxy, 2-
(Benzothiophen-2-yl) ethoxy, 2- (6-
Methoxybenzothiophen-2-yl) ethoxy, 2-
(6-acetoxybenzothiophen-2-yl) ethoxy, 2- (benzimidazol-2-yl) ethoxy,
2- (5-methoxybenzimidazol-2-yl) ethoxy, 2- (5-acetoxyimidazol-2-yl) ethoxy, 2- (chroman-2-yl) ethoxy,
2- (2,5,7,8-tetramethyl-6-hydroxychroman-2-yl) ethoxy or 2- (6-acetoxy-2,5,7,8-tetramethylchroman-2-
Yl) ethoxy group and the like.

17) a heterocyclic or heteroaromatic ring having 1 to 4 carbon atoms which may have a substituent selected from the β group
Among alkylthio groups having 1 to 4 carbon atoms, alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, halogenated alkyl groups having 1 to 4 carbon atoms, 1 carbon atoms Acyloxy group having 1 to 4 carbon atoms, alkylenedioxy group having 1 to 4 carbon atoms, aralkyl group having 7 to 11 carbon atoms, aralkyloxy group having 7 to 12 carbon atoms, 1 to 4 carbon atoms An alkylsulfonyl group having 1 to 4 carbon atoms, a halogen atom, a monoalkylamino group having 1 to 4 carbon atoms, a dialkylamino having the same or different and each alkyl having 1 to 4 carbon atoms Group, thiol group, alkylsulfinyl group having 1 to 4 carbon atoms, alkylsulfonyl group having 1 to 4 carbon atoms Amino group or an alkylsulfonyl alkylamino group having the same or different and each alkyl is of 1 to 4 carbon atoms, is as defined group α mentioned above. It is preferably an alkyl group having 1 to 4 carbon atoms, a hydroxy group, or an aralkyl group having 7 to 11 carbon atoms.

The heterocyclic ring may be the same or different and contains 5 or 6 containing 1 to 3 nitrogen, oxygen and sulfur atoms.
It is a membered saturated or unsaturated ring. A heteroaromatic ring consists of a monocyclic or bicyclic ring system. When it comprises a two-ring system, at least one ring is at least a heterocyclic ring. In the case of a two-ring system, the ring is a condensed ring, and one ring may be a heterocyclic ring and the other ring may be a carbocyclic ring, or a bicyclic coheterocyclic ring. 5 or 6 heterocycles
It is a membered saturated or unsaturated ring, and the carbocycle is an aryl group having 6 to 10 carbon atoms.

An alkylthio group having 1 to 4 carbon atoms having a heterocyclic ring or a heteroaromatic ring which may have a substituent selected from the group β is, for example, 1-substituted methylthio,
Substituted ethylthio, 2-substituted ethylthio, 1-substituted propylthio, 2-substituted propylthio, 3-substituted propylthio, 1-substituted isopropylthio, 2-substituted isopropylthio, 1-substituted butylthio, 2-substituted butylthio, 3-substituted
Substituted butylthio, 4-substituted butylthio, 1-substituted isobutylthio, 2-substituted isobutylthio, 3-substituted isobutylthio, 1-substituted s-butylthio, 2-substituted s-butylthio, or 3-substituted s-butylthio; Preferably, it is 1-substituted methylthio or 2-substituted ethylthio.

The unsubstituted heterocyclic ring or unsubstituted heteroaromatic ring has the same meaning as described in the above 16), and is preferably a pyridyl group, a benzofuranyl group, a benzothiophenyl group, a benzimidazolyl group, or a chromanyl group. And more preferably a pyridyl group or a chromanyl group.

Accordingly, α is a heterocyclic ring or a heteroaromatic ring which may have a substituent selected from the β group.
The alkylthio group having from 1 to 4 is an arbitrary combination of a heterocyclic or heteroaromatic ring which may have a substituent selected from the group β described above and an alkylthio group having from 1 to 4 carbon atoms. For example, (pyridin-2-yl) methylthio, (5-methoxypyridin-2-yl)
Methylthio, (5-acetoxypyridin-2-yl) methylthio, (benzofuran-2-yl) methylthio,
(6-methoxybenzofuran-2-yl) methylthio,
(6-acetoxybenzofuran-2-yl) methylthio, (benzothiophen-2-yl) methylthio, (6
-Methoxybenzothiophen-2-yl) methylthio,
(6-acetoxybenzothiophen-2-yl) methylthio, (benzimidazol-2-yl) methylthio,
(5-methoxybenzimidazol-2-yl) methylthio, (5-acetoxybenzimidazol-2-yl) methylthio, (chroman-2-yl) methylthio,
(2,5,7,8-tetramethyl-6-hydroxychroman-2-yl) methylthio, 2- (pyridin-2-yl) ethylthio, 2- (5-ethylpyridin-2-yl) ethylthio, 2- (5-methoxypyridin-2-yl) ethylthio, 2- (benzofuran-2-yl) ethylthio, 2- (6-methoxybenzofuran-2-yl)
Ethylthio, 2- (6-acetoxybenzofuran-2-
Yl) ethylthio, 2- (benzothiophen-2-yl) ethylthio, 2- (6-methoxybenzothiophen-2-yl) ethylthio, 2- (6-acetoxybenzothiophen-2-yl) ethylthio, 2- (benzo Imidazol-2-yl) ethylthio, 2- (5-methoxybenzimidazol-2-yl) ethylthio, 2- (5
-Acetoxyimidazol-2-yl) ethylthio, 2
-(Chroman-2-yl) ethylthio, or 2-
(2,5,7,8-tetramethyl-6-hydroxychroman-2-yl) ethylthio group.

Accordingly, in the α group, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, or a heterocyclic ring which may have a substituent selected from the β group is preferred. Or 1 carbon atom having a heteroaromatic ring
An alkoxy group having from 4 to 4, more preferably β
It is an alkoxy group having 1 to 4 carbon atoms having a heterocyclic ring or a heteroaromatic ring which may have a substituent selected from the group.

Accordingly, the aryl group having 6 to 10 carbon atoms in which R may have a substituent selected from the α group includes the unsubstituted aryl group described above and the unsubstituted aryl group described above. Group and R are any combination of substituents selected from the α group, such as phenyl, 4-methylphenyl, 4-methoxyphenyl, trifluoromethylphenyl, 4-acetoxyphenyl, methylenedioxyphenyl, Methylthiophenyl, fluorophenyl,
Chlorophenyl, 4- (dimethylamino) phenyl, methylsulfinylphenyl, methylsulfonylaminophenyl, N-methylsulfonyl-N-methylaminophenyl, 4-[(pyridin-2-yl) methoxy] phenyl, 4-[(5- Methoxypyridin-2-yl) methoxy] phenyl, 4-[(5-acetoxypyridin-2-
Yl) methoxy] phenyl, 4-[(benzofuran-2
-Yl) methoxy] phenyl, 4-[(6-methoxybenzofuran-2-yl) methoxy] phenyl, 4-
[(6-acetoxybenzofuran-2-yl) methoxy] phenyl, 4-[(benzothiophen-2-yl)
Methoxy] phenyl, 4-[(6-methoxybenzothiophen-2-yl) methoxy] phenyl, 4-[(6-
Acetoxybenzothiophen-2-yl) methoxy] phenyl, 4-[(benzimidazol-2-yl) methoxy] phenyl, 4-[(5-methoxybenzimidazol-2-yl) methoxy] phenyl, 4- [ (5-acetoxybenzimidazol-2-yl) methoxy] phenyl, 4-[(chroman-2-yl) methoxy] phenyl, 4-[(2,5,7,8-tetramethyl-6-hydroxychroman-2 -Yl) methoxy] phenyl, 4
-[(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl) methoxy] phenyl, 4- [2-
(Pyridin-2-yl) ethoxy] phenyl, 4- [2
-(5-ethylpyridin-2-yl) ethoxy] phenyl, 4- [2- (5-methoxypyridin-2-yl) ethoxy] phenyl, 4- [2- (benzofuran-2-yl) ethoxy] phenyl, 4- [2- (6-methoxybenzofuran-2-yl) ethoxy] phenyl, 4- [2
-(6-acetoxybenzofuran-2-yl) ethoxy] phenyl, 4- [2- (benzothiophen-2-yl) ethoxy] phenyl, 4- [2- (6-methoxybenzothiophen-2-yl) ethoxy] Phenyl, 4-
[2- (6-acetoxybenzothiophen-2-yl)
Ethoxy] phenyl, 4- [2- (benzimidazol-2-yl) ethoxy] phenyl, 4- [2- (5-methoxybenzimidazol-2-yl) ethoxy] phenyl, 4- [2- (5 -Acetoxyimidazole-2-
Yl) ethoxy] phenyl, 4- [2- (chroman-2)
-Yl) ethoxy] phenyl, 4- [2- (2,5,
7,8-tetramethyl-6-hydroxychroman-2-
Yl) ethoxy] phenyl, 4-[(pyridin-2-yl) methylthio] phenyl, 4-[(5-methoxypyridin-2-yl) methylthio] phenyl, 4-[(5-
Acetoxypyridin-2-yl) methylthio] phenyl, 4-[(benzofuran-2-yl) methylthio] phenyl, 4-[(6-methoxybenzofuran-2-yl) methylthio] phenyl, 4-[(6-acetoxybenzofuran) -2-yl) methylthio] phenyl, 4-
[(Benzothiophen-2-yl) methylthio] phenyl, 4-[(6-methoxybenzothiophen-2-yl) methylthio] phenyl, 4-[(6-acetoxybenzothiophen-2-yl) methylthio] phenyl,
-[(Benzimidazol-2-yl) methylthio] phenyl, 4-[(5-methoxybenzimidazole-2
-Yl) methylthio] phenyl, 4-[(5-acetoxybenzimidazol-2-yl) methylthio] phenyl, 4-[(chroman-2-yl) methylthio] phenyl, 4-[(2,5,7,8 -Tetramethyl-6-hydroxychroman-2-yl) methylthio] phenyl, 4
-[2- (pyridin-2-yl) ethylthio] phenyl, 4- [2- (5-ethylpyridin-2-yl) ethylthio] phenyl, 4- [2- (5-methoxypyridin-2-yl) ethylthio ] Phenyl, 4- [2- (benzofuran-2-yl) ethylthio] phenyl, 4- [2
-(6-Methoxybenzofuran-2-yl) ethylthio] phenyl, 4- [2- (6-acetoxybenzofuran-2-yl) ethylthio] phenyl, 4- [2- (benzothiophen-2-yl) ethylthio] phenyl , 4
-[2- (6-methoxybenzothiophen-2-yl)
Ethylthio] phenyl, 4- [2- (6-acetoxybenzothiophen-2-yl) ethylthio] phenyl,
-[2- (benzimidazol-2-yl) ethylthio] phenyl, 4- [2- (5-methoxybenzimidazol-2-yl) ethylthio] phenyl, 4- [2-
(5-acetoxyimidazol-2-yl) ethylthio] phenyl, 4- [2- (chroman-2-yl) ethylthio] phenyl, or 4- [2- (2,5,7,8)
-Tetramethyl-6-hydroxychroman-2-yl)
[Ethylthio] phenyl group.

Accordingly, the heterocyclic group and aromatic heterocyclic group in which R may have a substituent selected from α group include the unsubstituted heterocyclic group and unsubstituted aromatic heterocyclic group described above and And any combination of the unsubstituted heterocyclic group and the unsubstituted aromatic heterocyclic group described in the above with a substituent selected from the α group, for example, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl , Benzofuran-7-yl, benzothiophen-4-yl, benzothiophene-
5-yl, benzothiophen-6-yl, benzothiophen-7-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl,
8-quinolyl, chromen-5-yl, chromen-6-yl, chromen-7-yl, chromen-8-yl, 5-chromanyl, 6-chromanyl, 7-chromanyl, 8-chromanyl, 5-methylbenzofuran-4 -Yl, 5-ethylbenzofuran-4-yl, 5-methoxybenzofuran-4-yl, 5-acetoxybenzofuran-4-yl,
7-methylbenzofuran-5-yl, 7-ethylbenzofuran-5-yl, 7-methoxybenzofuran-5-yl, 7-acetoxybenzofuran-5-yl, 4-methylbenzofuran-6-yl, 4-ethylbenzofuran-
6-yl, 4-methoxybenzofuran-6-yl, 4-
Acetoxybenzofuran-6-yl, 5-methylbenzofuran-7-yl, 5-ethylbenzofuran-7-yl, 5-methoxybenzofuran-7-yl, 5-acetoxybenzofuran-7-yl, 6-methylbenzothiophen-4 -Yl, 6-ethylbenzothiophen-4-yl, 6-methoxybenzothiophen-4-yl, 6-acetoxybenzothiophen-4-yl, 7-methylbenzothiophen-5-yl, 7-ethylbenzothiophen-5 -Yl, 7-methoxybenzothiophen-5-yl, 7-acetoxybenzothiophen-5-yl, 6
-Methyl-2-quinolyl, 7-ethyl-3-quinolyl,
6-methoxy-4-quinolyl, 7-acetoxy-5-quinolyl, 3-methyl-6-quinolyl, 4-ethyl-7-
Quinolyl, 5-methoxy-8-quinolyl, 2-methylchromen-5-yl, 3-ethylchromen-6-yl, 3
-Methoxychromen-7-yl, 4-acetoxycyclomen-8-yl, 3-methylchroman-5-yl, 2-acetoxychroman-6-yl, 2-benzylchroman-6
-Yl, 2-methoxychroman-7-yl, or 2-
And acetoxycycloman-8-yl group.

The preferred R in the compounds (1) and (2) is 1) a phenyl group substituted by an alkoxy group having 1 to 2 carbon atoms; 2) an acyloxy group having 1 to 4 carbon atoms 3) a phenyl group substituted with an alkoxy group having 1 or 2 carbon atoms having a heterocyclic or heteroaromatic ring substituted with methyl, ethyl, hydroxy, or benzyl; 4)

[0040]

Embedded image

[0041]

Embedded image And more preferably, 4-methoxyphenyl, 4-methoxyphenyl,
Acetoxyphenyl, the above groups (3) to (17); most preferably, 4-acetoxyphenyl;

[0042]

Embedded image It is.

When X represents an amino-protecting group, the protecting group is a phenyl group which may have 1 to 3 substituents (nitro group, alkoxy group having 1 to 2 carbon atoms). A substituted or unsubstituted alkyl group having 1 to 5 carbon atoms and having 1 to 5 carbon atoms, such as benzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, di (4-methoxyphenyl)
A methyl, triphenylmethyl or 4-methoxyphenyldiphenylmethyl group, preferably a benzyl or triphenylmethyl group, more preferably a triphenylmethyl group.

[0044]

The organic solvent used is not particularly limited as long as it does not affect the reaction.
It is a mixed solvent of an ether solvent, an alcohol solvent, and water, and examples of the amide solvent include dimethylformamide, diethylformamide, dimethylacetamide, and dimethylpropionamide. Acetamide. More preferably, it is dimethylformamide.

As ether solvents, diethyl ether, diisopropyl ether, tetrahydrofuran,
Examples thereof include 1,4-dioxane, and preferred is tetrahydrofuran and 1,4-dioxane. More preferably, it is tetrahydrofuran.

As alcohol solvents, methanol,
Ethanol, n-propanol, isopropanol, n
-Butanol, s-butanol, isobutanol, t-
Butanol, etc., preferably ethanol,
s-butanol and isobutanol. More preferably, they are ethanol and s-butanol. The ratio of the mixed solvent used in the present production method is 5 if the solvent used is a mixed solvent of an amide solvent and water or an alcohol solvent.
The ratio is 1 to 1 to 5, preferably 2 to 1 to 1.
When the solvent used is a mixed solvent of an ether solvent and water or an alcohol solvent, the ratio is 10: 1 to 1: 1 and preferably 4: 1 to 2: 1.

Examples of the metal hydride used include sodium borohydride, lithium borohydride, calcium borohydride, zinc borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride, tetrapropyl borohydride Ammonium, tetrabutylammonium borohydride and the like can be mentioned, and preferred are alkali metal borohydride compounds such as sodium borohydride, lithium borohydride and calcium borohydride. More preferably, it is sodium borohydride.

The amount of the metal hydride used is from 1.0 to 10 equivalents, preferably from 1.
0 to 2.0 equivalents.

The reaction temperature is between 0 ° C. and 80 ° C., preferably between 20 ° C. and 40 ° C.

The reaction time is 1 hour to 8 hours, preferably 1 hour to 2 hours.

The obtained target compound can be purified, if necessary, by a conventional method, for example, column chromatography, recrystallization and the like.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

[0053]

【Example】

Example 1 3-triphenylmethyl-5- {4- [2- (tetrahydropyran-2-yloxy) ethoxy] benzyl} thiazolidine-2,4-dione

[0054]

Embedded image 3-Triphenylmethyl-5- {4- [2- (tetrahydropyran-2-yloxy) ethoxy] benzylidene} thiazolidine-2,4-dione (200 mg) was dissolved in 1 ml of dimethylformamide and 1 ml of ethanol, and the mixture was brought to room temperature. With sodium borohydride (12.
9 mg) was added. After stirring for 1 hour, 10 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with 20 ml of ethyl acetate.
After washing the organic layer with 10 ml of 14% aqueous ammonium chloride,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude yellow oil. The crude oil was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to obtain 153 mg (yield: 76%) of the target compound.

¹ H-nuclear magnetic resonance spectrum (CDCl ₃ ,
400 MHz) δ ppm; 1.54-1.83 (6H,
m), 3.06 (1H, dd, J = 9.0, 14.2H
z), 3.41 (1H, dd, J = 3.9, 14.2H
z), 3.51-3.54 (1H, m), 3.79-
3.92 (2H, m), 4.04-4.15 (3H,
m), 4.36 (1H, dd, J = 3.9, 9.0H)
z), 4.71 (1H, s), 6.87 (2H, d, J
= 8.5 Hz), 7.12 (2H, d, J = 8.5H)
z). Example 2 3-triphenylmethyl-5- {4- [2- (tetrahydropyran-2-yloxy) ethoxy] benzyl} thiazolidine-2,4-dione 3-triphenylmethyl-5- {4- [2- (Tetrahydropyran-2-yloxy) ethoxy] benzylidenedithiazolidine-2,4-dione (200 mg) was dissolved in 2 ml of terahydrofuran and 0.5 ml of s-butanol, and sodium borohydride (12.9 mg) was added. And stirred at 40 ° C. for 6.5 hours. 10 ml of 14% aqueous ammonium chloride was added, and the mixture was extracted with 20 ml of ethyl acetate. The organic layer was washed with 10% aqueous 14% ammonium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude yellow oil. The crude oil was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1),
153 mg (76% yield) of the target compound was obtained.

The physical properties of the obtained target compound were the same as those of Example 1. Example 3 3-triphenylmethyl-5- (4- {2- [1- (4
-Pyridin-2-ylphenyl) ethylideneaminooxy] ethoxy {benzyl) thiazolidine-2,4-dione

[0057]

Embedded image 3-triphenylmethyl-5- (4- {2- [1- (4
-Pyridin-2-ylphenyl) ethylideneaminooxy] ethoxy {benzylidene) thiazolidine-2,4-
Sodium borohydride (10.6 mg) was added to a suspension of dione (200 mg) in dimethylformamide (2 ml) and ethanol (1 ml) at room temperature, followed by stirring for 1 hour. 7%
20 ml of ammonium chloride water was added, and 20 ml of ethyl acetate was added.
Extracted. Organic layer is 20m with 14% ammonium chloride solution
After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude white-yellow foam. The crude foam was purified by silica gel chromatography (hexane: ethyl acetate: methylene chloride = 6: 4: 1) to obtain 169 mg (yield: 86%) of the target compound.

The ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ ,
400 MHz) δ ppm; 2.26 (3H, s), 3.
06 (1H, dd, J = 8.8, 14.2 Hz);
38 (1H, dd, J = 3.9, 14.2 Hz);
27 (2H, t, J = 4.9 Hz), 4.34 (1H,
dd, J = 3.9, 8.8 Hz), 4.55 (2H,
t, J = 4.9 Hz), 6.89 (2H, d, J = 8.
8Hz), 7.10-7.32 (18H, m), 7.7
2-7.76 (4H, m), 8.00 (2H, d, J =
8.6 Hz), 8.69 (1H, d, J = 4.9H)
z). Example 4 3-triphenylmethyl-5- [4- (2,5,7,8
-Tetramethyl-6-benzyloxychroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione

[0059]

Embedded image 3-triphenylmethyl-5- [4- (2,5,7,8
-Tetramethyl-6-benzyloxychroman-2-ylmethoxy) benzylidene] thiazolidine-2,4-dione (200 mg) was dissolved in 1 ml of dimethylformamide and 1 ml of ethanol, and sodium borohydride (9.8 mg) was added at room temperature. ) And stirred for 1 hour. 10 ml of 14% aqueous ammonium chloride was added, and the mixture was extracted with 20 ml of ethyl acetate. The organic layer was washed with 10% aqueous 14% ammonium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude yellow oil. The crude oil was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to obtain 156 mg (yield 78%) of the desired compound.

The ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ ,
400 MHz) δ ppm; 1.43 (3H, s), 1.
88-1.94 (1H, m), 2.08-2.18 (1
H, m), 2.10 (3H, s), 2.14 (3H,
s), 2.22 (3H, s), 2.56-2.68 (2
H, m), 3.06 (1H, dd, J = 8.8, 14.
2Hz), 3.40 (1H, dd, J = 3.9, 14.
2 Hz), 3.88 (1H, d, J = 9.0 Hz),
3.97 (1H, d, J = 9.0 Hz), 4.35 (1
H, dd, J = 3.9, 8.8 Hz), 4.69 (2
H, s), 6.86 (2H, d, J = 8.5 Hz),
7.10-7.50 (22H, m). Example 5 3-Triphenylmethyl-5- (4-acetoxybenzyl) thiazolidine-2,4-dione

[0061]

Embedded image 3-triphenylmethyl-5- (4-acetoxybenzylidene) thiazolidine-2,4-dione (200 mg)
Was dissolved in 1 ml of dimethylformamide and 1 ml of s-butanol.
Dissolve and add sodium borohydride (12.9m
g) was added and stirred for 1.5 hours. 10 ml of 14% aqueous ammonium chloride was added, and 20 ml of ethyl acetate was extracted. The organic layer was washed with 10% aqueous 14% ammonium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude yellow oil. The crude oil was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to obtain 119 mg of the desired compound (yield: 69%), and 3-triphenylmethyl-5- (4- (4-hydroxy-4-acetoxy) -hydrolyzed acetoxy group. (Hydroxybenzyl) thiazolidine-2,4-dione 18m
g (11% yield). 3-triphenylmethyl-5- (4-acetoxybenzylidene) thiazolidine-2,4-dione: ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MHz) δpp
m; 2.29 (3H, s), 3.08 (1 h, dd, J
= 9.3, 14.2 Hz), 3.48 (1H, dd, J)
= 3.9, 14.2 Hz), 4.38 (1H, dd, J)
= 3.9, 9.3 Hz), 7.03 (2H, d, J =
8.6 Hz), 7.16-7.35 (18H, m).

Reference Example 1 2- (2-bromoethoxy) tetrahydropyran 2-bromoethanol (114.5 ml) was dissolved in 200 ml of methylene chloride, and under ice-cooling, 3,4-dihydro-2H-pyran (150 g). Was added dropwise. After stirring at room temperature for 6 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in 1000 ml of ethyl acetate, and 500 ml of saturated sodium bicarbonate was added.
After washing with water, the solvent was distilled off under reduced pressure.
56 g (99.9% yield) was obtained. ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 1.52-1.91 (4H, m);
47-3.56 (3H, m), 3.77 (1H, dt,
J = 6.4, 11.1 Hz), 3.89 (1H, dd)
d, J = 3.5, 8.4, 11.0 Hz), 4.02
(1H, dt, J = 6.4, 11.1 Hz).

Reference Example 2 5- {4- [2- (tetrahydropyran-2-yloxy) ethoxy] benzylidene} thiazolidine-2,4-
Dione 4-hydroxybenzaldehyde (10 g) was dissolved in 100 ml of dimethylformamide, and potassium carbonate (1 g) was dissolved.
2.5 g) and 2- (2-bromoethoxy) tetrahydropyran (18.9 g) were added, and the mixture was stirred at 80 ° C. After 1 hour, the solid was filtered and 100 ml of ethyl acetate, 10%
100 ml of a saline solution was added, and the mixture was separated. The organic layer was washed with 100 ml of 10% saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was dissolved in 200 ml of ethanol. Thiazolidine-2,4-dione (10 g) and piperidine (8.5 ml) were added, and the mixture was heated under reflux. After 17.5 hours, the solvent was distilled off under reduced pressure. 200 ml of ethyl acetate was added, washed twice with 100 ml of water, washed with 100 ml of 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crude yellow crystals. 100 ml of diisopropyl ether and 200 ml of n-hexane were added to the crude crystals, and the mixture was stirred at room temperature for 30 minutes, and the crystals were filtered to obtain 24.06 g of the desired compound as yellow crystals. ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 1.17-1.80 (6H, m);
45-3.52 (1H, m), 3.75-3.95 (2
H, m), 4.00-4.08 (1H, m), 4.11.
-4.19 (2H, m), 4.64-4.69 (1H,
m), 6.95 (2H, d, J = 8.8 Hz), 7.3
7 (2H, d, J = 8.8 Hz), 7.72 (1H,
s), 8.63 (1H, s).

Reference Example 3 3-Triphenylmethyl-5- {4- [2- (tetrahydropyran-2-yloxy) ethoxy] benzylidene} thiazolidine-2,4-dione 5- {4- [2- (tetrahydropyran -2-yloxy) ethoxy] benzylidenedithiazolidine-2,4-
Triphenylmethyl chloride (4.39 g) and triethylamine (2.4 ml) were added to a solution of dione (5 g) in 50 ml of methylene chloride and the mixture was stirred at room temperature.
After 1.5 hours, 50 ml of methylene chloride was added, and 50 ml of water was added.
After washing with water, the solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate (10 ml) was added to the residue, and when crystals precipitated, 100 ml of diisopropyl ether was added. After stirring at room temperature for 30 minutes, the crystals were filtered to obtain 7.17 g (yield: 85%) of the target compound. ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 1.54-1.88 (6H, m);
52-3.54 (1H, m), 3.80-3.91 (2
H, m), 4.04-4.21 (3H, m), 4.69.
-4.71 (1H, m), 6.99 (2H, d, J =
8.8 Hz), 7.17-7.47 (17H, m),
7.70 (1H, s).

Reference Example 4 Potassium permanganate (75.5 g) was added to a mixture of 4- (2-pyridyl) benzoic acid 2- (p-tolyl) pyridine (30 g) in 120 ml of t-butanol / 120 ml of water at room temperature. Was added. The reaction solution was
After slowly raising the temperature to 5 ° C and stirring at the same temperature for 3 hours,
Cooled to 0 ° C. 18 ml of methanol was added dropwise, and 15
After stirring at the same temperature for each minute, insolubles were removed by filtration. The filtrate was adjusted to pH 4 with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration.
28.7 g (yield: 81.3 g) of the target compound as white crystals.
%)Obtained. Melting point 235-237 ° C ¹ H-nuclear magnetic resonance spectrum (DMSO-d ₆ , 400M
Hz) δ ppm; 7.42 (1H, ddd, J = 1.
0, 4.8, 7.5 Hz), 7.94 (1H, ddd,
J = 1.8, 7.5, 7.8 Hz), 8.04-8.0.
8 (1H, m), 8.06 (2H, d, J = 8.8H
z), 8.22 (2H, d, J = 8.8 Hz), 8.7
2 (1H, ddd, = 1.0, 1.8, 4.8 Hz),
13.1 (1H, s).

Reference Example 5 4- (2-pyridyl) acetophenone oxime 2- (2-pyridyl) benzoic acid 28.7 g of toluene 3
52 ml of thionyl chloride was added to the 00 ml suspension at room temperature. After stirring the reaction solution at 80 to 90 ° C. for 3 hours, the solvent was distilled off under reduced pressure. To a solution of the residue in 360 ml of methylene chloride,
N, O-dimethylhydroxylamine hydrochloride 1 at room temperature
After adding 9.7 g, 74 ml of triethylamine was added under ice-cooling.
Was added dropwise. After the reaction solution was stirred at room temperature for 1.5 hours, water was added. After separating the organic layer, the aqueous layer was extracted with methylene chloride. After the organic layers were combined and dried over magnesium sulfate, the solvent was distilled off under reduced pressure. 240 ml of a 1M methylmagnesium bromide / tetrahydrofuran solution was added dropwise to a solution of the obtained residue in 150 ml of tetrahydrofuran under ice cooling. After the reaction solution was stirred at room temperature for 1 hour, it was slowly poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with 10% saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 21.6 g of hydroxyamine hydrochloride was added to a suspension of the obtained residue in 180 ml of methanol at room temperature, followed by stirring for 1 hour. At room temperature, 28% sodium methoxide /
60 ml of a methanol solution and 300 ml of water were sequentially added.
After stirring for 1 hour under ice cooling, the precipitated crystals were collected by filtration,
24 g (yield 78%) of the target compound was obtained as white crystals. 175-176 ° C ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 2.33 (3H, s), 7.29-7.
34 (1H, m), 7.76 (2H, d, J = 8.8H)
z), 7.75-7.88 (2H, m), 8.04 (2
H, d, J = 8.8 Hz), 8.76 (1H, d, J =
4.8 Hz), 9.00 (1H, s).

Reference Example 6 2- [1- (4-pyridin-2-ylphenyl) ethylideneaminooxy] ethanol 4- (2-pyridyl) acetophenone oxime (2
g), a mixture of ethylene carbonate (1.05 g) and dimethylacetamide (2 ml) was stirred at 150 ° C. for 1.5 hours. After cooling the reaction solution to room temperature, ethyl acetate 15
Then, the mixture was washed with 15 ml of water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude oil. The obtained crude oil was dissolved in toluene (6 ml), and ethyl cyclohexane (12 ml) was added dropwise thereto at room temperature, and the mixture was further stirred under ice-cooling for 30 minutes. The precipitated crystals were collected by filtration and dried under reduced pressure.
95 g (83.4% yield) was obtained. Melting point 81-83 ° C ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 2.29 (3H, s), 2.59 (1
H, t, J = 6.0 Hz), 3.92-3.96 (2
H, m), 4.31-4.34 (2H, m) 7.21-
7.25 (1H, m), 7.69-7.77 (2H,
m), 7.72 (2H, d, J = 8.4 Hz), 7.9
9 (2H, d, J = 8.4 Hz), 8.68 (1H,
d, J = 4.8 Hz).

Reference Example 7 2- [1- (4-pyridin-2-ylphenyl) ethylideneaminooxy] ethyl methanesulfonate 2- [1- (4-pyridin-2-ylphenyl) ethylideneaminooxy] ethano- (5 g) was dissolved in 20 ml of methylene chloride, and triethylamine (4.0 ml) and methanesulfonyl chloride (1.8) were dissolved under ice-cooling.
ml) was added dropwise and stirred for 30 minutes. 20 ml of water
And dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the desired compound as pale brown crystals (6.81 g).
(100% yield). ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MHz) δ ppm; 2.30 (3
H, s), 3.04 (3H, s), 4.47 (2H,
m), 4.56 (2H, m), 7.28 (1H, d, J
= 5.4 Hz), 7.78 (4H, m), 8.03 (2
H, d, J = 8.3 Hz), 8.72 (1H, d, J =
4.6 Hz).

Reference Example 8 4- {2- [1- (4-pyridin-2-ylphenyl)]
Ethylideneaminooxy] ethoxydibenzaldehyde methanesulfonic acid 2- [1- (4-pyridine-2-
A solution of (ylphenyl) ethylideneaminooxy] ethyl ether (2 g) in 20 ml of dimethylformamide,
4-Hydroxybenzaldehyde (0.76 g) and potassium carbonate (0.86 g) were added. After stirring at 80 ° C. for 7 hours, the solvent was distilled off under reduced pressure. The residue was taken up in ethyl acetate 100
and washed three times with 50 ml of water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2.03 g of the target compound as tan crystals (yield: 100).
%)Obtained. ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 2.28 (3H, s), 4.40 (2
H, t, J = 5.1 Hz), 4.59 (2H, t, J =
5.1 Hz), 7.07 (2H, d, J = 8.8H)
z), 7.26-7.29 (1H, m), 7.76-
7.85 (6H, m), 8.03 (2H, d, J = 8.
8Hz), 8.73 (1H, d, J = 4.9Hz),
9.89 (1H, s).

Reference Example 9 5- (4- {2- [1- (4-pyridin-2-ylphenyl) ethylideneaminooxy] ethoxy} benzylidene) thiazolidine-2,4-dione 4- {2- [1- (4-pyridin-2-ylphenyl)
[Ethylideneaminooxy] ethoxydibenzaldehyde (2.03 g), thiazolidine-2,4-dione (0.
Piperidine (0.1 ml) was added to a ethanol solution (73 g) of ethanol (20 ml), and the mixture was refluxed for 12 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to give 2.08 g of the desired compound as yellow crystals.
(80.4% yield). ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 2.24 (3H, s), 4.39 (2
H, m), 4.51 (2H, m), 7.17 (2H,
d, J = 8.8 Hz), 7.37 (1H, ddd, J =
0.96, 4.6, 7.3 Hz), 7.56 (2H,
d, J = 8.8 Hz), 7.76 (1H, s), 7.7
9 (2H, d, J = 8.5 Hz), 7.90 (1H, d
t, J = 1.7, 7.8 Hz), 8.00 (1H, d,
J = 8.1 Hz), 8.13 (2H, d, J = 8.5H)
z), 8.68 (1H, dt, J = 0.96, 4.8H)
z), 12.5 (1H, s).

Reference Example 10 3-Triphenylmethyl-5- (4- {2- [1- (4
-Pyridin-2-ylphenyl) ethylideneaminooxy] ethoxy {benzylidene) thiazolidine-2,4-
Dione 5- (4- {2- [1- (4-pyridin-2-ylphenyl) ethylideneaminooxy] ethoxy} benzylidene) thiazolidine-2,4-dione (1 g), triphenylmethyl chloride (0.67 g) To a suspension of methylene chloride in 10 ml of triethylamine (0.36 ml)
The mixture was stirred at room temperature for 1.5 hours. 10 ml of methylene chloride was added to the reaction solution, and the mixture was washed twice with 10 ml of water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 20 ml of methanol was added to the residue to form a suspension. After stirring at room temperature for 1 hour, the crystals were collected by filtration and dried under reduced pressure.
1.42 g of the target compound as white yellow crystals (yield 92.
8%). ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 2.27 (3H, s), 4.35 (2
H, t, J = 4.6 Hz), 4.57 (2H, t, J =
4.6 Hz), 7.02 (2H, d, J = 8.6H)
z), 7.17-7.29 (10H, m), 7.39
(2H, d, J = 8.6 Hz), 7.46 (6H, d,
J = 7.8 Hz), 7.71 (1H, s), 7.76
(4H, d, J = 8.0H), 8.02 (2H, d, J
= 8.3 Hz), 8.71 (1H, d, J = 4.6H)
z).

Reference Example 11 6-benzyloxy-2,5,7,8-tetramethylchroman-2-methylmethanesulfonate 6-hydroxyl-2,5,7,8-tetramethylchroman-2-carboxylic acid Sodium hydroxide (9.6 kg) and benzyl chloride (19.0 kg) were added to a 100 liter solution of acid (25.03 kg) in dimethylformamide.
Stir at 20-25 ° C. Two hours later, 200 l of water was added, and the mixture was washed with 50 l of toluene. Concentrated hydrochloric acid 1 in aqueous layer
4.8 kg was added, stirred for 2 hours, and left overnight. The precipitated crystals were collected by filtration, and 100 L of methanol was added to the obtained crystals to form a suspension, which was allowed to stand overnight. The crystals were collected by filtration and dried under reduced pressure. The obtained crystals were suspended in 260 liters of toluene, and a 70% sodium bis (2-methoxyethoxy) aluminum hydride / toluene solution was added dropwise at 15 to 25 ° C. After stirring at 25 ° C. for 2 hours, 9 liters of acetone were added dropwise, followed by 17.5 liters of concentrated hydrochloric acid. After liquid separation, the aqueous layer was extracted with 50 L of toluene, and the combined organic layers were washed twice with 100 L of water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. To the residue were added 65 l of isopropanol and 65 l of water, and the mixture was stirred at 20 to 25 ° C for 1 hour. Further, 65 liters of water was added, and the mixture was stirred at 0 to 5 ° C for 2 hours. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 29.1 kg (yield: 89.1%) of the target compound. 6-benzyloxy obtained
2,5,7,8-tetramethylchroman-2-ethano-
(56.57 g) was dissolved in 560 ml of methylene chloride, and methanesulfonyl chloride (25.54
g) was added dropwise and refluxed for 1 hour. After washing the reaction solution with water, the solvent was distilled off under reduced pressure. Methanol was added to the residue, and the precipitated crystals were collected by filtration, and 68.43 g (yield 97.43 g) of the desired compound was obtained.
6%). ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 60 MH
z) δ ppm; 1.30 (3H, s), 1.70-2.
03 (2H, m), 2.10 (3H, s), 2.13
(3H, s), 2.20 (3H, s), 2.43-2.
87 (2H, m), 2.97 (3H, s), 4.17
(2H, s), 4.67 (2H, s), 7.10-7.
63 (5H, m).

Reference Example 12 5- [4- (6-benzyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzylidene] thiazolidine-2,4-dione 6-benzyloxy-2,5 , 7,8-Tetramethylchroman-2-methylmethanesulfonate (5 g), 4-
Potassium carbonate (1.89 g) was added to a 50 ml solution of hydroxybenzaldehyde (1.67 g) in dimethylformamide.
g), and the mixture was stirred at 150 ° C. for 30 hours. After cooling to room temperature, 50 ml of water was added to the reaction solution, and 75 ml of ethyl acetate was added.
Extracted times. The combined organic layer was washed twice with 100 ml of 14% aqueous ammonium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude black oil. The obtained crude oil was dissolved in 60 ml of ethanol, and thiazolidine-2,4-dione (2.18 g) and piperidine (1.
8 ml) and refluxed for 8.5 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in 150 ml of ethyl acetate, and 36 ml of 1N hydrochloric acid, 50 ml of water, and 50% of 5% aqueous sodium hydrogen carbonate solution were added.
After washing with ml, activated carbon (0.5 g) was added and stirred for 30 minutes. After filtering off the activated carbon, the solvent was distilled off under reduced pressure. The residue was washed with 50 ml of methanol, stirred at room temperature for 1 hour, and the crystals were collected by filtration and dried under reduced pressure to give 3.84 g of the desired compound.
(58.5% yield). ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 1.44 (3H, s), 1.92 (1
H, dt, J = 6.8, 13.4 Hz), 2.08 (3
H, s), 2.08-2.18 (1H, m), 2.18
(3H, s), 2.22 (3H, s), 2.63-2.
67 (2H, m), 3.98 (1H, d, J = 9.3H)
z), 4.06 (1H, d, J = 9.3 Hz), 4.7
0 (2H, s), 7.02 (2H, d, J = 8.8H)
z), 7.32-7.51 (7H, m), 7.82 (1
H, s), 8.71 (1H, s).

Reference Example 13 3-Triphenylmethyl-5- [4- (6-benzyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzylidene] thiazolidine-2,4-dione 5- To a solution of [4- (6-benzyloxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzylidene] thiazolidine-2,4-dione (1 g) in methylene chloride (10 ml) was added triphenylmethyl chloride (0 .68 g) and triethylamine (0.42 ml), and the mixture was stirred at room temperature for 5 hours. 10 ml of methylene chloride was added to the reaction solution, washed twice with 10 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate (5 ml) and diisopropyl ether (20 ml) were added to the residue, the mixture was heated to 50 ° C., the insolubles were removed by filtration at the same temperature, and the solvent was distilled off under reduced pressure. The residue was washed with methanol (20 ml), stirred at room temperature for 30 minutes, and the crystals were collected by filtration and dried under reduced pressure to obtain 1.29 g (yield: 88.4%) of the desired compound. ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 1.43 (3H, s), 1.91 (1
H, dt, J = 6.8, 13.7 Hz), 2.07 (3
H, s), 2.07-2.17 (1H, m), 2.17
(3H, s), 2.24 (3H, s), 2.62-2.
66 (2H, m), 3.96 (1H, d, J = 9.3H)
z), 4.04 (1H, d, J = 9.3 Hz), 4.6
9 (2H, s), 6.98 (2H, d, J = 8.6H)
z), 7.17-7.50 (22H, m), 7.70
(1H, s).

Reference Example 14 5- (4-hydroxybenzylidene) thiazolidine-
2,4-dione 4-hydroxybenzaldehyde (5 g), thiazolidine-2,4-dione (5.27 g) and ethanol 50 m
1 and then piperidine (4.5 ml).
Refluxed for 0.5 hour. The solvent was distilled off under reduced pressure, 25 ml of acetone was added to the residue, and the mixture was stirred for 1 hour under ice cooling. The precipitated crystals were collected by filtration and dried under reduced pressure. 100 m of water of the obtained crystals
10% sodium hydroxide aqueous solution
After adjusting to 10, the mixture was washed twice with 50 ml of methylene chloride. The aqueous layer was adjusted to pH 2.5 with 6N aqueous hydrochloric acid,
Minutes. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 7.20 g of the desired compound (yield: 79.6%). ¹ H-nuclear magnetic resonance spectrum (DMSO-d ₆ , 400
MHz) δ ppm; 6.93 (2H, dt, J = 2.
2,8.8 Hz), 7.36 (2H, dt, J = 2.
2,8.8 Hz), 7.70 (1H, s), 12.0
(1H, s).

Reference Example 15 5- (4-acetoxybenzylidene) thiazolidine-
2,4-dione 5- (4-hydroxybenzylidene) thiazolidine-
2,4-dione (3 g) in dimethylformamide 15 m
To this solution, triethylamine (2.8 ml) and acetic anhydride (1.9 ml) were added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. After adding 45 ml of water to the reaction solution and stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration and dried under reduced pressure to give 3.36 g of the desired compound.
(94% yield). ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 2.33 (3H, s), 7.22 (d,
J = 8.8 Hz), 7.53 (2H, d, J = 8.8H)
z), 7.75 (1H, s), 12.2 (1H, s).

Reference Example 16 3-triphenylmethyl-5- (4-acetoxybenzylidene) thiazolidine-2,4-dione 5- (4-acetoxybenzylidene) thiazolidine-
To a solution of 2,4-dione (1 g) in 10 ml of methylene chloride was added, under ice-cooling, triphenylmethyl chloride (1.27 g) and triethylamine (0.69 ml), and the mixture was stirred at room temperature for 40 minutes. 10 ml of methylene chloride was added to the reaction solution, and the mixture was washed twice with 10 ml of water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
After adding 2 ml of ethyl acetate to the residue and depositing crystals, 20 ml of diisopropyl ether was added and the mixture was stirred under ice-cooling for 30 minutes. The precipitated crystals were collected by filtration and dried under reduced pressure to give 2.10 g (yield 93%) of the target compound as an ethyl acetate complex. ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δ ppm; 1.26 (3H, t, J = 7.1H
z), 2.04 (3H, s), 2.31 (3H, s),
4.12 (2H, q, J = 7.1 Hz), 7.18−
7.29 (10H, m), 7.44-7.47 (9H,
m), 7.72 (1H, s).

[0079]

According to the production method of the present invention, the 5-benzylthiazolidine-2,4-dione derivative (2) can be obtained in high yield, and is effective as an industrial production method.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 417/12 263 C07D 417/12 263 309 309 311 311 471/04 107 471/04 107E

Claims (7)

[Claims] 1. A compound of the general formula Wherein R is an aryl group having 6 to 10 carbon atoms which may have a substituent selected from the following α group, and a heterocyclic group which may have a substituent selected from the following α group Alternatively, it represents a heteroaromatic ring group which may have a substituent selected from the following α group, and X represents a protecting group for an amino group. Wherein the compound represented by the general formula is reacted with a metal hydride in an organic solvent. [Wherein, R and X are as defined above. Of a 5-benzylthiazolidine-2,4-dione derivative having the formula: (Α group) alkyl group having 1 to 4 carbon atoms, hydroxy group, alkoxy group having 1 to 4 carbon atoms, halogenated alkyl group having 1 to 4 carbon atoms, 1 carbon atom
Acyloxy group having 1 to 4 carbon atoms, alkylenedioxy group having 1 to 4 carbon atoms, aralkyl group having 7 to 11 carbon atoms, aralkyloxy group having 7 to 12 carbon atoms, 1 to 4 carbon atoms An alkylsulfonyl group having 1 to 4, an alkylthio group having 1 to 4 carbon atoms,
Halogen atom, nitro group, amino group, monoalkylamino group having 1 to 4 carbon atoms, dialkylamino group having the same or different and each alkyl having 1 to 4 carbon atoms, thiol group, 1 to 4 carbon atoms An alkylsulfinyl group having 1 to 4 carbon atoms, an alkylsulfonylamino group having 1 to 4 carbon atoms, an alkylsulfonylalkylamino group having the same or different and each alkyl having 1 to 4 carbon atoms, a sulfone group, a sulfonamide group, the following β group An alkoxy group having 1 to 4 carbon atoms having a heterocyclic or heteroaromatic ring which may have a substituent selected from:
Or an alkylthio group having 1 to 4 carbon atoms having a heterocyclic or heteroaromatic ring which may have a substituent selected from the following β group. (Β group) alkyl group having 1 to 4 carbon atoms, hydroxy group, alkoxy group having 1 to 4 carbon atoms, halogenated alkyl group having 1 to 4 carbon atoms, 1 carbon atom
Acyloxy group having 1 to 4 carbon atoms, alkylenedioxy group having 1 to 4 carbon atoms, aralkyl group having 7 to 11 carbon atoms, aralkyloxy group having 7 to 12 carbon atoms, 1 to 4 carbon atoms An alkylsulfonyl group having 1 to 4, an alkylthio group having 1 to 4 carbon atoms,
Halogen atom, nitro group, amino group, monoalkylamino group having 1 to 4 carbon atoms, dialkylamino group having the same or different and each alkyl having 1 to 4 carbon atoms, thiol group, 1 to 4 carbon atoms An alkylsulfinyl group having 1 to 4 carbon atoms, an alkylsulfonylamino group having 1 to 4 carbon atoms, an alkylsulfonylalkylamino group having the same or different and each alkyl having 1 to 4 carbon atoms, a sulfone group or a sulfonamide group. 2. A compound of the general formula Wherein R is Embedded image And X represents a protecting group for an amino group. Wherein the compound represented by the general formula is reacted with a metal hydride in an organic solvent. [Wherein, R and X are as defined above. Of a 5-benzylthiazolidine-2,4-dione derivative having the formula: 3. The method of claim 1, wherein the metal hydride is sodium borohydride,
Claims 1 and 4 which are lithium borohydride, calcium borohydride, zinc borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride, tetrapropylammonium borohydride, or tetrabutylammonium borohydride. 2
The manufacturing method described. 4. The method according to claim 1, wherein the metal hydride is sodium borohydride. 5. The process according to claim 1, wherein the organic solvent is a mixed solvent of an amide-based or ether-based organic solvent and water or an alcohol-based organic solvent. 6. The organic solvent according to claim 1, wherein the organic solvent is dimethylformamide or dimethylacetamide, or a mixed solvent of tetrahydrofuran or 1,4-dioxane and water or a linear or molecular alkyl alcohol having 1 to 4 carbon atoms. And the production method according to claim 2. 7. The method according to claim 1, wherein the organic solvent is a mixed solvent of dimethylformamide and ethanol or a mixed solvent of tetrahydrofuran and s-butanol.